The overlap between vascular disease and Alzheimer’s disease - lessons from pathology
Open accessAbstract
Recent epidemiological and clinico-pathological data indicate considerable overlap between cerebrovascular disease (CVD) and Alzheimer's disease (AD) and suggest additive or synergistic effects of both pathologies on cognitive decline. The most frequent vascular pathologies in the aging brain and in AD are cerebral amyloid angiopathy and small vessel disease. Up to 84% of aged subjects show morphological substrates of CVD in addition to AD pathology. AD brains with minor CVD, similar to pure vascular dementia, show subcortical vascular lesions in about two-thirds, while in mixed type dementia (AD plus vascular dementia), multiple larger infarcts are more frequent. Small infarcts in patients with full-blown AD have no impact on cognitive decline but are overwhelmed by the severity of Alzheimer pathology, while in early stages of AD, cerebrovascular lesions may influence and promote cognitive impairment, lowering the threshold for clinically overt dementia. Further studies are warranted to elucidate the many hitherto unanswered questions regarding the overlap between CVD and AD as well as the impact of both CVD and AD pathologies on the development and progression of dementia.
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Written from the paper’s full text.
TL;DR
This review synthesizes pathological and clinicopathological evidence that cerebrovascular disease (CVD) and Alzheimer’s disease (AD) frequently overlap, with additive or synergistic effects on cognitive decline. It emphasizes that vascular lesions may lower the threshold for dementia in early AD, while severe AD pathology often overwhelms the cognitive impact of small vascular lesions.
Key findings
- Up to 84% of aged subjects show morphological substrates of CVD in addition to AD pathology; cerebral amyloid angiopathy (CAA) is present in 82% to 98% of AD patients, and small vessel disease (SVD) is common in both aging and AD.
- In pure vascular dementia (VaD), about 68% of cases show lacunar/strategic subcortical infarcts and 32.5% show multiple large cortico-subcortical infarcts; in mixed dementia (AD + severe CVD), 56.6% show multiple large/lobar or cortico-subcortical lesions and 43.4% show small subcortical lacunar, micro-infarcts, or strategic infarcts.
- Small infarcts in full-blown AD have no impact on cognitive decline and are overwhelmed by Alzheimer pathology, whereas in early AD, cerebrovascular lesions may promote cognitive impairment and lower the threshold for clinically overt dementia.
- Converging autopsy, amyloid PET, functional MRI, and CSF biomarker evidence indicates that AD and CVD exert additive rather than interactive adverse effects on cognitive health, though interactions between vascular factors and amyloidosis/tauopathy remain unresolved.
Methods
- Narrative review of epidemiological, clinico-pathological, and autopsy studies on the overlap between CVD and AD, including data from large cohorts such as the National Alzheimer’s Coordinating Center (NACC) database and the Rush Memory and Aging Project/Religious Orders Study.
- The paper summarizes prevalence and topographical distribution of cerebrovascular lesions across AD, VaD, mixed dementia, and aged controls, using tables from prior autopsy series (e.g., VaD total 188; mixed dementia n = 83; NACC 5,715 autopsy cases).
- Main analysis is qualitative synthesis of reported frequencies, odds ratios, and clinicopathological correlations; no new primary data or systematic meta-analysis are presented.
Limitations
- The paper states that further studies are warranted to elucidate unanswered questions about CVD–AD overlap and that there is still a lack of consensus on incorporating vascular disease into clinical and neuropathological classification schemes for dementias.
- It notes that sample selection may strongly bias results: community samples tend to show greater cerebrovascular pathology than hospital-based samples, and mixed AD/CVD prevalence was higher in the community-based RUSH Memory and Aging Project (44%) than in the RUSH Religious Order Study (28%).
- The text also raises doubts about PiB-PET as representative of Aβ loads in the living brain and states that differentiation of mixed AD/CVD with CSF biomarkers may be difficult; evident from the text, this is a narrative review without a systematic search or quantitative pooling, so findings depend on heterogeneous autopsy cohorts and diagnostic criteria.
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Cites
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Claims the paper makes
0 of 57 cited sources checked · 0 supported · 0 flagged
- Findingnone given
In AD brains with minor CVD the majority of cerebrovascular lesions are lacunar infarcts in basal ganglia and white matter, and multiple micro-infarcts.
“In AD brains with minor CVD the majority of CVLs are lacunar infarcts in basal ganglia and white matter, and multiple micro-infarcts.”
Quote in the paperSubstantial claim - Findingnone given
In mixed type dementia (AD plus vascular dementia), multiple larger infarcts are more frequent.
“while in mixed type dementia (AD plus vascular dementia), multiple larger infarcts are more frequent.”
Quote in the paperNot a substantial claim - Findingown data
Mixed dementia (AD + severe CVD) is more frequently characterized by large or lobar infarcts, and multiple cortico-subcortical lesions (56.6%) than small subcortical lacunar infarcts, micro-infarcts, or strategic infarcts (43.4%).
“By contrast, mixed dementia (AD + severe CVD), according to our experience, is more frequently characterized by large or lobar infarcts, and multiple cortico-subcortical lesions (56.6%) than small subcortical lacunar infarcts, micro-infarcts, or strategic infarcts (43.4%, Table 2)”
Quote in the paperSubstantial claim - Findingnone given
AD brains with minor CVD, similar to pure vascular dementia, show subcortical vascular lesions in about two-thirds.
“AD brains with minor CVD, similar to pure vascular dementia, show subcortical vascular lesions in about two-thirds”
Quote in the paperNot a substantial claim - Premisecitation
Up to 84% of aged subjects show morphological substrates of cerebrovascular disease in addition to Alzheimer's disease pathology.
“Up to 84% of aged subjects show morphological substrates of CVD in addition to AD pathology.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [1] Petrovitch H, Ross GW, Steinhorn SC, Abbott RD, Markesberry W, Davis DG, Nelson J, Hardman J, Masaki KH, Vogt MR, Launer LJ, White LR: AD lesions and infarcts in demented and no-demented Japanese-American men. Ann Neurol. 2005, 57: 98-103. source
Not checked in the free run.
- Interpretationreasoning
AD pathology (mainly neurofibrillary tangles and neuritic plaques) is the main morphological substrate of clinical dementia.
“These data add further evidence for AD pathology (mainly neurofibrillary tangles and neuritic plaques) being the main morphological substrate of clinical dementia [51],[79],[80].”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [51] Bennett DA, Wilson RS, Arvanitakis Z, Boyle PA, de Toledo-Morrell L, Schneider JA: Selected findings from the religious orders study and rush memory and aging project. J Alzheimers Dis. 2013, 33: S397-S403. source
Not checked in the free run.
- cites [79] Nelson PT, Jicha GA, Schmitt FA, Liu H, Davis DG, Mendiondo MS, Abner EL, Markesbery WR: Clinicopathologic correlations in a large Alzheimer disease center autopsy cohort: neuritic plaques and neurofibrillary tangles “do count” when staging disease severity. J Neuropathol Exp Neurol. 2007, 66: 1136-1146. source
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- cites [80] Nelson PT, Pious NM, Jicha GA, Wilcock DM, Fardo DW, Estus S, Rebeck GW: APOE-epsilon2 and APOE-epsilon4 correlate with increased amyloid accumulation in cerebral vasculature. J Neuropathol Exp Neurol. 2013, 72: 708-715. source
Not checked in the free run.
- Interpretationreasoning
Small cerebrovascular lesions alone, seen in 10% to 50% of aged cognitively unimpaired controls, are not likely to account for a single cause of dementia.
“while small CVLs alone, seen in 10% to 50% of aged cognitively unimpaired controls, are not likely to account for a single cause of dementia.”
Quote in the paperSubstantial claim - Premisecitation
AD pathology alone more frequently accounts for dementia than both macroscopic and microscopic infarcts.
“However, AD pathology alone more frequently accounts for dementia than both macroscopic and microscopic infarcts [15]”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [15] Troncoso JC, Zonderman AB, Resnick SM, Crain B, Pletnikova O, O’Brien RJ: Effect of infarcts on dementia in the Baltimore longitudinal study of aging. Ann Neurol. 2008, 64: 168-176. source
Not checked in the free run.
- Interpretationreasoning
In early stages of AD, cerebrovascular lesions may influence and promote cognitive impairment, lowering the threshold for clinically overt dementia.
“while in early stages of AD, cerebrovascular lesions may influence and promote cognitive impairment, lowering the threshold for clinically overt dementia.”
Quote in the paperSubstantial claim - Interpretationreasoning
The combination of two or more pathological processes may influence the severity of cognitive deficits, unmasking preclinical dementia due to mild AD lesions.
“The combination of two or more pathological processes may influence the severity of cognitive deficits, unmasking preclinical dementia due to mild AD lesions”
Quote in the paperSubstantial claim - Premisecitation
CVD lowers the threshold for dementia in subjects with a pathological diagnosis of AD.
“neuropathological studies report that CVD lowers the threshold for dementia in subjects with a pathological diagnosis of AD [5],[6],[8],[9],[13],[17],[23],[51],[53],[81]-[83].”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [5] Toledo JB, Arnold SE, Raible K, Brettschneider J, Xie SX, Grossman M, Monsell SE, Kukull WA, Trojanowski JQ: Contribution of cerebrovascular disease in autopsy confirmed neurodegenerative disease cases in the National Alzheimer’s Coordinating Centre. Brain. 2013, 136: 2697-2706. source
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- cites [6] Chui HC, Zarow C, Mack WJ, Ellis WG, Zheng L, Jagust WJ, Mungas D, Reed BR, Kramer JH, Decarli CC, Weiner MW, Vinters HV: Cognitive impact of subcortical vascular and Alzheimer’s disease pathology. Ann Neurol. 2006, 60: 677-687. source
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- cites [8] Esiri MM, Joachim C, Sloan C, Christie S, Agacinski G, Bridges LR, Wilcock GK, Smith AD: Cerebral subcortical small vessel disease in subjects with pathologically confirmed Alzheimer disease: a clinicopathologic study in the Oxford Project to Investigate Memory and Ageing (OPTIMA). Alzheimer Dis Assoc Disord. 2014, 28: 30-35. source
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- Premisecitation
Cerebrovascular lesions are found in the majority of late-onset AD cases.
“Cerebrovascular lesions are found in the majority of late-onset AD and only in half of early-onset AD cases [160].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [160] Carotenuto A, Rea R, Colucci L, Ziello AR, Molino I, Carpi S, Traini E, Amenta F, Fasanaro AM: Late and early onset dementia: what is the role of vascular factors? A retrospective study. J Neurol Sci. 2012, 322: 170-175. source
Not checked in the free run.
- Premisenone given
The most frequent vascular pathologies in the aging brain and in Alzheimer's disease are cerebral amyloid angiopathy and small vessel disease.
“The most frequent vascular pathologies in the aging brain and in AD are cerebral amyloid angiopathy and small vessel disease.”
Quote in the paperNot a substantial claim - Premisereasoning
Small infarcts in patients with full-blown AD have no impact on cognitive decline.
“Small infarcts in patients with full-blown AD have no impact on cognitive decline”
Quote in the paperNot a substantial claim - Premisecitation
In late stages of AD, concomitant subcortical vascular lesions do not significantly influence the overall state and progression of cognitive decline.
“in late stages of AD, concomitant SVLs do not significantly influence the overall state and progression of cognitive decline [45],[54],[76]”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [45] Jellinger KA: Small concomitant cerebrovascular lesions are not important for cognitive decline in severe Alzheimer disease. Arch Neurol. 2001, 58: 520-521. source
Not checked in the free run.
- cites [54] Lee JH, Olichney JM, Hansen LA, Hofstetter CR, Thal LJ: Small concomitant vascular lesions do not influence rates of cognitive decline in patients with Alzheimer disease. Arch Neurol. 2000, 57: 1474-1479.
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- cites [76] Bennett DA, Schneider JA, Bienias JL, Evans DA, Wilson RS: Mild cognitive impairment is related to Alzheimer disease pathology and cerebral infarctions. Neurology. 2005, 64: 834-841. source
Not checked in the free run.
- Premisecitation
Cerebrovascular lesions are found in half of early-onset AD cases.
“Cerebrovascular lesions are found in the majority of late-onset AD and only in half of early-onset AD cases [160].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [160] Carotenuto A, Rea R, Colucci L, Ziello AR, Molino I, Carpi S, Traini E, Amenta F, Fasanaro AM: Late and early onset dementia: what is the role of vascular factors? A retrospective study. J Neurol Sci. 2012, 322: 170-175. source
Not checked in the free run.
- Premisecitation
Among 418 non-demented participants of the Religious Order Study (mean age 88.5 ± 5.3 years), only 37.5% were free of any CVD.
“Among 418 non-demented participants of the Religious Order Study (mean age 88.5 ± 5.3 years), 35% showed macroscopic brain infarcts and 14.8% arteriosclerosis, while only 37.5% were free of any CVD [168].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [168] Buchman AS, Leurgans SE, Nag S, Bennett DA, Schneider JA: Cerebrovascular disease pathology and Parkinsonian signs in old age. Stroke. 2011, 42: 3183-3189. source
Not checked in the free run.
- Premisecitation
In a community-based sample of 72 cognitively normal older individuals (mean age 74.9 ± 5.7 years), a substantial number harbor neurodegeneration without Aβ burden.
“A recent cross-sectional study in a community-based sample of 72 cognitively normal older individuals (mean age 74.9 ± 5.7 years) confirmed that a substantial number harbor neurodegeneration without Aβ burden, but association of neurodegenerative lesions with CVD can emerge through non-Aβ pathways within regions most affected by AD [170].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [170] Wirth M, Villeneuve S, Haase CM, Madison CM, Oh H, Landau SM, Rabinovici GD, Jagust WJ: Associations between Alzheimer disease biomarkers, neurodegeneration, and cognition in cognitively normal older people. JAMA Neurol. 2013, 70: 1512-1519.
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- Premisecitation
Various degrees of CAA have been found in up to 75% of cognitively normal seniors.
“Various degrees of CAA have been found in up to 75% of cognitively normal seniors [167].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [167] Jentoft M, Parisi J, Dickson D, Johnson K, Boeve B, Knopman D, Petersen R: Neuropathologic findings in 32 nondemented elderly subjects (abs.). J Neuropathol Exp Neurol. 2011, 70: 531.
Not checked in the free run.
- Premisecitation
Association of neurodegenerative lesions with CVD can emerge through non-Aβ pathways within regions most affected by AD.
“A recent cross-sectional study in a community-based sample of 72 cognitively normal older individuals (mean age 74.9 ± 5.7 years) confirmed that a substantial number harbor neurodegeneration without Aβ burden, but association of neurodegenerative lesions with CVD can emerge through non-Aβ pathways within regions most affected by AD [170].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [170] Wirth M, Villeneuve S, Haase CM, Madison CM, Oh H, Landau SM, Rabinovici GD, Jagust WJ: Associations between Alzheimer disease biomarkers, neurodegeneration, and cognition in cognitively normal older people. JAMA Neurol. 2013, 70: 1512-1519.
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- Premisecitation
In non-demented elderly subjects, multiple confounding pathologies, in particular CVLs, are present in up to 10%.
“Many studies emphasized multiple confounding pathologies in non-demented elderly subjects, in particular CVLs, e.g., small or large cerebral infarcts, lacunes, and WMLs, in up to 10% [10],[165]-[167].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [10],[165]-[167]
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- Premisecitation
Among 100 non-demented elderly, moderate intracranial atherosclerosis was present in 17% of subjects.
“Among 100 non-demented elderly, mild, moderate, and severe intracranial atherosclerosis was present in 31%, 17%, and 6% of subjects, respectively.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [169] Jellinger KA, Attems J: Neuropathology and general autopsy findings in nondemented aged subjects. Clin Neuropathol. 2012, 31: 87-98. source
Not checked in the free run.
- Premisecitation
Community samples tend to show greater degrees of cerebrovascular pathology compared to hospital-based samples.
“Community samples tend to show greater degrees of cerebrovascular pathology as compared to hospital based samples; and the prevalence of mixed AD/CVD was higher in the community-based RUSH Memory and Aging Project (44%) than in the RUSH Religious Order Study (28%).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [164] Tsuang D, Simpson KL, Li G, Barnhart RL, Edland SD, Bowen J, McCormick W, Teri L, Nochlin D, Larson EB, Thompson ML, Leverenz JB: Evaluation of selection bias in an incident-based dementia autopsy case series. Alzheimer Dis Assoc Disord. 2005, 19: 67-73. source
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- Premisecitation
In a 90+ study, there was extensive overlap in pathology among those with and without dementia.
“However, in a 90+ study, there was extensive overlap in pathology among those with and without dementia; 22% of demented subjects did not have significant pathology to account for their cognitive impairment [163].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [163] Corrada MM, Berlau DJ, Kawas CH: A population-based clinicopathological study in the oldest-old: the 90+ study. Curr Alzheimer Res. 2012, 9: 709-717. source
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- Premisecitation
The prevalence of mixed AD/CVD was higher in the community-based RUSH Memory and Aging Project (44%) than in the RUSH Religious Order Study (28%).
“Community samples tend to show greater degrees of cerebrovascular pathology as compared to hospital based samples; and the prevalence of mixed AD/CVD was higher in the community-based RUSH Memory and Aging Project (44%) than in the RUSH Religious Order Study (28%).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [164] Tsuang D, Simpson KL, Li G, Barnhart RL, Edland SD, Bowen J, McCormick W, Teri L, Nochlin D, Larson EB, Thompson ML, Leverenz JB: Evaluation of selection bias in an incident-based dementia autopsy case series. Alzheimer Dis Assoc Disord. 2005, 19: 67-73. source
Not checked in the free run.
- Premisecitation
In a 90+ study, 22% of demented subjects did not have significant pathology to account for their cognitive impairment.
“However, in a 90+ study, there was extensive overlap in pathology among those with and without dementia; 22% of demented subjects did not have significant pathology to account for their cognitive impairment [163].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [163] Corrada MM, Berlau DJ, Kawas CH: A population-based clinicopathological study in the oldest-old: the 90+ study. Curr Alzheimer Res. 2012, 9: 709-717. source
Not checked in the free run.
- Premisecitation
Among 418 non-demented participants of the Religious Order Study (mean age 88.5 ± 5.3 years), 14.8% showed arteriosclerosis.
“Among 418 non-demented participants of the Religious Order Study (mean age 88.5 ± 5.3 years), 35% showed macroscopic brain infarcts and 14.8% arteriosclerosis, while only 37.5% were free of any CVD [168].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [168] Buchman AS, Leurgans SE, Nag S, Bennett DA, Schneider JA: Cerebrovascular disease pathology and Parkinsonian signs in old age. Stroke. 2011, 42: 3183-3189. source
Not checked in the free run.
- Premisecitation
Among 100 non-demented elderly, mild intracranial atherosclerosis was present in 31% of subjects.
“Among 100 non-demented elderly, mild, moderate, and severe intracranial atherosclerosis was present in 31%, 17%, and 6% of subjects, respectively.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [169] Jellinger KA, Attems J: Neuropathology and general autopsy findings in nondemented aged subjects. Clin Neuropathol. 2012, 31: 87-98. source
Not checked in the free run.
- Premisecitation
Among 418 non-demented participants of the Religious Order Study (mean age 88.5 ± 5.3 years), 35% showed macroscopic brain infarcts.
“Among 418 non-demented participants of the Religious Order Study (mean age 88.5 ± 5.3 years), 35% showed macroscopic brain infarcts and 14.8% arteriosclerosis, while only 37.5% were free of any CVD [168].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [168] Buchman AS, Leurgans SE, Nag S, Bennett DA, Schneider JA: Cerebrovascular disease pathology and Parkinsonian signs in old age. Stroke. 2011, 42: 3183-3189. source
Not checked in the free run.
- Premisecitation
There are considerable differences in the pathological burden in relation to age of onset of dementia.
“There are considerable differences in the pathological burden in relation to age of onset of dementia, suggesting that late onset is associated with increased vascular pathology and lower AD burden [161],[162].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [161],[162]
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- Premisecitation
Cerebrovascular effects of Aβ render the aged brain more vulnerable to ischemic injury.
“both human and experimental studies in transgenic mice overexpressing amyloid precursor protein suggest that cerebrovascular effects of Aβ render the aged brain more vulnerable to ischemic injury [172].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [172] Garde E, Lykke Mortensen E, Rostrup E, Paulson OB: Decline in intelligence is associated with progression in white matter hyperintensity volume. J Neurol Neurosurg Psychiatry. 2005, 76: 1289-1291. source
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- Interpretationreasoning
The type of study sample may strongly bias results.
“Therefore, the type of study sample may strongly bias results and should be mentioned as a possible contribution to variability of findings.”
Quote in the paperSubstantial claim - Premisecitation
Among 100 non-demented elderly, only 9% were free of CVLs.
“A lacunar state in basal ganglia and/or white matter was observed in 73%, hippocampal sclerosis in 3%, and mixed cerebral pathologies in 6%, whereas only 9% were free of CVLs [169].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [169] Jellinger KA, Attems J: Neuropathology and general autopsy findings in nondemented aged subjects. Clin Neuropathol. 2012, 31: 87-98. source
Not checked in the free run.
- Premisecitation
Among 100 non-demented elderly, severe intracranial atherosclerosis was present in 6% of subjects.
“Among 100 non-demented elderly, mild, moderate, and severe intracranial atherosclerosis was present in 31%, 17%, and 6% of subjects, respectively.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [169] Jellinger KA, Attems J: Neuropathology and general autopsy findings in nondemented aged subjects. Clin Neuropathol. 2012, 31: 87-98. source
Not checked in the free run.
- Premisecitation
Among 100 non-demented elderly, a lacunar state in basal ganglia and/or white matter was observed in 73%.
“A lacunar state in basal ganglia and/or white matter was observed in 73%, hippocampal sclerosis in 3%, and mixed cerebral pathologies in 6%, whereas only 9% were free of CVLs [169].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [169] Jellinger KA, Attems J: Neuropathology and general autopsy findings in nondemented aged subjects. Clin Neuropathol. 2012, 31: 87-98. source
Not checked in the free run.
- Premisecitation
Among 100 non-demented elderly, mixed cerebral pathologies were observed in 6%.
“A lacunar state in basal ganglia and/or white matter was observed in 73%, hippocampal sclerosis in 3%, and mixed cerebral pathologies in 6%, whereas only 9% were free of CVLs [169].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [169] Jellinger KA, Attems J: Neuropathology and general autopsy findings in nondemented aged subjects. Clin Neuropathol. 2012, 31: 87-98. source
Not checked in the free run.
- Premisecitation
Sample selection in incident-based dementia autopsy series has an effect (a caveat).
“A specific caveat in this respect is the effect of sample selection in incident-bases dementia autopsy series [164].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [164] Tsuang D, Simpson KL, Li G, Barnhart RL, Edland SD, Bowen J, McCormick W, Teri L, Nochlin D, Larson EB, Thompson ML, Leverenz JB: Evaluation of selection bias in an incident-based dementia autopsy case series. Alzheimer Dis Assoc Disord. 2005, 19: 67-73. source
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- Premisecitation
WMLs increase the risk of dementia, particularly in patients with lacunar infarcts.
“They impair frontal functions regardless of their location [175],[176] and increase the risk of dementia, particularly in patients with lacunar infarcts [177],[178], causing functional network disruption in cognitively-impaired individuals compared with age-matched healthy elderly controls [179],[180].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [177],[178]
Not checked in the free run.
- Premisecitation
Recent evidence comparing PiB-PET with post-mortem or biopsy results raised doubts about PiB-PET as representative of Aβ loads in the living brain.
“However, recent evidence comparing PiB-PET with post-mortem or biopsy results raised doubts about this method as representative of Aβ loads in the living brain [191],[192] and PiB-positivity was observed in 55% of non-demented subjects over 80 [193].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [191],[192]
Not checked in the free run.
- Interpretationreasoning
The combination of both AD and vascular or other pathological processes, as seen in many elderly persons, may coexist in the earlier stages of cognitive decline.
“Hence, the combination of both AD and vascular or other pathological processes, as seen in many elderly persons, may coexist in the earlier stages of cognitive decline and may influence its progression and severity, thus representing a major diagnostic challenge not only for clinicians but also for neuropathologists.”
Quote in the paperSubstantial claim - Interpretationreasoning
Changes in microvasculature auto-regulation may lead to myelin loss, frequently seen in aged and diseased brains.
“Both atherosclerosis and CAA cause changes in microvasculature auto-regulation and thus may lead to myelin loss, frequently seen in aged and diseased brains, suggesting shared risk factors for all pathological changes seen in AD and CVD.”
Quote in the paperSubstantial claim - Interpretationnone given
There is still a lack of consensus regarding the optimal means of incorporating vascular disease into clinical and neuropathological classification schemes for dementias.
“Despite multiple attempts, there is still a lack of consensus regarding the optimal means of incorporating vascular disease into clinical and neuropathological classification schemes for dementias.”
Quote in the paperSubstantial claim - Premisecitation
Modern CSF biomarkers may support a direct relationship between SVD and AD pathology.
“Modern CSF biomarkers may support a direct relationship between SVD and AD pathology [195], although in the Alzheimer Disease Neuroimaging Initiative that is focused on AD, no interactions were noted between vascular risk factors and AD biomarkers [26].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [195] Kester MI, Goos JD, Teunissen CE, Benedictus MR, Bouwman FH, Wattjes MP, Barkhof F, Scheltens P, van der Flier WM: Associations between cerebral small-vessel disease and Alzheimer disease pathology as measured by cerebrospinal fluid biomarkers. JAMA Neurol. 2014, 71: 855-862. source
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- Premisecitation
PiB-positivity was observed in 55% of non-demented subjects over 80.
“However, recent evidence comparing PiB-PET with post-mortem or biopsy results raised doubts about this method as representative of Aβ loads in the living brain [191],[192] and PiB-positivity was observed in 55% of non-demented subjects over 80 [193].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [193] Mathis CA, Kuller LH, Klunk WE, Snitz BE, Price JC, Weissfeld LA, Rosario BL, Lopresti BJ, Saxton JA, Aizenstein HJ, McDade EM, Kamboh MI, DeKosky ST, Lopez OL: In vivo assessment of amyloid-beta deposition in nondemented very elderly subjects. Ann Neurol. 2013, 73: 751-761. source
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- Premisecitation
WMLs progress with age.
“WMLs may be caused by both CVD (hypoperfusion) and AD (retrograde degeneration), they progress with age, and they are a considerable risk factor for cognitive impairment [120],[173],[174].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [120],[173],[174]
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- Premisecitation
A number of in vivo studies using functional MRI and amyloid and tau PET will enable the identification of AD and CVD patients in clinical and research settings.
“While structural MRI results have limited security and specificity, a number of in vivo studies using functional MRI [187] and amyloid and tau PET (e.g., PiB, florbetabin, flutemetamole, etc.) [188]-[190] will enable the identification of AD and CVD patients in clinical and research settings.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [187]-[190]
Not checked in the free run.
- Interpretationreasoning
There are shared risk factors for all pathological changes seen in AD and CVD.
“Both atherosclerosis and CAA cause changes in microvasculature auto-regulation and thus may lead to myelin loss, frequently seen in aged and diseased brains, suggesting shared risk factors for all pathological changes seen in AD and CVD.”
Quote in the paperSubstantial claim - Premisecitation
WMLs may be caused by both CVD (hypoperfusion) and AD (retrograde degeneration).
“WMLs may be caused by both CVD (hypoperfusion) and AD (retrograde degeneration), they progress with age, and they are a considerable risk factor for cognitive impairment [120],[173],[174].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [120],[173],[174]
Not checked in the free run.
- Interpretationnone given
Both atherosclerosis and CAA cause changes in microvasculature auto-regulation.
“Both atherosclerosis and CAA cause changes in microvasculature auto-regulation and thus may lead to myelin loss, frequently seen in aged and diseased brains, suggesting shared risk factors for all pathological changes seen in AD and CVD.”
Quote in the paperSubstantial claim - Premisecitation
The recent development of in vivo amyloid imaging enables further pathological breakdown of SVD into pure forms and mixed dementia based on the absence or presence of amyloid pathology in the brain.
“The recent development of in vivo amyloid imaging enables further pathological breakdown of SVD into pure forms and mixed dementia based on the absence or presence of amyloid pathology in the brain [194].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [194] Roh JH, Lee JH: Recent updates on subcortical ischemic vascular dementia. J Stroke. 2014, 16: 18-26. source
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- Premisecitation
Together with cortical microinfarcts, WMLs may contribute to the progression of cognitive impairment.
“Together with cortical microinfarcts, WMLs may contribute to the progression of cognitive impairment, but do not necessarily interact with AD pathology to increase the likelihood of dementia beyond their additive effect [20].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [20] Costanza A, Xekardaki A, Kovari E, Gold G, Bouras C, Giannakopoulos P: Microvascular burden and Alzheimer-type lesions across the age spectrum. J Alzheimers Dis. 2012, 32: 643-652. source
Not checked in the free run.
- The authors state this as an assumption: WMLs contribute to cognitive decline.
- Premisecitation
WMLs impair frontal functions regardless of their location.
“They impair frontal functions regardless of their location [175],[176] and increase the risk of dementia, particularly in patients with lacunar infarcts [177],[178], causing functional network disruption in cognitively-impaired individuals compared with age-matched healthy elderly controls [179],[180].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [175],[176]
Not checked in the free run.
- Premisenone given
Structural MRI results have limited security and specificity.
“While structural MRI results have limited security and specificity, a number of in vivo studies using functional MRI [187] and amyloid and tau PET (e.g., PiB, florbetabin, flutemetamole, etc.) [188]-[190] will enable the identification of AD and CVD patients in clinical and research settings.”
Quote in the paperSubstantial claim - Premisecitation
WMLs and lacunes may be independently associated with cognitive dysfunction.
“Although WMLs and lacunes may be independently associated with cognitive dysfunction [181],[182], WMLs in AD are significantly correlated to cortical and medial temporal lobe atrophy [181]-[183], and, thus, are assumed to contribute to cognitive decline [184].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [181],[182]
Not checked in the free run.
- Premisecitation
The neuropathological evaluation of focal and white matter gliosis may have no clinical validity.
“Further, the neuropathological evaluation of focal and white matter gliosis may have no clinical validity [185].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [185] Kövari E, Gold G, Herrmann FR, Canuto A, Hof PR, Michel JP, Bouras C, Giannakopoulos P: Cortical microinfarcts and demyelination significantly affect cognition in brain aging. Stroke. 2004, 35: 410-414. source
Not checked in the free run.
- Interpretationreasoning
The combination of AD and vascular or other pathological processes may influence the progression and severity of cognitive decline.
“Hence, the combination of both AD and vascular or other pathological processes, as seen in many elderly persons, may coexist in the earlier stages of cognitive decline and may influence its progression and severity, thus representing a major diagnostic challenge not only for clinicians but also for neuropathologists.”
Quote in the paperSubstantial claim - Interpretationreasoning
Differentiation of mixed AD/CVD with CSF biomarkers may be difficult.
“Therefore, differentiation of mixed AD/CVD with CSF biomarkers may be difficult.”
Quote in the paperSubstantial claim - Premisecitation
In the Alzheimer Disease Neuroimaging Initiative, no interactions were noted between vascular risk factors and AD biomarkers.
“Modern CSF biomarkers may support a direct relationship between SVD and AD pathology [195], although in the Alzheimer Disease Neuroimaging Initiative that is focused on AD, no interactions were noted between vascular risk factors and AD biomarkers [26].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [26] Lo RY, Jagust WJ: Vascular burden and Alzheimer disease pathologic progression. Neurology. 2012, 79: 1349-1355. source
Not checked in the free run.
- Premisecitation
WMLs cause functional network disruption in cognitively-impaired individuals compared with age-matched healthy elderly controls.
“They impair frontal functions regardless of their location [175],[176] and increase the risk of dementia, particularly in patients with lacunar infarcts [177],[178], causing functional network disruption in cognitively-impaired individuals compared with age-matched healthy elderly controls [179],[180].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [179],[180]
Not checked in the free run.
- Premisecitation
WMLs do not necessarily interact with AD pathology to increase the likelihood of dementia beyond their additive effect.
“Together with cortical microinfarcts, WMLs may contribute to the progression of cognitive impairment, but do not necessarily interact with AD pathology to increase the likelihood of dementia beyond their additive effect [20].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [20] Costanza A, Xekardaki A, Kovari E, Gold G, Bouras C, Giannakopoulos P: Microvascular burden and Alzheimer-type lesions across the age spectrum. J Alzheimers Dis. 2012, 32: 643-652. source
Not checked in the free run.
- Premisecitation
WMLs in AD are significantly correlated to cortical and medial temporal lobe atrophy.
“Although WMLs and lacunes may be independently associated with cognitive dysfunction [181],[182], WMLs in AD are significantly correlated to cortical and medial temporal lobe atrophy [181]-[183], and, thus, are assumed to contribute to cognitive decline [184].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [181]-[183]
Not checked in the free run.
- Premisecitation
WMLs are a considerable risk factor for cognitive impairment.
“WMLs may be caused by both CVD (hypoperfusion) and AD (retrograde degeneration), they progress with age, and they are a considerable risk factor for cognitive impairment [120],[173],[174].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [120],[173],[174]
Not checked in the free run.
- May combine two claims. 7
- Classified as probably not a substantial claim. 1
May combine two claims.
InterpretationreasoningRecent epidemiological and clinico-pathological data indicate considerable overlap between cerebrovascular disease and Alzheimer's disease and suggest additive or synergistic effects of both pathologies on cognitive decline.
“Recent epidemiological and clinico-pathological data indicate considerable overlap between cerebrovascular disease (CVD) and Alzheimer’s disease (AD) and suggest additive or synergistic effects of both pathologies on cognitive decline.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationLate onset of dementia is associated with increased vascular pathology and lower AD burden.
“There are considerable differences in the pathological burden in relation to age of onset of dementia, suggesting that late onset is associated with increased vascular pathology and lower AD burden [161],[162].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [161],[162]
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationAmong 100 non-demented elderly, hippocampal sclerosis was observed in 3%.
“A lacunar state in basal ganglia and/or white matter was observed in 73%, hippocampal sclerosis in 3%, and mixed cerebral pathologies in 6%, whereas only 9% were free of CVLs [169].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [169] Jellinger KA, Attems J: Neuropathology and general autopsy findings in nondemented aged subjects. Clin Neuropathol. 2012, 31: 87-98. source
Not checked in the free run.
May combine two claims.
InterpretationcitationThe pathogenic chain of these and other deleterious effects, in a vicious circle, finally produces structural cerebral disintegration (lacunes, infarcts, WMLs) with compromised neuronal metabolism, mitochondrial deficiency, oxidative stress, protein degradation, failure promoting cytoskeletal lesions with deposition of Aβ, and formation of neuritic lesions.
“The pathogenic chain of these and other deleterious effects, in a vicious circle, finally produces either structural cerebral disintegration (lacunes, infarcts, WMLs) with compromised neuronal metabolism, mitochondrial deficiency, oxidative stress, protein degradation, failure promoting cytoskeletal lesions with deposition of Aβ, and formation of neuritic lesions (e.g., neurofibrillary tangles).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [147] Jellinger KA, Attems J: Neuropathological evaluation of mixed dementia. J Neurol Sci. 2007, 257: 80-87. source
Not checked in the free run.
May combine two claims.
PremisecitationMicrovascular changes in the aged brain and in AD induce impairment of cerebral perfusion, including decreased regional blood flow, reduced glucose transport and utilization, loss of vascular innervation, impaired neurovascular regulation, and ultrastructural changes in capillaries and basement membranes due to Aβ deposition, with breakdown of the BBB and impaired amyloid clearance.
“Microvascular changes in the aged brain and in AD induce impairment of cerebral perfusion, in particular decrease of regional blood flow, reduction of glucose transport and utilization, loss of vascular innervation with special impact on the cholinergic and transmitter deficits in AD [171], impairment of neurovascular regulation, ultrastructural changes in capillaries and basement membranes due to”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [171] Roman GC, Kalaria RN: Vascular determinants of cholinergic deficits in Alzheimer disease and vascular dementia. Neurobiol Aging. 2006, 27: 1769-1785. source
Not checked in the free run.
May combine two claims.
InterpretationcitationThese factors induce brain atrophy with cognitive and memory impairment.
“These factors induce brain atrophy with cognitive and memory impairment (Figure 1) [147], although the complex cascade of these and other noxious factors needs further elucidation.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [147] Jellinger KA, Attems J: Neuropathological evaluation of mixed dementia. J Neurol Sci. 2007, 257: 80-87. source
Not checked in the free run.
May combine two claims.
PremisecitationBoth hypertension and CAA are associated with an increased prevalence of CVLs.
“Both hypertension and CAA are associated with an increased prevalence of CVLs [157]”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [157] Jellinger KA, Attems J: Prevalence and pathogenic role of cerebrovascular lesions in Alzheimer’s disease. J Neurol Sci. 2005, 229-230: 37-41. source
Not checked in the free run.
May combine two claims.
PremisecitationCVD is an important cause of cognitive impairment in the elderly, both by itself or as a catalyst for the conversion of low-grade AD to overt dementia.
“CVD has been suggested to be an important cause of cognitive impairment in the elderly, both by itself or as a catalyst for the conversion of low-grade AD to overt dementia [186].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [186] Kalaria RN, Kenny RA, Ballard CG, Perry R, Ince P, Polvikoski T: Towards defining the neuropathological substrates of vascular dementia. J Neurol Sci. 2004, 226: 75-80. source
Not checked in the free run.
The authors state this as an assumption.
WMLs contribute to cognitive decline.
“and, thus, are assumed to contribute to cognitive decline [184].”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The biological mechanisms behind the positive epidemiological correlation between Alzheimer's disease and cardiometabolic traits are not well understood.
“Studies have consistently found a positive epidemiological correlation between Alzheimer’s disease (AD) and cardiometabolic traits, yet the biological mechanisms behind this correlation is not well understood [1–4].”
From Multi-trait association studies discover pleiotropic loci between Alzheimer’s disease and cardiometabolic traits (2021) · cites this paper as [1]
There is a positive epidemiological correlation between Alzheimer's disease and cardiometabolic traits.
“Studies have consistently found a positive epidemiological correlation between Alzheimer’s disease (AD) and cardiometabolic traits, yet the biological mechanisms behind this correlation is not well understood [1–4].”
From Multi-trait association studies discover pleiotropic loci between Alzheimer’s disease and cardiometabolic traits (2021) · cites this paper as [1]
Overlapping pathologies among dementia patients indicate a wide range of biological heterogeneity within AD.
“Moreover, the growing recognition of overlapping pathologies (e.g., Lewy body inclusions, TDP-43 pathology, vascular lesions, etc.) among dementia patients indicates a wide range of biological heterogeneity within AD that necessitates a broader approach to scientific investigations of its pathophysiology [37–39].”
From Systems-based proteomics to resolve the biology of Alzheimer’s disease beyond amyloid and tau (2021) · cites this paper as [38]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Table 1 infarct locations sum to 58, not 61
MinorThe listed counts under "Multiple infarcts," treating slash-separated counts as separate values, sum to 58. The table reports 61.
Reported 61 · recomputed 58
“Multiple infarcts (61 = 32.5%)”
Table 3 has conflicting source citations
MinorThe table caption attributes Table 3 to reference 130, while the text introducing the same table cites reference 147.
“Table: Table 3 Common lesions in AD, VaD, MIX, and aged controls (from[130])”
“The type and average prevalence of CVLs in AD, VaD, mixed dementia, and aged controls is shown in Table 3[147].”
Control vascular-pathology categories exceed 100%
MinorThe reported control percentages for no essential vascular pathology, minor pathology, moderate pathology, and severe pathology total 102.5%, although these are presented as categories of the same controls.
“compared to 66.8% in age-matched controls, all showing low Braak stages (P <0.01).”
“Minor and moderate vascular pathology in AD were about twice as frequent as in controls (26.2% vs. 12.2% and 20.9% vs. 11.3%; P <0.01). On the other hand, severe vascular pathology did not significantly differ between both groups (10.2% vs. 12.2%).”
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BackgroundWhite matter lesions impair frontal lobe function regardless of their location
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BackgroundDiabetes, Alzheimer disease, and vascular dementia
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BackgroundInfluentialNeurological Diseases in Relation to the Blood–Brain Barrier
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BackgroundPathological correlates of dementia in a longitudinal, population‐based sample of aging
Sonnen, J. A., Larson, E. B., Crane, P. K., Haneuse, S., Li, G., Schellenberg, G. D., Craft, S., Leverenz, J. B., & Montine, T. J. (2007) · Annals of Neurology · doi:10.1002/ana.21208 · Cited by 432 · cited 1× · see citing works
“The burden of vascular and AD-type pathologies are leading and independent causes of dementia in the elderly [4,9-15], suggesting additive or synergistic effects of both types of lesions on cognitive impairment [2,3,5,9,16-29].”
BackgroundMicroinfarct Pathology, Dementia, and Cognitive Systems
Arvanitakis, Z., Leurgans, S. E., Barnes, L. L., Bennett, D. A., & Schneider, J. A. (2011) · Stroke · doi:10.1161/strokeaha.110.595082 · Cited by 404 · cited 1× · see citing works
“A recent study assessed CVD in 5,715 autopsy cases of the National Alzheimer’s Coordinating Center (NACC) database, and confirmed previous data on the prevalence of CVD in AD and the additive or interactive deleterious effect of both AD and vascular pathologies on cognition [6,9,47,50,51].”
BackgroundThal, D. R., Ghebremedhin, E., Orantes, M., & Wiestler, O. D. (2003) · Journal of Neuropathology & Experimental Neurology · doi:10.1093/jnen/62.12.1287 · Cited by 384 · see citing works
The Neuropathology of Older Persons with and Without Dementia from Community versus Clinic Cohorts
Schneider, J. A., Aggarwal, N. T., Barnes, L., Boyle, P., & Bennett, D. A. (2009) · Journal of Alzheimer's Disease · doi:10.3233/jad-2009-1227 · Cited by 372 · cited 2× · see citing works
“, small or large cerebral infarcts, lacunes, and WMLs, in up to 10% [10,165-167].”
BackgroundCerebral amyloid angiopathy and its relationship to Alzheimer’s disease
Thal, D. R., Griffin, W. S. T., de Vos, R. A. I., & Ghebremedhin, E. (2008) · Acta Neuropathologica · doi:10.1007/s00401-008-0366-2 · Cited by 372 · cited 1× · see citing works
“Due to the location of the underlying vessel disorder, multiple cortical CMIs are often associated with CAA, whereas subcortical microinfarcts are mainly linked to SVD or atherosclerosis-related embolism [135].”
BackgroundReview: sporadic cerebral amyloid angiopathy
Attems, J., Jellinger, K., Thal, D. R., & Van Nostrand, W. (2011) · Neuropathology and Applied Neurobiology · doi:10.1111/j.1365-2990.2010.01137.x · Cited by 371 · cited 2× · see citing works
“The occipital lobe has been reported to be the site most frequently and severely affected by CAA, followed by either frontal, temporal, or parietal lobes [89,90].”
BackgroundSelf-citationLacunar stroke is associated with diffuse blood-brain barrier dysfunction
Wardlaw, J. M., Doubal, F., Armitage, P., Chappell, F., Carpenter, T., Muñoz Maniega, S., Farrall, A., Sudlow, C., Dennis, M., & Dhillon, B. (2009) · Annals of Neurology · doi:10.1002/ana.21549 · Cited by 364 · cited 1× · see citing works
“BBB dysfunctions related to SVD leading to a leakage of plasma proteins into enlarged perivascular spaces [61,128] have been described in WMLs and lacunar stroke [129,130].”
BackgroundKovács, G. G., Milenković, I., Wöehrer, A., Höftberger, R., Gelpí, E., Haberler, C., Hönigschnabl, S., Reiner‐Concin, A., Heinzl, H., Jungwirth, S., et al. (2013) · Acta Neuropathologica · doi:10.1007/s00401-013-1157-y · Cited by 360 · cited 1× · see citing works
“8% [47], while the majority (24% to 93%) showed mixed pathologies [158,159].”
BackgroundPathology and pathogenesis of vascular cognitive impairment—a critical update
Jellinger, K. A. (2013) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2013.00017 · Cited by 353 · cited 2× · see citing works
“In contrast to AD and mixed dementia, the prevalence of pure VaD decreased after 80 years of age [145,158].”
BackgroundResultSelf-citationNeuropathological assessment of the lesions of significance in vascular dementia
Esiri, M. M., Wilcock, G. K., & Morris, J. H. (1997) · Journal of Neurology, Neurosurgery & Psychiatry · doi:10.1136/jnnp.63.6.749 · Cited by 347 · cited 2× · see citing works
“However, the role of combined cerebrovascular pathology and AD in dementia is still under discussion and data obtained from epidemiological and clinico-pathological studies regarding their relation are controversial [13,17,22,23,52-55].”
BackgroundVascular pathology in the aged human brain
Grinberg, L. T., & Thal, D. R. (2010) · Acta Neuropathologica · doi:10.1007/s00401-010-0652-7 · Cited by 345 · cited 2× · see citing works
“, hypertensive vasculopathy), or microvascular degeneration (tortuosity, fibro- and lipohyalinosis,); – Blood–brain barrier (BBB) dysfunction causing white matter lesions (WMLs), microinfarctions, lacunes or lacunar infarcts, and microbleeds [17,87].”
BackgroundMRI predictors of cognition in subcortical ischemic vascular disease and Alzheimer's disease
Mungas, D., Jagust, W. J., Reed, B. R., Kramer, J. H., Weiner, M. W., Schuff, N., Norman, D., Mack, W. J., Willis, L., & Chui, H. C. (2001) · Neurology · doi:10.1212/wnl.57.12.2229 · Cited by 341 · see citing works
Neuropathologic correlates of white matter hyperintensities
Young, V. G., Halliday, G. M., & Kril, J. J. (2008) · Neurology · doi:10.1212/01.wnl.0000319691.50117.54 · Cited by 336 · cited 2× · see citing works
“Damage to the vasculature may, in turn, impair the BBB integrity as one mechanism by which WMLs may evolve [124].”
BackgroundContribution of Vascular Risk Factors to the Progression in Alzheimer Disease
Helzner, E., Luchsinger, J. A., Scarmeas, N., Cosentino, S., Brickman, A. M., Glymour, M. M., & Stern, Y. (2009) · Archives of Neurology · doi:10.1001/archneur.66.3.343 · Cited by 329 · cited 1× · see citing works
“, atrial fibrillation and congestive heart failure, have also been linked to the pathogenesis and progression of AD and are among the most important modifiable risk factors for AD [35-42].”
BackgroundHeterogeneity in age-related white matter changes
Schmidt, R., Schmidt, H., Haybaeck, J., Loitfelder, M., Weis, S., Cavalieri, M., Seiler, S., Enzinger, C., Ropele, S., Erkinjuntti, T., et al. (2011) · Acta Neuropathologica · doi:10.1007/s00401-011-0851-x · Cited by 327 · cited 2× · see citing works
“WMLs may be caused by both CVD (hypoperfusion) and AD (retrograde degeneration), they progress with age, and they are a considerable risk factor for cognitive impairment [120,173,174].”
BackgroundSelf-citationSmall Vessel Disease and General Cognitive Function in Nondisabled Elderly
van der Flier, W. M., van Straaten, E. C. W., Barkhof, F., Verdelho, A., Madureira, S., Pantoni, L., Inzitari, D., Erkinjuntti, T., Crisby, M., Waldemar, G., et al. (2005) · Stroke · doi:10.1161/01.str.0000179092.59909.42 · Cited by 324 · cited 1× · see citing works
“Although WMLs and lacunes may be independently associated with cognitive dysfunction [181,182], WMLs in AD are significantly correlated to cortical and medial temporal lobe atrophy [181-183], and, thus, are assumed to contribute to cognitive decline [184].”
BackgroundMuch of late life cognitive decline is not due to common neurodegenerative pathologies
Boyle, P. A., Wilson, R. S., Yu, L., Barr, A. M., Honer, W. G., Schneider, J. A., & Bennett, D. A. (2013) · Annals of Neurology · doi:10.1002/ana.23964 · Cited by 323 · cited 1× · see citing works
“However, much of the variation in cognitive decline remains unexplained, suggesting that other important determinants of cognitive decline remain to be identified [156].”
BackgroundBrain microbleeds and Alzheimer’s disease: innocent observation or key player?
Cordonnier, C., & van der Flier, W. M. (2011) · Brain · doi:10.1093/brain/awq321 · Cited by 310 · see citing works
Vascular factors predict rate of progression in Alzheimer disease
Mielke, M. M., Rosenberg, P. B., Tschanz, J. T., Cook, L., Corcoran, C. M., Hayden, K. M., Norton, M. C., Rabins, P. V., Green, R. C., Welsh-Bohmer, K. A., et al. (2007) · Neurology · doi:10.1212/01.wnl.0000279520.59792.fe · Cited by 309 · cited 1× · see citing works
“, atrial fibrillation and congestive heart failure, have also been linked to the pathogenesis and progression of AD and are among the most important modifiable risk factors for AD [35-42].”
BackgroundEvidence that Alzheimer’s disease is a microvascular disorder: the role of constitutive nitric oxide
de la Torre, J. C., & Stefano, G. B. (2000) · Brain Research Reviews · doi:10.1016/s0165-0173(00)00043-6 · Cited by 307 · cited 1× · see citing works
“Vascular disease is thought by many authors to play a major role in the pathogenesis of AD and some even consider AD as being rather a primarily vascular than a neurodegenerative disorder [22,68-74].”
BackgroundRelation of cerebral infarctions to dementia and cognitive function in older persons
Schneider, J. A., Wilson, R. S., Cochran, E. J., Bienias, J. L., Arnold, S. E., Evans, D. A., & Bennett, D. A. (2003) · Neurology · doi:10.1212/01.wnl.0000055863.87435.b2 · Cited by 305 · cited 1× · see citing works
“The burden of vascular and AD-type pathologies are leading and independent causes of dementia in the elderly [4,9-15], suggesting additive or synergistic effects of both types of lesions on cognitive impairment [2,3,5,9,16-29].”
BackgroundAmyloid PET imaging in Alzheimer’s disease: a comparison of three radiotracers
Initiative, T. A. D. N., Landau, S. M., Thomas, B. A., Thurfjell, L., Schmidt, M. E., Margolin, R. A., Mintun, M. A., Pontecorvo, M. J., Baker, S. L., & Jagust, W. J. (2014) · European Journal of Nuclear Medicine and Molecular Imaging · doi:10.1007/s00259-014-2753-3 · Cited by 294 · cited 1× · see citing works
“) [188-190] will enable the identification of AD and CVD patients in clinical and research settings.”
BackgroundNelson, P. T., Jicha, G. A., Schmitt, F. A., Liu, H., Davis, D. G., Mendiondo, M. S., Abner, E. L., & Markesbery, W. R. (2007) · Journal of Neuropathology and Experimental Neurology · doi:10.1097/nen.0b013e31815c5efb · Cited by 292 · cited 1× · see citing works
“These data add further evidence for AD pathology (mainly neurofibrillary tangles and neuritic plaques) being the main morphological substrate of clinical dementia [51,79,80].”
BackgroundTowards defining the neuropathological substrates of vascular dementia
Kalaria, R. N., Kenny, R. A., Ballard, C. G., Perry, R., Ince, P., & Polvikoski, T. (2004) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2004.09.019 · Cited by 291 · cited 1× · see citing works
“Conclusions CVD has been suggested to be an important cause of cognitive impairment in the elderly, both by itself or as a catalyst for the conversion of low-grade AD to overt dementia [186].”
BackgroundSchrag, M., McAuley, G. A., Pomakian, J., Jiffry, A., Tung, S., Mueller, C., Vinters, H. V., Haacke, E. M., Holshouser, B. A., Kido, D. K., et al. (2009) · Acta Neuropathologica · doi:10.1007/s00401-009-0615-z · Cited by 287 · cited 1× · see citing works
“In addition to the presence of superficial siderosis, cerebral microbleeds, cortical microinfarcts, and hypointensities in MRI images [106-109], the use of Pittsburgh Compound-B (PiB)positron emission tomography (PET) is useful in detecting CAA intra vitam [110,111], and a significant decrease of both Aβ-40 and Aβ-42…”
BackgroundAtherosclerosis and AD: Analysis of data from the US National Alzheimer’s Coordinating Center
Honig, L. S., Kukull, W., & Mayeux, R. (2005) · Neurology · doi:10.1212/01.wnl.0000150886.50187.30 · Cited by 284 · see citing works
Topakian, R., Barrick, T. R., Howe, F. A., & Markus, H. S. (2010) · Journal of Neurology, Neurosurgery & Psychiatry · doi:10.1136/jnnp.2009.172072 · Cited by 281 · cited 1× · see citing works
“BBB dysfunctions related to SVD leading to a leakage of plasma proteins into enlarged perivascular spaces [61,128] have been described in WMLs and lacunar stroke [129,130].”
BackgroundNeuropathological evaluation of mixed dementia
Jellinger, K. A., & Attems, J. (2007) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2007.01.045 · Cited by 273 · cited 2× · see citing works
“These factors induce brain atrophy with cognitive and memory impairment (Figure 1) [147], although the complex cascade of these and other noxious factors needs further elucidation.”
BackgroundSelf-citationCerebrovascular atherosclerosis correlates with Alzheimer pathology in neurodegenerative dementias
Yarchoan, M. M., Xie, S. X., Kling, M. A., Toledo, J. B., Wolk, D. A., Lee, E. B., Deerlin, V. M. V., Lee, V. M. Y., Trojanowski, J. Q., & Arnold, S. E. (2012) · Brain · doi:10.1093/brain/aws271 · Cited by 261 · cited 1× · see citing works
“atherosclerosis in the circle of Willis has been specifically linked to AD [138-140], and the presence of largevessel CVD was strongly associated with an increased frequency of neuritic plaques, suggesting a common etiology or a reciprocal regulation for atherosclerosis and AD [138,141].”
BackgroundCerebral Microinfarcts: A Systematic Review of Neuropathological Studies
Brundel, M., de Bresser, J., van Dillen, J. J., Kappelle, L. J., & Biessels, G. J. (2012) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/jcbfm.2011.200 · Cited by 258 · see citing works
Cognitive impact of subcortical vascular and Alzheimer’s disease pathology
Chui, H. C., Zarow, C., Mack, W. J., Ellis, W. G., Zheng, L., Jagust, W. J., Mungas, D., Reed, B. R., Kramer, J. H., DeCarli, C. C., et al. (2006) · Annals of Neurology · doi:10.1002/ana.21009 · Cited by 247 · cited 4× · see citing works
“A recent study assessed CVD in 5,715 autopsy cases of the National Alzheimer’s Coordinating Center (NACC) database, and confirmed previous data on the prevalence of CVD in AD and the additive or interactive deleterious effect of both AD and vascular pathologies on cognition [6,9,47,50,51].”
BackgroundResultInfluentialIhara, M., Polvikoski, T. M., Hall, R., Slade, J. Y., Perry, R. H., Oakley, A. E., Englund, E. M., O'Brien, J. T., Ince, P. G., & Kalaria, R. N. (2010) · Acta Neuropathologica · doi:10.1007/s00401-009-0635-8 · Cited by 242 · cited 1× · see citing works
“WMLs may be caused by both CVD (hypoperfusion) and AD (retrograde degeneration), they progress with age, and they are a considerable risk factor for cognitive impairment [120,173,174].”
BackgroundVascular pathologies and cognition in a population-based cohort of elderly people
Fernando, M. S., & Ince, P. G. (2004) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2004.09.004 · Cited by 239 · cited 1× · see citing works
“The proportion of multiple CVL was higher in the demented group, while only 21% of clinically-demented patients showed “pure” AD pathology at post-mortem, indicating that most patients had mixed disease [152].”
ResultBeach, T. G., Wilson, J. R., Sue, L. I., Newell, A., Poston, M., Cisneros, R., Pandya, Y., Esh, C. L., Connor, D. J., Sabbagh, M. N., et al. (2006) · Acta Neuropathologica · doi:10.1007/s00401-006-0136-y · Cited by 232 · cited 1× · see citing works
“atherosclerosis in the circle of Willis has been specifically linked to AD [138-140], and the presence of largevessel CVD was strongly associated with an increased frequency of neuritic plaques, suggesting a common etiology or a reciprocal regulation for atherosclerosis and AD [138,141].”
BackgroundAtherosclerosis, dementia, and Alzheimer disease in the Baltimore Longitudinal Study of aging cohort
Dolan, H., Crain, B. J., Troncoso, J. C., Resnick, S. M., Zonderman, A. B., & O’Brien, R. (2010) · Annals of Neurology · doi:10.1002/ana.22055 · Cited by 232 · cited 2× · see citing works
“Assessment of 175 autopsy cases in the Baltimore Longitudinal Study of Aging cohort found no relationship between the degree of atherosclerosis in the aorta, heart, and intracranial vessels and the degree of AD pathology, while the presence of intracranial atherosclerosis significantly increased the odds of dementia,…”
AD lesions and infarcts in demented and non‐demented Japanese‐American men
Petrovitch, H., Ross, G. W., Steinhorn, S. C., Abbott, R. D., Markesbery, W., Davis, D., Nelson, J., Hardman, J., Masaki, K., Vogt, M. R., et al. (2005) · Annals of Neurology · doi:10.1002/ana.20318 · Cited by 230 · see citing works
Charidimou, A., Meegahage, R., Fox, Z., Peeters, A., Vandermeeren, Y., Laloux, P., Baron, J.-C., Jager, H. R., & Werring, D. J. (2013) · Journal of Neurology, Neurosurgery & Psychiatry · doi:10.1136/jnnp-2012-304434 · Cited by 225 · cited 2× · see citing works
“Correlations of these criteria with post-mortem neuropathological findings indicate that the diagnosis of probable CAA-related hemorrhage can be made intra vitam with high accuracy [102-105].”
BackgroundVascular Dementia in a Population-Based Autopsy Study
Knopman, D. S., Parisi, J. E., Boeve, B. F., Cha, R. H., Apaydın, H., Salviati, A., Edland, S. D., & Rocca, W. A. (2003) · Archives of Neurology · doi:10.1001/archneur.60.4.569 · Cited by 221 · cited 1× · see citing works
“Criteria for pure VaD using imaging results (Mayo Clinic criteria) showed 75% sensitivity and 81% specificity [151].”
MethodThe enigma of vascular cognitive disorder and vascular dementia
Jellinger, K. A. (2007) · Acta Neuropathologica · doi:10.1007/s00401-006-0185-2 · Cited by 221 · cited 4× · see citing works
“4%, Table 2), suggesting different pathogenic mechanisms between these types of disorders [2,3].”
BackgroundInfluentialSelf-citationRelation of neuropathology to cognition in persons without cognitive impairment
Bennett, D. A., Wilson, R. S., Boyle, P. A., Buchman, A. S., & Schneider, J. A. (2012) · Annals of Neurology · doi:10.1002/ana.23654 · Cited by 220 · cited 1× · see citing works
“The burden of vascular and AD-type pathologies are leading and independent causes of dementia in the elderly [4,9-15], suggesting additive or synergistic effects of both types of lesions on cognitive impairment [2,3,5,9,16-29].”
BackgroundEffect of infarcts on dementia in the Baltimore longitudinal study of aging
Troncoso, J. C., Zonderman, A. B., Resnick, S. M., Crain, B., Pletnikova, O., & O'Brien, R. J. (2008) · Annals of Neurology · doi:10.1002/ana.21413 · Cited by 219 · cited 2× · see citing works
“However, AD pathology alone more frequently accounts for dementia than both macroscopic and microscopic infarcts [15] and, in late stages of AD, concomitant SVLs do not significantly influence the overall state and progression of cognitive decline [45,54,76], the severity and extent of AD pathology overwhelming the ra…”
BackgroundArima, H., Tzourio, C., Anderson, C. S., Woodward, M., Bousser, M., MacMahon, S. W., Neal, B. C., & Chalmers, J. P. (2010) · Stroke · doi:10.1161/strokeaha.109.563932 · Cited by 218 · cited 1× · see citing works
“Of note, the majority of cases with CAA-related ICH had hypertension, suggesting that hypertension is an important additional causal factor in CAA-related ICHs [95,96].”
BackgroundVascular determinants of cholinergic deficits in Alzheimer disease and vascular dementia.
Román, G. C., & Kalaria, R. N. (2006) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2005.10.004 · Cited by 213 · cited 1× · see citing works
“Microvascular changes in the aged brain and in AD induce impairment of cerebral perfusion, in particular decrease of regional blood flow, reduction of glucose transport and utilization, loss of vascular innervation with special impact on the cholinergic and transmitter deficits in AD [171], impairment of neurovascular…”
BackgroundCerebral infarcts in patients with autopsy-proven Alzheimer's disease
Heyman, A., Fillenbaum, G. G., Welsh-Bohmer, K. A., Gearing, M., Mirra, S. S., Mohs, R. C., Peterson, B. L., & Pieper, C. F. (1998) · Neurology · doi:10.1212/wnl.51.1.159 · Cited by 206 · cited 1× · see citing works
“On the other hand, CVD has been associated with worse cognitive performance in AD and neuropathological studies report that CVD lowers the threshold for dementia in subjects with a pathological diagnosis of AD [5,6,8,9,13,17,23,51,53,81-83].”
BackgroundCortical Microinfarcts and Demyelination Significantly Affect Cognition in Brain Aging
Kövari, E., Gold, G., Herrmann, F. R., Canuto, A., Hof, P. R., Michel, J.-P., Bouras, C., & Giannakopoulos, P. (2004) · Stroke · doi:10.1161/01.str.0000110791.51378.4e · Cited by 202 · cited 1× · see citing works
“Further, the neuropathological evaluation of focal and white matter gliosis may have no clinical validity [185].”
BackgroundCerebrospinal fluid amyloid β<sub>40</sub> is decreased in cerebral amyloid angiopathy
Verbeek, M. M., Kremer, B. P. H., Rikkert, M. O., Van Domburg, P. H. M. F., Skehan, M. E., & Greenberg, S. M. (2009) · Annals of Neurology · doi:10.1002/ana.21694 · Cited by 202 · cited 1× · see citing works
“In addition to the presence of superficial siderosis, cerebral microbleeds, cortical microinfarcts, and hypointensities in MRI images [106-109], the use of Pittsburgh Compound-B (PiB)positron emission tomography (PET) is useful in detecting CAA intra vitam [110,111], and a significant decrease of both Aβ-40 and Aβ-42…”
BackgroundWhite, L. (2009) · Journal of Alzheimer's Disease · doi:10.3233/jad-2009-1178 · Cited by 193 · cited 1× · see citing works
“There are considerable differences in the pathological burden in relation to age of onset of dementia, suggesting that late onset is associated with increased vascular pathology and lower AD burden [161,162].”
BackgroundBrayne, C., the Cambridge City over-75s Cohort (CC75C) study neuropathology collaboration, Richardson, K., Matthews, F. E., Fleming, J., Hunter, S., Xuereb, J. H., Paykel, E., Mukaetova-Ladinska, E. B., Huppert, F. A., et al. (2009) · Journal of Alzheimer's Disease · doi:10.3233/jad-2009-1182 · Cited by 191 · see citing works
Attems, J., Jellinger, K. A., & Lintner, F. (2005) · Acta Neuropathologica · doi:10.1007/s00401-005-1064-y · Cited by 188 · cited 1× · see citing works
“The occipital lobe has been reported to be the site most frequently and severely affected by CAA, followed by either frontal, temporal, or parietal lobes [89,90].”
BackgroundSelf-citationCerebrovascular lesions induce transient -amyloid deposition
Garcia-Alloza, M., Gregory, J., Kuchibhotla, K. V., Fine, S., Wei, Y., Ayata, C., Frosch, M. P., Greenberg, S. M., & Bacskai, B. J. (2011) · Brain · doi:10.1093/brain/awr300 · Cited by 187 · cited 1× · see citing works
“SVD-induced ApoE leakage was associated with AD and accumulation of β-amyloid (Aβ) in perivascular astrocytes [61] and transient induction of Aβ deposition [62].”
BackgroundDegenerative and vascular lesions of the brain have synergistic effects in dementia of the elderly
Zekry, D., Duyckaerts, C. J., Moulias, R., Belmin, J., Geoffre, C., Herrmann, F. R., & Hauw, J. (2002) · Acta Neuropathologica · doi:10.1007/s00401-001-0493-5 · Cited by 184 · cited 4× · see citing works
“However, the role of combined cerebrovascular pathology and AD in dementia is still under discussion and data obtained from epidemiological and clinico-pathological studies regarding their relation are controversial [13,17,22,23,52-55].”
BackgroundInfluentialDuering, M., Csanadi, E., Gesierich, B., Jouvent, E., Herve, D., Seiler, S., Belaroussi, B., Ropele, S., Schmidt, R., Chabriat, H., et al. (2013) · Brain · doi:10.1093/brain/awt184 · Cited by 183 · cited 1× · see citing works
“SVD is a frequent cause of white matter lesions (WMLs; leukoaraiosis) that are increasingly detected by neuroimaging [118-121].”
BackgroundGregoire, S. M., Charidimou, A., Gadapa, N., Dolan, E., Antoun, N. M., Peeters, A. P., Vandermeeren, Y., Laloux, P., Baron, J., Jäger, H. R., et al. (2011) · Brain · doi:10.1093/brain/awr172 · Cited by 183 · cited 1× · see citing works
“Of note, the majority of cases with CAA-related ICH had hypertension, suggesting that hypertension is an important additional causal factor in CAA-related ICHs [95,96].”
BackgroundEffects of White Matter Lesions and Lacunes on Cortical Function
Reed, B., Eberling, J. L., Mungas, D., Weiner, M. W., Kramer, J. H., & Jagust, W. J. (2004) · Archives of Neurology · doi:10.1001/archneur.61.10.1545 · Cited by 182 · cited 1× · see citing works
“They impair frontal functions regardless of their location [175,176] and increase the risk of dementia, particularly in patients with lacunar infarcts [177,178], causing functional network disruption in cognitively-impaired individuals compared with age-matched healthy elderly controls [179,180].”
BackgroundHawkes, C. A., Sullivan, P. M., Hands, S. L., Weller, R. O., Nicoll, J. A. R., & Carare, R. O. (2012) · PLoS ONE · doi:10.1371/journal.pone.0041636 · Cited by 177 · see citing works
Wirth, M., Villeneuve, S., Haase, C. M., Madison, C. M., Oh, H., Landau, S. M., Rabinovici, G. D., & Jagust, W. J. (2013) · JAMA Neurology · doi:10.1001/jamaneurol.2013.4013 · Cited by 171 · cited 1× · see citing works
“7 years) confirmed that a substantial number harbor neurodegeneration without Aβ burden, but association of neurodegenerative lesions with CVD can emerge through non-Aβ pathways within regions most affected by AD [170].”
BackgroundMicroinfarcts, brain atrophy, and cognitive function: The Honolulu Asia Aging Study Autopsy Study
Launer, L. J., Hughes, T. M., & White, L. R. (2011) · Annals of Neurology · doi:10.1002/ana.22520 · Cited by 171 · cited 1× · see citing works
“AD has been reported to present frequently together with SVD, microvascular injury, and microscopic CVLs [8,16,47,56-60].”
BackgroundIn vivo evaluation of a novel tau imaging tracer for Alzheimer’s disease
Villemagne, V. L., Furumoto, S., Fodero‐Tavoletti, M. T., Mulligan, R. S., Hodges, J. R., Harada, R., Yates, P. A., Piguet, O., Pejoska, S., Doré, V., et al. (2014) · European Journal of Nuclear Medicine and Molecular Imaging · doi:10.1007/s00259-013-2681-7 · Cited by 170 · cited 1× · see citing works
“) [188-190] will enable the identification of AD and CVD patients in clinical and research settings.”
BackgroundProgression of white matter lesions and hemorrhages in cerebral amyloid angiopathy
Chen, Y. W., Gurol, M. E., Rosand, J. M., Viswanathan, A., Rakich, S. M., Groover, T. R., Greenberg, S. M., & Smith, E. E. (2006) · Neurology · doi:10.1212/01.wnl.0000223613.57229.24 · Cited by 167 · cited 3× · see citing works
“CAA may cause lobar intracerebral hemorrhages (ICH) and microbleeds [91]; it is indeed considered a risk factor for non-traumatic ICHs in the elderly and is present in up to 20% of all cases with ICH [92].”
Background. Identification of Alzheimer and vascular lesion thresholds for mixed dementia.
Gold, G., Giannakopoulos, P., Herrmann, F. R., Bouras, C., & Kovari, E. (2007) · Brain · doi:10.1093/brain/awm228 · Cited by 163 · cited 1× · see citing works
“However, AD pathology alone more frequently accounts for dementia than both macroscopic and microscopic infarcts [15] and, in late stages of AD, concomitant SVLs do not significantly influence the overall state and progression of cognitive decline [45,54,76], the severity and extent of AD pathology overwhelming the ra…”
BackgroundA Population-Based Clinicopathological Study in the Oldest-Old: The 90+ Study
M. Corrada, M., J. Berlau, D., & H. Kawas, C. (2012) · Current Alzheimer Research · doi:10.2174/156720512801322537 · Cited by 162 · cited 1× · see citing works
“However, in a 90+ study, there was extensive overlap in pathology among those with and without dementia; 22% of demented subjects did not have significant pathology to account for their cognitive impairment [163].”
BackgroundKester, M. I., Goos, J. D. C., Teunissen, C. E., Benedictus, M. R., Bouwman, F. H., Wattjes, M. P., Barkhof, F., Scheltens, P., & van der Flier, W. M. (2014) · JAMA Neurology · doi:10.1001/jamaneurol.2014.754 · Cited by 161 · cited 1× · see citing works
“Modern CSF biomarkers may support a direct relationship between SVD and AD pathology [195], although in the Alzheimer Disease Neuroimaging Initiative that is focused on AD, no interactions were noted between vascular risk factors and AD biomarkers [26].”
BackgroundCapizzano, A. A. (2004) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp.2003.019273 · Cited by 160 · see citing works
Park, J., Seo, S. W., Kim, C., Kim, G. H., Noh, H. J., Kim, S. T., Kwak, K., Yoon, U., Lee, J. M., Lee, J. W., et al. (2013) · Annals of Neurology · doi:10.1002/ana.23845 · Cited by 160 · cited 1× · see citing works
“Deep cerebral microbleeds (CMB) are mainly linked to subcortical SVD, while both subcortical SVD and CAA interact to increase the risk of lobar CMBs [122,123].”
BackgroundVascular burden and Alzheimer disease pathologic progression
Lo, R. Y., Jagust, W. J., Weiner, M., Aisen, P., Weiner, M., Aisen, P., Petersen, R., Jack, C. R., Jagust, W., Trojanowki, J. Q., et al. (2012) · Neurology · doi:10.1212/wnl.0b013e31826c1b9d · Cited by 156 · cited 2× · see citing works
“Modern CSF biomarkers may support a direct relationship between SVD and AD pathology [195], although in the Alzheimer Disease Neuroimaging Initiative that is focused on AD, no interactions were noted between vascular risk factors and AD biomarkers [26].”
BackgroundCortical superficial siderosis and intracerebral hemorrhage risk in cerebral amyloid angiopathy
Charidimou, A., Peeters, A. P., Jäger, R., Fox, Z., Vandermeeren, Y., Laloux, P., Baron, J.-C., & Werring, D. J. (2013) · Neurology · doi:10.1212/01.wnl.0000435298.80023.7a · Cited by 155 · cited 1× · see citing works
“Correlations of these criteria with post-mortem neuropathological findings indicate that the diagnosis of probable CAA-related hemorrhage can be made intra vitam with high accuracy [102-105].”
BackgroundWhite, L., Small, B. J., Petrovitch, H., Ross, G. W., Masaki, K., Abbott, R. D., Hardman, J., Davis, D., Nelson, J., & Markesbery, W. (2005) · Journal of Geriatric Psychiatry and Neurology · doi:10.1177/0891988705281872 · Cited by 155 · cited 1× · see citing works
“There are considerable differences in the pathological burden in relation to age of onset of dementia, suggesting that late onset is associated with increased vascular pathology and lower AD burden [161,162].”
BackgroundCerebral Microinfarcts Associated with Severe Cerebral β‐Amyloid Angiopathy
Soontornniyomkij, V., Lynch, M. D., Mermash, S., Pomakian, J., Badkoobehi, H., Clare, R., & Vinters, H. V. (2009) · Brain Pathology · doi:10.1111/j.1750-3639.2009.00322.x · Cited by 153 · cited 1× · see citing works
“CAA has been suggested to cause cortical microinfarcts [98,99], while others did not confirm such an association [100].”
ResultMeng, X.-F., Yu, J.-T., Wang, H.-F., Tan, M.-S., Wang, C., Tan, C.-C., & Tan, L. (2014) · Journal of Alzheimer s Disease · doi:10.3233/jad-140954 · Cited by 150 · cited 1× · see citing works
“Epidemiological studies have shown that AD and CVD share common risk factors such as hypertension during midlife, diabetes mellitus, smoking, apolipoprotein E (ApoE) ε4 isoforms, hypercholesterolemia, homocysteinemia, and, in particular, age [16,30-34].”
BackgroundAPOE-ε2 and APOE-ε4 Correlate With Increased Amyloid Accumulation in Cerebral Vasculature
Nelson, P. T., Pious, N. M., Jicha, G. A., Wilcock, D. M., Fardo, D. W., Estus, S., & Rebeck, G. W. (2013) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/nen.0b013e31829a25b9 · Cited by 150 · see citing works
Morphologic diagnosis of “vascular dementia” — A critical update
Jellinger, K. A. (2008) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2008.03.006 · Cited by 150 · cited 1× · see citing works
“Epidemiological studies have shown that AD and CVD share common risk factors such as hypertension during midlife, diabetes mellitus, smoking, apolipoprotein E (ApoE) ε4 isoforms, hypercholesterolemia, homocysteinemia, and, in particular, age [16,30-34].”
BackgroundSelf-citationIntracranial atherosclerosis as a contributing factor to Alzheimer's disease dementia
Roher, A. E., Tyas, S. L., Maarouf, C. L., Daugs, I. D., Kokjohn, T. A., Emmerling, M. R., Garami, Z. F., Bëlohlávek, M., Sabbagh, M. N., Sue, L. I., et al. (2011) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2010.08.228 · Cited by 144 · cited 1× · see citing works
“atherosclerosis in the circle of Willis has been specifically linked to AD [138-140], and the presence of largevessel CVD was strongly associated with an increased frequency of neuritic plaques, suggesting a common etiology or a reciprocal regulation for atherosclerosis and AD [138,141].”
BackgroundPrevalence and pathogenic role of cerebrovascular lesions in Alzheimer disease
Jellinger, K. A., & Attems, J. (2004) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2004.11.018 · Cited by 143 · cited 2× · see citing works
“Both hypertension and CAA are associated with an increased prevalence of CVLs [157], and both human and experimental studies in transgenic mice overexpressing amyloid precursor protein suggest that cerebrovascular effects of Aβ render the aged brain more vulnerable to ischemic injury [172].”
BackgroundSelf-citationLewis, H. D., Beher, D., Cookson, N., Oakley, A. E., Piggott, M. A., Morris, C. M., Jaros, E., Perry, R., Ince, P. G., Kenny, R. A., et al. (2006) · Neuropathology and Applied Neurobiology · doi:10.1111/j.1365-2990.2006.00696.x · Cited by 143 · cited 1× · see citing works
“It was also suggested that more Aβ accumulates with age in brains of vascular dementia (VaD) subjects compared to elderly without CVD [66].”
BackgroundJellinger, K. A. (2007) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2006.09.002 · Cited by 139 · cited 4× · see citing works
“4%, Table 2), suggesting different pathogenic mechanisms between these types of disorders [2,3].”
BackgroundInfluentialSelf-citationHomocysteine and Cognitive Performance in the Framingham Offspring Study: Age Is Important
Elias, M. F., Sullivan, L. M., D'Agostino, R. B., Elias, P. K., Jacques, P. F., Selhub, J., Seshadri, S., Au, R., Beiser, A., & Wolf, P. A. (2005) · American Journal of Epidemiology · doi:10.1093/aje/kwi259 · Cited by 136 · cited 1× · see citing works
“Epidemiological studies have shown that AD and CVD share common risk factors such as hypertension during midlife, diabetes mellitus, smoking, apolipoprotein E (ApoE) ε4 isoforms, hypercholesterolemia, homocysteinemia, and, in particular, age [16,30-34].”
BackgroundCerebrovascular Disease Pathology and Parkinsonian Signs in Old Age
Buchman, A. S., Leurgans, S. E., Nag, S., Bennett, D. A., & Schneider, J. A. (2011) · Stroke · doi:10.1161/strokeaha.111.623462 · Cited by 133 · see citing works
Vascular disease and dementias: Paradigm shifts to drive research in new directions
Kling, M. A., Trojanowski, J. Q., Wolk, D. A., Lee, V. M. ‐., & Arnold, S. E. (2012) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2012.02.007 · Cited by 132 · cited 2× · see citing works
“Therefore, an integrating rather than a strictly taxonomic approach (instead of discriminating AD, VaD, and other diseases) to elucidate specific pathophysiological mechanisms that contribute to dementia phenotypes and neuropathological causes has been proposed [37].”
BackgroundCerebral amyloid PET imaging in Alzheimer’s disease
Jack, C. R., Barrio, J. R., & Kepe, V. (2013) · Acta Neuropathologica · doi:10.1007/s00401-013-1185-7 · Cited by 131 · cited 1× · see citing works
“However, recent evidence comparing PiB-PET with postmortem or biopsy results raised doubts about this method as representative of Aβ loads in the living brain [191,192] and PiB-positivity was observed in 55% of non-demented subjects over 80 [193].”
ResultToledo, J. B., Toledo, E., Weiner, M. W., Jack, C. R., Jagust, W., Lee, V. M. ‐., Shaw, L. M. J., & Trojanowski, J. Q. (2012) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2011.08.008 · Cited by 130 · see citing works
Smallwood, A., Oulhaj, A., Joachim, C., Christie, S., Sloan, C., Smith, A. D., & Esiri, M. (2012) · Neuropathology and Applied Neurobiology · doi:10.1111/j.1365-2990.2011.01221.x · Cited by 127 · cited 1× · see citing works
“However, the role of combined cerebrovascular pathology and AD in dementia is still under discussion and data obtained from epidemiological and clinico-pathological studies regarding their relation are controversial [13,17,22,23,52-55].”
BackgroundPrevalence and mechanisms of cortical superficial siderosis in cerebral amyloid angiopathy
Charidimou, A., Jäger, H. R., Fox, Z. V., Peeters, A. P., Vandermeeren, Y., Laloux, P., Baron, J., & Werring, D. J. (2013) · Neurology · doi:10.1212/wnl.0b013e3182a08f2c · Cited by 126 · cited 2× · see citing works
“Correlations of these criteria with post-mortem neuropathological findings indicate that the diagnosis of probable CAA-related hemorrhage can be made intra vitam with high accuracy [102-105].”
BackgroundPrevalence and Impact of Cerebrovascular Lesions in Alzheimer and Lewy Body Diseases
Jellinger, K. A. (2010) · Neurodegenerative Diseases · doi:10.1159/000285518 · Cited by 124 · cited 2× · see citing works
“Both the incidence and severity of CVLs increased with higher neuritic Braak stages as was reported in a previous study [12].”
BackgroundResultSelf-citationvan der Flier, W. M. (2005) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp.2005.064998 · Cited by 124 · cited 1× · see citing works
“Although WMLs and lacunes may be independently associated with cognitive dysfunction [181,182], WMLs in AD are significantly correlated to cortical and medial temporal lobe atrophy [181-183], and, thus, are assumed to contribute to cognitive decline [184].”
BackgroundIncidence of cerebrovascular lesions in Alzheimer's disease: a postmortem study
Jellinger, K. A., & Attems, J. (2003) · Acta Neuropathologica · doi:10.1007/s00401-002-0634-5 · Cited by 121 · cited 1× · see citing works
“2% of AD cases, out of which 26% showed severe degrees [150].”
BackgroundSelf-citationDecline in intelligence is associated with progression in white matter hyperintensity volume
Garde, E. (2005) · Journal of Neurology, Neurosurgery & Psychiatry · doi:10.1136/jnnp.2004.055905 · Cited by 118 · cited 1× · see citing works
“Both hypertension and CAA are associated with an increased prevalence of CVLs [157], and both human and experimental studies in transgenic mice overexpressing amyloid precursor protein suggest that cerebrovascular effects of Aβ render the aged brain more vulnerable to ischemic injury [172].”
BackgroundAD brain pathology: Vascular origins?
Launer, L. J., Petrovitch, H., Ross, G. W., Markesbery, W., & White, L. R. (2008) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2007.03.008 · Cited by 117 · cited 1× · see citing works
“The burden of vascular and AD-type pathologies are leading and independent causes of dementia in the elderly [4,9-15], suggesting additive or synergistic effects of both types of lesions on cognitive impairment [2,3,5,9,16-29].”
BackgroundDu, A., Schuff, N. W., Chao, L. L., Kornak, J., Ezekiel, F., Jagust, W. J., Kramer, J. H., Reed, B., Miller, B. L., Norman, D. M., et al. (2004) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2004.05.002 · Cited by 116 · see citing works
Contribution of vascular pathology to the clinical expression of dementia
Altschul, D., Dickson, D. W., Lipton, R. B., Katz, M. J., Derby, C. A., Lee, S. H., Wang, C., & Verghese, J. (2008) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2008.09.011 · Cited by 114 · cited 2× · see citing works
“The burden of vascular and AD-type pathologies are leading and independent causes of dementia in the elderly [4,9-15], suggesting additive or synergistic effects of both types of lesions on cognitive impairment [2,3,5,9,16-29].”
BackgroundEffect of Vascular Lesions on Cognition in Alzheimer's Disease: A Community‐Based Study
Riekse, R. G., Leverenz, J. B., McCormick, W. C., Bowen, J. D., Teri, L. L., Nochlin, D., Simpson, K., Eugenio, C. J., Larson, E. B., & Tsuang, D. W. (2004) · Journal of the American Geriatrics Society · doi:10.1111/j.1532-5415.2004.52405.x · Cited by 109 · cited 1× · see citing works
“On the other hand, CVD has been associated with worse cognitive performance in AD and neuropathological studies report that CVD lowers the threshold for dementia in subjects with a pathological diagnosis of AD [5,6,8,9,13,17,23,51,53,81-83].”
BackgroundKövari, E., Herrmann, F. R., Hof, P. R., & Bouras, C. (2012) · Neuropathology and Applied Neurobiology · doi:10.1111/nan.12003 · Cited by 105 · cited 1× · see citing works
“CAA has been suggested to cause cortical microinfarcts [98,99], while others did not confirm such an association [100].”
ResultSerrano‐Pozo, A., Qian, J., Monsell, S. E., Frosch, M. P., Betensky, R. A., & Hyman, B. T. (2013) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/nen.0000000000000016 · Cited by 105 · cited 1× · see citing works
“Thus, concomitant CVD strongly correlated with cognitive impairment in this sample selected to represent the AD pathology continuum, confirming the uncertainty of AD clinico-pathological correlations based only on neurofibrillary tangles and Aβplaques [155].”
BackgroundThe vascular lesions in vascular and mixed dementia: the weight of functional neuroanatomy
Zekry, D., Duyckaerts, C. J., Belmin, J., Geoffre, C., Herrmann, F. R., Moulias, R., & Hauw, J. (2002) · Neurobiology of Aging · doi:10.1016/s0197-4580(02)00066-0 · Cited by 104 · cited 1× · see citing works
“However, AD pathology alone more frequently accounts for dementia than both macroscopic and microscopic infarcts [15] and, in late stages of AD, concomitant SVLs do not significantly influence the overall state and progression of cognitive decline [45,54,76], the severity and extent of AD pathology overwhelming the ra…”
BackgroundEffect of White Matter Changes on Cognitive Impairment in Patients With Lacunar Infarcts
Wen, H. M., Mok, V., Fan, Y. H., Lam, W. W. M., Tang, W. K., Wong, A., Huang, R. X., & Wong, K. S. (2004) · Stroke · doi:10.1161/01.str.0000133686.29320.58 · Cited by 101 · cited 1× · see citing works
“They impair frontal functions regardless of their location [175,176] and increase the risk of dementia, particularly in patients with lacunar infarcts [177,178], causing functional network disruption in cognitively-impaired individuals compared with age-matched healthy elderly controls [179,180].”
BackgroundIn vivo assessment of amyloid‐β deposition in nondemented very elderly subjects
Mathis, C. A., Kuller, L. H., Klunk, W. E., Snitz, B. E., Price, J. C., Weissfeld, L. A., Rosario, B. L., Lopresti, B. J., Saxton, J. A., Aizenstein, H. J., et al. (2013) · Annals of Neurology · doi:10.1002/ana.23797 · Cited by 98 · see citing works
The impact of cerebrovascular lesions in Alzheimer disease
Jellinger, K. A., & Mitter-Ferstl, E. (2003) · Journal of Neurology · doi:10.1007/s00415-003-0142-0 · Cited by 97 · see citing works
Self-citationDetection of isolated cerebrovascular β‐amyloid with pittsburgh compound B
Greenberg, S. M., Grabowski, T. J., Gurol, M. E., Skehan, M. E., Nandigam, R. N. K., Becker, J. A., Garcı́a-Alloza, M., Prada, C. M., Frosch, M. P., Rosand, J. M., et al. (2008) · Annals of Neurology · doi:10.1002/ana.21528 · Cited by 96 · cited 1× · see citing works
“In addition to the presence of superficial siderosis, cerebral microbleeds, cortical microinfarcts, and hypointensities in MRI images [106-109], the use of Pittsburgh Compound-B (PiB)positron emission tomography (PET) is useful in detecting CAA intra vitam [110,111], and a significant decrease of both Aβ-40 and Aβ-42…”
BackgroundVascular risk factors in dementia
Schmidt, R., Schmidt, H., & Fazekas, F. (2000) · Journal of Neurology · doi:10.1007/s004150050021 · Cited by 95 · cited 1× · see citing works
“Vascular disease is thought by many authors to play a major role in the pathogenesis of AD and some even consider AD as being rather a primarily vascular than a neurodegenerative disorder [22,68-74].”
BackgroundDiffusion-Weighted Imaging and Cognition in the Leukoariosis and Disability in the Elderly Study
Schmidt, R., Ropele, S., Ferro, J. M., Madureira, S., Verdelho, A., Petrovic, K. E., Gouw, A. A., van der Flier, W. M., Enzinger, C., Pantoni, L., et al. (2010) · Stroke · doi:10.1161/strokeaha.109.576629 · Cited by 95 · see citing works
Giannakopoulos, P., Gold, G., Kövari, E., von Gunten, A., Imhof, A., Bouras, C., & Hof, P. R. (2006) · Acta Neuropathologica · doi:10.1007/s00401-006-0144-y · Cited by 95 · cited 1× · see citing works
“Since 50% to 84% of the brains of persons who die aged 80 to 90+ show appreciable cerebrovascular lesions (CVL) [1], a specific problem is their impact in relation to AD pathology [2-8].”
BackgroundCognitive reserve, cortical plasticity and resistance to Alzheimer's disease
Esiri, M. M., & Chance, S. A. (2012) · Alzheimer's Research & Therapy · doi:10.1186/alzrt105 · Cited by 95 · see citing works
Lee, J. H., Olichney, J., Hansen, L. A., Hofstetter, C. R., & Thal, L. J. (2000) · Archives of Neurology · doi:10.1001/archneur.57.10.1474 · Cited by 94 · cited 2× · see citing works
“However, AD pathology alone more frequently accounts for dementia than both macroscopic and microscopic infarcts [15] and, in late stages of AD, concomitant SVLs do not significantly influence the overall state and progression of cognitive decline [45,54,76], the severity and extent of AD pathology overwhelming the ra…”
BackgroundViggars, A. P., Wharton, S. B., Simpson, J. E., Matthews, F. E., Brayne, C., Savva, G. M., Garwood, C. J., Drew, D., Shaw, P. J., & Ince, P. G. (2011) · Neuroscience Letters · doi:10.1016/j.neulet.2011.09.049 · Cited by 94 · cited 1× · see citing works
“Evidence of early increase of BBB changes and their progression with severity of AD-type pathology suggest that BBB dysfunction contributes to damage in the aging brain [132].”
BackgroundRecent Updates on Subcortical Ischemic Vascular Dementia
Roh, J. H., & Lee, J.-H. (2014) · Journal of Stroke · doi:10.5853/jos.2014.16.1.18 · Cited by 93 · cited 1× · see citing works
“The recent development of in vivo amyloid imaging enables further pathological breakdown of SVD into pure forms and mixed dementia based on the absence or presence of amyloid pathology in the brain [194].”
BackgroundFrontal lobe white matter hyperintensities and neurofibrillary pathology in the oldest old
Polvikoski, T. M., van Straaten, E. C. W., Barkhof, F., Sulkava, R., Aronen, H. J., Niinistö, L., Oinas, M., Scheltens, P., Erkinjuntti, T., & Kalaria, R. N. (2010) · Neurology · doi:10.1212/wnl.0b013e318200d6f9 · Cited by 88 · see citing works
Neuroanatomical localisation and clinical correlates of white matter lesions in the elderly
Artéro, S. (2004) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp.2003.023713 · Cited by 87 · cited 1× · see citing works
“WMLs may be caused by both CVD (hypoperfusion) and AD (retrograde degeneration), they progress with age, and they are a considerable risk factor for cognitive impairment [120,173,174].”
BackgroundUnexpectedly low prevalence of intracerebral hemorrhages in sporadic cerebral amyloid angiopathy
Attems, J., Lauda, F., & Jellinger, K. A. (2008) · Journal of Neurology · doi:10.1007/s00415-008-0674-4 · Cited by 87 · cited 1× · see citing works
“However, in a large autopsy cohort, the prevalence of ICH was similar in cases with and without CAA (around 5%) [93,94].”
ResultSelf-citationVascular abnormalities: the insidious pathogenesis of Alzheimer’s disease☆
Shi, J., Perry, G. L., Smith, M. A., & Friedland, R. P. (2000) · Neurobiology of Aging · doi:10.1016/s0197-4580(00)00119-6 · Cited by 86 · cited 1× · see citing works
“Vascular disease is thought by many authors to play a major role in the pathogenesis of AD and some even consider AD as being rather a primarily vascular than a neurodegenerative disorder [22,68-74].”
BackgroundAmyloid-β Positron Emission Tomography Imaging Probes: A Critical Review
Kepe, V., Moghbel, M. C., Långström, B., Zaidi, H., Vinters, H. V., Huang, S., Satyamurthy, N., Doudet, D. J., Mishani, E., Cohen, R. M., et al. (2013) · Journal of Alzheimer s Disease · doi:10.3233/jad-130485 · Cited by 86 · see citing works
White matter loss in healthy ageing: A postmortem analysis
Piguet, O., Double, K. L., Kril, J. J., Harasty, J., Macdonald, V., McRitchie, D. A., & Halliday, G. M. (2008) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2007.10.015 · Cited by 85 · see citing works
Judith Miklossy, A. (2003) · Neurological Research · doi:10.1179/016164103101202048 · Cited by 82 · cited 1× · see citing works
“Cerebral hypoperfusioninducing cortical microinfarcts may further aggravate cognitive decline in AD [75].”
BackgroundCurrent state and future directions of neurochemical biomarkers for Alzheimer's disease
de Jong, D., Kremer, B. P. H., Rikkert, M. G. M. O., & Verbeek, M. M. (2007) · Clinical Chemistry and Laboratory Medicine (CCLM) · doi:10.1515/cclm.2007.320 · Cited by 82 · cited 1× · see citing works
“In addition to the presence of superficial siderosis, cerebral microbleeds, cortical microinfarcts, and hypointensities in MRI images [106-109], the use of Pittsburgh Compound-B (PiB)positron emission tomography (PET) is useful in detecting CAA intra vitam [110,111], and a significant decrease of both Aβ-40 and Aβ-42…”
BackgroundUtter, S., Tamboli, I. Y., Walter, J., Upadhaya, A. R., Birkenmeier, G., Pietrzik, C. U., Ghebremedhin, E., & Thal, D. R. (2008) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/nen.0b013e3181836a71 · Cited by 79 · cited 3× · see citing works
“SVD-induced ApoE leakage was associated with AD and accumulation of β-amyloid (Aβ) in perivascular astrocytes [61] and transient induction of Aβ deposition [62].”
BackgroundA Review of the Major Vascular Risk Factors Related to Alzheimer's Disease
Polidori, M. C., Pientka, L., & Mecocci, P. (2012) · Journal of Alzheimer s Disease · doi:10.3233/jad-2012-120871 · Cited by 77 · cited 1× · see citing works
“, atrial fibrillation and congestive heart failure, have also been linked to the pathogenesis and progression of AD and are among the most important modifiable risk factors for AD [35-42].”
BackgroundRenard, D., Castelnovo, G., Wacongne, A., et al. (2012) · Journal of Neurology · doi:10.1007/s00415-012-6520-8 · Cited by 77 · cited 1× · see citing works
“In addition to the presence of superficial siderosis, cerebral microbleeds, cortical microinfarcts, and hypointensities in MRI images [106-109], the use of Pittsburgh Compound-B (PiB)positron emission tomography (PET) is useful in detecting CAA intra vitam [110,111], and a significant decrease of both Aβ-40 and Aβ-42…”
BackgroundCerebral Amyloid Angiopathy: A Common Cause of Cerebral Hemorrhage
Pezzini, A., Zotto, E. D., Volonghi, I., Giossi, A., Costa, P., & Padovani, A. (2009) · Current Medicinal Chemistry · doi:10.2174/092986709788682047 · Cited by 76 · cited 5× · see citing works
“The progression of WMLs in subjects with CAA has been associated with incident lobar ICHs [97].”
BackgroundInfluentialQiu, C., Xu, W., Winblad, B. G., & Fratiglioni, L. (2010) · Journal of Alzheimer s Disease · doi:10.3233/jad-2010-1361 · Cited by 75 · cited 1× · see citing works
“, atrial fibrillation and congestive heart failure, have also been linked to the pathogenesis and progression of AD and are among the most important modifiable risk factors for AD [35-42].”
BackgroundSelected Findings from the Religious Orders Study and Rush Memory and Aging Project
Bennett, D. A., Wilson, R. S., Arvanitakis, Z., Boyle, P. A., de Toledo-Morrell, L., & Schneider, J. A. (2012) · Journal of Alzheimer's Disease · doi:10.3233/jad-2012-129007 · Cited by 69 · cited 3× · see citing works
“These data add further evidence for AD pathology (mainly neurofibrillary tangles and neuritic plaques) being the main morphological substrate of clinical dementia [51,79,80].”
BackgroundCortical microinfarcts in Alzheimer's disease and subcortical vascular dementia
Okamoto, Y., Ihara, M., Fujita, Y., Ito, H., Takahashi, R., & Tomimoto, H. (2009) · Neuroreport · doi:10.1097/wnr.0b013e32832d2e6a · Cited by 68 · cited 1× · see citing works
“CAA has been suggested to cause cortical microinfarcts [98,99], while others did not confirm such an association [100].”
ResultOlichney, J. M., Ellis, R., Katzman, R., Sabbagh, M. N., & Hansen, L. (1997) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.1997.tb48511.x · Cited by 64 · cited 2× · see citing works
“In a series of 300 autopsy cases of AD, Kalaria and Ballard [148] reported 98% CAA, 100% microvascular degeneration, 31% infarcts of all sizes, and 7% intracerebral hemorrhage, while Olichney [149], in a cohort of 248 autopsy cases of AD, revealed a total of 48% CVLs, with 31% microinfarcts, 12.”
BackgroundInfluentialCapillary CAA and perivascular Aβ-deposition: Two distinct features of Alzheimer's disease pathology
Attems, J., Yamaguchi, H., Saido, T. C., & Thal, D. R. (2010) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2010.08.030 · Cited by 63 · cited 1× · see citing works
“In addition, pericapillary Aβ refers to Aβ depositions in the glia limitans and adjacent neuropil, whereas in capillary CAA Aβ depositions are present in the capillary wall [88].”
BackgroundSelf-citationInverse relation between Braak stage and cerebrovascular pathology in Alzheimer predominant dementia
Goulding, J. M. R., Signorini, D. F., Chatterjee, S., Nicoll, J. A. R., Stewart, J., Morris, R. G., & Lammie, G. A. (1999) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp.67.5.654 · Cited by 62 · see citing works
Prevalence and Pathology of Vascular Dementia in the Oldest-Old1
Jellinger, K. A., & Attems, J. (2010) · Journal of Alzheimer s Disease · doi:10.3233/jad-2010-100603 · Cited by 61 · cited 4× · see citing works
“6% to 57%) and mixed dementia (2% to 86%) [47].”
BackgroundInfluentialSelf-citationRichardson, K., Stephan, B. C. M., Ince, P. G., Brayne, C., & Matthews, F. E. (2012) · Current Alzheimer Research · doi:10.2174/156720512801322654 · Cited by 61 · cited 1× · see citing works
“In the Medical Research Council Cognitive Function and Ageing Study, vascular risk factors were not associated with an increased burden of AD pathology at death in old age, whereas cerebral small vessel disease (SVD) and cardiovascular disease were interrelated [43].”
BackgroundAre cerebrovascular factors involved in Alzheimer’s disease?
Kudo, T., Imaizumi, K., Tanimukai, H., Katayama, T., Sato, N., Nakamura, Y., Tanaka, T., Kashiwagi, Y., Jinno, Y., Tohyama, M., et al. (2000) · Neurobiology of Aging · doi:10.1016/s0197-4580(00)00129-9 · Cited by 60 · cited 1× · see citing works
“Vascular disease is thought by many authors to play a major role in the pathogenesis of AD and some even consider AD as being rather a primarily vascular than a neurodegenerative disorder [22,68-74].”
BackgroundAssociation of silent lacunar infarct with brain atrophy and cognitive impairment
Thong, J. Y. J., Hilal, S., Wang, Y., Soon, H. W., Dong, Y., Collinson, S. L., Anh, T. T., Ikram, M. K., Wong, T. Y., Venketasubramanian, N., et al. (2013) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp-2013-305310 · Cited by 59 · cited 1× · see citing works
“They have been shown to be associated with atrophy in multiple subcortical structures, ventricular enlargement, and widespread cortical thinning, supporting the assumption of a vascular contribution to neurodegeneration and cognitive impairment [134].”
BackgroundAdvances in molecular genetics and pathology of cerebrovascular disorders
Kalaria, R. N. (2001) · Trends in Neurosciences · doi:10.1016/s0166-2236(00)01836-1 · Cited by 56 · cited 1× · see citing works
“AD has been reported to present frequently together with SVD, microvascular injury, and microscopic CVLs [8,16,47,56-60].”
BackgroundAltered default-mode network activation in mild cognitive impairment compared with healthy aging
Vogelaere, F. D., Santens, P., Achten, E., Boon, P., & Vingerhoets, G. (2012) · Neuroradiology · doi:10.1007/s00234-012-1036-6 · Cited by 55 · cited 1× · see citing works
“They impair frontal functions regardless of their location [175,176] and increase the risk of dementia, particularly in patients with lacunar infarcts [177,178], causing functional network disruption in cognitively-impaired individuals compared with age-matched healthy elderly controls [179,180].”
BackgroundNonstroke Cardiovascular Disease and Risk of Alzheimer Disease and Dementia
Eriksson, U. K., Bennet, A. M., Gatz, M., Dickman, P. W., & Pedersen, N. L. (2010) · Alzheimer Disease & Associated Disorders · doi:10.1097/wad.0b013e3181d1b99b · Cited by 53 · see citing works
Research and practice in Alzheimer's disease 2002.
Vellas, B., & Fitten, L. J. (2002) · PubMed · Cited by 51 · see citing works
Sporadic cerebral amyloid angiopathy is not a frequent cause of spontaneous brain hemorrhage
Jellinger, K. A., Lauda, F., & Attems, J. (2007) · European Journal of Neurology · doi:10.1111/j.1468-1331.2007.01880.x · Cited by 51 · cited 1× · see citing works
“However, in a large autopsy cohort, the prevalence of ICH was similar in cases with and without CAA (around 5%) [93,94].”
ResultSelf-citationNeuropathology and general autopsy findings in nondemented aged subjects
Jellinger, K. A., & Attems, J. (2012) · Clinical Neuropathology · doi:10.5414/np300418 · Cited by 48 · cited 1× · see citing works
“A lacunar state in basal ganglia and/or white matter was observed in 73%, hippocampal sclerosis in 3%, and mixed cerebral pathologies in 6%, whereas only 9% were free of CVLs [169].”
BackgroundSelf-citationCurrent pathophysiological concepts in cerebral small vessel disease
Rincón, F., & Wright, C. B. (2014) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2014.00024 · Cited by 44 · see citing works
Small Vascular and Alzheimer Disease-Related Pathologic Determinants of Dementia in the Oldest-Old
Sinka, L., Kövari, E., Gold, G., Hof, P. R., Herrmann, F. R., Bouras, C., & Giannakopoulos, P. (2010) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/nen.0b013e3181ffc3b9 · Cited by 43 · cited 1× · see citing works
“AD has been reported to present frequently together with SVD, microvascular injury, and microscopic CVLs [8,16,47,56-60].”
BackgroundEsiri, M. M., Joachim, C., Sloan, C., Christie, S., Agacinski, G., Bridges, L. R., Wilcock, G. K., & Smith, A. D. (2014) · Alzheimer Disease & Associated Disorders · doi:10.1097/wad.0b013e31829b72f1 · Cited by 42 · cited 5× · see citing works
“AD has been reported to present frequently together with SVD, microvascular injury, and microscopic CVLs [8,16,47,56-60].”
BackgroundResultInfluentialEducation Differences in Life Expectancy With Cognitive Impairment
Matthews, F. E., Jagger, C., Miller, L. L., Brayne, C., & CFAS, M. (2009) · The Journals of Gerontology Series A · doi:10.1093/gerona/gln003 · Cited by 41 · cited 1× · see citing works
“Moderate to severe CAA is considered to be an independent risk factor for cognitive impairment [101].”
BackgroundStephan, B. C. M., Matthews, F. E., Ma, B., Terrera, G. M., Hunter, S., Davis, D. H. J., McKeith, I. G., Foster, G., Ince, P. G., & Brayne, C. (2012) · Journal of Alzheimer s Disease · doi:10.3233/jad-2011-110518 · Cited by 38 · cited 1× · see citing works
“The burden of vascular and AD-type pathologies are leading and independent causes of dementia in the elderly [4,9-15], suggesting additive or synergistic effects of both types of lesions on cognitive impairment [2,3,5,9,16-29].”
BackgroundJellinger, K. A. (2001) · Archives of Neurology · doi:10.1001/archneur.58.3.520 · Cited by 37 · cited 2× · see citing works
“However, AD pathology alone more frequently accounts for dementia than both macroscopic and microscopic infarcts [15] and, in late stages of AD, concomitant SVLs do not significantly influence the overall state and progression of cognitive decline [45,54,76], the severity and extent of AD pathology overwhelming the ra…”
BackgroundSelf-citationLuoto, T. M., Haikonen, S., Haapasalo, H. K., Goebeler, S., Huhtala, H., Erkinjuntti, T., & Karhunen, P. J. (2009) · European Neurology · doi:10.1159/000222779 · Cited by 37 · cited 1× · see citing works
“Others, however, saw no direct association between large-vessel cerebral atherosclerosis and AD pathology [142], suggesting that atherosclerosis of the intracranial vessels is an independent and important risk factor for dementia due to potentially reversible pathways unrelated to AD pathology and stroke [143].”
BackgroundEvaluation of Selection Bias in an Incident-Based Dementia Autopsy Case Series
Tsuang, D., Simpson, K. L., Li, G., Barnhart, R. L., Edland, S. D., Bowen, J., McCormick, W., Teri, L., Nochlin, D., Larson, E. B., et al. (2005) · Alzheimer Disease & Associated Disorders · doi:10.1097/01.wad.0000165507.67993.47 · Cited by 37 · cited 1× · see citing works
“A specific caveat in this respect is the effect of sample selection in incident-bases dementia autopsy series [164].”
BackgroundMicrovascular Burden and Alzheimer-Type Lesions Across the Age Spectrum
Costanza, A., Xekardaki, A., Kövari, E., Gold, G., Bouras, C., & Giannakopoulos, P. (2012) · Journal of Alzheimer's Disease · doi:10.3233/jad-2012-120835 · Cited by 36 · cited 2× · see citing works
“Together with cortical microinfarcts, WMLs may contribute to the progression of cognitive impairment, but do not necessarily interact with AD pathology to increase the likelihood of dementia beyond their additive effect [20].”
BackgroundMalykhin, N. V., Vahidy, S., Michielse, S., Coupland, N., Camicioli, R. M., Seres, P., & Carter, R. (2011) · Brain Structure and Function · doi:10.1007/s00429-011-0321-1 · Cited by 36 · cited 1× · see citing works
“They impair frontal functions regardless of their location [175,176] and increase the risk of dementia, particularly in patients with lacunar infarcts [177,178], causing functional network disruption in cognitively-impaired individuals compared with age-matched healthy elderly controls [179,180].”
BackgroundCerebral Cortical Microinfarcts at 7Tesla MRI in Patients with Early Alzheimer's Disease
van Veluw, S. J., on behalf of the Utrecht Vascular Cognitive Impairment study group, Heringa, S. M., Kuijf, H. J., Koek, H. L., Luijten, P. R., & Biessels, G. J. (2014) · Journal of Alzheimer s Disease · doi:10.3233/jad-131040 · Cited by 32 · cited 1× · see citing works
“A systemic review of CMIs reported frequencies of 43% in patients with AD and 24% in non-demented older adults [136], while a 7-Tesla MRI study revealed CMI occurrence in 55% of early AD and 45% of non-demented age-matched controls [137].”
BackgroundPathogenesis and Treatment of Vascular Cognitive Impairment
Jellinger, K. A. (2014) · Neurodegenerative Disease Management · doi:10.2217/nmt.14.37 · Cited by 30 · cited 1× · see citing works
“The pathophysiology of VaD has been critically reviewed recently [48,144-146].”
BackgroundSelf-citationCerebrovascular Pathology and Amyloid Plaque Formation in Alzheimer’s Disease
Lee, C.-W., Shih, Y., & Kuo, Y. (2014) · Current Alzheimer Research · doi:10.2174/1567205010666131119234308 · Cited by 28 · cited 1× · see citing works
“CVD has been shown to induce Aβ deposition, which may by itself cause CVD, in particular micro-vascular degeneration [63].”
BackgroundLate and early onset dementia: What is the role of vascular factors? A retrospective study
Carotenuto, A., Rea, R., Colucci, L., Ziello, A. R., Molino, I., Carpi, S., Traini, E., Amenta, F., & Fasanaro, A. M. (2012) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2012.07.066 · Cited by 27 · cited 1× · see citing works
“Cerebrovascular lesions are found in the majority of lateonset AD and only in half of early-onset AD cases [160].”
BackgroundRisk factors and neurodegenerative mechanisms in stroke related dementia.
Kalaria, R. N. (2012) · PubMed · Cited by 27 · see citing works
McAleese, K. E., Firbank, M., Hunter, D., Sun, L., Hall, R., Neal, J., Mann, D. M. A., Esiri, M. M., Jellinger, K. A., O'Brien, J. T., et al. (2012) · Neuropathology and Applied Neurobiology · doi:10.1111/j.1365-2990.2012.01310.x · Cited by 24 · cited 1× · see citing works
“Routine histological assessment may underrate mild to moderate subcortical vascular lesions, but MRI imaging of fixed post-mortem brains reliably reflects subcortical vascular pathology of the white matter [126,127].”
Self-citationBurhan, A. M., Bartha, R., Bocti, C., BORRIE, M. J., Laforce, R. J., Rosa‐Neto, P., & Soucy, J. (2013) · Alzheimer s Research & Therapy · doi:10.1186/alzrt200 · Cited by 24 · see citing works
Molecular Imaging of Alzheimer Disease Pathology
Kantarci, K. (2014) · American Journal of Neuroradiology · doi:10.3174/ajnr.a3847 · Cited by 23 · cited 1× · see citing works
“) [188-190] will enable the identification of AD and CVD patients in clinical and research settings.”
BackgroundOrtner, M., Kurz, A., Alexopoulos, P., Auer, F., Diehl-Schmid, J., Drzezga, A., Förster, S., Förstl, H., Perneczky, R., Sorg, C., et al. (2015) · Biological Psychiatry · doi:10.1016/j.biopsych.2014.01.019 · Cited by 17 · cited 1× · see citing works
“In AD neither Aβ load nor metabolic deficit are dependent on the age of disease onset, but patients with late-onset AD show a significantly higher amount of SVD that influences the association between metabolic deficit and clinical symptoms [117].”
BackgroundO'Brien, T. J., Wadley, V. G., Nicholas, A. P., et al. (2009) · Archives of Clinical Neuropsychology · doi:10.1093/arclin/acp029 · Cited by 17 · cited 1× · see citing works
“The burden of vascular and AD-type pathologies are leading and independent causes of dementia in the elderly [4,9-15], suggesting additive or synergistic effects of both types of lesions on cognitive impairment [2,3,5,9,16-29].”
BackgroundCerebrovascular lesions in elderly Japanese patients with Alzheimer's disease
Nagata, K., Takano, D., Yamazaki, T., Maeda, T., Satoh, Y., Nakase, T., & Ikeda, Y. (2012) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2012.07.001 · Cited by 16 · cited 1× · see citing works
“AD has been reported to present frequently together with SVD, microvascular injury, and microscopic CVLs [8,16,47,56-60].”
BackgroundChallenges in the Neuropathological Diagnosis of Dementias
Jellinger, K. A. (2012) · International Journal of Neuropathology · doi:10.7726/ijn.2013.1002 · Cited by 15 · cited 2× · see citing works
“The pathophysiology of VaD has been critically reviewed recently [48,144-146].”
BackgroundResultSelf-citationAmyloid and tau in the brain in sporadic Alzheimer’s disease: defining the chicken and the egg
Hawkes, C. A., Carare, R. O., & Weller, R. O. (2014) · Acta Neuropathologica · doi:10.1007/s00401-014-1243-9 · Cited by 14 · cited 1× · see citing works
“In addition, aging, per se, has an effect on cerebral arteries in relation to AD since such age related changes may impair the drainage of soluble Aβ out of the brain, which in turn leads to Aβ accumulation in vessel walls and brain parenchyma associated with perturbation of cerebral perfusion and loss of homeostasis…”
BackgroundA physiologic biomarker for cerebral amyloid angiopathy
Gurol, M. E., & Greenberg, S. M. (2013) · Neurology · doi:10.1212/01.wnl.0000435303.10519.15 · Cited by 7 · cited 1× · see citing works
“In addition to the presence of superficial siderosis, cerebral microbleeds, cortical microinfarcts, and hypointensities in MRI images [106-109], the use of Pittsburgh Compound-B (PiB)positron emission tomography (PET) is useful in detecting CAA intra vitam [110,111], and a significant decrease of both Aβ-40 and Aβ-42…”
BackgroundHulette, C. M., Ervin, J. F., Edmonds, Y., Antoine, S., Stewart, N., Szymanski, M. H., Hayden, K. M., Pieper, C. F., Burke, J. R., & Welsh-Bohmer, K. A. (2009) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/nen.0b013e31819e6334 · Cited by 6 · cited 1× · see citing works
“Activity of smooth muscle actin (SMA) was reduced in the brains of patients with late stage AD, while increased arteriolar SMA expression together with frequent Aβ plaques observed in the brains of non-demented subjects suggests that increased SMA expression might represent a physiological response to neurodegeneratio…”
Background
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1 of the 196 references couldn’t be matched to a known paper.
Research works printed but not linked: 2
- Crystal H, Dickson D: Cerebral infarcts in patients with autopsy proven Alzheimer’s disease. Neurobiol Aging. 2002, 23: 207.
- Jentoft M, Parisi J, Dickson D, Johnson K, Boeve B, Knopman D, Petersen R: Neuropathologic findings in 32 nondemented elderly subjects (abs.). J Neuropathol Exp Neurol. 2011, 70: 531.
Cited by
Sorted by citations
The Cellular Phase of Alzheimer’s Disease
De Strooper, B., & Karran, E. (2016) · Cell · doi:10.1016/j.cell.2015.12.056 · Cited by 1,990 · see citing works
Impact of multiple pathologies on the threshold for clinically overt dementia
Kapasi, A., DeCarli, C., & Schneider, J. A. (2017) · Acta Neuropathologica · doi:10.1007/s00401-017-1717-7 · Cited by 739 · see citing works
“Other common pathologies presented in persons with mixed pathologies are Lewy bodies [7, 131].”
BackgroundIadecola, C., Yaffe, K., Biller, J., Bratzke, L. C., Faraci, F. M., Gorelick, P. B., Gulati, M., Kamel, H., Knopman, D. S., Launer, L. J., et al. (2016) · Hypertension · doi:10.1161/hyp.0000000000000053 · Cited by 746 · see citing works
“Although dementia caused by AD and vascular dementia have traditionally been considered distinct nosological entities, increasing evidence indicates that these conditions often coexist.(8,9) Thus, the neuropathological hallmarks of AD, amyloid plaques and neurofibrillary tangles (NFTs), are frequently associated with…”
Blood-based biomarkers for Alzheimer disease: mapping the road to the clinic
Hampel, H., O’Bryant, S. E., Molinuevo, J. L., Zetterberg, H., Masters, C. L., Lista, S., Kiddle, S. J., Batrla, R., & Blennow, K. (2018) · Nature Reviews Neurology · doi:10.1038/s41582-018-0079-7 · Cited by 716 · see citing works
A Quarter Century of APOE and Alzheimer’s Disease: Progress to Date and the Path Forward
Belloy, M. E., Napolioni, V., & Greicius, M. D. (2019) · Neuron · doi:10.1016/j.neuron.2019.01.056 · Cited by 570 · see citing works
“To complicate matters further, cerebrovascular disease and AD often co-occur, particularly in older patients (Attems and Jellinger, 2014; Grinberg et al., 2010).”
High Cortisol and the Risk of Dementia and Alzheimer’s Disease: A Review of the Literature
Ouanes, S., & Popp, J. (2019) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2019.00043 · Cited by 481 · see citing works
Dominguez, L. J., Veronese, N., Vernuccio, L., Catanese, G., Inzerillo, F., Salemi, G., & Barbagallo, M. (2021) · Nutrients · doi:10.3390/nu13114080 · Cited by 433 · see citing works
“Specifically, vascular disease risk factors, more so in midlife, are associated with brain accumulation of beta-amyloid [71,72].”
BackgroundAssociation of Intensive vs Standard Blood Pressure Control With Cerebral White Matter Lesions
Nasrallah, I. M., Pajewski, N. M., Auchus, A. P., Chelune, G. J., Cheung, A. K., Cleveland, M. L., Coker, L. H., Crowe, M. G., Cushman, W. C., Cutler, J. A., et al. (2019) · JAMA · doi:10.1001/jama.2019.10551 · Cited by 427 · see citing works
Global Prevalence of Young-Onset Dementia: A Systematic Review and Meta-analysis
Hendriks, S., Peetoom, K., Bakker, C., van der Flier, W. M., Papma, J. M., Koopmans, R., Verhey, F. R. J., de Vugt, M., Köhler, S., Young-Onset Dementia Epidemiology Study Group, et al. (2021) · JAMA Neurology · doi:10.1001/jamaneurol.2021.2161 · Cited by 409 · see citing works
A major role for cardiovascular burden in age-related cognitive decline
Qiu, C., & Fratiglioni, L. (2015) · Nature Reviews Cardiology · doi:10.1038/nrcardio.2014.223 · Cited by 401 · see citing works
Traffic-related air pollution and dementia incidence in northern Sweden: a longitudinal study
Oudin, A., Forsberg, B., Adolfsson, A. N., Lind, N., Modig, L., Nordin, M., Nordin, S., Adolfsson, R., & Nilsson, L.-G. (2016) · Environmental Health Perspectives · doi:10.1289/ehp.1408322 · Cited by 358 · see citing works
Bennett, R. E., Robbins, A. B., Hu, M., Cao, X., Betensky, R. A., Clark, T., Das, S., & Hyman, B. T. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1710329115 · Cited by 299 · see citing works
“Mounting evidence indicates that, as assessed in life by MRI scans or at autopsy by neuropathological evaluation, “pure” AD is substantially less common than mixed dementias, in which tangles and plaques are accompanied by vascular changes (1, 2).”
BackgroundCerebrovascular disease in ageing and Alzheimer’s disease
Love, S., & Miners, J. S. (2016) · Acta Neuropathologica · doi:10.1007/s00401-015-1522-0 · Cited by 299 · see citing works
“ture was reviewed in detail by Attems and Jellinger [8].”
MethodZhong, B.-L., Chen, S.-L., Tu, X., & Conwell, Y. (2017) · The Journals of Gerontology Series B: Psychological Sciences and Social Sciences · doi:10.1093/geronb/gbw037 · Cited by 259 · see citing works
“…vessel disease, leading to increases in cerebral amyloid plaques, neurofibrillary tangles, and microinfarcts, the most common pathological correlates of late-life dementia (Attems & Jellinger, 2014; G. Cheng, Huang, Deng, & Wang, 2012; Faraco & Iadecola, 2013; Pregelj, 2008; Sharp et al., 2011).”
Rafnsson, S. B., Orrell, M., d’Orsi, E., Hogervorst, E., & Steptoe, A. (2020) · The Journals of Gerontology: Series B · doi:10.1093/geronb/gbx087 · Cited by 262 · see citing works
“Cardiovascular risk factors promote atherosclerotic small vessel disease and the neurofibrillary tangles characteristic of Alzheimer’s disease (Attems & Jellinger, 2014).”
BackgroundThe Vascular Impairment of Cognition Classification Consensus Study
Skrobot, O. A., O'Brien, J., Black, S., Chen, C., DeCarli, C., Erkinjuntti, T., Ford, G. A., Kalaria, R. N., Pantoni, L., Pasquier, F., et al. (2017) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2016.10.007 · Cited by 242 · see citing works
“CVD commonly contributes to many forms of dementia, including AD[26-28], and may be targeted with some success [29], although further research into possible associations and causal relationships is needed.”
Self-citationA natural experiment on the effect of herpes zoster vaccination on dementia
Eyting, M., Xie, M., Michalik, F., Heß, S., Chung, S., & Geldsetzer, P. (2025) · Nature · doi:10.1038/s41586-025-08800-x · Cited by 261 · see citing works
Corriveau, R. A., Bosetti, F., Emr, M., Gladman, J. T., Koenig, J. I., Moy, C. S., Pahigiannis, K., Waddy, S. P., & Koroshetz, W. (2016) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-016-0334-7 · Cited by 240 · see citing works
“1) (Breteler 2000a, b; Gorelick et al. 2011; Iadecola 2013; Attems and Jellinger 2014).”
Peters, R., Ee, N., Peters, J., Beckett, N., Booth, A., Rockwood, K., & Anstey, K. J. (2019) · Therapeutic Advances in Chronic Disease · doi:10.1177/2040622319880392 · Cited by 213 · see citing works
Cognitive impact of COVID-19: looking beyond the short term
Miners, J. S., Kehoe, P. G., & Love, S. (2020) · Alzheimer s Research & Therapy · doi:10.1186/s13195-020-00744-w · Cited by 248 · see citing works
The Neuroprotective Effects of Exercise: Maintaining a Healthy Brain Throughout Aging
Vecchio, L. M., Meng, Y., Xhima, K., Lipsman, N., Hamani, C., & Aubert, I. (2018) · Brain Plasticity · doi:10.3233/bpl-180069 · Cited by 230 · see citing works
Emerging Concepts in Vascular Dementia: A Review
Bir, S. C., Khan, M. W., Javalkar, V., Toledo, E. G., & Kelley, R. E. (2021) · Journal of Stroke and Cerebrovascular Diseases · doi:10.1016/j.jstrokecerebrovasdis.2021.105864 · Cited by 230 · see citing works
Insulin Resistance as a Link between Amyloid-Beta and Tau Pathologies in Alzheimer’s Disease
Mullins, R. J., Diehl, T. C., Chia, C. W., & Kapogiannis, D. (2017) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2017.00118 · Cited by 213 · see citing works
“…infarcts, leukoaraiosis (seen on magnetic resonance imaging (MRI) as white matter hyperintensities), cerebral amyloid angiopathy (CAA), microaneurysms, and small and large vessel ischemic/hemorrhagic stroke (Breteler, 2000; Gorelick et al., 2011; Attems and Jellinger, 2014; Corriveau et al., 2016).”
BackgroundKapasi, A., & Schneider, J. A. (2016) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2015.12.023 · Cited by 215 · see citing works
Matěj, R., Tesař, A., & Rusina, R. (2019) · Clinical Biochemistry · doi:10.1016/j.clinbiochem.2019.08.005 · Cited by 158 · see citing works
Multimorbidity burden and dementia risk in older adults: The role of inflammation and genetics
Grande, G., Marengoni, A., Vetrano, D. L., Roso‐Llorach, A., Rizzuto, D., Zucchelli, A., Qiu, C., Fratiglioni, L., & Calderón‐Larrañaga, A. (2021) · Alzheimer s & Dementia · doi:10.1002/alz.12237 · Cited by 162 · see citing works
Challenges of multimorbidity of the aging brain: a critical update
Jellinger, K. A., & Attems, J. (2015) · Journal of Neural Transmission · doi:10.1007/s00702-014-1288-x · Cited by 154 · see citing works
Self-citationA global view of the genetic basis of Alzheimer disease
Reitz, C., Pericak-Vance, M., Foroud, T., & Mayeux, R. (2023) · Nature Reviews Neurology · doi:10.1038/s41582-023-00789-z · Cited by 143 · see citing works
Millan, M. J. (2017) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2017.03.004 · Cited by 146 · see citing works
Blood pressure lowering and prevention of dementia: an individual patient data meta-analysis
Peters, R., Xu, Y., Fitzgerald, O., Aung, H. L., Beckett, N., Bulpitt, C., Chalmers, J., Forette, F., Gong, J., Harris, K., et al. (2022) · European Heart Journal · doi:10.1093/eurheartj/ehac584 · Cited by 142 · see citing works
de la Torre, J. (2018) · Journal of Alzheimer s Disease · doi:10.3233/jad-180004 · Cited by 150 · see citing works
“Not only do both dementias share nearly identical symptoms and signs, but both show comparable microstructural changes, negative impact on cognitive function and a link to more than two dozen vascular risk factors [60, 61].”
Alzheimer's Disease–Related Dementias Summit 2016: National research priorities
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Post-mortem assessment in vascular dementia: advances and aspirations
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“interact with pathophysiological processes in AD either independently of each other or through additive or synergistic effects on cognitive decline [39, 40].”
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“In addition, differences in vascular pathologies between different lobes and WM versus GM are reported, with the occipital lobe more severely affected by cerebral amyloid angiopathies, followed by frontal-, temporal-, and parietal lobes (Vinters et al., 1996; Attems and Jellinger, 2014).”
BackgroundGannon, O. J., Robison, L. S., Salinero, A. E., Abi-Ghanem, C., Mansour, F. M., Kelly, R. D., Tyagi, A., Brawley, R. R., Ogg, J. D., & Zuloaga, K. L. (2022) · Journal of Neuroinflammation · doi:10.1186/s12974-022-02466-2 · Cited by 127 · see citing works
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“may be present in 40–80% of VCI patients [11, 12].”
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“Taken together, these results might stem from contaminant cerebral vascular pathology and a relative rarity of biochemically pure AD, but could also indicate abundance of WM lesions (Attems and Jellinger, 2014, McAleese et al., 2016).”
Modular machine learning for Alzheimer's disease classification from retinal vasculature
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Systems-based proteomics to resolve the biology of Alzheimer’s disease beyond amyloid and tau
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Peri-Infarct Upregulation of the Oxytocin Receptor in Vascular Dementia
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“Fisher concluded that stroke alone could lead to dementia (21), the high rate of mixed pathology dementias from both AD and vascular damage has confounded efforts to combat VaD resulting from stroke or cerebrovascular disease alone (6, 22).”
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“Although there is no consensus reached regarding the causal relationship between a decreased cerebral blood flow (CBF) and decline of neuronal function, there is an increasing prevalence of coincident cerebrovascular deficiency and cognitive dysfunction with aging that is also well recognized in Alzheimer’s disease (A…”
BackgroundThe blood brain barrier in Alzheimer’s disease
Chakraborty, A., de Wit, N. M., van der Flier, W. M., & de Vries, H. E. (2017) · Vascular Pharmacology · doi:10.1016/j.vph.2016.11.008 · Cited by 118 · see citing works
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“There is strong evidence indicating a causal association between CVDs and dementias; and individuals with CVDs are at higher risk of developing AD (Attems and Jellinger, 2014; Santos et al., 2017; Tini et al., 2020).”
BackgroundPharmacological interventions for apathy in Alzheimer's disease
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“…following equation: Papp=(dQ/dt)*(1/A*C0*60) where dQ/dt is the amount of FITC-dextran transported per minute (ng/min), A is the surface area of the tissue (cm [Attems and Jellinger, 2014]), C0 is the initial concentration of FITC-Dextran (ng/ml) and 60 is the conversion from minutes to seconds.”
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“White matter hyperintensity (WMH), which is associated with increased water content and vascular changes [3], serves as an important clinical diagnostic criterion by which to identify CeVD status [4].”
BackgroundHDL from an Alzheimer's disease perspective
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Self-citationEndothelial Mitochondrial Dysfunction in Cerebral Amyloid Angiopathy and Alzheimer’s Disease
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Plasma hydrogen sulfide: A biomarker of Alzheimer's disease and related dementias
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Further understanding the connection between Alzheimer's disease and Down syndrome
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Toward precision medicine in Alzheimer’s disease
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“Adding to this complexity is frequent clinical and pathological overlap with other pathologies in particular Lewy Body disease (LBD) and cerebrovascular disease (4-6).”
BackgroundCerebral small vessel disease and Alzheimer’s disease
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“relationship between AD and cognitive impairment and VaD has been reported while CVD and stroke are related to high risk of both cognitive impairment and AD.(139,140) The manifestation of CVD in imaging is extremely similar to AD in the elderly, whereas imaging markers of subcortical vascular diseases (leukoaraiosis,…”
Tsartsalis, S., Sleven, H., Fancy, N., Wessely, F., Smith, A. M., Willumsen, N., Cheung, T. K. D., Rokicki, M. J., Chau, V., Ifie, E., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-46630-z · Cited by 95 · see citing works
“In the 3 rd paragraph of the “Quality control, dataset integration, dimension reduction and clustering” section, we briefly describe how cell type identification was performed based on the full of co-expressed genes that distinguish each cluster.”
<scp>mTOR</scp> signaling and Alzheimer's disease: What we know and where we are?
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“128 mTOR signaling through specific mechanisms active in endothelial and smooth muscle cells of vasculature regulates vascular function acutely and chronically.”
BackgroundVascular cognitive impairment and dementia: Mechanisms, treatment, and future directions
Mok, V., Cai, Y., & Markus, H. S. (2024) · International Journal of Stroke · doi:10.1177/17474930241279888 · Cited by 107 · see citing works
“53,54 In addition, preclinical and clinical evidence showed that SVD is an early initiating event in the development of A β .”
BackgroundA Life-Long Approach to Physical Activity for Brain Health
Macpherson, H., Teo, W.-P., Schneider, L. A., & Smith, A. E. (2017) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2017.00147 · Cited by 103 · see citing works
“…restricts blood flow, disrupts the integrity of the cerebral vessels and likely has further cascading effects on brain perfusion, resulting in disruption to homeostasis, increasing inflammation, neuronal dysfunction and cell death as well as inhibiting neuroplasticity (Attems and Jellinger, 2014).”
BackgroundInfluentialVascular risk factors and Alzheimer’s disease
O'Brien, J. T., & Markus, H. S. (2014) · BMC Medicine · doi:10.1186/s12916-014-0218-y · Cited by 94 · see citing works
“Jellinger and Attems [9] provide a detailed account of”
BackgroundThree-dimensional mapping of neurofibrillary tangle burden in the human medial temporal lobe
Yushkevich, P. A., Muñoz, M., Martin, M. M. I. D. O., Ittyerah, R., Lim, S., Ravikumar, S., Bedard, M. L., Pickup, S., Liu, W., Wang, J., et al. (2021) · Brain · doi:10.1093/brain/awab262 · Cited by 91 · see citing works
Blood Pressure Variability and Progression of Clinical Alzheimer Disease
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Review: Vascular dementia: clinicopathologic and genetic considerations
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Motoric cognitive risk syndrome: Integration of two early harbingers of dementia in older adults
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“Recent studies show AD is a multifactorial and heterogeneous disease with multiple contributors, including cerebrovascular disease (Schneider et al., 2007; Toledo et al., 2013; Attems and Jellinger, 2014; Sweeney et al., 2019; De Rueck et al., 2018).”
BackgroundAPP as a Protective Factor in Acute Neuronal Insults
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“These common pathways may then result in overlapping histopathological findings (de la Torre, 2002; Pluta et al., 2009, 2012; Attems and Jellinger, 2014).”
BackgroundWhite matter hyperintensities and CSF Alzheimer disease biomarkers in preclinical Alzheimer disease
Soldan, A., Pettigrew, C. A., Zhu, Y., Wang, M., Moghekar, A., Gottesman, R. F., Singh, B., Martinez, O., Fletcher, E. M., DeCarli, C. S., et al. (2019) · Neurology · doi:10.1212/wnl.0000000000008864 · Cited by 82 · see citing works
“Alzheimer disease (AD) and cerebrovascular disease frequently co-occur among older adults.(1) It remains unclear, however, whether these 2 pathologies independently affect the risk of cognitive impairment, or whether they have synergistic effects on cognitive decline.”
BackgroundAndrogens’ effects on cerebrovascular function in health and disease
Abi‐Ghanem, C., Robison, L. S., & Zuloaga, K. L. (2020) · Biology of Sex Differences · doi:10.1186/s13293-020-00309-4 · Cited by 88 · see citing works
“Moreover, VCID is comorbid in up to 80% of AD patients, resulting in multi-etiology dementia [109, 110].”
BackgroundCognitive disorder and dementia in type 2 diabetes mellitus
Ortíz, G. G., Huerta, M., González-Usigli, H., Torres-Sánchez, E. D., Delgado-Lara, D. L. C., Pacheco-Moisés, F. P., Mireles-Ramírez, M. A., Torres-Mendoza, B. M., Moreno-Cih, R. I., & Velázquez-Brizuela, I. E. (2022) · World Journal of Diabetes · doi:10.4239/wjd.v13.i4.319 · Cited by 90 · see citing works
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“Moreover, novel insights into resilience factors [48 & ,49 && ,50 && ] and brain–heart [23], brain–gut [51 && ,52 && ], brain– kidney [53 && ], and brain–lung connections [54 && ] also suggest the existence of broader neuroimmune and brain–body connections in manifestations of disease.”
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Microvascular Dysfunction Is Associated With Worse Cognitive Performance
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Brain Aging Among Racially and Ethnically Diverse Middle-Aged and Older Adults
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Associations of the metabolic syndrome and its components with cognitive impairment in older adults
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Brain amyloid and vascular risk are related to distinct white matter hyperintensity patterns
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“None of the guidelines for preclinical or predementia AD include WMHs in their biomarker models,24,32 and extensive WMH burden is an exclusion criterion in several recent clinical trials in predementia AD.”
BackgroundInfluentialMacklin, L. N., Griffith, C. M., Cai, Y., Rose, G. M., Yan, X., & Patrylo, P. R. (2016) · Experimental Gerontology · doi:10.1016/j.exger.2016.12.019 · Cited by 77 · see citing works
“…altered metabolic capacity (Mosconi et al., 2008; Struble et al., 2010), 3) changes in neurovascularization (Scheibel et al., 1989; Cai et al., 2010; Attems and Jellinger, 2014; Li et al., 2015; Snyder et al., 2015; Xue et al., 2015), 4) changes in cholinergic innervation (Coyle et al., 1983;…”
Systemic infection exacerbates cerebrovascular dysfunction in Alzheimer’s disease
Asby, D. J., Boche, D., Allan, S. M., Love, S., & Miners, J. S. (2021) · Brain · doi:10.1093/brain/awab094 · Cited by 79 · see citing works
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Cerebrovascular plasticity: Processes that lead to changes in the architecture of brain microvessels
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Neuroinflammatory Signaling in the Pathogenesis of Alzheimer’s Disease
Uddin, M. S., Kabir, M. T., Jalouli, M., Rahman, M. A., Jeandet, P., Behl, T., Alexiou, A. T., Albadrani, G. M., Abdel‐Daim, M. M., Perveen, A., et al. (2021) · Current Neuropharmacology · doi:10.2174/1570159x19666210826130210 · Cited by 76 · see citing works
“Numerous neuropathological, clinical, and epidemiological studies have revealed that vascular pathology is a crucial risk factor for AD development [187, 188].”
BackgroundAn MRI measure of degenerative and cerebrovascular pathology in Alzheimer disease
Brickman, A. M., Tosto, G., Gutierrez, J., Andrews, H., Gu, Y., Narkhede, A., Rizvi, B. M., Guzmán, V., Manly, J. J., Vonsattel, J. P., et al. (2018) · Neurology · doi:10.1212/wnl.0000000000006310 · Cited by 73 · see citing works
“On MRI, LOAD is manifest by medial temporal lobe and cortical atrophy, but white matter hyperintensities (WMHs) and brain infarcts are also frequent.(4,6) Structural MRI biomarker studies of LOAD often treat cerebrovascular disease and atrophy as distinct entities, but they coexist more frequently than not and the ons…”
BackgroundDisentangling the effects of Alzheimer’s and small vessel disease on white matter fibre tracts
Dewenter, A., Jacob, M. A., Cai, M., Gesierich, B., Hager, P., Kopczak, A., Biel, D., Ewers, M., Tuladhar, A., de Leeuw, F., et al. (2022) · Brain : a journal of neurology · doi:10.1093/brain/awac265 · Cited by 67 · see citing works
“As expected from epidemiological and histopathology studies, 6,7 concomitant SVD was found in the Alzheimer’s disease sample, with the largest difference in WMH burden between the A+T– group and matched A–”
Cerebral white matter lesions – associations with Aβ isoforms and amyloid PET
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“As knowledge and understanding has evolved, it has become increasingly diOicult to distinguish between these dementia subtypes, as there is considerable clinical and pathological overlap between them (Attems 2014; Mandal 2006).”
BackgroundInfluentialYu, W., Li, Y., Hu, J. P., Wu, J., & Huang, Y. (2022) · Journal of Clinical Medicine · doi:10.3390/jcm11164742 · Cited by 74 · see citing works
“Moreover, the pathological evidence of cerebral hypoperfusion was observed in both VCID and AD, mainly inflammation, trophic uncoupling, BBB disruption and WMLs, but with distinctions in the distribution and associated pathologies [7].”
BackgroundGallart‐Palau, X., Lee, B. S. T., Adav, S. S., Qian, J., Serra, A., Park, J. E., Lai, M. K. P., Chen, C., Kalaria, R. N., & Sze, S. K. (2016) · Molecular Brain · doi:10.1186/s13041-016-0205-7 · Cited by 70 · see citing works
“Affected individuals display a complex brain pathology characterized by senile plaques with microinfarcts, as well as a poorly understood degeneration of the small vessels that supply blood to the brain [4–7].”
BackgroundInteraction between cerebrovascular disease and Alzheimer pathology
Saito, S., & Ihara, M. (2016) · Current Opinion in Psychiatry · doi:10.1097/yco.0000000000000239 · Cited by 69 · see citing works
“© 2016 Wolters Kluwer cerebrovascular disease (CVD) has long been noted [4] and mixed Alzheimer’s disease/CVD pathology is commonly seen in patients with clinically diagnosed Alzheimer’s disease [5 && ].”
BackgroundSpecific Patterns of White Matter Alterations Help Distinguishing Alzheimer's and Vascular Dementia
Palesi, F., Rinaldis, A. D., Vitali, P., Castellazzi, G., Casiraghi, L., Germani, G., Bernini, S., Anzalone, N., Ramusino, M. C., Denaro, F. M., et al. (2018) · Frontiers in Neuroscience · doi:10.3389/fnins.2018.00274 · Cited by 71 · see citing works
“In older subjects and in the presence of cerebral amyloid angiopathy, AD patients can also present a certain degree of cerebrovascular lesions contributing to a mixed type of dementia (Attems and Jellinger, 2014).”
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“Scale bars in b: 50 μm; c: 10 μm as cerebrovascular-related amyloidogenesis has been found in over 80% of AD patients (Attems & Jellinger, 2014; Jellinger & Attems, 2005) and this condition positively correlates with a cognitive decline (Thal, Griffin, de Vos, & Ghebremedhin, 2008; Weller, Boche, &…”
BackgroundHerpes Zoster Vaccination and Dementia Occurrence
Pomirchy, M., Bommer, C., Pradella, F., Michalik, F., Peters, R. K., & Geldsetzer, P. (2025) · JAMA · doi:10.1001/jama.2025.5013 · Cited by 74 · see citing works
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- Authors
- Attems, J., & Jellinger, K. A.
- Affiliations
- Newcastle University (GB)
- Medical University of Vienna (AT)
- Corresponding author
- Attems, Johannes
- Venue
- BMC Medicine
- Published
- 2014-11-11
- Volume
- 12
- Issue
- 1
- Pages
- 206-206
- ISSN
- 1741-7015 (ISSN-L)
- PMC
- PMC4226890
- OpenAlex
- W2043522411
- Cited by
- 739
- References
- 196
- Citations by year
- 2026: 55 · 2025: 79 · 2024: 73 · 2023: 66 · 2022: 61 · 2021: 71 · 2020: 91 · 2019: 70 · 2018: 53 · 2017: 44 · 2016: 53 · 2015: 19 · 2014: 3
- FWCI
- 5.49
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- BMC Medicine (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Newcastle University ePrints (Newcastle Univesity) (cc-by)
- Funders
- Alzheimer's Society
- National Institute for Health and Care Research
- Dunhill Medical Trust (R173/1110)
- Newcastle University (G0400074)
- Newcastle upon Tyne Hospitals NHS Foundation Trust
- Medical Research Council (G0400074)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- Alzheimer's disease, cerebrovascular disease, cerebral amyloid angiopathy, cerebral small vessel disease, vascular dementia, mixed dementia, cognitive decline, dementia progression, subcortical infarcts
- MeSH terms
- Aging, Alzheimer Disease, Cerebrovascular Disorders, Humans
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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