scholarly journals Frontal white matter lesions in Alzheimer’s disease are associated with both small vessel disease and AD-associated cortical pathology

2021 ◽  
Author(s):  
Kirsty E. McAleese ◽  
Mohi Miah ◽  
Sophie Graham ◽  
Georgina M. Hadfield ◽  
Lauren Walker ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
White Matter ◽  
Regional Differences ◽  
Small Vessel Disease ◽  
White Matter Lesions ◽  
Small Vessel ◽  
Published Data ◽  
Axonal Loss ◽  
Vessel Disease

AbstractCerebral white matter lesions (WML) encompass axonal loss and demyelination and are assumed to be associated with small vessel disease (SVD)-related ischaemia. However, our previous study in the parietal lobe white matter revealed that WML in Alzheimer’s disease (AD) are linked with degenerative axonal loss secondary to the deposition of cortical AD pathology. Furthermore, neuroimaging data suggest that pathomechanisms for the development of WML differ between anterior and posterior lobes with AD-associated degenerative mechanism driving posterior white matter disruption, and both AD-associated degenerative and vascular mechanisms contributed to anterior matter disruption. In this pilot study, we used human post-mortem brain tissue to investigate the composition and aetiology of frontal WML from AD and non-demented controls to determine if frontal WML are SVD-associated and to reveal any regional differences in the pathogenesis of WML. Frontal WML tissue sections from 40 human post-mortem brains (AD, n = 19; controls, n = 21) were quantitatively assessed for demyelination, axonal loss, cortical hyperphosphorylated tau (HPτ) and amyloid-beta (Aβ) burden, and arteriolosclerosis as a measure of SVD. Biochemical assessment included Wallerian degeneration-associated protease calpain and the myelin-associated glycoprotein to proteolipid protein ratio as a measure of ante-mortem ischaemia. Arteriolosclerosis severity was found to be associated with and a significant predictor of frontal WML severity in both AD and non-demented controls. Interesting, frontal axonal loss was also associated with HPτ and calpain levels were associated with increasing Aβ burden in the AD group, suggestive of an additional degenerative influence. To conclude, this pilot data suggest that frontal WML in AD may result from both increased arteriolosclerosis and AD-associated degenerative changes. These preliminary findings in combination with previously published data tentatively indicate regional differences in the aetiology of WML in AD, which should be considered in the clinical diagnosis of dementia subtypes: posterior WML maybe associated with degenerative mechanisms secondary to AD pathology, while anterior WML could be associated with both SVD-associated and degenerative mechanisms.

scholarly journals Ventricular expansion, white matter hyperintensities, and global cognition in Alzheimer’s disease and normal aging

2020 ◽  
Author(s):  
Sabrina Adamo ◽  
Joel Ramirez ◽  
Melissa F. Holmes ◽  
Fuqiang Gao ◽  
Ljubica Zotovic ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
White Matter ◽  
White Matter Hyperintensities ◽  
Small Vessel Disease ◽  
Normal Aging ◽  
Small Vessel ◽  
Cognitive Test ◽  
Vessel Disease ◽  
Link Type

ABSTRACTBackgroundThe progression of Alzheimer’s Disease (AD) may be tracked by measuring the growth of the ventricular cerebrospinal fluid (vCSF) over time. AD is commonly comorbid with markers of cerebral small vessel disease (SVD), viewed on MRI as white matter hyperintensities (WMH). Larger WMH volumes are correlated with poorer cognitive test scores. Additionally, periventricular WMHs have a proposed relationship to the vCSF.PurposeThis study will examine ventricular expansion and its associations between periventricular/deep WMH and cognition in AD and normal aging.MethodsBaseline and 1-year follow-up data were collected from AD (n=117) and cognitively normal control (NCs; n=49) participants taking part in the Sunnybrook Dementia Study. MRI (1.5T) and scores from both the Mini-Mental State Examination (MMSE) and the Dementia Rating Scale (DRS) were assessed at each time point. Volumetric data was generated using a semi-automated pipeline and each individual’s vCSF and WMHs were transformed to an intermediate space to determine volumetric growth. Regressions were used to determine relationships between vCSF growth measures, SVD burden, and cognition, accounting for demographics and individual interscan intervals.ResultsThe AD group displayed 14.6% annual ventricular growth as opposed to NC who had only 11.8% annual growth. AD showed significant growth in vCSF (p < 0.001), a trend toward greater pWMH growth (p = 0.06) and no difference in dWMH growth volumes compared to NC. vCSF growth was positively associated with pWMH (β = 0.32, p < 0.001) but not dWMH growth in AD while in NC it was associated with both pWMH (β = 0.48, p < 0.001) and dWMH growth (β = 0.35, p = 0.02). In AD, vCSF growth was associated with the both the MMSE (β = -0.30, p < 0.001) and the DRS (β = -0.31, p < 0.001) in separate models.ConclusionsThe findings from this study suggest that in just under 1.5 years, the significantly rapid ventricular expansion observed in AD may be closely related to periventricular small vessel disease. As vCSF growth rates are an important biomarker of AD neurodegeneration that corresponds with cognitive decline, future research should further explore atrophy associated with periventricular vasculopathy.Trial RegistrationClinicalTrials.gov, NCT01800214. Registered on 27 February 2013.

scholarly journals Plasma soluble TREM2 is associated with white matter lesions independent of amyloid and tau

Brain ◽  
2021 ◽  
Author(s):  
Hsin-Hsi Tsai ◽  
Ya-Fang Chen ◽  
Ruoh-Fang Yen ◽  
Yen-Ling Lo ◽  
Kai-Chien Yang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
White Matter ◽  
Small Vessel Disease ◽  
Small Vessel ◽  
White Matter Hyperintensity ◽  
Vessel Disease ◽  
Soluble Trem2 ◽  
Amyloid Load ◽  
Cerebral Amyloid

Abstract Cerebral small vessel disease is one of the most common causes of cognitive decline and stroke. While several lines of evidence have established a relationship between inflammation and cerebrovascular pathology, the mechanistic link has not yet been elucidated. Recent studies suggest activation of immune mediators, including the soluble form of triggering receptor expressed on myeloid cells 2 (TREM2), may be critical regulators. In this study, we compared the plasma levels of soluble TREM2 and its correlations with neuroimaging markers and cerebral amyloid load in ten patients with Alzheimer’s disease and 66 survivors of spontaneous intracerebral haemorrhage with cerebral amyloid angiopathy or hypertensive small vessel disease, two of the most common types of sporadic small vessel disease. We performed brain MRI and 11C-Pittsburgh compound B PET for all participants to evaluate radiological small vessel disease markers and cerebral amyloid burden, and 18F-T807 PET in a subgroup of patients to evaluate cortical tau pathology. Plasma soluble TREM2 levels were comparable between patients with Alzheimer’s disease and small vessel disease (P=0.690). In patients with small vessel disease, plasma soluble TREM2 was significantly associated with white matter hyperintensity volume (P&lt;0.001), but not with cerebral amyloid load. Among patients with Alzheimer’s disease and cerebral amyloid angiopathy, plasma soluble TREM2 was independently associated with a tau-positive scan (P=0.001) and white matter hyperintensity volume (P=0.013), but not amyloid load (P=0.221). Our results indicate plasma soluble TREM2 is associated with white matter hyperintensity independent of amyloid and tau pathology. These findings highlight the potential utility of plasma soluble TREM2 as a strong predictive marker for small vessel disease-related white matter injury and hold clinical implications for targeting the innate immune response when treating this disease.

Different cognitive profiles between mild cognitive impairment due to cerebral small vessel disease and mild cognitive impairment of Alzheimer’s disease origin

2009 ◽  
Vol 15 (6) ◽  
pp. 898-905 ◽  
Author(s):  
AIHONG ZHOU ◽  
JIANPING JIA
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Processing Speed ◽  
Small Vessel Disease ◽  
Cerebral Small Vessel Disease ◽  
Small Vessel ◽  
Cognitive Domains ◽  
Vessel Disease

AbstractControversy surrounds the differences of the cognitive profile between mild cognitive impairment resulting from cerebral small vessel disease (MCI-SVD) and mild cognitive impairment associated with prodromal Alzheimer’s disease (MCI-AD). The aim of this study was to explore and compare the cognitive features of MCI-SVD and MCI-AD. MCI-SVD patients (n = 56), MCI-AD patients (n = 30), and normal control subjects (n = 80) were comprehensively evaluated with neuropsychological tests covering five cognitive domains. The performance was compared between groups. Tests that discriminated between MCI-SVD and MCI-AD were identified. Multiple cognitive domains were impaired in MCI-SVD group, while memory and executive function were mainly impaired in MCI-AD group. Compared with MCI-SVD, MCI-AD patients performed relatively worse on memory tasks, but better on processing speed measures. The AVLT Long Delay Free Recall, Digit Symbol Test, and Stroop Test Part A (performance time) in combination categorized 91.1% of MCI-SVD patients and 86.7% of MCI-AD patients correctly. Current study suggested a nonspecific neuropsychological profile for MCI-SVD and a more specific cognitive pattern in MCI-AD. MCI-AD patients demonstrated greater memory impairment with relatively preserved mental processing speed compared with MCI-SVD patients. Tests tapping these two domains might be potentially useful for differentiating MCI-SVD and MCI-AD patients. (JINS, 2009, 15, 898–905.)

Small Vessel Disease, but Neither Amyloid Load nor Metabolic Deficit, Is Dependent on Age at Onset in Alzheimer’s Disease

2015 ◽  
Vol 77 (8) ◽  
pp. 704-710 ◽  
Author(s):  
Marion Ortner ◽  
Alexander Kurz ◽  
Panagiotis Alexopoulos ◽  
Florian Auer ◽  
Janine Diehl-Schmid ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Small Vessel Disease ◽  
Age At Onset ◽  
Small Vessel ◽  
Vessel Disease ◽  
Amyloid Load

scholarly journals Longitudinal change of small-vessel disease-related brain abnormalities

2015 ◽  
Vol 36 (1) ◽  
pp. 26-39 ◽  
Author(s):  
Reinhold Schmidt ◽  
Stephan Seiler ◽  
Marisa Loitfelder
Keyword(s):  
White Matter ◽  
Treatment Effects ◽  
Small Vessel Disease ◽  
Surrogate Marker ◽  
White Matter Lesions ◽  
Surrogate Endpoint ◽  
Longitudinal Change ◽  
Small Vessel ◽  
Brain Abnormalities ◽  
Vessel Disease

Knowledge about the longitudinal change of cerebral small-vessel disease–related magnetic resonance imaging abnormalities increases our pathophysiologic understanding of cerebral microangiopathy. The change of specific lesion types may also serve as secondary surrogate endpoint in clinical trials. A surrogate endpoint needs to progress fast enough to allow monitoring of treatment effects within a reasonable time period, and change of the brain abnormality needs to be correlated with clinical change. Confluent white matter lesions show fast progression and correlations with cognitive decline. Thus, the change of confluent white matter lesions may be used as a surrogate marker in proof-of-concept trials with small patient numbers needed to show treatment effects on lesion progression. Nonetheless if the expected change in cognitive performance resulting from treatment effects on lesion progression is used as outcome, the sample size needed to show small to moderate treatment effects becomes very large. Lacunes may also fulfill the prerequisites of a surrogate marker, but in the general population the incidence of lacunes over short observational periods is small. For other small-vessel disease–related brain abnormalities including microbleeds and microstructural changes in normal-appearing white matter longitudinal change and correlations with clinical decline is not yet fully determined.

Staging: Relevance for Trial Design in Vascular Burden of the Brain

2003 ◽  
Vol 15 (S1) ◽  
pp. 231-239 ◽  
Author(s):  
Barry Reisberg ◽  
Steven H. Ferris ◽  
Thet Oo ◽  
Emile Franssen
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Small Vessel Disease ◽  
Small Vessel ◽  
Clinical Staging ◽  
Progressive Dementia ◽  
Vessel Disease ◽  
Vascular Burden ◽  
The Brain ◽  
Clinical Continuum

Cerebrovascular small vessel disease is now believed to be the major source of vascular burden of the brain. Cerebrovascular small vessel disease and Alzheimer's disease appear to represent pathophysiologic and clinical continua, rather than dichotomous entities. It appears that common etiopathologic mechanisms underlie the clinical presentation of both of these conditions. Therefore, the staging procedures that have been developed for the clinical continuum of age-associated memory impairment, mild cognitive impairment, and the progressive dementia of Alzheimer's disease appear to be applicable for the same continua in cerebrovascular small vessel disease. Although temporal and prognostic aspects have been studied for the Alzheimer's-related portions of this clinical staging continuum, they remain to be elucidated for cerebrovascular small vessel disease.

Detection of white matter lesions in cerebral small vessel disease

2013 ◽  
Author(s):  
Medhat M. Riad ◽  
Bram Platel ◽  
Frank-Erik de Leeuw ◽  
Nico Karssemeijer
Keyword(s):  
White Matter ◽  
Small Vessel Disease ◽  
White Matter Lesions ◽  
Cerebral Small Vessel Disease ◽  
Small Vessel ◽  
Vessel Disease
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