%0 Journal Article %J J Alzheimers Dis %D 2023 %T Multi-Site Cross-Site Inter-Rater and Test-Retest Reliability and Construct Validity of the MarkVCID White Matter Hyperintensity Growth and Regression Protocol. %A Bahrani, Ahmed A %A Abner, Erin L %A DeCarli, Charles S %A Barber, Justin M %A Sutton, Abigail C %A Maillard, Pauline %A Sandoval, Francisco %A Arfanakis, Konstantinos %A Yang, Yung-Chuan %A Evia, Arnold M %A Schneider, Julie A %A Habes, Mohamad %A Franklin, Crystal G %A Seshadri, Sudha %A Satizabal, Claudia L %A Caprihan, Arvind %A Thompson, Jeffrey F %A Rosenberg, Gary A %A Wang, Danny J J %A Jann, Kay B %A Zhao, Chenyang %A Lu, Hanzhang %A Rosenberg, Paul B %A Albert, Marilyn S %A Ali, Doaa G %A Singh, Herpreet %A Schwab, Kristin %A Greenberg, Steven M %A Helmer, Karl G %A Powel, David K %A Gold, Brian T %A Goldstein, Larry B %A Wilcock, Donna M %A Jicha, Gregory A %X

BACKGROUND: White matter hyperintensities (WMH) that occur in the setting of vascular cognitive impairment and dementia (VCID) may be dynamic increasing or decreasing volumes or stable over time. Quantifying such changes may prove useful as a biomarker for clinical trials designed to address vascular cognitive-impairment and dementia and Alzheimer's Disease.

OBJECTIVE: Conducting multi-site cross-site inter-rater and test-retest reliability of the MarkVCID white matter hyperintensity growth and regression protocol.

METHODS: The NINDS-supported MarkVCID Consortium evaluated a neuroimaging biomarker developed to track WMH change. Test-retest and cross-site inter-rater reliability of the protocol were assessed. Cognitive test scores were analyzed in relation to WMH changes to explore its construct validity.

RESULTS: ICC values for test-retest reliability of WMH growth and regression were 0.969 and 0.937 respectively, while for cross-site inter-rater ICC values for WMH growth and regression were 0.995 and 0.990 respectively. Word list long-delay free-recall was negatively associated with WMH growth (p < 0.028) but was not associated with WMH regression.

CONCLUSIONS: The present data demonstrate robust ICC validity of a WMH growth/regression protocol over a one-year period as measured by cross-site inter-rater and test-retest reliability. These data suggest that this approach may serve an important role in clinical trials of disease-modifying agents for VCID that may preferentially affect WMH growth, stability, or regression.

%B J Alzheimers Dis %V 96 %P 683-693 %8 2023 Nov 07 %G eng %N 2 %R 10.3233/JAD-230629 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Diffuse Amyloid-β Plaques, Neurofibrillary Tangles, and the Impact of APOE in Elderly Persons' Brains Lacking Neuritic Amyloid Plaques. %A Abner, Erin L %A Neltner, Janna H %A Jicha, Gregory A %A Patel, Ela %A Anderson, Sonya L %A Wilcock, Donna M %A Van Eldik, Linda J %A Nelson, Peter T %X

Data from a large autopsy series were analyzed to address questions pertinent to primary age-related tauopathy (PART) and Alzheimer's disease (AD): what factors are associated with increased severity of neurofibrillary degeneration in brains that lack neuritic amyloid plaques?; is there an association between Apolipoprotein E (APOE) alleles and PART pathologic severity independent of amyloid-β (Aβ) deposits?; and, how do the stains used to detect plaques and tangles impact the experimental results? Neuropathologic data were evaluated from elderly research volunteers whose brain autopsies were performed at University of Kentucky Alzheimer's Disease Center (UK-ADC; N = 145 subjects). All of the included subjects' brains lacked neuritic amyloid plaques according to the CERAD diagnostic criteria and the average final MMSE score before death was 26.8±4.6 stdev. The study incorporated evaluation of tissue with both silver histochemical stains and immunohistochemical stains to compare results; the immunohistochemical stains (Aβ and phospho-tau) were scanned and quantified using digital pathologic methods. Immunohistochemical stains provided important advantages over histochemical stains due to sensitivity and detectability via digital methods. When AD-type pathology was in its presumed earliest phases, neocortical parenchymal Aβ deposits were associated with increased medial temporal lobe neurofibrillary tangles. The observation supports the NIA-AA consensus recommendation for neuropathologic diagnoses, because even these "diffuse" Aβ deposits signal that AD pathobiologic mechanisms are occurring. Further, the data were most compatible with the hypothesis that the APOEɛ4 allele exerts its effect(s) via driving Aβ deposition, i.e., an "upstream" influence, rather than being associated directly with Aβ- independent PART pathology.

%B J Alzheimers Dis %V 64 %P 1307-1324 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30040735?dopt=Abstract %R 10.3233/JAD-180514 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Distinct White Matter Changes Associated with Cerebrospinal Fluid Amyloid-β1-42 and Hypertension. %A Al-Janabi, Omar M %A Brown, Christopher A %A Bahrani, Ahmed A %A Abner, Erin L %A Barber, Justin M %A Gold, Brian T %A Goldstein, Larry B %A Murphy, Ronan R %A Nelson, Peter T %A Johnson, Nathan F %A Shaw, Leslie M %A Smith, Charles D %A Trojanowski, John Q %A Wilcock, Donna M %A Jicha, Gregory A %X

BACKGROUND: Alzheimer's disease (AD) pathology and hypertension (HTN) are risk factors for development of white matter (WM) alterations and might be independently associated with these alterations in older adults.

OBJECTIVE: To evaluate the independent and synergistic effects of HTN and AD pathology on WM alterations.

METHODS: Clinical measures of cerebrovascular disease risk were collected from 62 participants in University of Kentucky Alzheimer's Disease Center studies who also had cerebrospinal fluid (CSF) sampling and MRI brain scans. CSF Aβ1-42 levels were measured as a marker of AD, and fluid-attenuated inversion recovery imaging and diffusion tensor imaging were obtained to assess WM macro- and microstructural properties. Linear regression analyses were used to assess the relationships among WM alterations, cerebrovascular disease risk, and AD pathology. Voxelwise analyses were performed to examine spatial patterns of WM alteration associated with each pathology.

RESULTS: HTN and CSF Aβ1-42 levels were each associated with white matter hyperintensities (WMH). Also, CSF Aβ1-42 levels were associated with alterations in normal appearing white matter fractional anisotropy (NAWM-FA), whereas HTN was marginally associated with alterations in NAWM-FA. Linear regression analyses demonstrated significant main effects of HTN and CSF Aβ1-42 on WMH volume, but no significant HTN×CSF Aβ1-42 interaction. Furthermore, voxelwise analyses showed unique patterns of WM alteration associated with hypertension and CSF Aβ1-42.

CONCLUSION: Associations of HTN and lower CSF Aβ1-42 with WM alteration were statistically and spatially distinct, suggesting independent rather than synergistic effects. Considering such spatial distributions may improve diagnostic accuracy to address each underlying pathology.

%B J Alzheimers Dis %V 66 %P 1095-1104 %8 2018 Nov 23 %G eng %N 3 %R 10.3233/JAD-180663 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Matrix Metalloproteinase in Blood-Brain Barrier Breakdown in Dementia. %A Weekman, Erica M %A Wilcock, Donna M %K Animals %K Blood-Brain Barrier %K Dementia %K Humans %K Matrix Metalloproteinase 2 %K Matrix Metalloproteinase 9 %X

The neurovascular unit, which consists of astrocytic end-feet, neurons, pericytes, and endothelial cells, plays a key role in maintaining brain homeostasis by forming the blood-brain barrier and carefully controlling local cerebral blood flow. When the blood-brain barrier is disrupted, blood components can leak into the brain, damage the surrounding tissue and lead to cognitive impairment. This disruption in the blood-brain barrier and subsequent impairment in cognition are common after stroke and during cerebral amyloid angiopathy and Alzheimer's disease. Matrix metalloproteinases are proteases that degrade the extracellular matrix as well as tight junctions between endothelial cells and have been implicated in blood-brain barrier breakdown in neurodegenerative diseases. This review will focus on the roles of MMP2 and MMP9 in dementia, primarily post-stroke events that lead to dementia, cerebral amyloid angiopathy, and Alzheimer's disease.

%B J Alzheimers Dis %V 49 %P 893-903 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26599057?dopt=Abstract %R 10.3233/JAD-150759