Genetic Associations of Autopsy-Confirmed Vascular Dementia Subtypes

Jones, Emma; Kalaria, Rajesh N.; Sharp, Sally I.; O’Brien, John; Francis, Paul T.; Ballard, Clive

doi:10.1159/000327171

Cited by 19 publications

(14 citation statements)

References 80 publications

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“…CADASIL, a genetic form of SVaD, is associated with Notch3 mutations whose location may differ by geography or demography (Chabriat et al, 2009). The identification of phenotypes that can be reliably and effectively determined in large samples of subjects is a critical challenge for genetic studies of VCI (Leblanc et al, 2006; Jones et al, 2011). …”

Section: Pathogenic Factorsmentioning

confidence: 99%

Pathology and pathogenesis of vascular cognitive impairment—a critical update

Jellinger¹

2013

Front. Aging Neurosci.

294

219

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Vascular cognitive impairment (VCI) [vascular cognitive disorder (VCD), vascular dementia] describes a continuum of cognitive disorders ranging from mild cognitive impairment (MCI) to dementia, in which vascular brain injury involving regions important for memory, cognition and behavior plays an important role. Clinical diagnostic criteria show moderate sensitivity (ca 50%) and variable specificity (range 64–98%). In Western clinical series, VaD is suggested in 8–10% of cognitively impaired elderly subjects. Its prevalence in autopsy series varies from 0.03 to 58%, with means of 8 to 15% (in Japan 22–35%). Major types of sporadic VaD are multi-infarct encephalopathy, small vessel and strategic infarct type dementias, subcortical arteriosclerotic leukoencephalopathy (SAE) (Binswanger), multilacunar state, mixed cortico-subcortical type, granular cortical atrophy (rare), postischemic encephalopathy, and a mixture of cerebrovascular lesions (CVLs). They result from systemic, cardiac and local large or small vessel disease (SVD); their pathogenesis is multifactorial. Hereditary forms of VaD caused by gene mutations are rare. Cognitive decline is commonly associated with widespread small ischemic vascular lesions involving subcortical brain areas (basal ganglia and hemispheral white matter). The lesions affect neuronal networks involved in cognition, memory, and behavior (thalamo-cortical, striato-subfrontal, cortico-subcortical, limbic systems). CVLs often coexist with Alzheimer-type lesions and other pathologies; 25–80% of elderly demented show mixed pathologies. The lesion pattern of “pure” VaD differs from that in mixed dementia (AD + CVLs) suggesting different pathogenesis of both phenotypes. Minor CVLs, except for severe amyloid angiopathy, appear not essential for cognitive impairment in full-blown AD, while both mild AD-type pathology and SVD may interact synergistically in promoting dementia. However, in a large percentage of non-demented elderly individuals, both AD-related and vascular brain pathologies have been reported. Despite recent suggestions for staging and grading CVLs in specific brain areas, due to the high variability of CVLs associated with cognitive impairment, no validated neuropathological criteria are currently available for VaD and mixed dementia. Further clinico-pathological studies and harmonization of neuropathological procedures are needed to validate the diagnostic criteria for VaD and mixed dementia in order to clarify the impact of CVLs and other coexistent pathologies on cognitive impairment as a basis for further successful therapeutic options.

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Section: Pathogenic Factorsmentioning

confidence: 99%

Pathology and pathogenesis of vascular cognitive impairment—a critical update

Jellinger¹

2013

Front. Aging Neurosci.

294

219

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“…Despite this association, however, Sjögren et al [16, 17] failed to observe any effect of APOE ε4 on CSF levels of NFL; these results suggest that the ε4 allele may not be implicated in subcortical axonal degeneration, despite its association with increased AD risk and, to a lower degree, with cerebrovascular disease [18]. …”

Section: Introductionmentioning

confidence: 99%

Levels of cerebrospinal fluid neurofilament light protein in healthy elderly vary as a function of TOMM40 variants

Bruno

Pomara

Nierenberg

et al. 2012

Experimental Gerontology

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Neurofilament light (NFL) proteins in cerebrospinal fluid (CSF) are a marker of neuronal damage, especially subcortical axonal injury and white matter disease. Subjects with Alzheimer’s disease (AD) have shown elevated levels of CSF NFL as compared to controls. However, the presence of the APOE ε4 allele, an established risk factor for AD, was not found to associate with higher CSF NFL concentrations. We examined whether TOMM40 variants, which have been reported to influence age of onset of AD and are in linkage disequilibrium with APOE, have an effect on CSF NFL levels, in 47 healthy, cognitively intact individuals with or without APOE ε4. Our results show that the presence of APOE ε4 alone does not affect CSF NFL levels significantly; however APOE and TOMM40 appear to interact. Subjects with APOE ε4 have higher CSF NFL levels than non- ε4 carriers, only when they do not carry a short poly-T variant of TOMM40, which is associated with later age of onset of AD, and may act as protective against the dose effect of ε4.

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“…12,13 Compared with other types of dementia, VD has a better prognosis and can be prevented to a certain extent. It is very important to discuss the risk factors, since targeted prevention has important clinical significance.…”

Section: Discussionmentioning

confidence: 99%

Association Between MTHFR Gene Polymorphisms, Smoking, and the Incidence of Vascular Dementia

Jin

Hou

Ding

et al. 2013

Asia Pac J Public Health

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This study investigated the relationship between N5,N10-methylene tetrahydrofolic acid reductase (MTHFR) polymorphisms, smoking, and vascular dementia (VD). Polymerase chain reaction-restriction fragment length polymorphism analysis was used to analyze the frequency of the C/T polymorphism at position 677 of the MTHFR gene in 304 VD patients and 300 control patients with nondementia cerebral infarction. The CC, CT, and TT genotype frequencies of the MTHFR gene were 43.42%, 32.57%, and 24.01%, respectively, in the VD group, and 50.67%, 32.00%, and 17.33%, respectively, in the control group. The T allele frequency was significantly higher in the VD group than in the control group (P < .05). Among patients who smoked, the relative risk of VD in patients with the TT genotype and T allele was higher than in the control group (P < .05). Therefore, the smoking group with the T allele has the highest risk of VD, and synergy appears to exist between the MTHFR gene polymorphisms and smoking in susceptibility to VD.

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Genetic Associations of Autopsy-Confirmed Vascular Dementia Subtypes

Cited by 19 publications

References 80 publications

Pathology and pathogenesis of vascular cognitive impairment—a critical update

Pathology and pathogenesis of vascular cognitive impairment—a critical update

Levels of cerebrospinal fluid neurofilament light protein in healthy elderly vary as a function of TOMM40 variants

Association Between MTHFR Gene Polymorphisms, Smoking, and the Incidence of Vascular Dementia

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