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Cited by 3,811Dementia and Cognitive Impairment ResearchNeurological Disease Mechanisms and TreatmentsAcute Ischemic Stroke Management

Vascular Contributions to Cognitive Impairment and Dementia: A Statement for Healthcare Professionals From the American Heart Association/American Stroke Association

Open access
Gorelick, Philip B., Scuteri, Angelo, Black, Sandra E., DeCarli, Charles, Greenberg, Steven M., Iadecola, Costantino, Launer, Lenore J., Laurent, Stephane +14 more·2011·Stroke
DOI 10.1161/str.0b013e3182299496PMC PMC3778669
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Abstract

Background and Purpose—: This scientific statement provides an overview of the evidence on vascular contributions to cognitive impairment and dementia. Vascular contributions to cognitive impairment and dementia of later life are common. Definitions of vascular cognitive impairment (VCI), neuropathology, basic science and pathophysiological aspects, role of neuroimaging and vascular and other associated risk factors, and potential opportunities for prevention and treatment are reviewed. This statement serves as an overall guide for practitioners to gain a better understanding of VCI and dementia, prevention, and treatment. Methods—: Writing group members were nominated by the writing group co-chairs on the basis of their previous work in relevant topic areas and were approved by the American Heart Association Stroke Council Scientific Statement Oversight Committee, the Council on Epidemiology and Prevention, and the Manuscript Oversight Committee. The writing group used systematic literature reviews (primarily covering publications from 1990 to May 1, 2010), previously published guidelines, personal files, and expert opinion to summarize existing evidence, indicate gaps in current knowledge, and, when appropriate, formulate recommendations using standard American Heart Association criteria. All members of the writing group had the opportunity to comment on the recommendations and approved the final version of this document. After peer review by the American Heart Association, as well as review by the Stroke Council leadership, Council on Epidemiology and Prevention Council, and Scientific Statements Oversight Committee, the statement was approved by the American Heart Association Science Advisory and Coordinating Committee. Results—: The construct of VCI has been introduced to capture the entire spectrum of cognitive disorders associated with all forms of cerebral vascular brain injury—not solely stroke—ranging from mild cognitive impairment through fully developed dementia. Dysfunction of the neurovascular unit and mechanisms regulating cerebral blood flow are likely to be important components of the pathophysiological processes underlying VCI. Cerebral amyloid angiopathy is emerging as an important marker of risk for Alzheimer disease, microinfarction, microhemorrhage and macrohemorrhage of the brain, and VCI. The neuropathology of cognitive impairment in later life is often a mixture of Alzheimer disease and microvascular brain damage, which may overlap and synergize to heighten the risk of cognitive impairment. In this regard, magnetic resonance imaging and other neuroimaging techniques play an important role in the definition and detection of VCI and provide evidence that subcortical forms of VCI with white matter hyperintensities and small deep infarcts are common. In many cases, risk markers for VCI are the same as traditional risk factors for stroke. These risks may include but are not limited to atrial fibrillation, hypertension, diabetes mellitus, and hypercholesterolemia. Furthermore, these same vascular risk factors may be risk markers for Alzheimer disease. Carotid intimal-medial thickness and arterial stiffness are emerging as markers of arterial aging and may serve as risk markers for VCI. Currently, no specific treatments for VCI have been approved by the US Food and Drug Administration. However, detection and control of the traditional risk factors for stroke and cardiovascular disease may be effective in the prevention of VCI, even in older people. Conclusions—: Vascular contributions to cognitive impairment and dementia are important. Understanding of VCI has evolved substantially in recent years, based on preclinical, neuropathologic, neuroimaging, physiological, and epidemiological studies. Transdisciplinary, translational, and transactional approaches are recommended to further our understanding of this entity and to better characterize its neuropsychological profile. There is a need for prospective, quantitative, clinical-pathological-neuroimaging studies to improve knowledge of the pathological basis of neuroimaging change and the complex interplay between vascular and Alzheimer disease pathologies in the evolution of clinical VCI and Alzheimer disease. Long-term vascular risk marker interventional studies beginning as early as midlife may be required to prevent or postpone the onset of VCI and Alzheimer disease. Studies of intensive reduction of vascular risk factors in high-risk groups are another important avenue of research.

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Crossref · 10.1161/str.0b013e3182299496

Cites

526 of 526 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

136 of 627 cited sources checked · 45 supported · 6 flagged · accuracy not yet measured

  • Premisecitation

    High waist-hip ratio strengthened the association with hypertension and dementia in the highest quartile of waist-hip ratio.

    “High waist-hip ratio strengthened the association with hypertension and dementia in the highest quartile of waist-hip ratio.”
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      The Results (page unavailable) report no significant association between late-life waist–hip ratio and dementia. The Discussion (page unavailable) likewise states that the authors found no association for waist–hip ratio in old age; it does not report a strengthened hypertension–dementia association in the highest waist–hip-ratio quartile. (LLM, conf=0.78)

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    A 6-month study in elderly women supports a potent nonpharmacological intervention improving executive control in older women at high risk of cognitive decline.

    “A study of 6 months’ duration in elderly women provides support, using rigorous controlled methodology, for a potent nonpharmacological intervention that improves executive control processes for older women at high risk of cognitive decline.473”
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      The Discussion reports a five-year trial of daily low-dose aspirin, a pharmacological intervention, in men and women over 50—not a six-month nonpharmacological study in elderly women. It found no significant cognitive benefit, including on measures of executive function. (LLM, conf=0.90)

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    White matter lesions also occur in older subjects and patients with Alzheimer disease in epidemiological studies.

    “However, WMLs also occur in older subjects and patients with Alzheimer disease in epidemiological studies.”
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    Several studies have shown that patients with mild cognitive impairment can return to normal cognition.

    “Several studies have shown that patients with MCI can return to normal cognition.”
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      The Materials and Methods (p. 2) say this paper reports cognitive performance at a baseline visit, not whether patients later returned to normal cognition. The Discussion (p. 5) says cognitive dysfunction may persist after depression is treated, but does not address recovery from mild cognitive impairment. Searches for return to normal cognition and cognitive recovery found no supporting passage. (LLM, conf=0.76)

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    Infarcts occur commonly in older people with and without dementia.

    “occur commonly in older people with and without dementia”
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    Premisecitation

    Vascular oxidative stress and inflammation impede proliferation, migration, and differentiation of oligodendrocyte progenitor cells and compromise repair of damaged white matter.

    “Vascular oxidative stress and inflammation impede the proliferation, migration, and differentiation of oligodendrocyte progenitor cells and compromise repair of the damaged white matter.108,132,133”
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    • cites [108] source
    • cites [132] source

      The Discussion (page unavailable) reports that cultured rat OPCs were vulnerable to hydrogen-peroxide oxidative stress, and the paper states that OPCs contribute to white-matter repair. It does not show that vascular oxidative stress or inflammation impedes OPC proliferation, migration, or differentiation, or directly demonstrate impaired repair of damaged white matter. (LLM, conf=0.88)

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      The Discussion states that the inflammatory response associated with demyelination provides a powerful impetus for remyelination—the opposite of the claim that inflammation impedes repair. The paper attributes impaired progenitor recruitment and differentiation to aging, but the cited passages do not establish vascular oxidative stress as their cause. No page number is supplied in our copy. (LLM, conf=0.86)

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    Interpretationnone given

    It is unclear what confounding factors were taken into account in these analyses.

    “It is unclear what confounding factors were taken into account in these analyses.322”
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      The Methods section explicitly states which factors were included in the adjusted models, including demographics, cardiovascular and dementia risk factors, smoking, physical activity, and ApoE genotype. The claim that it is unclear which confounding factors were taken into account is therefore contrary to the cited paper's account. (LLM, conf=0.89)

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    Premisecitation

    Risk of new-onset dementia after stroke is approximately twice that of age- and sex-matched controls and averages about 10% after first stroke, depending on location, volume, severity, and early complications.

    “The risk of new-onset dementia after a stroke is approximately twice the rate for age- and sex-matched control subjects270 and averages ≈10% after the first stroke, depending on the location, volume of damaged brain tissue,30 clinical severity, and presence of early poststroke complications (seizure, delirium, hypoxia, hypotension).”
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      The citation is attached to the claim that new-onset dementia risk is approximately twice that of age- and sex-matched controls. The Results report an adjusted odds ratio of 9.4 for dementia after stroke versus stroke-free controls, and the methods say the groups differed by sex; the study assessed dementia three months after stroke rather than establishing new onset. The later ≈10% and complication claims are not attached to this citation. (LLM, conf=0.90)

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    Study design and conductcitation

    Published trials enrolled patients at low dementia risk (young mean age) and with high baseline MMSE.

    “(3) patients at low risk for dementia (young mean age)441,445 and with high baseline MMSE;”
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      The Methods (Selection) explicitly exclude pharmaceutical clinical trial volunteers and restrict the review to community-dwelling adults aged 60 or older. The Results (Cognitive Dysfunction) describe population-based prospective studies with mean baseline ages including 68.9, 75.6, and 83 years, rather than trials characterized by a young mean age. The paper mentions MMSE as an outcome measure but does not establish that participants had high baseline MMSE scores. (LLM, conf=0.82)

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    Premisecitation

    Executive dysfunction has not been shown to specifically point to cerebrovascular disease, whereas a pattern of memory deficits may be associated more with Alzheimer disease and its associated pathology than with cerebrovascular disease.

    “Executive dysfunction has not been shown to specifically point to cerebrovascular disease, whereas a pattern of memory deficits may be associated more with Alzheimer disease and its associated pathology than with cerebrovascular disease.”
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    Premisecitation

    Chronic macroscopic infarcts are very common, occurring in approximately one third to one half of older people, a frequency far greater than the frequency of clinical stroke.

    “Chronic macroscopic infarcts are very common, occurring in approximately one third to one half of older people,13,54–56 a frequency far greater than the frequency of clinical stroke.”
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      The Results (Probable AD in the community versus clinic; page unavailable) report that macroscopic infarcts were more common in the community cohort than in the clinic cohort. The available passages do not establish that they occurred in one third to one half of older people or that their frequency was far greater than that of clinical stroke. (LLM, conf=0.81)

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    Premisecitation

    Other common vascular brain pathologies in older people include white matter degeneration and primary vessel disease such as arteriolosclerosis/lipohyalinosis, atherosclerosis, and cerebral amyloid angiopathy.

    “There are other common vascular pathologies in the brains of older people, including white matter degeneration70,71 and primary vessel disease (ie, arteriolosclerosis/lipohyalinosis, atherosclerosis, and cerebral amyloid angiopathy [CAA]).70,72,73”
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      The Discussion (page not available) says sclerotic medullary arteries are commonly seen in older people and that some are associated with diffuse ischemic white matter change. The Results (page not available) describe fibrohyaline thickening but state that atherosclerosis and amyloid angiopathy were not observed in the medullary arteries. This paper therefore supports part of the broad claim, not the full list of vessel diseases as common findings in its studied arteries. (LLM, conf=0.88)

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    Premisecitation

    Although the specific importance of subcortical infarcts and interaction has not been confirmed, subsequent studies have established that infarcts are additive with Alzheimer disease pathology in lowering cognitive function and increasing the odds of dementia or clinical Alzheimer disease.

    “Although the specific importance of subcortical infarcts and interaction has not been confirmed, subsequent studies have established that infarcts are additive with Alzheimer disease pathology in lowering cognitive function17,57 and increasing the odds of dementia17,18,62,63 or clinical Alzheimer disease.61”
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    Premisecitation

    Most people with dementia and almost half of those with clinically probable Alzheimer disease have mixed pathology, most commonly Alzheimer disease and infarcts.

    “In addition, most people with dementia12 and almost half of those with clinically probable Alzheimer disease61 have mixed pathology, most commonly Alzheimer disease and infarcts.”
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    Premisecitation

    In animal models, hypertension, aging, and diabetes impair endothelium-dependent responses in the cerebral microcirculation and blunt functional hyperemia.

    “In animal models, the major risk factors for VCI and Alzheimer disease —hypertension, aging, and diabetes110—impair endothelium-dependent responses in the cerebral microcirculation and blunt functional hyper-emia.101,111,112”
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      The Discussion (page unavailable) reports that aging impairs endothelial function in mouse cerebral arteries and states that neurovascular coupling decreases with aging. The study tested isolated basilar arteries, not functional hyperemia, and the cited passages do not establish the claimed effects of hypertension or diabetes. (LLM, conf=0.88)

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    Premisecitation

    Endothelial mediators serve functions including local flow distribution, immune surveillance, and hemostatic balance.

    “These endothelial mediators subserve functions as varied as local flow distribution,91 immune surveillance (in concert with perivascular cells),92 and hemostatic balance.93”
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    Premisecitation

    Cerebral smooth muscle cells of patients with Alzheimer disease have increased constrictor tone, which may contribute to the cerebral blood flow reduction observed in this condition.

    “Cerebral smooth muscle cells of patients with Alzheimer disease have increased constrictor tone,118 which may contribute to the CBF reduction observed in this condition.100”
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    Premisecitation

    In vascular cognitive impairment and Alzheimer disease, microvessels have thickened basement membranes, become tortuous, and are reduced in number.

    “Microvessels have thickened basement membranes, become tortuous, and are reduced in number.71,105–107”
    Quote in the paperSubstantial claim1 of 4 sources checked
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      The Introduction describes tortuosity in arterioles supplying the deep white matter in leukoaraiosis, while the Abstract reports reduced microvascular density in leukoaraiosis and preliminary evidence of reduced density in Alzheimer’s disease. Neither passage describes thickened basement membranes, and the tortuosity finding is not established for Alzheimer’s disease. Page numbers are unavailable in our copy. (LLM, conf=0.88)

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    Premisecitation

    The brain depends on a continuous blood supply, and interruption of cerebral blood flow leads to brain dysfunction and death.

    “The brain depends on a continuous blood supply, and interruption of cerebral blood flow (CBF) leads to brain dysfunction and death.86”
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    Premisecitation

    Endothelial cells exert trophic actions critical for brain development, neuroplasticity, and repair, with endothelial growth factors orchestrating neuroblast migration and differentiation.

    “Endothelial cells exert trophic actions that are critical in brain development, neuroplasticity, and repair when endothelial growth factors orchestrate the migration and differentiation of neuroblasts.96–99”
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      The Discussion reports that endothelial cells secrete factors regulating neuronal differentiation in vitro and that vascular ligands guide neuroblast migration after stroke. It does not establish that those ligands orchestrate neuroblast differentiation, or that these actions are critical across brain development and neuroplasticity. The relevant indexed passages have no page numbers. (LLM, conf=0.86)

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    Premisecitation

    Low-density lipoprotein receptor-related protein-1, a critical amyloid beta brain clearance receptor, is downregulated in cerebral blood vessels of patients with Alzheimer disease, leading to accumulation of amyloid around blood vessels and worsening of vascular dysfunction.

    “the low-density lipoprotein receptor–related protein-1, a critical Aβ brain clearance receptor, is downregulated in cerebral blood vessels of patients with Alzheimer disease, leading to accumulation of amyloid around blood vessels and worsening of vascular dysfunction.129”
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    Premisecitation

    Pittsburgh Compound B retention is not specific for cerebral amyloid angiopathy as opposed to Alzheimer disease because the compound binds to both vascular and parenchymal amyloid, but the two pathologies may be distinguishable in part by the relative occipital predominance of labeling in cerebral amyloid angiopathy.

    “Pittsburgh Compound B retention is not specific for CAA as opposed to Alzheimer disease, because the compound binds to both vascular and parenchymal amyloid158; however, the 2 pathologies may be distinguishable in part by the relative occipital predominance of labeling in CAA.156,157”
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    Premisecitation

    A single nucleotide polymorphism in the COL4A1 gene was associated with pulse wave velocity, an index of arterial stiffness, in a population.

    “a single nucleotide polymorphism in the COL4A1 gene was associated with pulse wave velocity, an index of arterial stiffness, in a population.180”
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    Premisecitation

    Multiple strictly lobar hemorrhages without other definite causes have been defined by the Boston criteria as probable cerebral amyloid angiopathy and validated against neuropathologically or genetically diagnosed cerebral amyloid angiopathy.

    “The presence of multiple strictly lobar hemorrhages in the absence of other definite causes such as head trauma, brain tumor, or supratherapeutic anticoagulation has been defined by the Boston criteria as “probable CAA” and validated against neuropathologically or genetically diagnosed CAA.153,154”
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    Premisecitation

    The lumen-intima and media-adventitia separation can be determined to within about 0.1 mm on longitudinal B-mode ultrasound images of the extracranial carotid arteries where these interfaces are readily apparent.

    “The lumen-intima and media-adventitia separation can be determined to within ≈0.1 mm on longitudinal B-mode ultrasound images of the extracranial carotid arteries where these interfaces are readily apparent.183,184”
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      The Subjects and Methods section (page not specified in our copy) describes measurements of the far-wall intimal-medial thickness in extracranial carotid arteries and reports approximately 0.10 mm axial resolution. That is the minimum spacing at which adjacent boundaries can be distinguished, not a demonstrated measurement accuracy of within 0.1 mm; the paper also does not specify longitudinal images for this claim. (LLM, conf=0.82)

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    Premisecitation

    Mutations of the COL4A1 type IV collagen subunit gene have also been reported in association with congenital porencephaly, leukoencephalopathy, or intracerebral hemorrhage.

    “Mutations of the COL4A1 type IV collagen subunit gene have also been reported in association with congenital porencephaly, leukoencephalopathy, or intracerebral hemorrhage.178,179”
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    Premisecitation

    Other potential diagnostic approaches for cerebral amyloid angiopathy include detection of reduced amyloid beta in cerebrospinal fluid and increased retention of Pittsburgh Compound B on positron emission tomography imaging.

    “Other potential diagnostic approaches have been explored, including detection of reduced Aβ in cerebrospinal fluid155 or increased retention of the amyloid ligand Pittsburgh Compound B on positron emission tomography imaging.156,157”
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    Premisecitation

    Although no treatments have been identified to modify the course of CADASIL, cardiovascular risk factors such as hypertension, elevated hemoglobin A1c, and smoking may be associated with a worse clinical and radiographic phenotype.

    “Although no treatments have been identified to modify the course of CADASIL, it is notable that cardiovascular risk factors such as hypertension, elevated hemoglobin A1c, and smoking may be associated with a worse clinical and radiographic phenotype.171,172”
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      The Results (Presence of CM and associated factors; Cerebral microhaemorrhages and neurological outcome, pages unavailable) associate hypertension and elevated HbA1c with microhaemorrhages, and systolic blood pressure with poor functional outcome. The Discussion says treatment benefits remain to be tested. But the study does not support including smoking: its tables show no significant association with either microhaemorrhages or poor functional outcome. (LLM, conf=0.90)

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    Interpretationcitation

    Several pathways may connect aortic stiffness to microvascular brain damage, including endothelial dysfunction and oxidative stress, mutually reinforcing remodeling of large and small arteries, and exposure of small vessels to high-pressure fluctuations in the cerebral circulation.

    “Several pathways may link aortic stiffness to microvascular brain damage. They include endothelial dysfunction and oxidative stress,209 a mutually reinforcing remodeling of large and small vessels (ie, large-/small-artery cross talk),210 and exposure of small vessels to the high-pressure fluctuations of the cerebral circulation,211”
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    Premisecitation

    Retinal arterial narrowing correlates with increased arterial stiffness and cerebral small-vessel disease.

    “Retinal arterial narrowing correlates with increased arterial stiffness219 and cerebral small-vessel disease.218,220,221”
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    Premisecitation

    Age-related arterial stiffening (arteriosclerosis) is associated with quantitatively less elastin and more collagen but is also associated with qualitative changes in the arterial wall.

    “The well-known, age-related arterial stiffening process (arteriosclerosis) is associated with quantitatively less elastin and more collagen but is also associated with qualitative changes in the arterial wall.143,199,200”
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      In “Determinants of Arterial Stiffness” (page not available), the paper links aging to thinning and fragmentation of elastic fibers, increased collagenous material, and qualitative changes in the arterial wall. It does not explicitly establish a quantitative decrease in elastin, so that part of the claim is not fully supported. (LLM, conf=0.83)

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      The Essential Hypertension section (page unavailable) says central arteries stiffen with age, elastic fibers lose their orderly arrangement and undergo thinning and fragmentation, and collagenous material increases. These passages support age-related stiffening, increased collagen, and qualitative wall changes, but they do not establish a quantitative decrease in elastin content. (LLM, conf=0.84)

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    Premisecitation

    The inverse relationship between carotid intima-media thickness and cognition was significant after controlling for age and education; some studies further adjusted for depressive symptoms and/or cardiovascular risk factor level.

    “This relationship was significant after controlling for age and education; some studies further adjusted for the presence of depressive symptoms187,189 and/or cardiovascular risk factor level.189”
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    Premisecitation

    Proposed mechanisms linking atherosclerotic cerebrovascular pathology to vascular cognitive impairment include thrombotic occlusion of large vessels with subsequent chronic cerebral hypoperfusion, cerebral embolism from ruptured or thrombotic carotid plaques targeting distal vessels, increased parenchymal oxidative stress, blood pressure dysregulation affecting blood-brain barrier integrity, and a

    “The mechanisms by which atherosclerotic cerebrovascular pathology might be associated with VCI include thrombotic occlusion of large vessels with subsequent chronic cerebral hypoperfusion; cerebral embolism originating from ruptured or thrombotic carotid plaques and targeting distal vessels; increased parenchymal oxidative stress; blood pressure dys-regulation affecting BBB integrity; and a common”
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    • cites [189] source

      The Discussion proposes chronic cerebral hypoperfusion as a mechanism linking subclinical vascular disease to cognitive impairment. It does not specify thrombotic large-vessel occlusion as its cause, or describe plaque-derived embolism, parenchymal oxidative stress, or blood-pressure dysregulation affecting blood–brain barrier integrity. No page number is available in our copy. (LLM, conf=0.88)

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    • cites [195] source
    • cites [196] source

      The Discussion (page not provided) proposes chronic cerebral hypoperfusion as a contributor to brain dysfunction in patients with cardiovascular disease. The Abstract (page not provided) also links atherosclerosis to cerebral vessel changes and blood-pressure abnormalities to impaired cerebral hemodynamics. Our copy does not support the specified mechanisms of large-vessel thrombotic occlusion, carotid-plaque embolism, oxidative stress, or blood-pressure effects on blood–brain barrier integrity. (LLM, conf=0.88)

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    • cites [197] source
    • cites [198] source

      The “Carotid Disease and the Brain” section (page unavailable) proposes large-vessel occlusion with hypoperfusion and embolism from ruptured or thrombotic carotid plaques. It does not describe the hypoperfusion as chronic or propose oxidative stress or blood-pressure dysregulation affecting blood–brain barrier integrity as mechanisms. (LLM, conf=0.90)

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    Premisecitation

    Age-specific definitions of extensive WMLs can be created and are useful for defining risk for VCI in a community cohort.

    “Importantly, age-specific definitions of extensive WMLs can be created240 and prove useful in defining risk for VCI in a community cohort.240”
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    • cites [240] source

      The Methods (MRI scans; page not provided) define extensive white matter hyperintensity volume using age-specific thresholds. The Results and Discussion report that this measure predicted incident dementia in a community cohort and amnestic MCI only among participants aged 60 or older. The study did not specifically establish risk for vascular cognitive impairment (VCI). (LLM, conf=0.86)

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    Premisecitation

    WMLs are associated with incident MCI, dementia, and death.

    “Similarly, WMLs have been associated with declining scores in the modified MMSE and the Digit Symbol Substitution Test,246,247 as well as with incident MCI, dementia, and death.240”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [240] source

      The Results sections on dementia, MCI, and mortality associate white matter hyperintensity measures with incident dementia and death. For MCI, however, the paper finds no overall association; increased risk of amnestic MCI appears only in certain subgroups, including participants aged 60 or older. The unqualified reference to incident MCI overstates that finding. (LLM, conf=0.88)

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    Premisecitation

    Prevalence estimates of silent cerebral infarction on MRI in community-based samples range from 5.8% to 17.7%, averaging 11%, and vary by age, ethnicity, comorbidities, and imaging technique.

    “Estimates of the prevalence of silent cerebral infarction on MRI in community-based samples vary between 5.8% and 17.7%, with an average of 11%, depending on age, ethnicity, presence of comorbidities, and imaging techniques.237”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [237] source

      The Abstract’s Background and Purpose gives the 5.8%–17.7% range for community-based MRI samples and attributes variation to age, ethnicity, comorbidities, and imaging techniques. It does not give an 11% average across those samples; the Abstract’s Results report 10.7% for the Framingham sample alone. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Most studies suggest that CVBI measures are usually associated with non-memory-related cognitive deficits, but a number also show similar associations with memory impairment.

    “Interestingly, although most studies suggest that these measures of CVBI are usually associated with non–memory-related cognitive deficits,241 a number of studies also show similar associations with memory impairment.240,242,243”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [241] source
    • cites [240] source
    • cites [242] source

  • May combine two claims.

    Premisecitation

    Most silent cerebral infarcts are single lesions, most often located in the basal ganglia (52%), followed by other subcortical (35%) and cortical (11%) areas.

    “Most have a single lesion, and the infarcts are most often located in the basal ganglia (52%), followed by other subcortical (35%) and cortical (11%) areas.237”
    Quote in the paperNot a substantial claim1 of 1 sources checked

  • May combine two claims.

    Premisecitation

    In the Framingham study, silent cerebral infarction prevalence is about 10% in the fifth to seventh decades, rises to 17% in the eighth decade, and approaches 30% in the ninth decade.

    “In the Framingham study, for example, the prevalence of silent cerebral infarction between the fifth and seventh decades of life is ≈10% but increases rapidly in the eighth decade to 17% and in the ninth decade to nearly 30%.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [237] source

      The Results report 10.7% prevalence overall in the Framingham Offspring sample and an increase with age, from under 8% at ages 30–49 to over 15% at ages 70–89. Our copy does not give the claimed decade-specific figures of 17% in the eighth decade or nearly 30% in the ninth; the Results refer to Figure 1 for age-specific data without stating those values in the retrieved text. (LLM, conf=0.83)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Hippocampal volumes are associated with both hippocampal sclerosis and Alzheimer disease.

    “Gray matter volumes, however, were associated with both vascular and Alzheimer disease processes, and hippocampal volumes were associated with both hippocampal sclerosis and Alzheimer disease.”
    Quote in the paperSubstantial claim1 of 1 sources checked

  • May combine two claims.

    Premisecitation

    The presence of SBI more than doubles the risk of dementia and the risk of stroke.

    “For example, the presence of SBI more than doubles the risk of dementia and risk of stroke.240,244,245”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [240] source

      The indexed Results summary reports that MRI-defined brain infarcts (BI) were associated with more than double the risk of incident stroke (HR 2.84) and dementia (HR 6.12). However, the Methods define BI by MRI appearance, not by whether the infarct was silent; the Results also include participants with prior stroke. The reported estimates therefore do not specifically establish the claim for silent brain infarcts (SBI). (LLM, conf=0.83)

      Experimental — accuracy not yet measured
    • cites [244] source
    • cites [245] source

  • May combine two claims.

    Premisecitation

    In a study of pathological correlates of in vivo MRI evidence of CVBI, WMLs were highly correlated with pathological features of ischemic white matter injury but not with Alzheimer disease pathology.

    “In a study that examined the pathological correlates of in vivo MRI evidence of CVBI,82 WMLs were highly correlated with pathological features of ischemic white matter injury but not Alzheimer disease pathology.”
    Quote in the paperSubstantial claim1 of 1 sources checked

  • May combine two claims.

    Premisecitation

    Cognitive tests for VCI are to a degree nonspecific for vascular disease, and different criteria for VaD identify different sets of people.

    “The cognitive tests for VCI are, to a degree, nonspecific for vascular disease, and different criteria for VaD identify different sets of people.29”
    Quote in the paperNot a substantial claim1 of 1 sources checked

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Recent studies show that, similar to Western countries, Alzheimer disease is the leading cause of dementia in Asian populations.

    “Recent studies have shown that similar to Western countries, Alzheimer disease is the leading cause of dementia in Asian populations.275”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [275] source

      The Results (p. 3) report that Alzheimer’s disease accounted for most dementia cases in this US cohort, supporting the Western comparison. The paper does not report whether it is the leading cause of dementia in Asian populations, which is the claim’s central point. (LLM, conf=0.82)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    In a pooled analysis of major European population-based studies, VaD was prevalent in 1.6% of subjects over 65 years, with large variation in 5-year age-specific prevalence.

    “In a pooled analysis of major European population–based studies, VaD was prevalent in 1.6% of subjects >65 years of age, but there was a large variation in 5-year age-specific prevalence.264”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [264] source

      The Results and Statistical analysis sections describe a Boston dietary-questionnaire validation sample, not a pooled analysis of European population-based studies. Searches for vascular dementia, 1.6% prevalence, and five-year age-specific prevalence found no passage addressing the claim. (LLM, conf=0.76)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    One study found an association of lower circulating vitamin D levels with poorer cognitive function, but another found no association.

    “Recently, 1 study found an association of lower circulating vitamin D levels with poorer cognitive function,294 but another found no association.295”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [294] source
    • cites [295] source

  • May combine two claims.

    Premisecitation

    The age-related increase in VaD follows the pattern of stroke, although dementia after stroke may be more frequent in people under 80 years old.

    “This age-related increase in VaD follows the pattern of stroke,269 although dementia after stroke may be more frequent in people <80 years old.270”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [269] source

      The Results report that all-cause dementia incidence increased with age among people aged 90 and older, and that 22% of examiner-diagnosed cases were vascular dementia. They do not report age-specific vascular dementia rates or compare their pattern with stroke. The separate claim about dementia after stroke in people under 80 is attached to citation 270, not this source. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
    • cites [270] source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A recent study reported VaD prevalence in developing countries ranging from 0.6% to 2.1%.

    “A recent study reporting on the prevalence of VaD in developing countries reported a range of 0.6% to 2.1%.3,33”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [3] source
    • cites [33] source

  • May combine two claims.

    Premisecitation

    Chronic hyperglycemia, increased insulin, metabolic syndrome, and diabetes are associated with VCI, VaD, or dementia with stroke.

    “Chronic hyperglycemia, increased insulin, the metabolic syndrome, and diabetes are associated with VCI,337,345–348 as well as VaD or dementia with stroke.349,350”
    Quote in the paperSubstantial claim2 of 6 sources checked
    • cites [337] source
    • cites [345] source
    • cites [346] source
    • cites [347] source

      The Comment and Results (pages unavailable) link metabolic syndrome and high fasting glucose to cognitive impairment in older women. They do not establish an association specifically with vascular cognitive impairment (VCI), and the paper does not report an association for increased insulin. The citing sentence assigns its separate claim about vascular dementia or dementia with stroke to other citations. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [348] source
    • cites [349] source

  • May combine two claims.

    Premisecitation

    Body mass index measured in midlife is more strongly associated with VCI, whereas body weight measured later in life has an inverse association with cognitive impairment, with obesity associated with lower risk of dementia.

    “Body mass index measured in midlife is more strongly associated with VCI, whereas body weight measured later in life has an inverse association with cognitive impairment, where obesity is associated with a lower risk of dementia.320”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [320] source

      The Introduction says high BMI has been associated with dementia, and the Results report that women overweight or obese in midlife had a higher blood–brain barrier permeability measure 24 years later. The paper does not establish a stronger association specifically with vascular cognitive impairment (VCI), compare midlife BMI with later-life weight as predictors of cognitive impairment, or report that later-life obesity lowers dementia risk. The cited passages have no page numbers in our copy. (LLM, conf=0.83)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Physical activity may increase brain neurotrophins such as brain-derived neurotrophic factor, improve cerebrovascular functioning and brain perfusion, reduce response to stress, and increase brain plasticity through synaptogenesis and neurogenesis.

    “Physical activity may increase brain neurotrophins, such as brain-derived neurotrophic factor, improve cerebrovascular functioning and brain perfusion, reduce response to stress, and increase brain plasticity through synaptogenesis and neurogenesis.302”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [302] source

      Split into 2 atoms — 0 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 2 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    A recent review identified older age, lower education, prestroke cognitive impairment, diabetes, and atrial fibrillation as factors increasing risk, but second stroke was one of the strongest predictors of cognitive decline after initial stroke.

    “A recent review identified older age, lower education, prestroke cognitive impairment, diabetes, and atrial fibrillation as factors that increased the risk, but one of the strongest predictors of cognitive decline after an initial stroke was the occurrence of a second stroke.269,270”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [269] source

      Split into 2 atoms — 0 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured
    • cites [270] source

  • May combine two claims.

    Premisecitation

    Reduced cardiac output is associated with executive dysfunction (mainly sequencing and planning difficulties) and regional WMLs adjacent to subcortical nuclei.

    “Specifically, reduced cardiac output has been associated with executive dysfunction (mainly sequencing and planning difficulties)381 and regional WMLs adjacent to the subcortical nuclei.382”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [381] source

      The Discussion mentions white matter lesions in relation to diabetes, but does not link them to cardiac output or locate them adjacent to subcortical nuclei. Searches for reduced cardiac output and regional white matter lesions found no passage addressing that association. Citation 382 is attached to the white-matter-lesion part of the citing sentence. (LLM, conf=0.76)

      Experimental — accuracy not yet measured
    • cites [382] source

      The Discussion reports that, among older adults with cardiovascular disease, reduced cardiac output was associated with executive dysfunction and white matter hyperintensities. It does not specify sequencing or planning difficulties, or locate the lesions adjacent to subcortical nuclei. The paper’s own Results found only a borderline association with a combined executive-function/information-processing score. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Management of vascular risks and symptomatic pharmacotherapy targeting VaD has been the primary approach.

    “Management of vascular risks and symptomatic pharmacotherapy targeting VaD has been the primary approach.390”
    Quote in the paperNot a substantial claim1 of 1 sources checked

  • May combine two claims.

    Premisecitation

    Balanced nutrition in early life is important for normal neurocognitive development, which continues until late adolescence.

    “The importance of balanced nutrition in early life for normal neurocognitive development, a process that is not finished until late adolescence, has been widely recognized.427”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [427] source

      The Medical and Public Health Implications section links maternal nutrition and early development with the infant’s cognitive development, supporting the importance of early-life nutrition. It does not say that neurocognitive development continues until late adolescence; no page number is available in our copy. (LLM, conf=0.81)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Cognitive rehabilitation and cognitive stimulation have not proven effective.

    “Cognitive rehabilitation and cognitive stimulation so far have not proven effective.419,420”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [419] source

      The Methods and Results sections describe trials comparing vinpocetine with placebo, and the Discussion concludes that evidence for vinpocetine's benefit is inconclusive. Searches for cognitive rehabilitation, cognitive stimulation, and nonpharmacological interventions found no passage assessing whether either approach has proven effective. Page numbers were not available in our copy. (LLM, conf=0.76)

      Experimental — accuracy not yet measured
    • cites [420] source

  • May combine two claims.

    Premisecitation

    Donepezil produced cognitive benefit in VaD, but global and functional efficacy was less consistent across individual studies.

    “Cognitive benefit was found, but global and functional efficacy was less consistent in the individual studies.396,400”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [396] source

      The Discussion (page unavailable) examines white matter hyperintensities and cognition, and says their effect on response to cholinesterase inhibitors remains to be determined. Searches for donepezil and for global and functional treatment outcomes found no passage assessing those outcomes in vascular dementia. (LLM, conf=0.75)

      Experimental — accuracy not yet measured
    • cites [400] source

  • May combine two claims.

    Premisecitation

    Results of studies on late-life blood pressure and dementia are less consistent, with most finding no association with hypertension or an association with low blood pressure and dementia.

    “Results of studies on blood pressure measured in late life and dementia are less consistent, with most finding no association with hypertension or an association with low blood pressure and dementia.343,428”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [343] source
    • cites [428] source

      The Common cause hypothesis and Reverse causality sections discuss cognitive ageing and illness in older people, but neither addresses blood pressure and dementia. Searches for late-life blood pressure, hypertension, and dementia found no passage reporting the claimed pattern of study results. (LLM, conf=0.74)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    In HYVET-COG, treatment had no effect on dementia risk or cognitive decline.

    “The treatment was found to have no effect on the risk of dementia or cognitive decline.444”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [444] source

      The Introduction (page unavailable) says HYVET-COG confirmed a non-significant reduction in dementia risk, which supports a finding of no statistically significant effect—not proof of no effect. It does not report HYVET-COG's cognitive-decline result; the no-difference finding for cognitive decline in the Discussion concerns PRoFESS patients instead. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    In 3 studies there was no association between hypertension treatment and Alzheimer disease risk, whereas in others there was a decreased Alzheimer disease risk among those receiving antihypertensive treatment.

    “In 3 studies there was no association between hypertension treatment and risk of Alzheimer disease,432–434 whereas in others there was a decreased risk of Alzheimer disease among those receiving antihypertensive treatment.429,431,435–437”
    Quote in the paperSubstantial claim1 of 5 sources checked
    • cites [432] source
    • cites [433] source
    • cites [434] source
    • cites [429] source
    • cites [431] source

  • May combine two claims.

    Premisecitation

    In type 2 diabetes, cognitive dysfunction independently predicts clinical outcomes but does not modify effects of BP lowering or glucose control on major cardiovascular events.

    “It was concluded that cognitive dysfunction is an independent predictor of clinical outcomes in patients with type 2 diabetes mellitus but does not modify the effects of blood pressure lowering or glucose control on the risk of major cardiovascular events.458”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [458] source

      The Background lists diabetes as a possible baseline risk factor, but the Discussion addresses whether blood-pressure lowering prevents cognitive decline or dementia in hypertensive patients without prior cerebrovascular disease. Searches for the claimed independent prediction and for glucose control and major cardiovascular events found no passage addressing those findings in patients with type 2 diabetes. (LLM, conf=0.76)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Statin therapy protects against stroke in primary and secondary studies, based on meta-analysis and SPARCL.

    “Treatment with statin therapy has been documented to protect against stroke, both in primary460 and secondary studies, based on data from meta-analysis36 and a single trial, Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL).461”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [460] source
    • cites [36] source
    • cites [461] source

      The Introduction (p. 2) describes ADVANCE as studying blood-pressure lowering and intensive glucose control, and the Discussion (p. 7) discusses stroke in relation to blood-pressure treatment. Searches for statins, SPARCL, and meta-analysis found no passage in our copy addressing the claimed protection against stroke in primary or secondary studies. (LLM, conf=0.76)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Observational studies document that people consuming a Mediterranean diet have better cognition and lower dementia risk than those consuming other diets.

    “A few observational studies have documented that people who consume a Mediterranean diet have better cognition and less risk of dementia than people consuming other diets.470”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [470] source

      The Introduction (page unavailable) discusses observational findings about NSAID use and Alzheimer’s risk, not Mediterranean diets. Searches for “Mediterranean diet” and “diet cognition dementia risk” found no passage in our copy addressing diet, cognition, or a dietary comparison. (LLM, conf=0.76)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    These meta-analyses varied in model type (fixed or random) and patient selection.

    “These studies had variable methods in relation to model type (fixed or random) and selection of patients.453,454”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [453] source

      The Subjects and Methods section describes statistical analyses of the Syst-Eur trial, not a comparison of meta-analyses. Searches for fixed versus random models, patient selection, and meta-analysis found no passage in our copy addressing the claimed variation in methods. Page numbers were not available in the indexed passages. (LLM, conf=0.76)

      Experimental — accuracy not yet measured
    • cites [454] source

  • May combine two claims.

    Premisecitation

    In a Finnish cohort, combined elevated systolic BP, hypercholesterolemia, and obesity increased Alzheimer disease risk about sixfold, while each factor alone increased risk about twofold.

    “For example, in a cohort in Finland, the combination of elevated systolic blood pressure, hypercholesterolemia, and obesity increased the risk of Alzheimer disease by ≈6 times, whereas individually, any of these factors alone increased risk by ≈2 times.494”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [494] source

      Subjects and Methods (p. 2) describes a Finnish cohort of patients with ischemic stroke, while the Discussion (p. 4) compares criteria for diagnosing vascular dementia. Our copy does not address Alzheimer disease risk from the specified combination of blood pressure, cholesterol, and obesity, or report the claimed sixfold and twofold increases (searched those factors and risk estimates). (LLM, conf=0.78)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisenone given

    Carotid intimal-medial thickness and arterial stiffness are emerging as markers of arterial aging and may serve as risk markers for vascular cognitive impairment.

    “Carotid intimal-medial thickness and arterial stiffness are emerging as markers of arterial aging and may serve as risk markers for VCI.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationnone given

    The neuropathology of late-life cognitive impairment often involves a mixture of Alzheimer disease and microvascular brain damage, which may overlap and synergize to increase cognitive impairment risk.

    “The neuropathology of cognitive impairment in later life is often a mixture of Alzheimer disease and microvascular brain damage, which may overlap and synergize to heighten the risk of cognitive impairment.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    Dementia criteria based on memory deficits are derived from concepts proposed for Alzheimer disease, but these may not be suitable for the dementia syndrome associated with cerebrovascular disease, in which memory-related structures could be intact, resulting in relatively preserved memory functions.

    “Dementia criteria based on memory deficits are derived from concepts proposed for Alzheimer disease, but these may not be suitable for the dementia syndrome associated with cerebrovascular disease, in which memory-related structures (eg, mesial temporal lobe, thalamus) could be intact, resulting in relatively preserved memory functions.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [27] source
    • cites [28] source

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Vascular contributions to cognitive impairment and dementia in later life are common.

    “Vascular contributions to cognitive impairment and dementia of later life are common.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisereasoning

    These risks may include atrial fibrillation, hypertension, diabetes mellitus, and hypercholesterolemia.

    “These risks may include but are not limited to atrial fibrillation, hypertension, diabetes mellitus, and hypercholesterolemia.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    As the diagnostic threshold is expanded, frequency rates increase accordingly.

    “As the threshold is expanded, the frequency rates increase accordingly.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    This synergistic effect between Alzheimer disease and cerebrovascular disease pathology may explain why patients with mesial temporal lobe atrophy have an increased risk of dementia after stroke compared with those without atrophy, because hippocampal atrophy may also be caused by vascular disease.

    “This synergistic effect between Alzheimer disease and cerebrovascular disease pathology may explain why patients with mesial temporal lobe atrophy, presumably attributable to Alzheimer disease, have an increased risk of dementia after stroke compared with those without atrophy, because hippocampal atrophy may also be caused by vascular disease.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [38] source
    • cites [39] source

  • May combine two claims.

    Premisecitation

    All of the major criteria for vascular dementia have a different definition of dementia, and this results in challenges in reliability studies.

    “All of the major criteria for VaD have a different definition of dementia, and this results in challenges in reliability studies.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [26] source

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    These same vascular risk factors may be risk markers for Alzheimer disease.

    “Furthermore, these same vascular risk factors may be risk markers for Alzheimer disease.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationnone given

    Although some authors propose that symptoms should appear within 3 months after a stroke, this is arbitrary, and symptoms may develop after this time frame.

    “Although some authors propose that the symptoms should appear within 3 months after a stroke,30 this is arbitrary, and symptoms may develop after this time frame.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    Currently, no specific treatments for vascular cognitive impairment have been approved by the US Food and Drug Administration.

    “Currently, no specific treatments for VCI have been approved by the US Food and Drug Administration.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Some studies contend that mixed pathologies, including degenerative components caused by Alzheimer disease and vascular factors, are the most common explanation for cognitive impairment in aging.

    “Some studies contend that mixed pathologies, including the degenerative components caused by Alzheimer disease and vascular factors, are the most common explanation for cognitive impairment in aging.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [12] source
    • cites [13] source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductreasoning

    Formal search strategies were used for evaluation of clinical trial information.

    “Formal search strategies, however, were used as indicated for evaluation of clinical trial information.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductreasoning

    Some of the literature review was based on the expert panel's knowledge of the field and therefore may be subject to bias.

    “Some of the literature review was based on the expert panel's knowledge of the field and therefore may be subject to bias.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Consensus-based recommendations for standardized imaging, cognitive, and pathological protocols have been developed.

    “Importantly, consensus-based recommendations for standardized imaging, cognitive, and pathological protocols have been developed.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [5] source
    • cites [8] source

  • May combine two claims.

    Premisecitation

    The more liberal criteria for vascular dementia proposed by Hachinski et al result in large numbers, whereas the more conservative NINDS-AIREN criteria yield more modest rates.

    “the more liberal criteria for VaD proposed by Hachinski et al result in large numbers, whereas the more conservative criteria such as those of the National Institute of Neurological Disorders and Stroke–Association Internationale pour la Recherché et l'Enseignement en Neurosciences (NINDS-AIREN) yield more modest rates.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [10] source
    • cites [11] source

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Understanding of vascular cognitive impairment has evolved substantially in recent years, based on preclinical, neuropathologic, neuroimaging, physiological, and epidemiological studies.

    “Understanding of VCI has evolved substantially in recent years, based on preclinical, neuropathologic, neuroimaging, physiological, and epidemiological studies.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Although Tomlinson et al described 100 mL of tissue loss as sufficient for dementia, those with lesser volumes of loss also had dementia.

    “Indeed, although Tomlinson et al described 100 mL of tissue loss as sufficient for dementia, those with lesser volumes of loss also had dementia.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [51] source

  • May combine two claims.

    Premisecitation

    Depression or depressive symptoms can severely influence patients' activities of daily living and cognitive performance, although some symptoms can revert with treatment, and consequently cognition can improve.

    “these behaviors (depression or depressive symptoms) can severely influence patients’ activities of daily living and cognitive performance, although some symptoms can revert with treatment (eg, depression), and consequently cognition can improve.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [47] source
    • cites [48] source

  • May combine two claims.

    Interpretationreasoning

    Determining the volume or number necessary for vascular cognitive impairment or dementia has proved difficult, and unlike with Alzheimer disease, there are no currently accepted neuropathological criteria to confirm a clinical diagnosis of vascular cognitive impairment.

    “However, determining the volume or number necessary for VCI or dementia has proved difficult, and unlike with Alzheimer disease and other neurodegenerative diseases, there are no currently accepted neuropathological criteria to confirm a clinical diagnosis of VCI.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In clinical-pathological studies, larger volumes and an increased number of macroscopic infarcts are associated with an increased likelihood of dementia.

    “In clinical-pathological studies, larger volumes39,51 and an increased number11,13,39,55,56 of macroscopic infarcts are as sociated with an increased likelihood of dementia.”
    Quote in the paperSubstantial claim0 of 6 sources checked
    • cites [39] source
    • cites [51] source
    • cites [11] source
    • cites [13] source
    • cites [55] source
    • cites [56] source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    For decades it has been recognized that cerebrovascular disease is associated with dementia.

    “For decades it has been recognized that cerebrovascular disease is associated with dementia”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [11] source
    • cites [51] source

  • May combine two claims.

    Interpretationcitation

    This research area is complicated by the difficulty of clinically differentiating Alzheimer disease or vascular cognitive impairment from mixed disease, which may be more common than either pure Alzheimer disease or pure vascular cognitive impairment.

    “This research area is complicated by the difficulty of clinically differentiating Alzheimer disease or VCI from mixed (Alzheimer disease plus cerebrovascular disease) disease, which may be more common than either “pure” Alzheimer disease or “pure” VCI.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [9] source

  • May combine two claims.

    Interpretationnone given

    Primary vessel disease may be associated with focal or diffuse tissue damage or may result in nonmorphologic functional changes.

    “whereas primary vessel disease may be associated with focal (eg, infarct) or diffuse tissue damage (eg, white matter degeneration) or may result in nonmorphologic functional changes.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    One study showed that only people with Alzheimer disease pathology with subcortical infarcts had dementia, raising the possibility of an interaction (a multiplicative effect) between the 2 pathologies.

    “One study showed that only people with Alzheimer disease pathology with subcortical infarcts had dementia, raising the possibility of an interaction (a multiplicative effect) between the 2 pathologies.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [16] source

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Premisenone given

    Vascular and degenerative pathologies are common in later life and often coexist.

    “Vascular and degenerative pathologies are 2 common disorders in later life and often coexist”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    The interplay between macroscopic and microscopic infarcts and other vascular and degenerative pathologies in the development of clinical Alzheimer disease and vascular cognitive impairment is complex.

    “The interplay between macroscopic and microscopic infarcts and other vascular and degenerative pathologies in the development of clinical Alzheimer disease and VCI is complex.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationnone given

    Vascular and degenerative pathologies each separately increase the likelihood of cognitive impairment and dementia.

    “and each separately adds to the likelihood of cognitive impairment and dementia.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    Vascular and degenerative pathologies may result in overlapping clinical and imaging phenotypes.

    “In addition, vascular and degenerative pathologies may result in overlapping clinical and imaging phenotypes.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Loss of energy-saving saltatory conduction increases metabolic demands and enhances local energy deficit and hypoxia.

    “loss of energy-saving saltatory conduction increases metabolic demands and enhances local energy deficit and hypoxia.128”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [128] source

  • May combine two claims.

    Premisecitation

    Amyloid beta is a potent vasoconstrictor and suppresses endothelium-dependent responses, functional hyperemia, and cerebrovascular autoregulation.

    “Aβ is a potent vasoconstrictor113,114 and suppresses endothelium-dependent responses, functional hyperemia, and cerebrovascular autoregulation.115–117”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [113] source
    • cites [114] source
    • cites [115] source
    • cites [116] source
    • cites [117] source

  • May combine two claims.

    Premisecitation

    Plasma amyloid beta is elevated in some patients with vascular cognitive impairment and Alzheimer disease, induces cerebrovascular insufficiency, and may contribute to white matter alterations observed in both conditions.

    “Plasma Aβ, which is elevated in some patients with VCI and Alzheimer disease, induces cerebrovascular insufficiency and could play a role in the white matter alterations observed in both conditions.130,131”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [130] source
    • cites [131] source

  • May combine two claims.

    Premisecitation

    Free radicals can induce inflammation by activating redox-sensitive proinflammatory transcription factors, and oxidative stress-induced endothelial dysfunction can release vascular endothelial growth factor and prostanoids, promoting vascular leakage, protein extravasation, and cytokine production.

    “Although free radicals can induce inflammation by activating redox-sensitive proinflammatory transcription factors, the endothelial dysfunction induced by oxidative stress can release vascular endothelial growth factor and prostanoids, which promote vascular leakage, protein extravasation, and cytokine production.125”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [125] source

  • May combine two claims.

    Premisecitation

    In Alzheimer disease and cerebral amyloid angiopathy, accumulation of amyloid beta in the media of cortical arterioles weakens the vessel wall and increases the chance of lobar hemorrhages.

    “in Alzheimer disease and CAA, accumulation of Aβ in the media of cortical arterioles weakens the vessel wall and increases the chance of lobar hemorrhages.109”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [109] source

  • May combine two claims.

    Premisecitation

    Arterioles exhibit onion-skin-type changes and undergo hyaline degeneration (lipohyalinosis), a cause of microhemorrhages.

    “Arterioles exhibit signs of “onion skin”–type changes and undergo hyaline degeneration (lipohyalinosis), a cause of microhemorrhages.105”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [105] source

  • May combine two claims.

    Premisecitation

    In models of autoimmune white matter injury, extravasation of plasma protein triggers vascular inflammation and axonal demyelination, which disrupts saltatory conduction and slows nerve impulse transmission.

    “In models of autoimmune white matter injury, extravasation of plasma protein triggers vascular inflammation and axonal demyelination,127 which in turn disrupts saltatory conduction,128 slowing the transmission of nerve impulses.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [127] source
    • cites [128] source

  • May combine two claims.

    Premisecitation

    Cerebral amyloid angiopathy appears in about 10% to 30% of unselected brain autopsies and 80% to 100% when accompanying Alzheimer disease is present.

    “CAA appears in ≈10% to 30% of unselected brain autopsies and 80% to 100% when in the presence of accompanying Alzheimer disease.136”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [136] source

  • May combine two claims.

    Premisenone given

    Diagnostic approaches to cerebral amyloid angiopathy and CADASIL have improved, but no disease-modifying therapies have been identified.

    “Diagnostic approaches to CAA (and to CADASIL, the most common form of hereditary small-vessel disease) have improved, but no disease-modifying therapies have been identified.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationnone given

    Vascular oxidative stress and inflammation underlie many deleterious effects and are potential therapeutic targets.

    “Vascular oxidative stress and inflammation underlie many of these deleterious effects and are potential therapeutic targets.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Few animal models of cognitive impairment and white matter damage exist, but models recapitulating features of cerebral amyloid angiopathy, CADASIL, cerebral hypoperfusion, and hypertensive vasculopathy have been developed, mainly in rodents.

    “Although there are relatively few animal models of cognitive impairment and white matter damage, models recapitulating features of CAA, CADASIL, cerebral hypoperfusion, and hypertensive vasculopathy have been developed, mainly in rodents.5”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [5] source

  • May combine two claims.

    Premisenone given

    Carotid wall thickening and aortic stiffening likely reflect atherosclerosis and arteriosclerosis, respectively.

    “They include carotid wall thickening and aortic stiffening, which also likely reflect atherosclerosis and arteriosclerosis, respectively.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationnone given

    Neurovascular dysfunction increases the brain's susceptibility to injury by altering regulation of cerebral blood supply, disrupting blood-brain barrier function, and reducing trophic support and repair potential of the injured brain.

    “Neurovascular dysfunction increases the brain's susceptibility to injury by (a) altering regulation of the cerebral blood supply, (b) disrupting BBB function, and (c) reducing the trophic support and repair potential of the injured brain.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    CADASIL can present clinically as migraines with aura, mood disturbances, recurrent strokes, or cognitive impairment, and radiographically as extensive white matter lesions, lacunar infarcts, microbleeds, and brain atrophy.

    “This disorder can present clinically as migraines with aura, mood disturbances, recurrent strokes, or cognitive impairment163 and radiographically by the appearance of extensive WMLs, lacunar infarcts, microbleeds, and brain atrophy.164”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [163] source
    • cites [164] source

  • May combine two claims.

    Premisecitation

    Cerebral amyloid angiopathy can trigger vascular or perivascular inflammation, manifesting as vasogenic edema of subcortical white matter and more rapidly progressive cognitive decline.

    “CAA can also trigger vascular or perivascular inflammation,150,151 manifesting as vasogenic edema of subcortical white matter and more rapidly progressive cognitive decline.152”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [150] source
    • cites [151] source
    • cites [152] source

  • May combine two claims.

    Premisenone given

    Rodent models are well suited to genetic manipulations and large-scale studies but can be problematic because of their small amount of white matter and limited behavioral repertoire.

    “Rodent models, although well suited to genetic manipulations and large-scale studies, can be problematic because of their small amount of white matter and limited behavioral repertoire.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    T2*-weighted gradient-echo MRI sequences provide substantially increased sensitivity for detection of cerebral microbleeds and are key to the diagnosis of probable cerebral amyloid angiopathy.

    “T2*-weighted gradient-echo MRI sequences provide substantially increased sensitivity for detection of cerebral microbleeds and are key to the diagnosis of probable CAA.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given

    Other hereditary small-vessel syndromes of the brain are rare and have generally not been reported as causes of sporadic disease via de novo mutation.

    “Other hereditary small-vessel syndromes of the brain are rare and have generally not been reported as causes of sporadic disease via de novo mutation.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Central systolic blood pressure and pulse pressure can be estimated noninvasively either from the radial artery waveform using a transfer function or from the common carotid waveform.

    “Central systolic blood pressure and pulse pressure can be estimated noninvasively either from the radial artery waveform, using a transfer function, or from the common carotid waveform.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Microbleeds seen on MRI and microinfarcts discovered at autopsy occur more frequently among people diagnosed with dementia during life.

    “Furthermore, the relative contributions to VCI of microbleeds seen on MRI or microinfarcts discovered at autopsy remain uncertain, although both occur with increased frequency among people diagnosed with dementia during life.77,233”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [77] source
    • cites [233] source

  • May combine two claims.

    Premisenone given

    Carotid intima-media thickness can reflect media thickening in response to increased blood pressure in hypertensive patients, intima thickening in response to atherosclerotic risk factors, or most often a combination of both.

    “Carotid IMT can reflect either a media thickening in response to the increase in blood pressure in hypertensive patients, an intima thickening in response to atherosclerotic risk factors, or most often a combination of both.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Common cardiovascular factors likely influence both intima-media thickness and vascular cognitive impairment independently, but the consequences of vascular disease may also directly affect cognitive function.

    “In all likelihood, common cardiovascular factors influence both IMT and VCI independently, but the consequences of vascular disease may also directly affect cognitive function.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Both aortic pulse wave velocity and central systolic blood pressure and pulse pressure predict cardiovascular events independent of classic cardiovascular risk factors.

    “Both aortic pulse wave velocity and central systolic blood pressure and pulse pressure predict cardiovascular events independent of classic cardiovascular risk factors.182”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [182] source

  • May combine two claims.

    Premisecitation

    Small-vessel disease increases with age and is accelerated by vascular risk factors, especially hypertension and diabetes.

    “Small-vessel disease increases with age and is accelerated by vascular risk factors, most notably, hypertension and diabetes.223”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [223] source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationnone given

    VCI may have a variety of clinical presentations that depend on the setting in which patients are evaluated.

    “As previously discussed, VCI may have a variety of clinical presentations that may depend on the setting in which patients are evaluated.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    Analysis of the aortic pressure waveform allows calculation of central systolic blood pressure and pulse pressure, which are influenced by aortic stiffness and the geometry and vasomotor tone of small arteries.

    “The analysis of aortic pressure waveform allows the calculation of central systolic blood pressure and pulse pressure, which are influenced by aortic stiffness and the geometry and vasomotor tone of small arteries.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Left hemisphere, anterior and posterior cerebral artery distribution, multiple infarcts, and strategic infarcts have been associated with poststroke dementia in at least two studies.

    “Left hemisphere, anterior and posterior cerebral artery distribution, multiple infarcts, and strategic infarcts have been associated with PSD in at least 2 studies.40”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [40] source

  • May combine two claims.

    Premisecitation

    Measures of cerebral gray matter and hippocampal volume were both associated with declines in memory performance.

    “Conversely, measures of cerebral gray matter and hippocampal volume were both associated with declines in memory performance.256”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [256] source

  • May combine two claims.

    Premisecitation

    WMLs share risk factors with stroke, although advancing age remains a strong effect.

    “WMLs also share risk factors with stroke,239 although advancing age remains a strong effect.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [239] source

  • May combine two claims.

    Premisecitation

    Silent cerebral infarcts, white matter changes, and global and medial temporal lobe atrophy are associated with increased risk of poststroke dementia.

    “Among neuroimaging findings, silent cerebral infarcts, white matter changes, and global and medial temporal lobe atrophy are associated with increased risk of PSD.252”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [252] source

  • May combine two claims.

    Premisecitation

    Patients with poststroke dementia have functional impairment and high mortality rates.

    “Patients with PSD have degrees of functional impairment and high mortality rates.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [252] source

  • May combine two claims.

    Premisecitation

    In a Rochester community-based stroke study, dementia prevalence was 30% immediately after stroke, and new-onset dementia incidence increased from 7% at 1 year to 48% at 25 years.

    “In a Rochester, MN, community-based study of stroke, the prevalence of dementia was 30% immediately after stroke, and the incidence of new-onset dementia increased from 7% after 1 year to 48% after 25 years.250”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [250] source

  • May combine two claims.

    Premisecitation

    WMLs are more common than silent infarcts and are generally present in most people over 30 years of age, increasing steadily with advancing age.

    “WMLs are even more common and are generally present in most people >30 years of age,231 increasing steadily in extent with advancing age.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [231] source

  • May combine two claims.

    Premisecitation

    Risk of dementia after stroke is higher with increased age, fewer years of education, history of diabetes mellitus and atrial fibrillation, and recurrent stroke.

    “Risk of dementia is higher with increased age and fewer years of education, history of diabetes mellitus and atrial fibrillation, and recurrent stroke.251”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [251] source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationnone given

    Prevalence estimates of VaD vary widely.

    “Prevalence estimates of VaD vary widely.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    After age 65, prevalence and incidence of VaD increase exponentially with age, although trends after 90 years are not well established.

    “In general, however, after age 65 years, there is an exponential increase in prevalence and incidence of VaD as age increases,265,266 although the trends after 90 years of age have not been well established.4,267,268”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [265]
    • cites [266] source
    • cites [4] source

  • May combine two claims.

    Interpretationcitation

    The clinical presentation and course of CVBI are highly variable, and the classic phenotype of stepwise decline with stroke is a relatively uncommon presentation for VCI.

    “The clinical presentation and course of CVBI are highly variable, with the classic phenotype of stepwise decline in association with stroke10 being a relatively uncommon presentation for VCI.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [10] source

  • May combine two claims.

    Interpretationreasoning

    Structural MRI provides a fairly sensitive and specific marker for CVBI, but the relationship between CVBI and cognitive impairment is confounded by frequent Alzheimer disease changes and co-occurrence of cerebrovascular depression.

    “Structural MRI provides a fairly sensitive and specific marker for CVBI, but the relationship between CVBI and cognitive impairment is confounded by the frequent presence of Alzheimer disease changes of the brain and co-occurrence of depression on a cerebrovascular basis.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Antioxidants, including vitamins E, C, and beta carotene, consumed as part of the diet or as supplements, have been reported to reduce the risk of cognitive impairment.

    “Antioxidants, which include vitamins E,282 C, and beta carotene,283 consumed either as a part of the diet (fruits and vegetables) or as supplements, have been reported to reduce the risk of cognitive impairment.284”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [282] source
    • cites [283] source
    • cites [284] source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Some studies report a higher incidence of VaD in men than women, although a pooled analysis of incidence studies found no difference.

    “Some studies report a higher incidence of VaD in men than in women,4,271 although a pooled analysis of incidence studies found no difference.272”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [4] source
    • cites [271] source
    • cites [272] source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Fish oil n-3 polyunsaturated fatty acids are of interest because of their antioxidant and antiinflammatory properties and because they are major components of brain membrane phospholipids and play a critical role in neuronal function.

    “Fish oil n-3 polyunsaturated fatty acids are of interest because of their antioxidant and antiinflammatory properties and because they are major components of membrane phospholipids in the brain and play a critical role in neuronal function.288”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [288] source

  • May combine two claims.

    Premisecitation

    The apolipoprotein E ε4 allele is associated with increased levels of cardiovascular risk factors and is a strong indicator of genetic risk for Alzheimer disease.

    “The apolipoprotein E ε4 allele is associated with increased levels of cardiovascular risk factors276 and is a strong indicator of genetic risk for Alzheimer disease.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [276] source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    MCI may not differ by sex.

    “MCI may not differ by sex,273 but additional studies are needed to answer this question.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [273] source

  • May combine two claims.

    Premisecitation

    Incidence of VaD appears higher in blacks than whites or in Hispanics with a history of stroke, possibly reflecting group differences in cerebrovascular risk profile.

    “The incidence of VaD appears to be higher in blacks than in whites4 or in Hispanics with a history of stroke,274 possibly reflecting group differences in cerebrovascular risk profile.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [4] source
    • cites [274] source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    There are a number of possible explanations or confounders in relation to education level and VCI.

    “Thus, there are a number of possible explanations or confounders in relation to education level and VCI.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Vascular risk factors are also importantly associated with Alzheimer disease, mixed dementia, and amnestic MCI.

    “We recognize that this is a somewhat arbitrary choice, because many articles and reviews show that vascular risk factors are also importantly associated with Alzheimer disease, mixed dementia, and amnestic MCI.110,260,261”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [110] source
    • cites [260] source
    • cites [261] source

  • May combine two claims.

    Premisenone given

    Prospective cohort findings for diastolic blood pressure and cognitive decline are less consistent, but many report an inverse relation.

    “Findings from these prospective cohort studies for diastolic blood pressure and cognitive decline are less consistent; however, many have reported a similar inverse relation.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In longitudinal cohort studies, higher systolic blood pressure is associated with greater late-life cognitive decline, although some studies report J- or U-shaped relations.

    “In longitudinal cohort studies, higher systolic blood pressure has been associated with greater late-life cognitive decline, although some studies have reported a J- or U-shaped relation.342”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [342] source

  • May combine two claims.

    Interpretationreasoning

    Data on later-life blood pressure and hypertension in relation to cognition are inconsistent, leaving the issue of treating blood pressure in older people open.

    “The data on the role of blood pressure and hypertension in later life are not consistent, leaving open the issue of blood pressure treatment in older people.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Studies vary in the amount of alcohol associated with a positive effect, the relative significance for global, memory, and executive function, and whether the effect varies by sex.

    “However, studies vary in the amount of alcohol associated with a positive effect; the relative significance of global, memory, and executive function; and whether the effect varies by sex.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationcitation

    Nicotine may stimulate cholinergic pathways in the brain, which could help explain domain-specific effects of smoking on cognition.

    “possibly because nicotine may also stimulate cholinergic pathways within the brain.326”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [326] source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationnone given

    There is a relative paucity of data on the type and frequency of physical activity and its short- and long-term benefits for preservation of brain health.

    “There is a relative paucity of data on the type and frequency of physical activity and what the short- and long-term benefits of physical activity are for preservation of brain health.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Long-term regular physical activity, including vigorous activity and walking, is strongly associated with higher cognitive function, less cognitive decline, and less VaD.

    “However, long-term regular physical activity, including vigorous activity and walking, was strongly associated with higher levels of cognitive function, less cognitive decline, and less VaD.303–306”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [303] source
    • cites [304] source
    • cites [305] source

  • May combine two claims.

    Premisenone given

    Depression may affect cognitive functions and may mimic cognitive decline.

    “Depression may impact cognitive functions and may mimic cognitive decline.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Midlife systolic and diastolic blood pressure, history of hypertension, and total cholesterol level predict VCI.

    “Midlife systolic and diastolic blood pressure, history of hypertension, and total cholesterol level predict VCI.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In the CAIDE study, midlife total cholesterol significantly predicted cognitive impairment 21 years later, and the association was attenuated after accounting for statin therapy.

    “In the Finnish study Cardiovascular Risk Factors Aging and Dementia (CAIDE), midlife measures of total cholesterol significantly predicted cognitive impairment 21 years later, an association that was attenuated after accounting for statin therapy.354”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [354] source

  • May combine two claims.

    Premisecitation

    Severe chronic kidney disease is associated with metabolic (uremic) and hypertensive encephalopathy and increased stroke risk.

    “Severe chronic kidney disease has been associated with metabolic (uremic) and hypertensive encephalopathy and an increased risk of stroke.366”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [366] source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationnone given

    These findings have been reported across multiple populations.

    “These findings have been reported across multiple populations.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Late-life cohort findings on cholesterol vary, with some showing higher cholesterol associated with lower risk and others with higher VaD risk.

    “Findings in late-life cohorts vary, with some finding higher levels of cholesterol associated with a lower risk356 and others finding a higher risk for VaD.357”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [356] source
    • cites [357] source

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    There are scarce data relating flow-mediated endothelial dilatation with cognition.

    “There are scarce data relating flow-mediated endothelial dilatation (brachial artery reactivity) with cognition.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationreasoning

    Differences in atrial fibrillation findings could be related to age or sex (weaker effect in women and older people) and to administration and effectiveness of anticoagulation.

    “Some of these differences could be related to age or sex (the effect was weaker in women and older people) and the administration and effectiveness of anticoagulation.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationreasoning

    The relation of late-life VCI to later-life blood pressure and cholesterol remains uncertain and requires further study, although higher exposure may prove beneficial.

    “The relation of late-life VCI to measures of blood pressure and cholesterol in later life remains uncertain and requires further study, although higher levels of exposure to these risk factors may prove to be beneficial.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Inconsistencies in cholesterol findings may reflect timing of measurements relative to age, older people being less likely to receive lipid-lowering therapy, and clinical onset of dementia.

    “As with blood pressure, inconsistencies may reflect timing of the cholesterol measurements relative to age, older people possibly being less likely to receive lipid-lowering therapy (“generational effect”), and clinical onset of dementia.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    Coronary artery bypass graft is associated with poorer initial cognitive function and higher late-life dementia risk.

    “Coronary artery bypass graft has been associated with poorer initial cognitive function and a higher late-life dementia risk.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationnone given

    Many facets of dementia care do not involve therapies directed at disease modification.

    “Many facets of dementia care do not involve therapies directed at disease modification.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Cochrane reviews concluded donepezil studies provide the best available evidence for a beneficial effect in VaD and galantamine for mixed states, while benefit of memantine and rivastigmine is still not proven.

    “Cochrane reviews of VaD trials concluded that donepezil studies have provided the best available evidence for a beneficial effect for VaD397 and galantamine for mixed states,402 whereas a benefit of memantine410 and rivastigmine is still not proven.404”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [397] source
    • cites [402] source
    • cites [410] source

  • May combine two claims.

    Premisecitation

    A subsequent pure VaD study (n=788) showed cognitive treatment benefits, including an executive measure but not daily functions, with an overall trend for global benefit (P=0.06).

    “A subsequent study of “pure” VaD patients (n=788) showed cognitive treatment benefits, including benefit for an executive measure but not for daily functions; however, there was an overall trend for global benefit (P=0.06).401”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [401] source

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    Over the past decade, the role of vascular brain disease as a cause of cognitive impairment has become increasingly evident, alone or combined with Alzheimer disease.

    “Over the past decade, the role of vascular brain disease as a cause of cognitive impairment has become increasingly evident, alone or combined with Alzheimer disease.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In a recent study, more deaths occurred in the donepezil treatment group, attributed to a lower-than-expected death rate in the placebo group.

    “In a recent study, however, more deaths occurred in the donepezil treatment group; this was attributed to the less than expected death rate in the placebo group.398”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [398] source

  • May combine two claims.

    Premisecitation

    The association with dementia appears stronger for vascular factors measured in midlife than in old age, suggesting midlife may be a critical period.

    “The timing of such interventions may be important, because the association with dementia appears to be stronger for vascular factors and when measured in midlife rather than in old age, which suggests that midlife may be a critical period.424”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [424] source

  • May combine two claims.

    Premisecitation

    An 18-week donepezil study in 168 CADASIL patients had a neutral result but showed benefit in executive function measures in secondary analysis.

    “An 18-week study of donepezil in 168 patients with CADASIL had a neutral result but showed benefit in executive function measures in secondary analysis.408”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [408] source

  • Classified as probably not a substantial claim.

    Interpretationcitation

    Hippocampal volume may need to be accounted for in future VaD trials.

    “This finding suggests that hippocampal volume may need to be accounted for in future VaD trials.398”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [398] source

  • May combine two claims.

    Interpretationreasoning

    Disease of coronary or peripheral arterial circulations, atrial fibrillation, and clinically detectable renal and cardiac failure have each been associated with cognitive impairment.

    “In an analogous manner, disease of the coronary or peripheral arterial circulations, atrial fibrillation, and clinically detectable renal and cardiac failure have each been associated with cognitive impairment.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Galantamine produced statistically significant less decline in cognition, function, and behavior, driven by the mixed AD/VaD subgroup, while placebo subjects declined.

    “There was statistically significant less decline in cognition, function, and behavior with galantamine, driven by the mixed subgroup, whereas subjects treated with placebo showed decline.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [403] source

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    Vascular and metabolic risk factors should be regarded as potential major targets for prevention of dementia.

    “Vascular and metabolic risk factors should therefore be regarded as potential major targets for the prevention of dementia.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    It has been estimated that among 106 million Alzheimer disease cases expected worldwide by 2050, about 23 million could be avoided if onset were delayed by 2 years.

    “It has been estimated, for example, that among the 106 million cases of Alzheimer disease expected worldwide by the year 2050, ≈23 million could be avoided completely if it were possible to delay the onset of disease by 2 years.423”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [423] source

  • May combine two claims.

    Interpretationreasoning

    The increased dementia risk after stroke is caused in part by loss of brain tissue, but may also reflect a direct effect of vascular risk factors on both stroke risk and cognitive function.

    “Although this is caused in part by loss of brain tissue, it may also reflect a direct effect of vascular risk factors on both risk of stroke and cognitive function.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    One meta-analysis commented that cognitive benefits of cholinergic agents and memantine were of uncertain clinical significance in VaD, and more data are required before widespread use.

    “One meta-analysis commented that the cognitive benefits of cholinergic agents and memantine were of uncertain clinical significance in VaD, and more data are required before widespread use of these agents is to be considered.411”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [411] source

  • May combine two claims.

    Interpretationreasoning

    Specific pharmacotherapy trials targeting VaD have shown consistent, modest cognitive improvements with donepezil, galantamine, and memantine, but functional and global benefits have been less consistent, with evidence only from 2 large donepezil trials.

    “Specific pharmacotherapy trials targeting VaD have shown consistent, modest cognitive improvements with donepezil, galantamine, and memantine, but functional and global benefits have been less consistent, with evidence only from 2 large donepezil trials.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationnone given

    There are few randomized controlled trials and methodological limitations in existing studies of cognitive rehabilitation/stimulation.

    “However, there are few randomized controlled trials, and there are methodological limitations in existing studies in the area.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Donepezil trials focused on pure VaD (n=1219), with placebo groups stable over 6 months, requiring improvement to show efficacy.

    “The donepezil trials focused on “pure” VaD (n=1219), in which placebo groups were stable over 6 months, requiring improvement to show efficacy.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Nonpharmacological approaches have also been tried.

    “Nonpharmacological approaches have also been tried.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Rivastigmine has been less well studied, but beneficial effects on an executive measure were found in a 22-month open-label controlled study (n=16) and in a double-blind placebo-controlled trial targeting vascular cognitive impairment, no dementia (n=50).

    “Rivastigmine has been less well studied, but beneficial effects on an executive measure were found in a 22-month, open-label controlled (n=16) study409 and in a double-blind placebo-controlled trial targeting vascular cognitive impairment, no dementia (n=50).405”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [409] source
    • cites [405] source

  • May combine two claims.

    Premisecitation

    In longitudinal studies of antihypertensive drugs and dementia risk, mean follow-up was ≤5 years for most studies, except 2 studies with 13 and 19 years follow-up and younger participants at inclusion.

    “Mean duration of follow-up was ≤5 years for most studies, except 2 studies with a follow-up of 13429 and 19430 years and that included participants who were a younger age at inclusion.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [429] source
    • cites [430] source

  • May combine two claims.

    Premisecitation

    Acupuncture showed cognitive benefit in a rodent model of VaD, but a Cochrane review of acupuncture in human VaD was inconclusive.

    “Acupuncture showed cognitive benefit in a rodent model of VaD,421 but a Cochrane review of acupuncture in human VaD was inconclusive,422”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [421] source
    • cites [422] source

  • May combine two claims.

    Interpretationreasoning

    Trials failed partly because standard cognitive measures showed only modest benefit and undersampled executive functioning.

    “Reasons include only modest benefit on standard cognitive measures, which undersampled executive functioning”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premiseown data

    In PROGRESS, during 4-year follow-up, dementia was diagnosed in 410 patients, 108 after stroke.

    “During the 4-year follow-up, dementia was diagnosed in 410 patients, of whom 108 had dementia preceded by a stroke.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Comparing angiotensin receptor blockers with an angiotensin-converting enzyme inhibitor is a remarkable attempt to overcome confounding by indication because the two drug classes are similar in novelty and price.

    “By comparing angiotensin receptor blockers with an angiotensin-converting enzyme inhibitor, 2 classes of drug similar in novelty and price, this study is a remarkable attempt to overcome confounding by indication.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premiseown data

    In the Syst-Eur extension, nitrendipine treatment reduced both Alzheimer disease and VaD.

    “In the extension study, both Alzheimer disease and VaD were reduced by treatment with nitrendipine.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    The findings on diuretic class effects were based on limited follow-up, relatively small numbers of dementia cases, and confounding by indication.

    “These findings, however, were based on a limited follow-up, a relatively small number of dementia cases, and confounding by indication.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    The Veterans Affairs study had relatively short follow-up and did not assess ethnic disparities.

    “Furthermore, the follow-up was relatively short, and ethnic disparities were not assessed.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    Syst-Eur was stopped early after median 2 years because nitrendipine significantly reduced stroke risk.

    “The trial was stopped prematurely after a median follow-up period of 2 years on evidence of significant benefits from treatment with nitrendipine for lowering the risk of stroke.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductnone given

    Published trials had small numbers of incident cases and low statistical power.

    “(4) small numbers of incident cases and low statistical power;”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationnone given

    Use of administrative databases is subject to limitations such as lack of precision in dementia/Alzheimer disease diagnosis and inability to account for major confounders such as educational level.

    “The use of administrative databases, however, is subject to limitations such as a lack of precision concerning diagnosis of dementia and Alzheimer disease or the impossibility of taking into account potential major confounders such as educational level.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductreasoning

    In SCOPE, control patients received antihypertensive drugs during the trial for ethical reasons, reducing between-group BP differences and study power.

    “Although initially planned as a trial of an angiotensin receptor blocker versus placebo, during the trial and for ethical reasons, antihypertensive drugs were administered to patients in the control group. Therefore, between-group blood pressure differences and the study power were reduced.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In PROGRESS, combination perindopril plus diuretic reduced systolic BP by 12 mm Hg, diastolic by 5 mm Hg, and stroke risk by 43%.

    “Combination therapy reduced systolic and diastolic blood pressure by 12 and 5 mm Hg, respectively, and stroke risk by 43%.451”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [451] source

  • May combine two claims.

    Premisecitation

    Two analyses of the same study showed different results by follow-up duration: no effect on dementia and Alzheimer disease with 2.2 years follow-up, and a 5% reduction in dementia risk per year of treatment (6% for Alzheimer disease) with much longer follow-up.

    “Interestingly, 2 analyses of the same study showed different results according to the duration of follow-up: no effect on dementia and Alzheimer disease in a first study with only 2.2 years of follow-up432 and a 5% reduction in risk of dementia per year of treatment (6% for Alzheimer disease) in a study with a much longer follow-up.429”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [432] source
    • cites [429] source

  • May combine two claims.

    Premisecitation

    Longer duration of antihypertensive treatment and lower age were associated with a stronger protective effect against dementia.

    “Longer duration of treatment and lower age were associated with a stronger protective effect.429”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [429] source

  • May combine two claims.

    Interpretationreasoning

    A few studies suggest a greater effect of some classes of antihypertensive therapy, but evidence remains limited and subject to bias, so no firm conclusion can be drawn.

    “A few studies suggest a greater effect of some classes of antihypertensive therapy, but the evidence remains limited and is subject to bias so that no firm conclusion can be drawn about this relationship.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Some observational studies suggest aspirin benefits cognition, while others do not confirm this.

    “Some observational studies have suggested a beneficial effect of aspirin on cognition,465,466 although this was not confirmed in others.467,468”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [465] source
    • cites [466] source
    • cites [467]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [468] source

  • May combine two claims.

    Premisecitation

    Long-duration diabetes increases risk of cognitive decline, dementia, depression, and other aging phenotypes.

    “Patients with diabetes of long duration are at increased risk of cognitive decline, dementia, and depression, as well as other phenotypes associated with aging.438a”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites 438a

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Interpretationnone given

    Diabetes is an important risk factor for mental symptoms and cognitive impairment, but available data are mostly observational.

    “Diabetes is an important risk factor for mental symptoms and cognitive impairment, but available data are based mostly on observational studies.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Meta-analyses are subject to limitations similar to therapeutic trials and yield no substantial additional information.

    “They are subject to limitations similar to those of therapeutic trials and do not yield any substantial additional information.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Evidence generally lacks for positive benefit of antiaggregants and vitamin supplementation on cognitive function.

    “There is generally a lack of evidence for a positive benefit of antiaggregants and vitamin supplementation on cognitive function.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premiseown data

    Only one meta-analysis found significantly decreased dementia risk, but it was embedded in the HYVET report and scantily described, especially selection criteria.

    “Only 1 trial found that the risk for dementia was significantly decreased, but it was embedded in the report of the HYVET results, and its description was scant, especially concerning selection criteria for the studies.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Depression and anxiety are more prevalent in established type 2 diabetes.

    “This is often accompanied by other disturbances of mental function, such as depression or anxiety, all of these conditions being described as being more prevalent in established type 2 diabetes mellitus.438a”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites 438a

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Interpretationnone given

    Evidence from observational studies on statin effects on cognitive function is scant and low-level.

    “There is scant evidence from observational studies on the effects of statin therapy on cognitive function, and the level of evidence is low.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationnone given

    Observational studies suggest some benefit of antihypertensive treatment on Alzheimer disease risk, apparently greater in the youngest old than the oldest.

    “Observational studies point to some benefit of antihypertensive treatment on the risk for Alzheimer disease, the treatment being apparently more effective in the youngest old than in the oldest people.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Treatment of hyperglycemia prevents microvascular and some macrovascular events, based on a recent meta-analysis.

    “The treatment of hyperglycemia is associated with prevention of both microvascular and, to some degree, macrovascular events, based on data from a recent meta-analysis.457”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [457] source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationnone given

    Intensive control-induced hypoglycemia may affect cognitive function in older people with diabetes, an aspect not yet explored.

    “The possible effect of intensive control–induced hypoglycemia on cognitive function represents a relevant and yet-to-be-explored aspect in older people with diabetes.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    In severe hyperglycemia, cognitive dysfunction is acutely impaired by hyperosmolar influences and electrolyte disturbances, which acute insulin therapy can improve.

    “In severe cases of hyperglycemia, the cognitive dysfunction is acutely impaired by hyperosmolar influences and electrolyte disturbances, conditions that are possible to improve by acute insulin therapy.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    Although statin therapy prevents stroke, it does not prevent cognitive decline in the elderly.

    “Although lipid control by statin therapy is able to prevent stroke, these drugs do not prevent cognitive decline in the elderly.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Meta-analyses neither prove nor disprove efficacy of antihypertensive treatment on dementia risk.

    “Meta-analyses neither prove nor disprove the efficacy of antihypertensive treatment on the risk of dementia.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Interpretationcitation

    It has been proposed that pathogenic mechanisms converge in vascular and neurodegenerative processes causing cognitive impairment.

    “Therefore, it has been proposed that there may be a convergence of pathogenic mechanisms in vascular and neurodegenerative processes that cause impairment of cognition.101,493”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [101] source
    • cites [493] source

  • May combine two claims.

    Premisecitation

    An angiogenesis hypothesis for Alzheimer disease exists, and genes may contribute to neurovascular unit dysfunction in that disease.

    “In fact, there is an angiogenesis hypothesis for Alzheimer disease and a possible role for genes in neurovascular unit dysfunction in Alzheimer disease.107,492”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [107] source
    • cites [492] source

  • May combine two claims.

    Interpretationcitation

    Covert brain injury from subclinical CVBI, stroke, and vascular risk factors may relate to neuropsychological deficits and add to VCI and later manifest stroke sequelae.

    “In addition, as subclinical CVBI, stroke, and vascular risk factors have been a major focus of this statement, a better understanding of the prevention of “silent” strokes and WMLs (ie, “covert” brain injury) is necessary, because these events may be associated with neuropsychological deficits and contribute to VCI and eventual manifest stroke sequelae risk.498”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [498] source
    • Rests on an assumption: Silent strokes outnumber clinically manifest strokes by more than nine to one.
    • Rests on an assumption: The proportion of people with milder VCI is about twice that with severe VCI (VaD).
205 of 205

  • The authors state this as an assumption.

    The underlying neuropathological substrate of amnestic mild cognitive impairment is pure Alzheimer disease pathology rather than vascular or mixed pathology.

    “assuming the underlying neuropathological substrate of amnestic MCI is pure Alzheimer disease pathology rather than vascular or mixed pathology”

  • The paper relies on this without support.

    Neuroimaging detects macroscopic infarcts about 3 mm or more in size, but microscopic infarcts and small-vessel disease are currently not within the resolution of most scans.

    “First, neuroimaging detects macroscopic infarcts, ≈3 mm or more in size, but microscopic infarcts and small-vessel disease (eg, arteriolosclerosis) are currently not within the resolution of most scans.”

  • The paper relies on this without support.

    Stiffer large arteries are associated with increased left ventricular mass.

    “Additionally, stiffer large arteries are associated with increased left ventricular mass.”

  • The paper relies on this without support.

    No study has investigated the relationship between small-artery remodeling and cognitive decline or white matter lesions.

    “To the best of our knowledge, no study has investigated the relationship between small-artery remodeling and cognitive decline or WMLs.”

  • The paper relies on this without support.

    In community-based studies, evidence of CVBI and cognitive impairment is often found without a history of a strokelike event.

    “For example, in community-based studies, evidence of CVBI and cognitive impairment is often found without a history of a strokelike event.”

  • The paper relies on this without support.

    Late-life depression may be accompanied by a higher frequency of brain white matter damage and other subcortical lesions, such as lacunar infarcts.

    “There may be a higher frequency of brain white matter damage and other subcortical lesions, such as lacunar infarcts.”

  • The paper relies on this without support.

    Depression with a cerebrovascular basis may respond to treatment with certain selective serotonin-reuptake inhibitors.

    “Depression with a cerebrovascular basis may respond to treatment with certain selective serotonin-reuptake inhibitors.”

  • The paper relies on this without support.

    The activity of biomarkers in the brain generally cannot be measured directly.

    “The activity of biomarkers in the brain generally cannot be measured directly.”

  • The paper relies on this without support.

    The only clear risk for cognitive impairment from alcohol intake is heavy alcohol use.

    “The risks and benefits of alcohol intake have been debated for years, with the only clear risk for cognitive impairment being heavy alcohol use.”

  • The paper relies on this without support.

    Smoking's effects on the cardiovascular system and neurons are mediated generally by oxidative stress and inflammation.

    “Smoking has well-known effects on the cardiovascular system and neurons, which are mediated generally by oxidative stress and inflammation.”

  • The paper relies on this without support.

    Inflammation is a key process linking many cardiovascular risk factors to vascular and neuronal damage.

    “Inflammation is a key process linking many cardiovascular risk factors to vascular and neuronal damage.”

  • The paper relies on this without support.

    During midlife, the population-attributable risk of dementia is highest for hypertension, up to 30% of late-life dementia cases.

    “In relation to the role of vascular risk factors, during midlife the population-attributable risk of dementia has been reported to be highest for hypertension (up to 30% of cases of late-life dementia).”

  • The paper relies on this without support.

    Smoking is a risk factor for stroke-associated dementia.

    “Smoking is a risk factor for stroke-associated dementia.”

  • The paper relies on this without support.

    Hyperlipidemia or dyslipidemia is a metabolic condition of importance for cognitive function.

    “Hyperlipidemia or dyslipidemia is a metabolic condition of importance for cognitive function.”

  • The paper relies on this without support.

    Cognitive function is an important predictor of morbidity and mortality in the elderly.

    “Cognitive function, an important predictor of morbidity and mortality in the elderly, however, is frequently not screened for in clinical practice as part of global cardiovascular risk and target-organ damage assessments.”

  • The paper relies on this without support.

    Silent strokes outnumber clinically manifest strokes by more than nine to one.

    “It is estimated that “silent” strokes outnumber clinically manifest ones by a factor of >9:1”

  • The paper relies on this without support.

    The proportion of people with milder VCI is about twice that with severe VCI (VaD).

    “and the proportion of those with a milder form of VCI is approximately 2-fold greater than those with a severe form of VCI (ie, VaD).”
17 of 17

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?

  • Neither of the previous guidelines includes advances in understanding the pathophysiology and measurement of cerebral small vessel disease.

    “neither include advances in understanding the pathophysiology and measurement of SVD”

    From Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration (2013) · cites this paper as [12]

    The cited statement discusses small-vessel disease pathophysiology in §6.3, including vascular risk factors and proposed mechanisms. It also describes methods for measuring small-artery remodeling there and the capabilities and limits of neuroimaging in §3.6. That is contrary to the claim that it does not include these topics. (LLM, conf=0.86)

    Checked by a reasoning model — may be wrong.

    Experimental — accuracy not yet measured

  • As pointed out by Gorelick et al., a comprehensive assessment strategy is necessary for examining vascular contributions to subtle cognitive impairment, MCI, and dementia; and it notably differs from those strategies expressed by McKhann et al. that bedside mental status testing-though not optimal-is acceptable or by the DSM-5 which recommends cognitive impairment be assessed either by neuropsych

    “As pointed out by Gorelick et al. [56], a comprehensive assessment strategy is necessary for examining vascular contributions to subtle cognitive impairment, MCI, and dementia; and it notably differs from those strategies expressed by McKhann et al. [6] that bedside mental status testing—though not optimal—is acceptable or by the DSM-5 which recommends cognitive impairment be assessed either by”

    From Neuropsychological Criteria for Mild Cognitive Impairment Improves Diagnostic Precision, Biomarker Associations, and Progression Rates (2014) · cites this paper as [56]

    Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

    Experimental — accuracy not yet measured

  • Multiple MVLs in standard sections of brain are associated with increased likelihood of cognitive impairment or dementia.

    “one MVL identified in standard sections of brain (Table 1 regions shaded green) is of unclear relationship to cognitive function, while multiple MVLs in these regions are associated with increased likelihood of cognitive impairment or dementia [24,52,62].”

    From National Institute on Aging–Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease: a practical approach (2012) · cites this paper as [24]

    Section 3.2 (page not available in our copy) reports that some studies associate multiple microscopic infarcts with dementia, even after accounting for macroscopic infarcts. It does not establish the claim for MVLs generally or specify that the lesions were identified in standard brain sections. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • One MVL identified in standard sections of brain is of unclear relationship to cognitive function.

    “one MVL identified in standard sections of brain (Table 1 regions shaded green) is of unclear relationship to cognitive function, while multiple MVLs in these regions are associated with increased likelihood of cognitive impairment or dementia [24,52,62].”

    From National Institute on Aging–Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease: a practical approach (2012) · cites this paper as [24]

    Section 3.2 (page unavailable) says the number of infarcts needed for cognitive impairment is difficult to determine and reports that multiple microscopic infarcts may be related to dementia. It does not specifically assess the cognitive significance of one MVL identified in standard brain sections. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • The American Heart Association statement included a class 2 recommendation for neuroimaging as part of clinical investigation of vascular cognitive impairment.

    “included a class 2 recommendation for neuroimaging as part of the clinical investigation of vascular cognitive impairment.”

    From Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration (2013) · cites this paper as [12]

Cites

Flagged first, then by citations

12 of the 538 references couldn’t be matched to a known paper.

Research works printed but not linked: 4

  1. World Health Organization. The ICD-10 Classification of Mental and Behavioral Disorders: Diagnostic Criteria for Research. Geneva, Switzerland: World Health Organization; 1993.
  2. Report of the Stroke Progress Review Group. Bethesda, MD: National Institute of Neurological Disorders and Stroke; 2002.
  3. Safar M, O'Rourke MF eds. Arterial Stiffness in Hypertension: Handbook of Hypertension, Volume 23. New York, NY: Elsevier; 2006.
  4. Roose S, Sneed JR. The current status of vascular depression. US Psychiatry. 2007; 1: 21–23.

Cited by

Sorted by citations

Related

Authors
Gorelick, P. B., Scuteri, A., Black, S. E., DeCarli, C., Greenberg, S. M., Iadecola, C., Launer, L. J., Laurent, S., Lopez, O. L., Nyenhuis, D., Petersen, R. C., Schneider, J. A., Tzourio, C., Arnett, D. K., Bennett, D. A., Chui, H. C., Higashida, R. T., Lindquist, R., Nilsson, P. M., Roman, G. C., Sellke, F. W., & Seshadri, S.
Affiliations
Alzheimer's Association (US)
ORCID
Venue
Stroke
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2011-09
Volume
42
Issue
9
Pages
2672-2713
ISSN
  • 0039-2499 (ISSN-L)
  • 1524-4628
DOI
10.1161/str.0b013e3182299496
PMC
PMC3778669
OpenAlex
W2527609605
Semantic Scholar
349ef695d4a2dbdc85f5b635237c9068ec61b2ba
Cited by
3,811
References
538
Citations by year
2026: 244 · 2025: 292 · 2024: 295 · 2023: 237 · 2022: 263 · 2021: 269 · 2020: 314 · 2019: 320 · 2018: 270 · 2017: 253 · 2016: 258 · 2015: 227 · 2014: 238 · 2013: 169 · 2012: 137
FWCI
23.75
Type
journal article
Language
en
Open access
Locations
  • Stroke (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • UNICA IRIS Institutional Research Information System (University of Cagliari) (submittedVersion)
  • UnissResearch (Università degli Studi di Sassari) (submittedVersion)
Funders
  • American Heart Association
  • Bristol-Myers Squibb
  • Pfizer
  • AstraZeneca
  • GlaxoSmithKline
  • Massachusetts General Hospital
  • University of Southern California
  • University of Minnesota
  • University of Pittsburgh
  • Minneapolis Heart Institute
  • Rush University
  • Daiichi-Sankyo
  • University of Toronto
  • Eisai
  • Servier
  • H. Lundbeck A/S
  • National Institutes of Health
  • University of Illinois at Urbana-Champaign
  • Weill Cornell Medical College
  • University of California, Davis
  • National Institute on Aging (P30AG010129, R01AG021028, R01AG020098, U19AG010483)
  • National Institute of Neurological Disorders and Stroke (R01NS017950)
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 › Epidemiology › Acute Ischemic Stroke Management
Keywords
vascular cognitive impairment, dementia, mild cognitive impairment, neurovascular unit, cerebral autoregulation, cerebral amyloid angiopathy, Alzheimer's disease, white matter hyperintensities, stroke risk factors, atrial fibrillation, hypertension, diabetes mellitus, hypercholesterolemia, neuroimaging, prevention, treatment
MeSH terms
Alzheimer Disease, American Heart Association, Mental Disorders, Cerebral Angiography, Humans, Male, Risk Factors, United States, Dementia, Vascular

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 2026-09-28.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-09-28.

Cited sources are checked by gpt-6-sol.

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.

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