Influence of White Matter Hyperintensities on Baseline and Longitudinal Amyloid-β in Cognitively Normal Individuals

2021 ◽  
pp. 1-11
Author(s):  
Fennie Choy Chin Wong ◽  
Seyed Ehsan Saffari ◽  
Chathuri Yatawara ◽  
Kok Pin Ng ◽  
Nagaendran Kandiah ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Executive Function ◽  
White Matter ◽  
White Matter Hyperintensities ◽  
Small Vessel Disease ◽  
Amyloid Β ◽  
Intracranial Volume ◽  
Linear Regression Models ◽  
Cognitively Normal

Background: The associations between small vessel disease (SVD) and cerebrospinal amyloid-β1-42 (Aβ1-42) pathology have not been well-elucidated. Objective: Baseline (BL) white matter hyperintensities (WMH) were examined for associations with month-24 (M24) and longitudinal Aβ1-42 change in cognitively normal (CN) subjects. The interaction of WMH and Aβ1-42 on memory and executive function were also examined. Methods: This study included 72 subjects from the Alzheimer’s Disease Neuroimaging Initiative. Multivariable linear regression models evaluated associations between baseline WMH/intracranial volume ratio, M24 and change in Aβ1-42 over two years. Linear mixed effects models evaluated interactions between BL WMH/ICV and Aβ1-42 on memory and executive function. Results: Mean age of the subjects (Nmales = 36) = 73.80 years, SD = 6.73; mean education years = 17.1, SD = 2.4. BL WMH was significantly associated with M24 Aβ1-42 (p = 0.008) and two-year change in Aβ1-42 (p = 0.006). Interaction between higher WMH and lower Aβ1-42 at baseline was significantly associated with worse memory at baseline and M24 (p = 0.003). Conclusion: BL WMH was associated with M24 and longitudinal Aβ1-42 change in CN. The interaction between higher WMH and lower Aβ1-42 was associated with poorer memory. Since SVD is associated with longitudinal Aβ1-42 pathology, and the interaction of both factors is linked to poorer cognitive outcomes, the mitigation of SVD may be correlated with reduced amyloid pathology and milder cognitive deterioration in Alzheimer’s disease.

scholarly journals Peripheral Markers of Vascular Endothelial Dysfunction Show Independent but Additive Relationships with Brain-Based Biomarkers in Association with Functional Impairment in Alzheimer’s Disease

2021 ◽  
pp. 1-13
Author(s):  
Jonathan D. Drake ◽  
Alison B. Chambers ◽  
Brian R. Ott ◽  
Lori A. Daiello ◽  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cell Adhesion ◽  
Adhesion Molecule ◽  
Functional Impairment ◽  
Amyloid Β ◽  
Intercellular Adhesion Molecule ◽  
Csf Biomarkers ◽  
Linear Regression Models ◽  
Cognitively Normal

Background: Cerebrovascular dysfunction confers risk for functional decline in Alzheimer’s disease (AD), yet the clinical interplay of these two pathogenic processes is not well understood. Objective: We utilized Alzheimer’s Disease Neuroimaging Initiative (ADNI) data to examine associations between peripherally derived soluble cell adhesion molecules (CAMs) and clinical diagnostic indicators of AD. Methods: Using generalized linear regression models, we examined cross-sectional relationships of soluble plasma vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and E-Selectin to baseline diagnosis and functional impairment (clinical dementia rating sum-of-boxes, CDR-SB) in the ADNI cohort (n = 112 AD, n = 396 mild cognitive impairment (MCI), n = 58 cognitively normal). We further analyzed associations of these biomarkers with brain-based AD biomarkers in a subset with available cerebrospinal fluid (CSF) data (n = 351). p-values derived from main effects and interaction terms from the linear regressions were used to assess the relationship between independent and dependent variables for significance (significance level was set at 0.05 a priori for all analysis). Results: Higher mean VCAM-1 (p = 0.0026) and ICAM-1 (p = 0.0189) levels were found in AD versus MCI groups; however, not in MCI versus cognitively normal groups. Only VCAM-1 was linked with CDR-SB scores (p = 0.0157), and APOE ɛ4 genotype modified this effect. We observed independent, additive associations when VCAM-1 and CSF amyloid-β (Aβ 42), total tau, phosphorylated tau (P-tau), or P-tau/Aβ 42 (all <  p = 0.01) were combined in a CDR-SB model; ICAM-1 showed a similar pattern, but to a lesser extent. Conclusion: Our findings indicate independent associations of plasma-based vascular biomarkers and CSF biomarkers with AD-related clinical impairment.

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 Prediabetes Is Associated With Brain Hypometabolism and Cognitive Decline in a Sex-Dependent Manner: A Longitudinal Study of Nondemented Older Adults

2021 ◽  
Vol 12 ◽  
Author(s):  
Erin E. Sundermann ◽  
Kelsey R. Thomas ◽  
Katherine J. Bangen ◽  
Alexandra J. Weigand ◽  
Joel S. Eppig ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Adverse Effect ◽  
Alzheimer's Disease ◽  
Executive Function ◽  
Fasting Blood Glucose ◽  
Amyloid Β ◽  
Total Sample ◽  
Interactive Effects ◽  
Intracranial Volume ◽  
Dependent Manner

Although type 2 diabetes is a well-known risk factor for Alzheimer's disease (AD), little is known about how its precursor—prediabetes—impacts neuropsychological function and brain health. Thus, we examined the relationship between prediabetes and AD-related biological and cognitive/clinical markers in a well-characterized sample drawn from the Alzheimer's Disease Neuroimaging Initiative. Additionally, because women show higher rates of AD and generally more atherogenic lipid profiles than men, particularly in the context of diabetes, we examined whether sex moderates any observed associations. The total sample of 911 nondemented and non-diabetic participants [normal control = 540; mild cognitive impairment (MCI) = 371] included 391 prediabetic (fasting blood glucose: 100–125 mg/dL) and 520 normoglycemic individuals (age range: 55–91). Linear mixed effects models, adjusted for demographics and vascular and AD risk factors, examined the independent and interactive effects of prediabetes and sex on 2–6 year trajectories of FDG-PET measured cerebral metabolic glucose rate (CMRglu), hippocampal/intracranial volume ratio (HV/IV), cerebrospinal fluid phosphorylated tau-181/amyloid-β1−42 ratio (p-tau181/Aβ1−42), cognitive function (executive function, language, and episodic memory) and the development of dementia. Analyses were repeated in the MCI subsample. In the total sample, prediabetic status had an adverse effect on CMRglu across time regardless of sex, whereas prediabetes had an adverse effect on executive function across time in women only. Within the MCI subsample, prediabetic status was associated with lower CMRglu and poorer executive function and language performance across time within women, whereas these associations were not seen within men. In the total sample and MCI subsample, prediabetes did not relate to HV/IV, p-tau181/Aβ1−42, memory function or dementia risk regardless of sex; however, among incident dementia cases, prediabetic status related to earlier age of dementia onset in women but not in men. Results suggest that prediabetes may affect cognition through altered brain metabolism, and that women may be more vulnerable to the negative effects of glucose intolerance.

scholarly journals The Temporal Relationships between White Matter Hyperintensities, Neurodegeneration, Amyloid β, and Cognition

2020 ◽  
Author(s):  
Mahsa Dadar ◽  
Richard Camicioli ◽  
Simon Duchesne ◽  
D. Louis Collins ◽  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
White Matter ◽  
Cognitive Decline ◽  
White Matter Hyperintensities ◽  
Amyloid Β ◽  
Disease Assessment ◽  
White Matter Hyperintensity ◽  
List Type ◽  
Temporal Relationships

ABSTRACTINTRODUCTIONCognitive decline in Alzheimer’s disease is associated with amyloid-β accumulation, neurodegeneration and cerebral small vessel disease, but the temporal relationships between these factors is not well established.METHODSData included white matter hyperintensity (WMH) load, grey matter (GM) atrophy and Alzheimer’s Disease Assessment Scale-Cognitive-Plus (ADAS13) scores for 720 participants and cerebrospinal fluid amyloid (Aβ1-42) for 461 participants from the Alzheimer’s Disease Neuroimaging Initiative. Linear regressions were used to assess the relationships between baseline WMH, GM, and Aβ1-42 to changes in WMH, GM, Aβ1-42, and cognition at one-year follow-up.RESULTSBaseline WMHs and Aβ1-42 predicted WMH increase and GM atrophy. Baseline WMHs, GM, and Aβ1-42 predicted worsening cognition. Only baseline Aβ1-42 predicted change in Aβ1-42.DISCUSSIONBaseline WMHs lead to greater future GM atrophy and cognitive decline, suggesting that WM damage precedes neurodegeneration and cognitive decline. Baseline Aβ1-42 predicted WMH increase, suggesting a potential role of amyloid in WM damage.Research in ContextSystematic Review: Both amyloid β and neurodegeneration are primary pathologies in Alzheimer’s disease. White matter hyperintensities (indicative of presence of cerebrovascular disease) might also be part of the pathological changes in Alzheimer’s. However, the temporal relationship between white matter hyperintensities, amyloid β, neurodegeneration, and cognitive decline is still unclear.Interpretation: Our results establish a potential temporal order between white matter hyperintensities, amyloid β, neurodegeneration, and cognitive decline, showing that white matter hyperintensities precede neurodegeneration and cognitive decline. The results provide some evidence that amyloid β deposition, in turn, precedes accumulation of white matter hyperintensities.Future Directions: The current findings reinforce the need for future longitudinal investigations of the mechanisms through which white matter hyperintensities impact the aging population in general and Alzheimer’s disease patients, in particular.

Cerebral Microbleeds and White Matter Hyperintensities are Associated with Cognitive Decline in an Asian Memory Clinic Study

2021 ◽  
Vol 18 ◽  
Author(s):  
Bibek Gyanwali ◽  
Benedict Lui ◽  
Chuen Seng Tang ◽  
Eddie Jun Yi Chong ◽  
Henri Vrooman ◽  
...  
Keyword(s):  
Executive Function ◽  
White Matter ◽  
Cognitive Decline ◽  
White Matter Hyperintensities ◽  
Small Vessel Disease ◽  
Cerebral Microbleeds ◽  
Future Research ◽  
Amyloid Angiopathy ◽  
Linear Regression Models ◽  
Interaction Factor

Background: Cerebral small vessel disease (SVD); lacunes, cerebral microbleeds (CMBs), and white matter hyperintensities (WMH) have a vital role in cognitive impairment and dementia. SVD in lobar location is related to cerebral amyloid angiopathy, whereas SVD in a deep location with hyper- tensive arteriopathy. It remains unclear how different locations of SVD affect long-term cognitive de- cline. The present study aimed to analyse the association between different locations and severity of SVD with global and domain-specific cognitive decline over the follow-up interval of 3 years. Methods: We studied 428 participants who had performed MRI scans at baseline and at least 3 neuro- psychological assessments. Locations of lacunes and CMBs were categorized into strictly lobar, strictly deep and mixed-location, WMH volume into anterior and posterior. The National Institute of Neurological Disorders and Stroke-Canadian Stroke Network Harmonization Neuropsychological Battery was used to assess cognitive function. To analyse the association between baseline location and severity of SVD with cognitive decline, linear regression models with generalized estimated equations were constructed to calculate the mean difference, 95% confidence interval and two-way interaction factor between time and SVD. Results: Increased numbers of baseline CMBs were associated with a decline in global cognition as well as a decline in executive function and memory domains. Location-specific analysis showed simi- lar results with strictly lobar CMBs. There was no association with strictly deep and mixed-location CMBs with cognitive decline. Baseline WMH volume was associated with a decline in global cogni- tion, executive function and memory. Similar results were obtained with anterior and posterior WMH volumes. Lacunes and their locations were not associated with cognitive decline. Conclusion: Strictly lobar CMBs, as well as WMH volume in anterior and posterior regions, were associated with cognitive decline. Future research focuses are warranted to evaluate interventions that may prevent cognitive decline related to SVD.

scholarly journals White Matter Hyperintensities in Autopsy-Confirmed Frontotemporal Lobar Degeneration and Alzheimer's Disease

2020 ◽  
Author(s):  
Philippe Desmarais ◽  
Andrew Gao ◽  
Julia Keith ◽  
Krista Lanctôt ◽  
Ekaterina Rogaeva ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
White Matter ◽  
Frontotemporal Lobar Degeneration ◽  
White Matter Hyperintensities ◽  
Neuropsychiatric Symptoms ◽  
Brain Mri ◽  
Regional Distribution ◽  
Corticobasal Degeneration ◽  
Linear Regression Models

Abstract BackgroundWe aimed to systematically describe the burden and distribution of white matter hyperintensities (WMH) and investigate correlations with neuropsychiatric symptoms in pathologically proven Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD).MethodsAutopsy-confirmed cases were identified from the Sunnybrook Dementia Study, including 15 cases of AD and 58 cases of FTLD (22 FTLD-TDP cases; 10 FTLD-Tau [Pick's] cases; 11 FTLD-Tau Corticobasal Degeneration cases; and 15 FTLD-Tau Progressive Supranuclear Palsy cases). Data analyses included ANCOVA to compare the burden of WMH on antemortem brain MRI between groups and adjusted linear regression models to identify associations between WMH burden and neuropsychiatric symptoms. ResultsBurden and regional distribution of WMH differed significantly between neuropathological groups (F5,77 = 2.67, P’ = 0.029), with the FTLD-TDP group having the highest mean volume globally (8,031.50 ± 8,889.15 mm3) and in frontal regions (4,897.45 ± 6,163.22 mm3). The AD group had the highest mean volume in occipital regions (468.25 ± 420.04 mm3). Total score on the Neuropsychiatric Inventory correlated with bilateral frontal WMH volume (β = 0.330, P = 0.006), depression correlated with bilateral occipital WMH volume (β = 0.401, P < 0.001), and apathy correlated with bilateral frontal WMH volume (β = 0.311, P = 0.009), all corrected for the false discovery rate. ConclusionsThese findings suggest that WMH are associated with neuropsychiatric manifestations in AD and FTLD and that WMH burden and regional distribution in neurodegenerative disorders differ according to the underlying neuropathological processes.

scholarly journals White matter hyperintensities in autopsy-confirmed frontotemporal lobar degeneration and Alzheimer’s disease

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Philippe Desmarais ◽  
Andrew F. Gao ◽  
Krista Lanctôt ◽  
Ekaterina Rogaeva ◽  
Joel Ramirez ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
White Matter ◽  
Frontotemporal Lobar Degeneration ◽  
White Matter Hyperintensities ◽  
Neuropsychiatric Symptoms ◽  
Brain Mri ◽  
Regional Distribution ◽  
Linear Regression Models ◽  
Image Guided

Abstract Background We aimed to systematically describe the burden and distribution of white matter hyperintensities (WMH) and investigate correlations with neuropsychiatric symptoms in pathologically proven Alzheimer’s disease (AD) and frontotemporal lobar degeneration (FTLD). Methods Autopsy-confirmed cases were identified from the Sunnybrook Dementia Study, including 15 cases of AD and 58 cases of FTLD (22 FTLD-TDP cases; 10 FTLD-Tau [Pick’s] cases; 11 FTLD-Tau Corticobasal Degeneration cases; and 15 FTLD-Tau Progressive Supranuclear Palsy cases). Healthy matched controls (n = 35) were included for comparison purposes. Data analyses included ANCOVA to compare the burden of WMH on antemortem brain MRI between groups, adjusted linear regression models to identify associations between WMH burden and neuropsychiatric symptoms, and image-guided pathology review of selected areas of WMH from each pathologic group. Results Burden and regional distribution of WMH differed significantly between neuropathological groups (F5,77 = 2.67, P’ = 0.029), with the FTLD-TDP group having the highest mean volume globally (8032 ± 8889 mm3) and in frontal regions (4897 ± 6163 mm3). The AD group had the highest mean volume in occipital regions (468 ± 420 mm3). Total score on the Neuropsychiatric Inventory correlated with bilateral frontal WMH volume (β = 0.330, P = 0.006), depression correlated with bilateral occipital WMH volume (β = 0.401, P < 0.001), and apathy correlated with bilateral frontal WMH volume (β = 0.311, P = 0.009), all corrected for the false discovery rate. Image-guided neuropathological assessment of selected cases with the highest burden of WMH in each pathologic group revealed presence of severe gliosis, myelin pallor, and axonal loss, but with no distinguishing features indicative of the underlying proteinopathy. Conclusions These findings suggest that WMH are associated with neuropsychiatric manifestations in AD and FTLD and that WMH burden and regional distribution in neurodegenerative disorders differ according to the underlying neuropathological processes.

scholarly journals White Matter Hyperintensities Are No Major Confounder for Alzheimer’s Disease Cerebrospinal Fluid Biomarkers

2021 ◽  
Vol 79 (1) ◽  
pp. 163-175
Author(s):  
Linda J.C. van Waalwijk van Doorn ◽  
Mohsen Ghafoorian ◽  
Esther M.C. van Leijsen ◽  
Jurgen A.H.R. Claassen ◽  
Andrea Arighi ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cerebrospinal Fluid ◽  
White Matter ◽  
White Matter Hyperintensities ◽  
Linear Regression Analysis ◽  
Amyloid Β ◽  
Csf Biomarkers ◽  
Csf Biomarker ◽  
T Tau

Background: The cerebrospinal fluid (CSF) biomarkers amyloid-β 1–42 (Aβ42), total and phosphorylated tau (t-tau, p-tau) are increasingly used to assist in the clinical diagnosis of Alzheimer’s disease (AD). However, CSF biomarker levels can be affected by confounding factors. Objective: To investigate the association of white matter hyperintensities (WMHs) present in the brain with AD CSF biomarker levels. Methods: We included CSF biomarker and magnetic resonance imaging (MRI) data of 172 subjects (52 controls, 72 mild cognitive impairment (MCI), and 48 AD patients) from 9 European Memory Clinics. A computer aided detection system for standardized automated segmentation of WMHs was used on MRI scans to determine WMH volumes. Association of WMH volume with AD CSF biomarkers was determined using linear regression analysis. Results: A small, negative association of CSF Aβ42, but not p-tau and t-tau, levels with WMH volume was observed in the AD (r2 = 0.084, p = 0.046), but not the MCI and control groups, which was slightly increased when including the distance of WMHs to the ventricles in the analysis (r2 = 0.105, p = 0.025). Three global patterns of WMH distribution, either with 1) a low, 2) a peak close to the ventricles, or 3) a high, broadly-distributed WMH volume could be observed in brains of subjects in each diagnostic group. Conclusion: Despite an association of WMH volume with CSF Aβ42 levels in AD patients, the occurrence of WMHs is not accompanied by excess release of cellular proteins in the CSF, suggesting that WMHs are no major confounder for AD CSF biomarker assessment.

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