Cognitive aging in persons with minimal amyloid-β and white matter hyperintensities

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.

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White Matter Hyperintensities Potentiate Hippocampal Volume Reduction in Non-Demented Older Individuals with Abnormal Amyloid-β

Journal of Alzheimer s Disease ◽

10.3233/jad-160474 ◽

2016 ◽

Vol 55 (1) ◽

pp. 333-342 ◽

Cited By ~ 12

Author(s):

Whitney M. Freeze ◽

Heidi I. L. Jacobs ◽

Ed H. Gronenschild ◽

Jacobus F. A. Jansen ◽

Saartje Burgmans ◽

...

Keyword(s):

White Matter ◽

White Matter Hyperintensities ◽

Amyloid Β ◽

Hippocampal Volume ◽

Volume Reduction ◽

Older Individuals

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White matter hyperintensities, cerebrospinal amyloid-β and dementia in Parkinson's disease

Journal of the Neurological Sciences ◽

10.1016/j.jns.2016.06.009 ◽

2016 ◽

Vol 367 ◽

pp. 284-290 ◽

Cited By ~ 15

Author(s):

Yaroslau Compta ◽

Mariateresa Buongiorno ◽

Núria Bargalló ◽

Francesc Valldeoriola ◽

Esteban Muñoz ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

White Matter ◽

White Matter Hyperintensities ◽

Amyloid Β

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

10.1101/2020.05.27.119586 ◽

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.

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Amyloid ß Impacts Future Freezing of Gait in Parkinson’s Disease Via White Matter Hyperintensities

10.1101/2020.10.29.360552 ◽

2020 ◽

Author(s):

Mahsa Dadar ◽

Janis Miyasaki ◽

Simon Duchesne ◽

Richard Camicioli

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

White Matter ◽

White Matter Hyperintensities ◽

Freezing Of Gait ◽

Amyloid Β ◽

Common Symptom ◽

Activity Levels ◽

Lewy Body Pathology ◽

The Impact

AbstractBackgroundFreezing of gait (FOG) is a common symptom in Parkinson’s Disease (PD) patients. Previous studies have reported relationships between FOG, substantia nigra (SN) degeneration, dopamine transporter (DAT) concentration, as well as amyloid β deposition. However, there is a paucity of research on the concurrent impact of white matter damage.ObjectivesTo assess the inter-relationships between these different co-morbidities, their impact on future FOG and whether they act independently of each other.MethodsWe used baseline MRI and longitudinal gait data from the Parkinson’s Progression Markers Initiative (PPMI). We used deformation based morphometry (DBM) from T1-weighted MRI to measure SN atrophy, and segmentation of white matter hyperintensities (WMH) as a measure of WM pathological load. Putamen and caudate DAT levels from SPECT as well as cerebrospinal fluid (CSF) amyloid β were obtained directly from the PPMI. Following correlation analyses, we investigated whether WMH burden mediates the impact of amyloid β on future FOG.ResultsSN DBM, WMH load, putamen and caudate DAT activity and CSF amyloid β levels were significantly different between PD patients with and without future FOG (p < 0.008). Mediation analysis demonstrated an effect of CSF amyloid β levels on future FOG via WMH load, independent of SN atrophy and striatal DAT activity levels.ConclusionsAmyloid β might impact future FOG in PD patients through an increase in WMH burden, in a pathway independent of Lewy body pathology.

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P1-352: WHITE MATTER HYPERINTENSITIES, AMYLOID-β, AND RISK OF COGNITIVE DECLINE IN HEALTHY OLDER PEOPLE

Alzheimer s & Dementia ◽

10.1016/j.jalz.2019.06.907 ◽

2019 ◽

Vol 15 ◽

pp. P385-P386

Author(s):

Nawaf Yassi ◽

Christa Dang ◽

Amir Fazlollahi ◽

Ying Xia ◽

Rosie Watson ◽

...

Keyword(s):

White Matter ◽

Older People ◽

Cognitive Decline ◽

White Matter Hyperintensities ◽

Amyloid Β

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Associations between amyloid β and white matter hyperintensities: A systematic review

Alzheimer s & Dementia ◽

10.1016/j.jalz.2017.01.026 ◽

2017 ◽

Vol 13 (10) ◽

pp. 1154-1167 ◽

Cited By ~ 33

Author(s):

Austyn Roseborough ◽

Joel Ramirez ◽

Sandra E. Black ◽

Jodi D. Edwards

Keyword(s):

Systematic Review ◽

White Matter ◽

White Matter Hyperintensities ◽

Amyloid Β

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

Journal of Alzheimer s Disease ◽

10.3233/jad-200496 ◽

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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