The ARTS Marker of Arteriolosclerosis: Instrumental and Clinical Validation.

Background: The ARTS biomarker is a fully automated software container that predicts the presence of arteriolosclerosis based on in‐vivo MRI data and demographic features. The present study describes findings from the instrumental and clinical validation of ARTS conducted by the MarkVCID consortium.

Method: Instrumental validation of ARTS involved assessment of inter‐rater reliability, test‐retest repeatability, and inter‐scanner reproducibility.

Limbic predominant age‐related TDP‐43 encephalopathy neuropathological change (LATE‐NC) is associated with lower volume in gray and white matter of the temporal and frontal lobes and basal ganglia: A deformation‐based brain morphometry study.

Background: Limbic‐predominant age‐related TDP‐43 encephalopathy neuropathological change (LATE‐NC) is common in older adults and has been associated with substantial cognitive impairment. However, the association of LATE‐NC with brain morphometry has not been thoroughly investigated. In this work, we examined the association of LATE‐NC with brain morphometric anomalies using deformation‐based morphometry (DBM) in a large community cohort of older adults that came to autopsy (N=897).

Multichannel template‐based spatial normalization precision in older adult brain QSM.

Background: Quantitative Susceptibility Mapping (QSM) offers significant potential for studying metal and iron homeostasis in the brain and serves as a diagnostic tool for various pathologies, such as Alzheimer’s disease. However, the precision of QSM spatial normalization for older adults depends on the quality and representativeness of the chosen template and the type of information used during image registration. This study compares three available QSM templates in terms of their representativeness and precision of inter‐subject matching for older adult QSM data.

MIND diet, Cerebrovascular Health, and Cognition among community‐dwelling Older Adults.

Background: White matter hyperintensities (WMH) and cerebral arteriosclerosis involving thickening of the vessel wall and stenosis of brain arterioles are common in older adults and associated with poor cognition. The Mediterranean‐DASH Intervention for Neurodegenerative Disease (MIND) diet is associated with better cognition. Little is known about the association of the MIND diet with cerebrovascular outcomes and if this association mediates the link between diet and cognition.

Limbic predominant age‐related TDP‐43 encephalopathy neuropathological change (LATE‐NC) is associated with lower volume in gray and white matter of the temporal and frontal lobes and basal ganglia: A deformation‐based brain morphometry study.

Background: Limbic‐predominant age‐related TDP‐43 encephalopathy neuropathological change (LATE‐NC) is common in older adults and has been associated with substantial cognitive impairment. However, the association of LATE‐NC with brain morphometry has not been thoroughly investigated. In this work, we examined the association of LATE‐NC with brain morphometric anomalies using deformation‐based morphometry (DBM) in a large community cohort of older adults that came to autopsy (N=897).

Intracranial atherosclerosis is linked to lower volume in the posterior portion of the hippocampus.

Background: Intracranial atherosclerosis is a common age‐related neuropathology that has been linked to cognitive decline and dementia and often mixed with Alzheimer’s and other neuropathologies. But the association of atherosclerosis with brain morphometric abnormalities has not been explored. This work combined Deformation‐based morphometry on ex‐vivo MRI with detailed neuropathological examination in a large number of community‐based older adults to investigate the association.

The ARTS Marker of Arteriolosclerosis: Instrumental and Clinical Validation.

Background: The ARTS biomarker is a fully automated software container that predicts the presence of arteriolosclerosis based on in‐vivo MRI data and demographic features. The present study describes findings from the instrumental and clinical validation of ARTS conducted by the MarkVCID consortium.

Method: Instrumental validation of ARTS involved assessment of inter‐rater reliability, test‐retest repeatability, and inter‐scanner reproducibility.

Limbic-predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC) is associated with abnormalities in white matter structural integrity and connectivity: An ex-vivo diffusion MRI and pathology investigation.

Limbic predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC) is common in older adults and is associated with neurodegeneration, cognitive decline and dementia. In this MRI and pathology investigation we tested the hypothesis that LATE-NC is associated with abnormalities in white matter structural integrity and connectivity of a network of brain regions typically harboring TDP-43 inclusions in LATE, referred to here as the "LATE-NC network". Ex-vivo diffusion MRI and detailed neuropathological data were collected on 184 community-based older adults.

Association of Age-Related Neuropathologic Findings at Autopsy With a Claims-Based Epilepsy Diagnosis in Older Adults.

Background And Objectives: Epilepsy is 1 of the 3 most common neurologic diseases of older adults, but few studies have examined its underlying pathologies in older age. We examined the associations of age-related brain pathologies with epilepsy in older persons.

Methods: Clinical and pathologic data came from 2 ongoing clinical pathologic cohort studies of community-dwelling older adults.

Atherosclerosis and Hippocampal Volumes in Older Adults: The Role of Age and Blood Pressure.

Background: Lower hippocampal volume is associated with late-life cognitive decline and is an important, but nonspecific marker for clinical Alzheimer's dementia. Cerebrovascular disease may also be associated with hippocampal volume. Here we study the role of intracranial large vessel disease (atherosclerosis) in association with hippocampal volume and the potential role of age, average late-life blood pressure across all visits, and other factors (sex, apolipoprotein ε4 [ ε4], and diabetes).

Changes in an in-vivo classifier of ARTerioloSclerosis (ARTS) with simultaneous change in cognition for older African Americans.

At autopsy, African American decedents often have mixed Alzheimer's and cerebrovascular brain pathologies including arteriolosclerosis. We applied a novel in-vivo classifier of ARTerioloSclerosis (ARTS) in 167 older African Americans (∼75y of age) with > 2 biennial 3 T MRI scans and > 3 years of associated cognitive follow-up to determine if ARTS scores (higher score=higher likelihood of arteriolosclerosis) changed over time and if this change associated with changes in cognition in the same individuals. Mixed effects regression models tested whether ARTS scores increased over time, while simultaneous mixed effects regression models estimated the simultaneous rates of change in both ARTS and cognition and the correlation of these changes.

Multi-Site Cross-Site Inter-Rater and Test-Retest Reliability and Construct Validity of the MarkVCID White Matter Hyperintensity Growth and Regression Protocol.

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.

Neuropathologic correlates of cerebral microbleeds in community-based older adults.

Cerebral microbleeds (CMBs) appearing as hypointense foci on T*-weighted magnetic resonance images are small hemorrhages that have been linked to cognitive decline and increased mortality. However, the neuropathologic correlates of CMBs in community-based older adults are poorly understood. The present study investigated the association of age-related neuropathologies with CMBs in community-based older adults.

Brain autopsies of critically ill COVID-19 patients demonstrate heterogeneous profile of acute vascular injury, inflammation and age-linked chronic brain diseases.

Background: This study examined neuropathological findings of patients who died following hospitalization in an intensive care unit with SARS-CoV-2.

Methods: Data originate from 20 decedents who underwent brain autopsy followed by ex-vivo imaging and dissection. Systematic neuropathologic examinations were performed to assess histopathologic changes including cerebrovascular disease and tissue injury, neurodegenerative diseases, and inflammatory response.

Limbic-predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC) is associated with lower R relaxation rate: an ex-vivo MRI and pathology investigation.

Limbic predominant age-related transactive response DNA binding protein 43 (TDP-43) encephalopathy neuropathological change (LATE-NC) is common in persons older than 80 years of age and is associated with cognitive decline and increased likelihood of dementia. The MRI signature of LATE-NC has not been fully determined. In this study, the association of LATE-NC with the transverse relaxation rate, R, was investigated in a large number of community-based older adults.

Association of White Matter Hyperintensities With Pathology and Progression of Parkinsonism in Aging.

Importance: Progressive parkinsonism is common in older adults without a diagnosis of Parkinson disease and is associated with adverse health outcomes, but its pathologic basis is controversial.

Objective: To examine if the burden of cerebral white matter hyperintensity (WMH), a common manifestation of cerebrovascular disease pathologies, is associated with the rate of progressive parkinsonism.

Design, Setting, And Participants: This community-based cohort study included participants recruited in 3 ongoing cohorts that began enrollment in 1994, 1997, and 2004.

ARTS: A novel In-vivo classifier of arteriolosclerosis for the older adult brain.

Brain arteriolosclerosis, one of the main pathologies of cerebral small vessel disease, is common in older adults and has been linked to lower cognitive and motor function and higher odds of dementia. In spite of its frequency and associated morbidity, arteriolosclerosis can only be diagnosed at autopsy. Therefore, the purpose of this work was to develop an in-vivo classifier of arteriolosclerosis based on brain MRI.

Neuropathologic Correlates of White Matter Hyperintensities in a Community-Based Cohort of Older Adults.

Background: The association of white matter hyperintensities (WMH) with age-related vascular and neurodegenerative pathologies remains incompletely understood.

Objective: The objective of this work was to elucidate the neuropathologic correlates of WMH in a large community-based cohort of older adults.

Methods: Cerebral hemispheres from 603 community-based older adults were imaged with MRI ex vivo.

Associations of amygdala volume and shape with transactive response DNA-binding protein 43 (TDP-43) pathology in a community cohort of older adults.

Transactive response DNA-binding protein 43 (TDP-43) pathology is common in old age and is strongly associated with cognitive decline and dementia above and beyond contributions from other neuropathologies. TDP-43 pathology in aging typically originates in the amygdala, a brain region also affected by other age-related neuropathologies such as Alzheimer's pathology. The purpose of this study was two-fold: to determine the independent effects of TDP-43 pathology on the volume, as well as shape, of the amygdala in a community cohort of older adults, and to determine the contribution of amygdala volume to the variance of the rate of cognitive decline after accounting for the contributions of neuropathologies and demographics.

Ex-vivo quantitative susceptibility mapping of human brain hemispheres.

Ex-vivo brain quantitative susceptibility mapping (QSM) allows investigation of brain characteristics at essentially the same point in time as histopathologic examination, and therefore has the potential to become an important tool for determining the role of QSM as a diagnostic and monitoring tool of age-related neuropathologies. In order to be able to translate the ex-vivo QSM findings to in-vivo, it is crucial to understand the effects of death and chemical fixation on brain magnetic susceptibility measurements collected ex-vivo. Thus, the objective of this work was twofold: a) to assess the behavior of magnetic susceptibility in both gray and white matter of human brain hemispheres as a function of time postmortem, and b) to establish the relationship between in-vivo and ex-vivo gray matter susceptibility measurements on the same hemispheres.

White Matter Integrity Reductions in Intermittent Explosive Disorder.

Intermittent explosive disorder (IED), as described in DSM-5, is the categorical expression of pathological impulsive aggression. Previous work has identified neurobiological correlates of the disorder in patterns of frontal-limbic brain activity and dysregulation of serotonergic neurotransmission. Given the importance of short- and-long range white matter connections of the brain in social and emotional behavior, studies of white matter connectivity in impulsive aggression are warranted.