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. Linear regression revealed an independent association of higher LATE-NC stage with lower diffusion anisotropy in a set of white matter connections forming a pattern of connectivity that is consistent with the stereotypical spread of this pathology in the brain. Graph theory analysis revealed an association of higher LATE-NC stage with weaker integration and segregation in the LATE-NC network. Abnormalities were significant in stage 3, suggesting that they are detectable in later stages of the disease. Finally, LATE-NC network abnormalities were associated with faster cognitive decline, specifically in episodic and semantic memory.

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. Epilepsy was ascertained using Medicare fee-for-service Parts A and B claims data that were linked to data from the cohort studies. The postmortem pathologic assessment collected indices of 9 pathologies including Alzheimer disease, hippocampal sclerosis, macroinfarcts, and cerebral amyloid angiopathy. The fixed brain hemisphere was imaged using 3T MRI scanners before the pathologic assessments in a subgroup of participants. RESULTS: The participants (n = 1,369) were on average 89.3 (6.6) years at death, and 67.0% were women. Epilepsy was identified in 58 (4.2%) participants. Cerebral amyloid angiopathy (odds ratio [OR] = 2.21, 95% CI 1.24-3.95, p = 0.007) and cortical macroinfarcts (OR = 2.74, 95% CI 1.42-5.28, p = 0.003) were associated with a higher odds of epilepsy. Of note, hippocampal sclerosis and Alzheimer disease pathology were not associated with epilepsy (both p's > 0.25), although hippocampal sclerosis was not common and thus hard to examine with the modest number of epilepsy cases here. In 673 participants with MRI data, the association of cerebral amyloid angiopathy and cortical macroinfarcts with epilepsy did not change after controlling for cortical gray matter atrophy, which was independently associated with a higher odds of epilepsy (OR = 1.06, 95% CI 1.02-1.10, p = 0.003). By contrast, hippocampal volume was not associated with epilepsy. DISCUSSION: Cerebrovascular pathologies and cortical atrophy were associated with epilepsy in older persons.

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 [APOE ε4], and diabetes). METHODS AND RESULTS: Data came from 765 community-based older people (91 years old on average at death; 72% women), from 2 ongoing clinical-pathologic cohort studies. Participants completed baseline assessment, annual standardized blood pressure measurements, vascular risk assessment for diabetes, and blood draws to determine APOE genotype, and at death, brains were removed and underwent ex vivo magnetic resonance imaging and neuropathologic evaluation for atherosclerosis pathology and other cerebrovascular and neurodegenerative pathologies. Linear regression models examined the association of atherosclerosis and hippocampal to hemisphere volume ratio and whether age at death, blood pressure, and other factors modified associations. In linear regression models adjusted for demographics and neurodegenerative and other cerebrovascular pathologies, atherosclerosis severity was associated with a lower hippocampal to hemisphere volume ratio. In separate models, we found the effect of atherosclerosis on the ratio of hippocampal to hemisphere volume was attenuated among advanced age at death or having higher systolic blood pressure (interaction terms P≤0.03). We did not find confounding or interactions with sex, diabetes, or APOE ε4. CONCLUSIONS: Atherosclerosis severity is associated with lower hippocampal volume, independent of neurodegenerative and other cerebrovascular pathologies. Higher systolic blood pressures and advanced age attenuate associations.

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. ARTS scores increased over time (estimate=0.030, SE=0.002, p < 0.0001). Faster increases in ARTS were associated with faster rates of global cognitive decline (r = -0.447, p = 0.006) and domain-specific cognitive functions. Applying an in-vivo marker of arteriolosclerosis in an African American cohort revealed that the likelihood of arteriolosclerosis increases over time, and participants whose ARTS scores increased more rapidly tended to have faster than average rates of cognitive decline.

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. 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.

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

Cerebral microbleeds (CMBs) appearing as hypointense foci on T2*-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. Cerebral hemispheres from 289 participants of the Rush Memory and Aging Project, Religious Orders Study, Minority Aging Research Study, and Rush Alzheimer's Disease Clinical Core underwent ex vivo MRI and detailed neuropathologic examination. Following Bonferroni correction, CMBs in the cerebrum overall and in the frontal lobe were associated with cerebral amyloid angiopathy, CMBs in the frontal lobe were also associated with arteriolosclerosis, and CMBs in the basal ganglia showed a borderline significant association with microinfarcts. These findings suggest that CMBs can aid in the prediction of small vessel disease in community-based older adults. Finally, CMBs were not associated with dementia, suggesting that CMBs in community-based older adults may not be linked to substantial cognitive impairment.

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. Cerebrospinal fluid (CSF) and fixed tissues were evaluated for the presence of viral RNA and protein. RESULTS: The mean age-at-death was 66.2 years (range: 26-97 years) and 14 were male. The patient's medical history included cardiovascular risk factors or diseases (n = 11, 55%) and dementia (n = 5, 25%). Brain examination revealed a range of acute and chronic pathologies. Acute vascular pathologic changes were common in 16 (80%) subjects and included infarctions (n = 11, 55%) followed by acute hypoxic/ischemic injury (n = 9, 45%) and hemorrhages (n = 7, 35%). These acute pathologic changes were identified in both younger and older groups and those with and without vascular risk factors or diseases. Moderate-to-severe microglial activation were noted in 16 (80%) brains, while moderate-to-severe T lymphocyte accumulation was present in 5 (25%) brains. Encephalitis-like changes included lymphocytic cuffing (n = 6, 30%) and neuronophagia or microglial nodule (most prominent in the brainstem, n = 6, 30%) were also observed. A single brain showed vasculitis-like changes and one other exhibited foci of necrosis with ball-ring hemorrhages reminiscent of acute hemorrhagic leukoencephalopathy changes. Chronic pathologies were identified in only older decedents: 7 brains exhibited neurodegenerative diseases and 8 brains showed vascular disease pathologies. CSF and brain samples did not show evidence of viral RNA or protein. CONCLUSIONS: Acute tissue injuries and microglial activation were the most common abnormalities in COVID-19 brains. Focal evidence of encephalitis-like changes was noted despite the lack of detectable virus. The majority of older subjects showed age-related brain pathologies even in the absence of known neurologic disease. Findings of this study suggest that acute brain injury superimposed on common pre-existing brain disease may put older subjects at higher risk of post-COVID neurologic sequelae.

Limbic-predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC) is associated with lower R2 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, R2, was investigated in a large number of community-based older adults. Cerebral hemispheres from 738 participants of the Rush Memory and Aging Project, Religious Orders Study, and Minority Aging Research Study, were imaged ex-vivo with multi-echo spin-echo MRI and underwent detailed neuropathologic examination. Voxel-wise analysis revealed a novel spatial pattern of lower R2 for higher LATE-NC stage, controlling for other neuropathologies and demographics. This pattern was consistent with the distribution of LATE-NC in gray matter, and also involved white matter providing temporo-temporal, fronto-temporal, and temporo-basal ganglia connectivity. Furthermore, analysis at different LATE-NC stages showed that R2 imaging may capture the general progression of LATE-NC, but only when TDP-43 inclusions extend beyond the amygdala.

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. Prior to death, participants were observed for a mean of 7.5 years, with annual clinical assessments. From 4427 participants enrolled in the 3 cohorts, 2134 died. Postmortem autopsy was performed in 1725 decedents, and 598 also had ex vivo brain magnetic resonance imaging. Participants were excluded if they were missing any of the 9 postmortem pathology indices (n = 22) or repeated parkinsonism assessment (n = 41) or had received a clinical diagnosis of Parkinson disease at any point before or during the study (n = 19). Data were analyzed from April 2020 to August 2021. Exposures: WMH burden was assessed using a modified Fazekas rating scale. Main Outcomes and Measures: Parkinsonism was assessed annually using 26 items of a modified motor portion of the Unified Parkinson's Disease Rating Scale. A summary score was developed from the item scores, with higher scores indicating more severe parkinsonism. Results: Of 516 included decedents, 364 (70.5%) were female, and the mean (SD) age at death was 90.2 (6.4) years. Higher WMH was associated with faster progressive parkinsonism (estimate, 0.024; SE, 0.008; P = .002). The attenuation of this association was greater when controlling for indices of cerebrovascular disease pathologies than when controlling for neurodegenerative pathologies (cerebrovascular disease: estimate, 0.019; SE, 0.008; P = .02; neurodegenerative: estimate, 0.022; SE, 0.008; P = .003), but both remained significant. Conclusions and Relevance: In this cohort study, higher levels of both WMH and indices of cerebrovascular disease pathologies in aging brains were associated with more rapid progressive parkinsonism. Further studies are needed to determine if in vivo brain imaging of older adults for evidence of WMH and aggressive medical treatment of vascular risk factors and diseases can reduce the occurrence or severity of late-life parkinsonism.

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. First, an ex-vivo classifier of arteriolosclerosis was developed based on features related to white matter hyperintensities, diffusion anisotropy and demographics by applying machine learning to ex-vivo MRI and pathology data from 119 participants of the Rush Memory and Aging Project (MAP) and Religious Orders Study (ROS), two longitudinal cohort studies of aging that recruit non-demented older adults. The ex-vivo classifier showed good performance in predicting the presence of arteriolosclerosis, with an average area under the receiver operating characteristic curve AUC = 0.78. The ex-vivo classifier was then translated to in-vivo based on available in-vivo and ex-vivo MRI data on the same participants. The in-vivo classifier was named ARTS (short for ARTerioloSclerosis), is fully automated, and provides a score linked to the likelihood a person suffers from arteriolosclerosis. The performance of ARTS in predicting the presence of arteriolosclerosis in-vivo was tested in a separate, 91% dementia-free group of 79 MAP/ROS participants and exhibited an AUC = 0.79 in persons with antemortem intervals shorter than 2.4 years. This level of performance in mostly non-demented older adults is notable considering that arteriolosclerosis can only be diagnosed at autopsy. The scan-rescan reproducibility of the ARTS score was excellent, with an intraclass correlation of 0.99, suggesting that application of ARTS in longitudinal studies may show high sensitivity in detecting small changes. Finally, higher ARTS scores in non-demented older adults were associated with greater decline in cognition two years after baseline MRI, especially in perceptual speed which has been linked to arteriolosclerosis and small vessel disease. This finding was shown in a separate group of 369 non-demented MAP/ROS participants and was validated in 72 non-demented Black participants of the Minority Aging Research Study (MARS) and also in 244 non-demented participants of the Alzheimer's Disease Neuroimaging Initiative 2 and 3. The results of this work suggest that ARTS may have broad implications in the advancement of diagnosis, prevention and treatment of arteriolosclerosis. ARTS is publicly available at https://www.nitrc.org/projects/arts/.

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. All participants underwent annual clinical evaluation, cognitive assessment, and neuropathologic examination. WMH burden was assessed using a modified Fazekas rating scale. Multiple ordinal logistic regression was used to test the association of WMH burden with an array of age-related neuropathologies, adjusting for demographics. Mixed effects models of cognition controlling for neuropathologies and demographics were used to determine whether WMH burden contributes to cognitive decline beyond measured pathologies. RESULTS: WMH burden in the whole group was associated with both vascular and Alzheimer's disease (AD) pathologies: arteriolosclerosis (p < 10-4), gross (p < 10-4), and microscopic infarcts (p = 0.04), and amyloid-ß plaques (p = 0.028). In non-demented participants (mild or no cognitive impairment) (N = 332), WMH burden was related to gross infarcts (p = 10-4) and arteriolosclerosis (p < 10-4), but not to AD pathology. Similarly, in those with no cognitive impairment (N = 178), WMH burden was related to gross infarcts (p = 8×10-4) and arteriolosclerosis (p = 0.014). WMH burden was associated with faster decline in perceptual speed in both the whole (p = 0.038) and non-demented (p = 0.006) groups. CONCLUSION: WMH burden has independent associations with vascular pathologies in older adults regardless of clinical status, and with AD pathology later in the progression of AD. Moreover, WMH burden may reflect additional tissue injury not captured with traditional neuropathologic indices.

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. Cerebral hemispheres from 198 participants of the Rush Memory and Aging Project and the Religious Orders Study were imaged with MRI ex vivo and underwent neuropathologic examination. Measures of amygdala volume and shape were extracted for all participants. Regression models controlling for neuropathologies and demographics showed an independent negative association of TDP-43 with the volume of the amygdala. Shape analysis revealed a unique pattern of amygdala deformation associated with TDP-43 pathology. Finally, mixed-effects models showed that amygdala volume explained an additional portion of the variance of the rate of decline in global cognition, episodic memory, semantic memory, and perceptual speed, above and beyond what was explained by demographics and neuropathologies.

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. Five brain hemispheres from community-dwelling older adults were imaged ex-vivo with QSM on a weekly basis for six weeks postmortem, and the longitudinal behavior of ex-vivo magnetic susceptibility in both gray and white matter was assessed. The relationship between in-vivo and ex-vivo gray matter susceptibility measurements was investigated using QSM data from eleven older adults imaged both antemortem and postmortem. No systematic change in ex-vivo magnetic susceptibility of gray or white matter was observed over time postmortem. Additionally, it was demonstrated that, gray matter magnetic susceptibility measured ex-vivo may be well modeled as a linear function of susceptibility measured in-vivo. In conclusion, magnetic susceptibility in gray and white matter measured ex-vivo with QSM does not systematically change in the first six weeks after death. This information is important for future cross-sectional ex-vivo QSM studies of hemispheres imaged at different postmortem intervals. Furthermore, the linear relationship between in-vivo and ex-vivo gray matter magnetic susceptibility suggests that ex-vivo QSM captures information linked to antemortem gray matter magnetic susceptibility, which is important for translation of ex-vivo QSM findings to in-vivo.

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. Diffusion tensor imaging (DTI) studies in the related conditions of antisocial and borderline personality disorder have produced preliminary evidence of disturbed white matter connectivity in these disorders, but to date there have been no DTI studies in IED. A total of 132 male and female adults between the ages of 18 and 55 years underwent Turboprop-DTI on a 3-Tesla MRI scanner. Of these, 42 subjects had IED, 40 were normal controls, and 50 were clinical psychiatric controls with psychiatric disorders without IED. All subjects were free of alcohol, psychotropic medications, or drugs of abuse. The diffusion tensor was calculated in each voxel and maps of fractional anisotropy (FA) were generated. Tract-based spatial statistics (TBSS) were used to compare FA along the white matter skeleton among the three subject groups. IED was associated with lower FA in two clusters located in the superior longitudinal fasciculus (SLF) when compared with the psychiatric and healthy controls. Impulsive aggression and borderline personality disorder, but not psychopathy or antisocial personality disorder, was associated with lower FA in the two clusters within the SLF. In conclusion, IED was associated with lower white matter integrity in long-range connections between the frontal and temporoparietal regions.