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Scientific Reports Mar 2020Although Heme Oxygenase-1 (HO-1) induction in various forms of kidney injury is protective, its role in age-related renal pathology is unknown. In the ageing kidney...
Although Heme Oxygenase-1 (HO-1) induction in various forms of kidney injury is protective, its role in age-related renal pathology is unknown. In the ageing kidney there is nephron loss and lesions of focal glomerulosclerosis, interstitial fibrosis, tubular atrophy and arteriolosclerosis. Underlying mechanisms include podocyte (visceral glomerular epithelial cell/GEC) injury. To assess whether HO-1 can attenuate ageing - related lesions, rats with GEC-targeted HO-1 overexpression (GEC rats) were generated using a Sleeping Beauty (SB) transposon system and extent of lesions over a 12-month period were assessed and compared to those in age-matched wild-type (WT) controls. GEC rats older than 6 months developed albuminuria that was detectable at 6 months and became significantly higher compared to age-matched WT controls at 12 months. In GEC rats, lesions of focal segmental and global glomerulosclerosis as well as tubulointerstitial lesions were prominent while podocytes were edematous with areas of foot process effacement and glomerular basement membrane thickening and wrinkling. GEC rats also developed hemoglobinuria and hemosiderinuria associated with marked tubular hemosiderin deposition and HO-1 induction, while there was depletion of splenic iron stores. Kidney injury was of sufficient magnitude to increase serum lactate dehydrogenase (LDH) and was oxidative in nature as shown by increased expression of 8-hydroxydeoxyguanosine (8-OHdg, a byproduct of oxidative DNA damage) in podocytes and tubular epithelial cells. These observations highlight a detrimental effect of podocyte-targeted HO-1 overexpression on ageing-related renal pathology and point to increased renal iron deposition as a putative underlying mechanism.
Topics: Aging; Albuminuria; Animals; Glomerulosclerosis, Focal Segmental; Heme Oxygenase-1; Hemosiderin; Kidney; Podocytes; Rats
PubMed: 32235880
DOI: 10.1038/s41598-020-62016-9 -
Alzheimer's & Dementia : the Journal of... Apr 2024Hypertension and diabetes are common cardiovascular risk factors that increase Alzheimer's disease (AD) risk. However, it is unclear whether AD risk differs in...
INTRODUCTION
Hypertension and diabetes are common cardiovascular risk factors that increase Alzheimer's disease (AD) risk. However, it is unclear whether AD risk differs in hypertensive individuals with and without diabetes.
METHODS
Cognitively normal individuals (N = 11,074) from the National Alzheimer's Coordinating Center (NACC) were categorized as having (1) hypertension with diabetes (HTN+/DM+), (2) hypertension without diabetes (HTN+/DM-), or (3) neither (HTN-/DM-). AD risk in HTN+/DM+ and HTN+/DM- was compared to HTN-/DM-. This risk was then investigated in those with AD neuropathology (ADNP), cerebral amyloid angiopathy (CAA), cerebrovascular neuropathology (CVNP), arteriolosclerosis, and atherosclerosis. Finally, AD risk in HTN-/DM+ was compared to HTN-/DM-.
RESULTS
Seven percent (N = 830) of individuals developed AD. HTN+/DM+ (hazard ratio [HR] = 1.31 [1.19-1.44]) and HTN+/DM- (HR = 1.24 [1.17-1.32]) increased AD risk compared to HTN-/DM-. AD risk was greater in HTN+/DM+ with ADNP (HR = 2.10 [1.16-3.79]) and CAA (HR = 1.52 [1.09-2.12]), and in HTN+/DM- with CVNP (HR = 1.54 [1.17-2.03]). HTN-/DM+ also increased AD risk (HR = 1.88 [1.30-2.72]) compared to HTN-/DM-.
DISCUSSION
HTN+/DM+ and HTN+/DM- increased AD risk compared to HTN-/DM-, but pathological differences between groups suggest targeted therapies may be warranted based on cardiovascular risk profiles.
HIGHLIGHTS
AD risk was studied in hypertensive (HTN+) individuals with/without diabetes (DM+/-). HTN+/DM+ and HTN+/DM- both had an increased risk of AD compared to HTN-/DM-. Post mortem analysis identified neuropathological differences between HTN+/DM+ and HTN+/DM-. In HTN+/DM+, AD risk was greater in those with AD neuropathology and CAA. In HTN+/DM-, AD risk was greater in those with cerebrovascular neuropathology.
Topics: Humans; Alzheimer Disease; Hypertension; Diabetes Mellitus; Cerebral Amyloid Angiopathy; Atherosclerosis
PubMed: 38425134
DOI: 10.1002/alz.13717 -
Journal of Neuropathology and... May 2024Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) is detectable at autopsy in more than one-third of people beyond age 85 years and... (Review)
Review
Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) is detectable at autopsy in more than one-third of people beyond age 85 years and is robustly associated with dementia independent of other pathologies. Although LATE-NC has a large impact on public health, there remain uncertainties about the underlying biologic mechanisms. Here, we review the literature from human studies that may shed light on pathogenetic mechanisms. It is increasingly clear that certain combinations of pathologic changes tend to coexist in aging brains. Although "pure" LATE-NC is not rare, LATE-NC often coexists in the same brains with Alzheimer disease neuropathologic change, brain arteriolosclerosis, hippocampal sclerosis of aging, and/or age-related tau astrogliopathy (ARTAG). The patterns of pathologic comorbidities provide circumstantial evidence of mechanistic interactions ("synergies") between the pathologies, and also suggest common upstream influences. As to primary mediators of vulnerability to neuropathologic changes, genetics may play key roles. Genes associated with LATE-NC include TMEM106B, GRN, APOE, SORL1, ABCC9, and others. Although the anatomic distribution of TDP-43 pathology defines the condition, important cofactors for LATE-NC may include Tau pathology, endolysosomal pathways, and blood-brain barrier dysfunction. A review of the human phenomenology offers insights into disease-driving mechanisms, and may provide clues for diagnostic and therapeutic targets.
Topics: Humans; TDP-43 Proteinopathies; Aging; Risk Factors; Limbic System; DNA-Binding Proteins; Aged, 80 and over; Dementia
PubMed: 38613823
DOI: 10.1093/jnen/nlae032 -
Stroke Mar 2021There is increasing recognition of the importance of cortical microinfarcts to overall brain health, cognition, and Alzheimer dementia. Cerebral small vessel pathologies...
BACKGROUND AND PURPOSE
There is increasing recognition of the importance of cortical microinfarcts to overall brain health, cognition, and Alzheimer dementia. Cerebral small vessel pathologies are associated with microinfarcts and frequently coexist with Alzheimer disease; however, the extent to which Aβ (amyloid beta) and tau pathology modulates microvascular pathogenesis is not fully understood. Study objective was to examine the relationship of small vessel pathologies, arteriolosclerosis, and cerebral amyloid angiopathy, with cortical microinfarcts in people with differing levels of Aβ or tau tangle burden.
METHODS
Participants were 1489 autopsied older people (mean age at death, 89 years; 67% women) from 1 of 3 ongoing clinical-pathological cohort studies of aging. Neuropathological evaluation identified cortical Aβ and tau tangle burden using immunohistochemistry in 8 brain regions, provided semiquantitative grading of cerebral vessel pathologies, and identified the presence of cortical microinfarcts. Logistic regression models adjusted for demographics and atherosclerosis and examined whether Aβ or tau tangle burden modified relations between small vessel pathologies and cortical microinfarcts.
RESULTS
Cortical microinfarcts were present in 17% of older people, moderate-to-severe cerebral amyloid angiopathy pathology in 36%, and arteriolosclerosis in 34%. In logistic regression models, we found interactions with Aβ and tau tangles, reflecting that the association between arteriolosclerosis and cortical microinfarcts was stronger in the context of greater Aβ (estimate, 0.15; SE=0.07; =0.02) and tau tangle burden (estimate, 0.13; SE=0.06; =0.02). Interactions also emerged for cerebral amyloid angiopathy, suggesting that the association between cerebral amyloid angiopathy and cortical microinfarcts is more robust in the presence of higher Aβ (estimate, 0.27; SE=0.07; <0.001) and tangle burden (estimate, 0.16; SE=0.06; =0.005).
CONCLUSIONS
These findings suggest that in the presence of elevated Aβ or tangle pathology, small vessel pathologies are associated with greater microvascular tissue injury, highlighting a potential link between neurodegenerative and vascular mechanisms.
Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Protein Precursor; Arteriosclerosis; Brain; Brain Infarction; Cerebral Amyloid Angiopathy; Female; Humans; Immunohistochemistry; Male; Regression Analysis; Vascular Diseases; tau Proteins
PubMed: 33567873
DOI: 10.1161/STROKEAHA.120.031073 -
Journal of Neurology Apr 2020The prevalence of modifiable vascular risk factors is increasing in young adults and may contribute to the growing frequency of stroke in this population. The...
INTRODUCTION
The prevalence of modifiable vascular risk factors is increasing in young adults and may contribute to the growing frequency of stroke in this population. The neuropathology and end-organ damage profile of young adult stroke patients with clinically advanced atherosclerosis or arteriosclerosis has not been studied.
METHODS
This retrospective study included patients aged 18-60 years admitted to our hospital from 1995 to 2017 with recurrent ischemic or hemorrhagic strokes, fatal stroke, or stroke associated with advanced small vessel disease (SVD) on brain MRI, who had no evidence for structural, genetic, inflammatory, or infectious etiology for stroke, and had adequate pathological materials available for analysis. The presence of atherosclerosis, arteriolosclerosis, left ventricular hypertrophy, and nephrosclerosis was evaluated.
RESULTS
Twelve patients (mean age 47 ± 9 years, range 31-57 years, 67% male) met inclusion criteria. Four had fatal intracerebral hemorrhage (ICH), three had recurrent non-fatal ICH, one had ICH with advanced SVD on MRI, and four had recurrent ischemic strokes including two with transient ischemic attacks. Pathological studies showed moderate/severe atherosclerosis in 64% and moderate/severe arteriolosclerosis in 42% of patients. Pathological data to evaluate end-organ damage were available for nine patients; eight showed left ventricular hypertrophy and all showed nephrosclerosis.
CONCLUSION
Young adult stroke patients with recurrent stroke, fatal stroke, or SVD on imaging have advanced atherosclerosis and arteriolosclerosis-related pathological changes in multiple organ systems. Aggressive control of atherosclerosis risk factors is warranted even in young individuals.
Topics: Adult; Cerebral Hemorrhage; Cerebral Small Vessel Diseases; Female; Hemorrhagic Stroke; Humans; Intracranial Arteriosclerosis; Ischemic Attack, Transient; Ischemic Stroke; Male; Middle Aged; Recurrence; Retrospective Studies; Risk Factors
PubMed: 31853711
DOI: 10.1007/s00415-019-09623-3 -
Annals of Clinical and Translational... Nov 2019Cognitive variability is a potentially important source of heterogeneity in longitudinal cognitive profiles. We examined the extent to which common age-related...
OBJECTIVE
Cognitive variability is a potentially important source of heterogeneity in longitudinal cognitive profiles. We examined the extent to which common age-related neuropathologies including Lewy bodies and Alzheimer's disease (AD) contribute to yearly variability in late life cognition.
METHODS
Data came from 1321 community-dwelling older adults who were followed annually for up to 23 years, died and underwent brain autopsy. Cognition was assessed via a comprehensive testing battery. Uniform neuropathologic evaluations assessed burdens of Lewy bodies, AD, infarcts, TDP, hippocampal sclerosis, amyloid angiopathy, atherosclerosis, and arteriolosclerosis. Using mixed effects models, yearly variability in cognition, characterized as within-person variability of annual cognitive scores, was regressed on the nine neuropathologic indices.
RESULTS
The average age of decedents was 90 years and 69% were female. At autopsy, about two thirds met the pathologic criteria for AD. Neocortical Lewy bodies were present in 13% of the individuals. Other neuropathologic conditions also were common. All neuropathologic indices except for microinfarcts were associated with cognitive decline. Individuals with neocortical Lewy bodies had almost twice the yearly variability in cognition compared to those without. Individuals with AD had about 70% more variability compared to those without. Yearly variability was present among persons with vascular diseases but to a lesser degree than neocortical Lewy bodies and AD.
INTERPRETATION
Lewy body pathology is associated with pronounced variability in annual cognitive assessments but this finding is not unique to this pathology. Comparable variability is present among persons with AD pathology and to a lesser extent among persons with cerebrovascular pathologies.
Topics: Aged; Aged, 80 and over; Aging; Brain; Cognition; Disease Progression; Female; Humans; Longitudinal Studies; Male; Neurocognitive Disorders
PubMed: 31568713
DOI: 10.1002/acn3.50857 -
Biomedical Engineering Online Oct 2023Cerebral microbleeds (CMBs) serve as neuroimaging biomarkers to assess risk of intracerebral hemorrhage and diagnose cerebral small vessel disease (CSVD). Therefore,...
BACKGROUND
Cerebral microbleeds (CMBs) serve as neuroimaging biomarkers to assess risk of intracerebral hemorrhage and diagnose cerebral small vessel disease (CSVD). Therefore, detecting CMBs can evaluate the risk of intracerebral hemorrhage and use its presence to support CSVD classification, both are conducive to optimizing CSVD management. This study aimed to develop and test a deep learning (DL) model based on susceptibility-weighted MR sequence (SWS) to detect CMBs and classify CSVD to assist neurologists in optimizing CSVD management. Patients with arteriolosclerosis (aSVD), cerebral amyloid angiopathy (CAA), and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) treated at three centers were enrolled between January 2017 and May 2022 in this retrospective study. The SWSs of patients from two centers were used as the development set, and the SWSs of patients from the remaining center were used as the external test set. The DL model contains a Mask R-CNN for detecting CMBs and a multi-instance learning (MIL) network for classifying CSVD. The metrics for model performance included intersection over union (IoU), Dice score, recall, confusion matrices, receiver operating characteristic curve (ROC) analysis, accuracy, precision, and F1-score.
RESULTS
A total of 364 SWS were recruited, including 336 in the development set and 28 in the external test set. IoU for the model was 0.523 ± 0.319, Dice score 0.627 ± 0.296, and recall 0.706 ± 0.365 for CMBs detection in the external test set. For CSVD classification, the model achieved a weighted-average AUC of 0.908 (95% CI 0.895-0.921), accuracy of 0.819 (95% CI 0.768-0.870), weighted-average precision of 0.864 (95% CI 0.831-0.897), and weighted-average F1-score of 0.829 (95% CI 0.782-0.876) in the external set, outperforming the performance of the neurologist group.
CONCLUSION
The DL model based on SWS can detect CMBs and classify CSVD, thereby assisting neurologists in optimizing CSVD management.
Topics: Humans; Retrospective Studies; Magnetic Resonance Imaging; Deep Learning; Cerebral Hemorrhage; Cerebral Small Vessel Diseases
PubMed: 37848906
DOI: 10.1186/s12938-023-01164-1 -
Alzheimer's & Dementia : the Journal of... Apr 2024White matter hyperintensities (WMH) are associated with key dementia etiologies, in particular arteriolosclerosis and amyloid pathology. We aimed to identify WMH...
INTRODUCTION
White matter hyperintensities (WMH) are associated with key dementia etiologies, in particular arteriolosclerosis and amyloid pathology. We aimed to identify WMH locations associated with vascular risk or cerebral amyloid-β (Aβ42)-positive status.
METHODS
Individual patient data (n = 3,132; mean age 71.5 ± 9 years; 49.3% female) from 11 memory clinic cohorts were harmonized. WMH volumes in 28 regions were related to a vascular risk compound score (VRCS) and Aß42 status (based on cerebrospinal fluid or amyloid positron emission tomography), correcting for age, sex, study site, and total WMH volume.
RESULTS
VRCS was associated with WMH in anterior/superior corona radiata (B = 0.034/0.038, p < 0.001), external capsule (B = 0.052, p < 0.001), and middle cerebellar peduncle (B = 0.067, p < 0.001), and Aß42-positive status with WMH in posterior thalamic radiation (B = 0.097, p < 0.001) and splenium (B = 0.103, p < 0.001).
DISCUSSION
Vascular risk factors and Aß42 pathology have distinct signature WMH patterns. This regional vulnerability may incite future studies into how arteriolosclerosis and Aß42 pathology affect the brain's white matter.
HIGHLIGHTS
Key dementia etiologies may be associated with specific patterns of white matter hyperintensities (WMH). We related WMH locations to vascular risk and cerebral Aβ42 status in 11 memory clinic cohorts. Aβ42 positive status was associated with posterior WMH in splenium and posterior thalamic radiation. Vascular risk was associated with anterior and infratentorial WMH. Amyloid pathology and vascular risk have distinct signature WMH patterns.
Topics: Humans; Female; Middle Aged; Aged; Aged, 80 and over; Male; White Matter; Arteriolosclerosis; Amyloid beta-Peptides; Dementia; Magnetic Resonance Imaging
PubMed: 38477469
DOI: 10.1002/alz.13765 -
Alzheimer's & Dementia (Amsterdam,... 2022Development of novel diagnostic tools is a top research priority in vascular dementia. A major obstacle is the lack of a simple, non-invasive method to visualize...
INTRODUCTION
Development of novel diagnostic tools is a top research priority in vascular dementia. A major obstacle is the lack of a simple, non-invasive method to visualize cerebral arteriolar walls in vivo. Retinal arterioles offer a window into the cerebral circulation.
METHODS
ntensity-ased etinal rteriolar isualization in ptical coherence tomography (I-bRAVO) was applied to evaluate mean wall thickness (MWT) and wall-to-lumen ratio (WLR) in 250 subjects with sporadic and genetic cerebral small vessel disease (CSVD), non-vascular neurodegenerative diseases (NVND), and healthy controls (HC) in association with imaging and cognitive markers.
RESULTS
MWT and WLR were higher in CSVD, associated with severity of vascular white matter lesions, and correlated with magnetic resonance imaging-based intracranial arteriolosclerosis score. WLR correlated with gray and white matter volume and differentiated asymptomatic sporadic CSVD from HC (area under the curve = 0.82).
DISCUSSION
I-bRAVO is a rapid, non-invasive tool. MWT and WLR were associated with imaging markers of CSVD and could contribute to early identification of sporadic CSVD.
PubMed: 35814617
DOI: 10.1002/dad2.12338 -
Journal of Alzheimer's Disease : JAD 2020The association of white matter hyperintensities (WMH) with age-related vascular and neurodegenerative pathologies remains incompletely understood.
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-β 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.
Topics: Aged; Aged, 80 and over; Aging; Alzheimer Disease; Amyloid Neuropathies; Autopsy; Cerebral Infarction; Cerebrovascular Disorders; Cognitive Dysfunction; Cohort Studies; Cost of Illness; Disease Progression; Female; Humans; Intracranial Arteriosclerosis; Magnetic Resonance Imaging; Male; Nervous System Diseases; Neuropsychological Tests; White Matter
PubMed: 31771057
DOI: 10.3233/JAD-190687