The Pathobiology of Vascular Dementia

In the paper

“In white matter lesions, HA is degraded by the hyaluronidase PH20 and its cleavage products inhibit the maturation of OPC into oligodendrocytes capable of myelination (Preston et al., 2013) (fig. 7).”

What the sources say

• Supported

  The Discussion describes the authors’ model in which PH20 degrades hyaluronan in CNS lesions and the resulting products inhibit OPC maturation. The Abstract’s Results report that PH20-generated HA digestion products inhibited OPC maturation into oligodendrocytes and remyelination in demyelinating lesions. (LLM, conf=0.94)

  cites Preston et al., 2013 source

In the paper

“Therefore, the neurovascular unit is an important checkpoint regulating the afferent and efferent arms of the immune system and shaping the immune responses of the brain.”

In the paper

“Recent clinical-pathological studies have highlighted the role of cerebrovascular disease, not only as a primary cause of cognitive impairment, but also as an adjuvant to the expression of dementia caused by other factors, including AD and other neurodegenerative pathologies (Gorelick et al., 2011; Schneider et al., 2007a; Toledo et al., 2013).”

What the sources say

• Not checked yetcites Gorelick et al., 2011 source
• Not checked yetcites Schneider et al., 2007a
• Not checked yetcites Toledo et al., 2013 source

In the paper

“occlusion of penetrating arterioles or venules, unlike pial vessels, cannot be effectively compensated by anastomotic branches (Blinder et al., 2013), and results in reductions in flow sufficient to produce small ischemic lesions akin to microinfarcts (Nguyen et al., 2011; Nishimura et al., 2010; Shih et al., 2013).”

What the sources say

• Not checked yetcites Blinder et al., 2013 source
• Not checked yetcites Nguyen et al., 2011 source
• Not checked yetcites Nishimura et al., 2010 source

In the paper

“regions of the deep white matter are supplied by long penetrating arterioles arising from the pial cortical network at the border between non-overlapping vascular territories of the anterior and middle cerebral arteries, and as such are more vulnerable to reductions in blood flow (Brown and Thore, 2011; De Reuck, 1971)”

What the sources say

• Not checked yetcites Brown and Thore, 2011 source
• Not checked yetcites De Reuck, 1971 source

In the paper

“Due to fewer synapses, white matter energy usage, and consequently blood flow, is 1/3 lower of that of the gray matter (Harris and Attwell, 2012).”

What the sources say

• Not checked yetcites Harris and Attwell, 2012

In the paper

“Vascular dementia, a heterogeneous group of brain disorders in which cognitive impairment is attributable to cerebrovascular pathologies, is responsible for at least 20% of cases of dementia, being second only to Alzheimer’s disease (AD) (Gorelick et al., 2011).”

What the sources say

• Not checked yetcites Gorelick et al., 2011 source

In the paper

“Therefore, neurovascular cells are trophically and metabolically interdependent, such that damage to one cell type removes a vital source of support to the whole unit and has deleterious consequences also for the other cell types.”

In the paper

“The brain vasculature has an intimate developmental, structural and functional relationship with the brain tissue, their cellular elements forming a functional domain termed the neurovascular unit (Iadecola, 2004).”

What the sources say

• Not checked yetcites Iadecola, 2004 source

In the paper

“Stroke doubles the risk for dementia (post-stroke dementia), and approximately 30% of stroke patients go on to develop cognitive dysfunction within 3 years (Allan et al., 2011; Leys et al., 2005; Pendlebury and Rothwell, 2009).”

What the sources say

• Not checked yetcites Allan et al., 2011 source
• Not checked yetcites Leys et al., 2005 source
• Not checked yetcites Pendlebury and Rothwell, 2009 source

In the paper

“The ApoE 4 allele is a well-established susceptibility gene for increased cardiovascular risk and Alzheimer disease (Verghese et al., 2011).”

What the sources say

• Not checked yetcites Verghese et al., 2011 source

In the paper

“The ApoE4 allele is associated with increased risk of CAA, whereas both ApoE2 and 4 increase the risk of lobar hemorrhages (Charidimou et al., 2012).”

What the sources say

• Not checked yetcites Charidimou et al., 2012 source

In the paper

“The most common of these is the CADASIL syndrome caused by a frame shift mutation of Notch-3 that either creates or eliminates a cystein residue (Chabriat et al., 2009).”

What the sources say

• Not checked yetcites Chabriat et al., 2009 source

In the paper

“Advanced age is a powerful risk factor for VCI, and the prevalence and incidence of cognitive impairment increases exponentially after age 65 (Gorelick et al., 2011).”

What the sources say

• Not checked yetcites Gorelick et al., 2011 source

In the paper

“Reductions in CBF by 40–50% are associated with suppression of brain activity and cognitive dysfunction, which are reversible upon re-establishing normal CBF levels (Marshall et al., 1999; Marshall, 2012; Tatemichi et al., 1995).”

What the sources say

• Not checked yetcites Marshall et al., 1999 source
• Not checked yetcites Marshall, 2012
• Not checked yetcites Tatemichi et al., 1995 source

In the paper

“Indeed, white matter lesions affect brain structure and function broadly, and are associated with reductions in frontal lobe glucose utilization (Decarli et al., 1995; Haight et al., 2013; Tullberg et al., 2004), global reduction in cortical blood flow (Appelman et al., 2008; Chen et al., 2013a; Dam et al., 2007; Kobari et al., 1990), disruption of brain connectivity (Lawrence et al., 2013; Sun et”

What the sources say

• Not checked yetcites Decarli et al., 1995 source
• Not checked yetcites Appelman et al., 2008 source
• Not checked yetcites Lawrence et al., 2013 source

In the paper

“Linkage studies in patients with white matter lesions on MRI have discovered several loci (Schmidt et al., 2012), but no specific gene has been identified and the findings await replication and validation (Lee and Kim, 2013; Markus, 2008).”

What the sources say

• Not checked yetcites Schmidt et al., 2012 source
• Not checked yetcites Lee and Kim, 2013 source
• Not checked yetcites Markus, 2008 source

In the paper

“GWAS of vascular dementia have shown small effect of SNPs in the androgen receptor gene locus (Schrijvers et al., 2012), a finding not observed in all ethnic groups (Lee and Kim, 2013).”

What the sources say

• Not checked yetcites Schrijvers et al., 2012 source
• Not checked yetcites Lee and Kim, 2013 source

In the paper

“The expansion of the white matter lesions correlates with the evolution of the cognitive impairment (Maillard et al., 2012), new lacunes causing a steeper decline, especially in motor speed and executive functions (Jokinen et al., 2011).”

What the sources say

• Not checked yetcites Maillard et al., 2012 source
• Not checked yetcites Jokinen et al., 2011 source

In the paper

“In addition, since myelination of previously naked fibers participates in neuroplasticity and skilled motor learning (Fields, 2010; Richardson et al., 2011), myelin damage could also compromise these important functions and contribute to cognitive impairment.”

What the sources say

• Not checked yetcites Fields, 2010 source
• Not checked yetcites Richardson et al., 2011 source

In the paper

“However, the education level does not influence the rate of progression of VCI and no longer has an impact in advanced disease (Elbaz et al., 2013; Zieren et al., 2013).”

What the sources say

• Not checked yetcites Elbaz et al., 2013 source
• Not checked yetcites Zieren et al., 2013 source

In the paper

“Confluent white matter lesions, the imaging correlate of which is termed leukoaraiosis (fig. 3), and lacunes, small (<1.5 cm) white matter infarcts typically in the basal ganglia, are common occurrence in VCI and are strongly associated with cardiovascular risk factors, especially hypertension, diabetes, hyperlipidemia and smoking (Gorelick et al., 2011; Wardlaw et al., 2013b).”

What the sources say

• Not checked yetcites Gorelick et al., 2011 source
• Not checked yetcites Wardlaw et al., 2013b

In the paper

“Resting flow is reduced in areas of leukoaraiosis and vascular reactivity attenuated (Kobari et al., 1990; Makedonov et al., 2013; Markus et al., 2000; 1994; Marstrand et al., 2002; O’Sullivan et al., 2002; Yao et al., 1992).”

What the sources say

• Not checked yetcites Kobari et al., 1990
• Not checked yetcites Makedonov et al., 2013 source
• Not checked yetcites Markus et al., 2000 source

In the paper

“Cerebrovascular autoregulation is impaired, increasing the susceptibility of the white matter to damage during fluctuation in blood pressure (Matsushita et al., 1994).”

What the sources say

• Not checked yetcites Matsushita et al., 1994 source

In the paper

“Furthermore, stiffness of large vessels and increased pulsatility are associated with reduced white matter CBF and are strong predictors of leukoaraiosis and lacunes (Brisset et al., 2013; Tarumi et al., 2011; Webb et al., 2012), independently of vascular risk factors (Kearney-Schwartz et al., 2009).”

What the sources say

• Not checked yetcites Brisset et al., 2013 source
• Not checked yetcites Tarumi et al., 2011 source
• Not checked yetcites Webb et al., 2012 source

In the paper

“Owing to their location at the distal border between different vascular territories (De Reuck, 1971) (fig 4) and to the susceptibility of their vasculature to risk factors (Brown and Thore, 2011), deep white matter tracts are particularly vulnerable to vascular insufficiency.”

What the sources say

• Not checked yetcites De Reuck, 1971 source
• Not checked yetcites Brown and Thore, 2011 source

In the paper

“Interestingly, CBF alterations have also been described in normal appearing white matter (O’Sullivan et al., 2002), suggesting that the flow reduction precedes and, as such, may contribute to the white matter damage.”

What the sources say

• Not checked yetcites O’Sullivan et al., 2002 source

In the paper

“EPC are reduced by stroke risk factors (Hill et al., 2003) and predict cardiovascular morbidity and mortality (Werner et al., 2005).”

What the sources say

• Not checked yetcites Hill et al., 2003 source
• Not checked yetcites Werner et al., 2005 source

In the paper

“The latter finding suggests that the BBB disruption could precede white matter injury and contribute to its development.”

In the paper

“Hypoxia-ischemia, which has been demonstrated in white matter lesions, is well known to damage endothelial cells leading to increased BBB leakage in vitro (Ahmad et al., 2012).”

What the sources say

• Not checked yetcites Ahmad et al., 2012 source

In the paper

“EPC are reduced in age associated white matter lesions, the reduction correlating with lesion burden (Jickling et al., 2009).”

What the sources say

• Not checked yetcites Jickling et al., 2009 source

In the paper

“BBB leakiness in white matter was found in lacunar strokes, but not cortical strokes (Wardlaw et al., 2008), raising the possibility of a specific association with small vessel disease of the deep white matter.”

What the sources say

• Not checked yetcites Wardlaw et al., 2008 source

In the paper

“NADPH oxidase, a multiunit enzyme particularly enriched in cerebral blood vessels (Miller et al., 2005), has emerges as an important source in vascular oxidative stress in aging, hypertension, hyperlipidemia and diabetes (Faraci, 2011), and inhibition or genetic inactivation of this enzyme has been shown to ameliorate the vascular dysfunction (Drummond et al., 2011).”

What the sources say

• Not checked yetcites Miller et al., 2005 source
• Not checked yetcites Faraci, 2011 source

In the paper

“Angiogenic T-cells are reduced in patients with vascular risk factors (Hur et al., 2007; Weil et al., 2011), and in hypertensive patients with small vessels disease (Rouhl et al., 2012b).”

What the sources say

• Not checked yetcites Hur et al., 2007 source
• Not checked yetcites Weil et al., 2011 source
• Not checked yetcites Rouhl et al., 2012b

In the paper

“Interestingly, EPC colony forming units are also reduced in AD patients, in whom the magnitude of the reduction correlates with the degree of cognitive impairment (Lee et al., 2009).”

What the sources say

• Not checked yetcites Lee et al., 2009 source

In the paper

“Cerebral hypoperfusion is associated with white matter inflammation and oxidative stress in rodent models (Dong et al., 2011; Huang et al., 2010; Ihara et al., 2001; Juma et al., 2011; Masumura et al., 2001; Reimer et al., 2011; Yoshizaki et al., 2008), indicating that hypoxia-ischemia is sufficient to trigger these responses.”

What the sources say

• Not checked yetcites Dong et al., 2011 source
• Not checked yetcites Huang et al., 2010 source
• Not checked yetcites Ihara et al., 2001 source

In the paper

“Such neurovascular dysfunction would aggravate the CBF reduction in critically perfused deep white matter regions and contribute to the white matter damage.”

In the paper

“Third, the permeability to MRI tracers is increased in white matter lesions (Hanyu et al., 2002; Taheri et al., 2011; Wardlaw et al., 2009) and in normal appearing white matter (Topakian et al., 2010).”

What the sources say

• Not checked yetcites Hanyu et al., 2002 source
• Not checked yetcites Taheri et al., 2011 source
• Not checked yetcites Wardlaw et al., 2009 source

In the paper

“In a similar model, the BBB alteration was found to be due to MMP9 production by oligodendrocyte precursors, which are increased in ischemic white matter injury in rodent models (Seo et al., 2013) and in patients with VCI (Candelario-Jalil et al., 2011).”

What the sources say

• Not checked yetcites Seo et al., 2013
• Not checked yetcites Candelario-Jalil et al., 2011 source

In the paper

“Endothelial dysfunction has two major pathogenic consequences: reductions in resting CBF in the marginally perfused white matter, and alterations in the permeability of the BBB.”

In the paper

“In addition, OPC produce MMP9, which, as seen in the previous sections, promotes BBB breakdown perpetuating the cytotoxic milieu underlying demyelination (Seo et al., 2013).”

What the sources say

• Not checked yetcites Seo et al., 2013

In the paper

“However, in MS patients CBF is reduced in the normal appearing white matter (Law et al., 2004), as well as in the gray matter (D’haeseleer et al., 2011).”

What the sources say

• Not checked yetcites Law et al., 2004 source
• Not checked yetcites D’haeseleer et al., 2011 source

In the paper

“These findings, raise the possibility that vascular risk factors suppress the production of angiogenic T-cells, reduce the repair potential of EPC, and contribute to the microvascular degeneration underlying leukoaraiosis and lacunar stroke.”

In the paper

“In addition, demyelination exposes the axons to the deleterious effects of cytokine and free radicals in the hypoxic white matter, which may impair axonal energy production leading to failure of the Na+/K+ ATPase.”

In the paper

“Myelination allows axons to conduct 100 times faster, and reduce energy expenditures by restricting the depolarization of the axonal membrane to the Na+ channel rich Ranvier nodes (Nave, 2010b).”

What the sources say

• Not checked yetcites Nave, 2010b

In the paper

“In its infantile form, the disease starts between 4 and 8 years of age and is characterized by a progressive cognitive decline associated with rampant inflammatory demyelination of the white matter (Moser et al., 2000).”

What the sources say

• Not checked yetcites Moser et al., 2000 source

In the paper

“Multiple sclerosis (MS) is the prototypical neuroinflammatory disease in which demyelination is thought to be related to a T-cell mediated autoimmune attack on myelin (McFarland and Martin, 2007).”

What the sources say

• Not checked yetcites McFarland and Martin, 2007 source

In the paper

“Vessels devoid of endothelium (string vessels) are often observed, reflecting a failure of endothelial repair, possibly due to EPC dysfunction or loss of neuron and/or glial-derived growth factors.”

In the paper

“Upregulation of VNa+1.2 channels increases the activity of the Na+/K+ ATPase, stressing further the energy budget of the marginally perfused white matter (Trapp and Stys, 2009).”

What the sources say

• Not checked yetcites Trapp and Stys, 2009 source

In the paper

“In addition to the brain dysfunction caused by slowing down the transmission of axon potentials, demyelination threatens the integrity of the axons and leads to axonal loss (Franklin and Ffrench-Constant, 2008; Matute and Ransom, 2012).”

What the sources say

• Not checked yetcites Franklin and Ffrench-Constant, 2008 source
• Not checked yetcites Matute and Ransom, 2012 source

In the paper

“Thus, loss of myelin deprives the axons of trophic support and increases their vulnerability.”

In the paper

“Furthermore, the adaptive upregulation of voltage-dependent Na+ channels (VNa+) in the denuded internodal axoplasm, attempting to preserve impulse propagation in demyelinated axons, leads to Na+ entry and aggravates the energy deficit and Ca2+ overload.”

What the sources say

• Not checked yetcites Trapp and Stys, 2009 source

In the paper

“In turn, excess intracellular Ca2+ activates protease dependent processes that lead to microtubule fragmentation and perturbation of axonal flow (Franklin and Ffrench-Constant, 2008; Matute and Ransom, 2012).”

What the sources say

• Not checked yetcites Franklin and Ffrench-Constant, 2008 source
• Not checked yetcites Matute and Ransom, 2012 source

In the paper

“Reductions in white matter CBF has also been found X-linked adrenoleukodystrophy (ALD), a disease caused by mutations in ABCD1, which encodes a peroxisomal membrane transporter protein, leading to accumulation of very long chain fatty acids in brain, spinal cord and adrenal glands (Moser et al., 2000).”

What the sources say

• Not checked yetcites Moser et al., 2000 source

In the paper

“Leukoaraiosis is associated with focal cortical thinning especially in frontal cortex, a finding correlated with executive dysfunction (Seo et al., 2012).”

What the sources say

• Not checked yetcites Seo et al., 2012 source

In the paper

“Hypoxia, inflammation and oxidative stress damage oligodendrocytes and leads to trophic uncoupling in the neurovascular unit, which, in turn, contribute to the damage to vascular cells and oligodendrocytes.”

In the paper

“Aged APP mice deficient in CD36 are protected from cerebrovascular alterations and behavioral deficits, effects associated with reduced CAA compared to controls, but no reduction of amyloid plaques (Park et al., 2013b).”

What the sources say

• Not checked yetcites Park et al., 2013b

In the paper

“As discussed in the section on “Mixed lesions”, AD brains have a wide variety of vascular lesions, suggesting a potential pathogenic interaction between vascular factors and AD.”

In the paper

“The vascular alterations induced by Aβ are abrogated by overexpression of the ROS scavenging enzyme superoxide dismutase or deficiency of the NADPH oxidase subunit NOX2 (Iadecola et al., 1999; Park et al., 2005; 2008)”

What the sources say

• Not checked yetcites Iadecola et al., 1999 source
• Not checked yetcites Park et al., 2005 source
• Not checked yetcites Park et al., 2008 source

In the paper

“These data suggest that the cerebrovascular effects of Aβ are not attributable to CAA or amyloid plaques, and are not a consequence of neuronal energy hypometabolism.”

In the paper

“Conversely, some studies (Jendroska et al., 1995; Ly et al., 2012), but not others (Aho et al., 2006; Mastaglia et al., 2003), have reported increased amyloid deposition in stroke patients, implicating that ischemia promotes AD pathology.”

What the sources say

• Not checked yetcites Jendroska et al., 1995 source
• Not checked yetcites Ly et al., 2012
• Not checked yetcites Aho et al., 2006 source

In the paper

“The realization that most cases of dementia have mixed pathological features has raised the intriguing possibility that vascular factors play role in AD and other neurodegenerative diseases.”

In the paper

“application of Aβ4 to the exposed cerebral cortex of mice reduces CBF and impairs the increase in CBF induced by endothelium-dependent vasodilators and functional hyperemia (Niwa et al., 2000a; 2000b)”

What the sources say

• Not checked yetcites Niwa et al., 2000a
• Not checked yetcites Niwa et al., 2000b

In the paper

“In advanced cases of AD, vascular lesions do not seem to have a major influence on the progression of the cognitive deficits, suggesting the AD pathology is the major driver of the cognitive dysfunction (Chui et al., 2006; Jellinger, 2001).”

What the sources say

• Not checked yetcites Chui et al., 2006 source
• Not checked yetcites Jellinger, 2001 source

In the paper

“functional hyperemia, endothelium-dependent responses and autoregulation are profoundly impaired in young mice overexpressing mutated forms of APP, in which brain Aβ is elevated, but there are no plaques, behavioral alterations, or reductions in resting glucose utilization (Niwa et al., 2000b; 2002; Tong et al., 2012)”

What the sources say

• Not checked yetcites Niwa et al., 2000b
• Not checked yetcites Niwa et al., 2002 source
• Not checked yetcites Tong et al., 2012 source

In the paper

“Cerebrovascular function is reduced in patients with early AD or at risk for AD (Claassen et al., 2009; Gao et al., 2013; Luckhaus et al., 2008; Mentis et al., 1996; Niedermeyer, 2006; Ruitenberg et al., 2005; Sabayan et al., 2012; Tanaka et al., 2002), implicating reduced cerebral perfusion in the pathobiology of the disease (Iadecola, 2004).”

What the sources say

• Not checked yetcites Claassen et al., 2009 source
• Not checked yetcites Gao et al., 2013 source
• Not checked yetcites Luckhaus et al., 2008 source

In the paper

“Furthermore, the correlation was strongest for vascular dementia and weakest for AD, suggesting that vascular risk factors may independently increase the likelihood of dementia without exacerbating AD pathology (Chui et al., 2012).”

What the sources say

• Not checked yetcites Chui et al., 2012

In the paper

“Indeed, rigorous blood pressure control reduces white matter damage and staves off cognitive decline (Sharp et al., 2011; Sörös et al., 2013).”

What the sources say

• Not checked yetcites Sharp et al., 2011 source
• Not checked yetcites Sörös et al., 2013

In the paper

“Some agents, like the neurotrophic factor cerebrolysin, showed a modest cognitive improvement, but the evidence is not sufficiently strong to justify clinical use (Chen et al., 2013b).”

What the sources say

• Not checked yetcites Chen et al., 2013b

In the paper

“VCI and vascular dementia are major contributors to age-relate dementing illnesses and comprise a heterogeneous group of cognitive disorders attributable to vascular causes.”

In the paper

“Furthermore, due to frequent overlap with AD, the diagnosis of VCI can be challenging, complicating the choice of the best therapeutic approach (Wang et al., 2012).”

What the sources say

• Not checked yetcites Wang et al., 2012 source

In the paper

“Physical and mental activity, social engagement, and a diet rich in antioxidants or polyunsaturated fatty acids reduce dementia risk (Aarsland et al., 2010; Akinyemi et al., 2013; Middleton and Yaffe, 2009; Verdelho et al., 2012).”

What the sources say

• Not checked yetcites Aarsland et al., 2010 source
• Not checked yetcites Akinyemi et al., 2013 source
• Not checked yetcites Middleton and Yaffe, 2009 source

In the paper

“A study in the UK population suggests that the prevalence of dementia may be decreasing, a finding interpreted to reflect the beneficial effects of controlling blood pressure and other risk factors (Matthews et al., 2013).”

What the sources say

• Not checked yetcites Matthews et al., 2013 source

In the paper

“Despite these positive results in models of hypoperfusion-induced white matter damage, there are no FDA approved treatments for VCI and vascular dementia (Butler and Radhakrishnan, 2012).”

What the sources say

• Not checked yetcites Butler and Radhakrishnan, 2012

In the paper

“Despite the diversity of the underlying brain pathology, the vascular alterations have a similar pathogenic bases, resulting from hypoperfusion, oxidative stress and inflammation, which in turn lead to endothelial damage, BBB breakdown, activation of innate immunity and disruption of trophic coupling between vascular and brain cells.”

In the paper

“The hemispheric white matter, which is particularly susceptible to the deleterious effects of vascular risk factors, is a major target of these vascular alterations.”

In the paper

“The role of hypoperfusion, BBB disruption, oxidative stress and inflammation is well established in animal models of white matter damage, but therapies based on these pathogenic mechanisms have not been successful.”

In the paper

“However, most of the evidence is based on observational studies, which have not been confirmed by randomized clinical trials of risk factor modification, stressing the need for further large scale studies (Dichgans and Zietemann, 2012; Middleton and Yaffe, 2009).”

What the sources say

• Not checked yetcites Dichgans and Zietemann, 2012 source
• Not checked yetcites Middleton and Yaffe, 2009 source

In the paper

“Vascular risk factors can increase amyloid accumulation and the risk of clinically defined AD.”