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Kidney International Reports Jun 2022Arteriolar microangiopathic (MA) lesions are independent risk factors for IgA nephropathy (IgAN) patient prognosis, and the underlying mechanism remains to be...
INTRODUCTION
Arteriolar microangiopathic (MA) lesions are independent risk factors for IgA nephropathy (IgAN) patient prognosis, and the underlying mechanism remains to be elucidated. The complement plays an important role in IgAN and thrombotic microangiopathy; however, its role in MA lesions in IgAN remains unclear.
METHODS
Immunohistochemistry was performed to detect arteriolar complement deposition. Enzyme-linked immunosorbent assay (ELISA) and whole-exome sequencing were performed to explore possible mechanism.
RESULTS
In this study, we found that patients with IgAN with MA lesions have more complement deposition, especially C4d, on renal arterioles than those in patients with arteriolosclerosis (AS) and patients with no vascular lesions (100% vs. 53% vs 14%, < 0.05). Furthermore, our large prospective cohort demonstrated that patients with IgAN with MA lesions had higher levels of Gd-IgA1 (median: 326.98 U/ml, interquartile range 303.46-370.5 vs. 319.22, 292.01-347.3 vs. 321.95, 291.68-350.68, = 0.014) and C3a (122.57 ± 42.07 vs. 93.79 ± 29.49 vs. 93.51 ± 45.87 ng/ml, = 0.01) than those in patients with AS and those with no vascular lesions. However, serum IgA1 and C3 levels were not significantly different. Finally, through whole-exome sequencing, we found that nearly half of the patients with MA lesions had rare genetic variations in complement-related genes.
CONCLUSION
Our results indicate that the complement is involved in the development of MA lesions in IgAN, which might be associated with the circulating complex containing Gd-IgA1.
PubMed: 35685318
DOI: 10.1016/j.ekir.2022.03.028 -
COVID-19 neuropathology at Columbia University Irving Medical Center/New York Presbyterian Hospital.Brain : a Journal of Neurology Oct 2021Many patients with SARS-CoV-2 infection develop neurological signs and symptoms; although, to date, little evidence exists that primary infection of the brain is a...
Many patients with SARS-CoV-2 infection develop neurological signs and symptoms; although, to date, little evidence exists that primary infection of the brain is a significant contributing factor. We present the clinical, neuropathological and molecular findings of 41 consecutive patients with SARS-CoV-2 infections who died and underwent autopsy in our medical centre. The mean age was 74 years (38-97 years), 27 patients (66%) were male and 34 (83%) were of Hispanic/Latinx ethnicity. Twenty-four patients (59%) were admitted to the intensive care unit. Hospital-associated complications were common, including eight patients (20%) with deep vein thrombosis/pulmonary embolism, seven (17%) with acute kidney injury requiring dialysis and 10 (24%) with positive blood cultures during admission. Eight (20%) patients died within 24 h of hospital admission, while 11 (27%) died more than 4 weeks after hospital admission. Neuropathological examination of 20-30 areas from each brain revealed hypoxic/ischaemic changes in all brains, both global and focal; large and small infarcts, many of which appeared haemorrhagic; and microglial activation with microglial nodules accompanied by neuronophagia, most prominently in the brainstem. We observed sparse T lymphocyte accumulation in either perivascular regions or in the brain parenchyma. Many brains contained atherosclerosis of large arteries and arteriolosclerosis, although none showed evidence of vasculitis. Eighteen patients (44%) exhibited pathologies of neurodegenerative diseases, which was not unexpected given the age range of our patients. We examined multiple fresh frozen and fixed tissues from 28 brains for the presence of viral RNA and protein, using quantitative reverse-transcriptase PCR, RNAscope® and immunocytochemistry with primers, probes and antibodies directed against the spike and nucleocapsid regions. The PCR analysis revealed low to very low, but detectable, viral RNA levels in the majority of brains, although they were far lower than those in the nasal epithelia. RNAscope® and immunocytochemistry failed to detect viral RNA or protein in brains. Our findings indicate that the levels of detectable virus in coronavirus disease 2019 brains are very low and do not correlate with the histopathological alterations. These findings suggest that microglial activation, microglial nodules and neuronophagia, observed in the majority of brains, do not result from direct viral infection of brain parenchyma, but more likely from systemic inflammation, perhaps with synergistic contribution from hypoxia/ischaemia. Further studies are needed to define whether these pathologies, if present in patients who survive coronavirus disease 2019, might contribute to chronic neurological problems.
Topics: Acute Kidney Injury; Adult; Aged; Aged, 80 and over; Bacteremia; Brain; Brain Infarction; COVID-19; Coronavirus Nucleocapsid Proteins; Female; Humans; Hypoxia-Ischemia, Brain; Inflammation; Intensive Care Units; Intracranial Hemorrhages; Male; Microglia; Middle Aged; Neurons; Phagocytosis; Phosphoproteins; Pulmonary Embolism; RNA, Viral; Renal Dialysis; Reverse Transcriptase Polymerase Chain Reaction; SARS-CoV-2; Spike Glycoprotein, Coronavirus; Survival Rate; T-Lymphocytes; Venous Thrombosis
PubMed: 33856027
DOI: 10.1093/brain/awab148 -
Brain : a Journal of Neurology Aug 2021The ageing brain is vulnerable to a wide array of neuropathologies. Prior work estimated that the three most studied of these, Alzheimer's disease, infarcts, and Lewy...
The ageing brain is vulnerable to a wide array of neuropathologies. Prior work estimated that the three most studied of these, Alzheimer's disease, infarcts, and Lewy bodies, account for ∼40% of the variation in late life cognitive decline. However, that estimate did not incorporate many other diseases that are now recognized as potent drivers of cognitive decline [e.g. limbic predominant age-related TDP-43 encephalopathy (LATE-NC), hippocampal sclerosis, other cerebrovascular conditions]. We examined the degree to which person-specific cognitive decline in old age is driven by a wide array of neuropathologies. Deceased participants (n = 1164) from two longitudinal clinical-pathological studies, the Rush Memory and Aging Project and Religious Orders Study, completed up to 24 annual evaluations including 17 cognitive performance tests and underwent brain autopsy. Neuropathological examinations provided 11 pathological indices, including markers of Alzheimer's disease, non- Alzheimer's disease neurodegenerative diseases (i.e. LATE-NC, hippocampal sclerosis, Lewy bodies), and cerebrovascular conditions (i.e. macroscopic infarcts, microinfarcts, cerebral amyloid angiopathy, atherosclerosis, and arteriolosclerosis). Mixed effects models examined the linear relation of pathological indices with global cognitive decline, and random change point models examined the relation of the pathological indices with the onset of terminal decline and rates of preterminal and terminal decline. Cognition declined an average of about 0.10 unit per year (estimate = -0.101, SE = 0.003, P < 0.001) with considerable heterogeneity in rates of decline (variance estimate for the person-specific slope of decline was 0.0094, P < 0.001). When considered separately, 10 of 11 pathological indices were associated with faster decline and accounted for between 2% and 34% of the variation in decline, respectively. When considered simultaneously, the 11 pathological indices together accounted for 43% of the variation in decline; Alzheimer's disease-related indices accounted for 30-36% of the variation, non-Alzheimer's disease neurodegenerative indices 4-10%, and cerebrovascular indices 3-8%. Finally, the 11 pathological indices combined accounted for less than a third of the variation in the onset of terminal decline (28%) and rates of preterminal (32%) and terminal decline (19%). Although age-related neuropathologies account for a large proportion of the variation in late life cognitive decline, considerable variation remains unexplained even after considering a wide array of neuropathologies. These findings highlight the complexity of cognitive ageing and have important implications for the ongoing effort to develop effective therapeutics and identify novel treatment targets.
Topics: Aged; Aged, 80 and over; Alzheimer Disease; Brain; Cerebral Arterial Diseases; Cognitive Dysfunction; Female; Humans; Male; Middle Aged; Neurodegenerative Diseases
PubMed: 33742668
DOI: 10.1093/brain/awab092 -
Frontiers in Neuroscience 2022Peak width of skeletonized mean diffusivity (PSMD) is a promising diffusion tensor imaging (DTI) marker that shows consistent and strong cognitive associations in the...
BACKGROUND
Peak width of skeletonized mean diffusivity (PSMD) is a promising diffusion tensor imaging (DTI) marker that shows consistent and strong cognitive associations in the context of different cerebral small vessel diseases (cSVD).
PURPOSE
Investigate whether PSMD (1) is higher in patients with Cerebral Amyloid Angiopathy (CAA) than those with arteriolosclerosis; (2) can capture the anteroposterior distribution of CAA-related abnormalities; (3) shows similar neuroimaging and cognitive associations in comparison to other classical DTI markers, such as average mean diffusivity (MD) and fractional anisotropy (FA).
MATERIALS AND METHODS
We analyzed cross-sectional neuroimaging and neuropsychological data from 90 non-demented memory-clinic subjects from a single center. Based on MRI findings, we classified them into probable-CAA (those that fulfilled the modified Boston criteria), subjects with MRI markers of cSVD not attributable to CAA (presumed arteriolosclerosis; cSVD), and subjects without evidence of cSVD on MRI (non-cSVD). We compared total and lobe-specific (frontal and occipital) DTI metrics values across the groups. We used linear regression models to investigate how PSMD, MD, and FA correlate with conventional neuroimaging markers of cSVD and cognitive scores in CAA.
RESULTS
PSMD was comparable in probable-CAA (median 4.06 × 10 mm/s) and cSVD (4.07 × 10 mm/s) patients, but higher than in non-cSVD (3.30 × 10 mm/s; < 0.001) subjects. Occipital-frontal PSMD gradients were higher in probable-CAA patients, and we observed a significant interaction between diagnosis and region on PSMD values [(2, 87) = 3.887, = 0.024]. PSMD was mainly associated with white matter hyperintensity volume, whereas MD and FA were also associated with other markers, especially with the burden of perivascular spaces. PSMD correlated with worse executive function (β = -0.581, < 0.001) and processing speed (β = -0.463, = 0.003), explaining more variance than other MRI markers. MD and FA were not associated with performance in any cognitive domain.
CONCLUSION
PSMD is a promising biomarker of cognitive impairment in CAA that outperforms other conventional and DTI-based neuroimaging markers. Although global PSMD is similarly increased in different forms of cSVD, PSMD's spatial variations could potentially provide insights into the predominant type of underlying microvascular pathology.
PubMed: 36440281
DOI: 10.3389/fnins.2022.1051038 -
Journal of Neuropathology and... Mar 2021Locus coeruleus (LC) neurodegeneration is associated with cognitive deterioration during the transition from normal cognition to mild cognitive impairment (MCI) and...
Locus coeruleus (LC) neurodegeneration is associated with cognitive deterioration during the transition from normal cognition to mild cognitive impairment (MCI) and Alzheimer disease (AD). However, the extent to which LC degenerative processes differentiate cognitively normal, "resilient" subjects bearing a high AD pathological burden from those with MCI or AD remains unclear. We approached this problem by quantifying the number of LC neurons and the percentage of LC neurons bearing AT8 tau pathology, TDP-43 pathology, or a marker for DNA/RNA oxidative damage, in well-characterized subjects diagnosed as normal cognition-low AD pathology (NC-LP), NC-high AD pathology (NC-HP), MCI, or mild/moderate AD. In addition, the severity of pontine arteriolosclerosis in each subject was compared across the groups. There was a trend for a step-wise ∼20% loss of LC neuron number between the NC-LP, NC-HP and MCI subjects despite a successive, significant ∼80%-100% increase in tau pathology between these groups. In contrast, increasing pontine arteriolosclerosis severity scores and LC oxidative stress burden significantly separated the NC-LP/HP and MCI/AD groups via comparative, correlation, and regression analysis. Pontine perfusion, as well as LC neuronal metabolic and redox function, may impact noradrenergic LC modulation of cognition during the preclinical and prodromal stages of AD.
Topics: Aged; Aged, 80 and over; Alzheimer Disease; Arteriolosclerosis; Brief Psychiatric Rating Scale; Cognitive Dysfunction; Cohort Studies; Diagnosis, Differential; Female; Humans; Locus Coeruleus; Male; Oxidative Stress; Pons; Resilience, Psychological
PubMed: 33709107
DOI: 10.1093/jnen/nlab017 -
Brain Pathology (Zurich, Switzerland) May 2021Limbic-predominant age-related transactive response DNA-binding protein 43 (TDP-43) encephalopathy neuropathologic change (LATE-NC) and microvascular pathologies,...
Limbic-predominant age-related transactive response DNA-binding protein 43 (TDP-43) encephalopathy neuropathologic change (LATE-NC) and microvascular pathologies, including microinfarcts, cerebral amyloid angiopathy (CAA), and arteriolosclerosis are common in old age. A relationship between LATE-NC and arteriolosclerosis has been reported in some but not all studies. The objectives of this study were to investigate the frequency of co-occurring LATE-NC and microvascular pathologies and test the hypothesis that arteriolosclerosis, specifically, is related to LATE-NC in brains from community-dwelling older persons. Analyses included 749 deceased participants with completed data on LATE-NC and microvascular pathology from 3 longitudinal clinical pathologic studies of aging. Given the specific interest in arteriolosclerosis, we expanded the examination of arteriolosclerosis to include not only the basal ganglia but also two additional white matter regions from anterior and posterior watershed territories. Ordinal logistic regression models examined the association of microvascular pathology with LATE-NC. LATE-NC was present in 409 (54.6%) decedents, of which 354 (86.5%) had one or multiple microvascular pathologies including 132 (32.3%) with moderate-severe arteriolosclerosis in basal ganglia, 195 (47.6%) in anterior watershed, and 144 (35.2%) in posterior watershed; 170 (41.5%) with moderate-severe CAA, and 150 (36.6%) with microinfarcts. In logistic regression models, only posterior watershed arteriolosclerosis, but not other regions of arteriolosclerosis was associated with a higher odds of more advanced LATE-NC stages (Odds Ratio = 1.12; 95% Confidence Interval = 1.01-1.25) after controlling for demographics, AD, and other age-related pathologies. Capillary CAA, but not the severity of CAA was associated with an increased odds of LATE-NC burden (Odds Ratio = 1.71; 95% Confidence Interval = 1.13-2.58). Findings were unchanged in analyses controlling for APOE ε4, vascular risk factors, or vascular diseases. These findings suggest that LATE-NC with microvascular pathology is a very common mixed pathology and small vessel disease pathology may contribute to LATE-NC in the aging brain.
Topics: Aged; Aged, 80 and over; Aging; Alzheimer Disease; Arteriolosclerosis; Brain; Brain Diseases; DNA-Binding Proteins; Female; Humans; Independent Living; Male; TDP-43 Proteinopathies
PubMed: 33624322
DOI: 10.1111/bpa.12939 -
Journal of Neuropathology and... Jan 2022Cerebrovascular disease (CVD) has been associated with cognitive impairment. Yet, our understanding of vascular contribution to cognitive decline has been limited by... (Observational Study)
Observational Study
Cerebrovascular disease (CVD) has been associated with cognitive impairment. Yet, our understanding of vascular contribution to cognitive decline has been limited by heterogeneity of definitions and assessment, as well as its occurrence in cognitively healthy aging. Therefore, we aimed to establish the natural progression of CVD associated with aging. We conducted a retrospective observational study of 63 cognitively healthy participants aged 19-84 years selected through the histological archives of the CHU de Québec. Assessment of CVD lesions was performed independently by 3 observers blinded to clinical data using the Vascular Cognitive Impairment Neuropathology Guidelines (VCING). We found moderate to almost perfect interobserver agreement for most regional CVD scores. Atherosclerosis (ρ = 0.758) and arteriolosclerosis (ρ = 0.708) showed the greatest significant association with age, followed by perivascular hemosiderin deposits (ρ = 0.432) and cerebral amyloid angiopathy (CAA; ρ = 0.392). Amyloid and tau pathologies were both associated with higher CVD load, but only CAA remained significantly associated with amyloid plaques after controlling for age. Altogether, these findings support the presence of multiple CVD lesions in the brains of cognitively healthy adults, the burden of which increases with age and can be quantified in a reproducible manner using standardized histological scales such as the VCING.
Topics: Adult; Aged; Aged, 80 and over; Aging; Brain; Cerebrovascular Disorders; Female; Humans; Male; Middle Aged; Observer Variation; Prevalence; Retrospective Studies; Severity of Illness Index
PubMed: 34875082
DOI: 10.1093/jnen/nlab125 -
JAMA Neurology Dec 2022It is not clear how common pure vascular cognitive impairment (VCI) is in the absence of Alzheimer disease (AD) and/or other neurodegenerative pathologies.
IMPORTANCE
It is not clear how common pure vascular cognitive impairment (VCI) is in the absence of Alzheimer disease (AD) and/or other neurodegenerative pathologies.
OBJECTIVE
To identify participants without AD and other neurodegenerative pathologies and determine the extent to which cerebrovascular disease pathologies were associated with cognitive impairment.
DESIGN, SETTING, AND PARTICIPANTS
This clinical pathological study included participants from 2 ongoing community-based cohorts that began enrollment in 1994 and 1997. Prior to death, participants were observed for a mean (SD) of 8.4 (5.3) years with annual assessments. From 2096 participants who died, 1799 (85.8%) underwent autopsy and 1767 had complete postmortem pathological examination data at the time of data analyses. To identify participants without neurodegenerative pathologies, we categorized them in 3 subgroups. A vascular subgroup was composed of participants without significant levels of neurodegenerative brain pathologies. A neurodegenerative subgroup was composed of participants without significant levels of cerebrovascular disease pathologies. A mixed subgroup was composed of the rest of the participants. Data were analyzed from May 2021 to July 2022.
EXPOSURES
Brain pathology indices obtained by postmortem pathological assessments.
MAIN OUTCOMES AND MEASURES
The primary outcome was cognitive impairment defined by presence of mild cognitive impairment or dementia. The secondary outcome was cognition assessed by 19 neuropsychological tests.
RESULTS
Of 1767 included participants, 1189 (67.3%) were women, and the mean (SD) age at death was 89.4 (6.6) years. In the vascular subgroup (n = 369), cognitive impairment was present in 156 participants (42.3%) and was associated with cerebrovascular disease pathologies (macroinfarcts: odds ratio [OR], 2.05; 95% CI, 1.49-2.82; P < .001; arteriolosclerosis in basal ganglia: OR, 1.35; 95% CI, 1.04-1.76; P = .03) but not AD or other neurodegenerative pathologies, an indication of pure VCI. In mixed-effects models including all the pathologies, only macroinfarcts were associated with a faster cognitive decline rate (estimate, -0.019; SE, 0.005; P < .001) in the vascular subgroup. Further analyses identified macroinfarcts in the frontal white matter to be associated with faster cognitive decline rate when macroinfarcts of cortical and subcortical brain regions were examined in a single model.
CONCLUSIONS AND RELEVANCE
In this study, pure VCI was not rare. Macroinfarcts, specifically in frontal white matter, were the main cerebrovascular disease pathologies associated with cognitive decline in pure VCI.
Topics: Female; Humans; Aged, 80 and over; Male; Cognitive Dysfunction; Alzheimer Disease; Brain; Neuropsychological Tests; Cerebrovascular Disorders
PubMed: 36279115
DOI: 10.1001/jamaneurol.2022.3472 -
Neurology Aug 2023The roles of Lewy body (LB) and separately of cerebrovascular disease (CVD) pathologies in the severity of parkinsonian signs are well recognized in old age. We...
BACKGROUND AND OBJECTIVES
The roles of Lewy body (LB) and separately of cerebrovascular disease (CVD) pathologies in the severity of parkinsonian signs are well recognized in old age. We investigated whether the 2 pathologies act synergistically to further potentiate the severity of parkinsonism beyond their separate effects.
METHODS
We used postmortem data of decedents from 3 longitudinal community-based studies of aging who underwent annual clinical evaluation to assess parkinsonian signs using 26 items of the motor portion of a modified Unified Parkinson Disease Rating Scale. A summary score was developed from each item score to construct a global parkinsonian score, with a higher score indicating more severe parkinsonism. A detailed neuropathologic evaluation was performed to identify LB, Alzheimer disease pathology, nigral neuronal loss, atherosclerosis, macroscopic infarcts, and other CVD pathologies (arteriolosclerosis, cerebral amyloid angiopathy, and microscopic infarcts). A series of regression models with terms for LB, CVD pathology, and the interaction of LB with CVD pathologies was fit for global parkinsonism proximate to death and for individual parkinsonian signs scores including, parkinsonian gait, rigidity, tremor, and bradykinesia.
RESULTS
In 1,753 participants (mean age at death = 89 years; 68% women), LB was observed in 26% of participants, and CVD pathologies were present in more than two-thirds of participants. LB and 3 CVD pathologies (atherosclerosis, arteriolosclerosis, and macroscopic infarcts) were each independently associated with the severity of global parkinsonism proximate to death (LB: β = 0.318, SE = 0.08, < 0.001; atherosclerosis: β = 0.373, SE = 0.079, < 0.001; arteriolosclerosis: β = 0.253, SE = 0.078, = 0.001; macroscopic infarcts: β = 0.333, SE = 0.077, < 0.001). A linear regression model adjusted for demographics, CVD, and neurodegenerative pathologies showed interaction between LB and macroscopic infarcts (β = 0.463, SE = 0.168, = 0.006), with LBs being associated with worse global parkinsonism when macroinfarcts are present. Similar interactions were found for atherosclerosis and LBs (β = 0.371, SE = 0.173, = 0.032) and for parkinsonian gait as the outcome (macroscopic infarcts: β = 0.662, SE = 0.239, = 0.005; atherosclerosis: β = 0.509, SE = 0.246, = 0.038). Findings were not affected when the 66 participants with a clinical diagnosis of Parkinson disease were excluded. By contrast, there were no interactions between LB and other CVD pathologies or between atherosclerosis and macroscopic infarcts for global parkinsonism proximate to death.
DISCUSSION
These findings suggest that atherosclerosis and macroscopic infarcts interact with LB pathology to increase the severity of parkinsonism beyond their additive effects in older persons.
Topics: Humans; Female; Aged; Aged, 80 and over; Male; Parkinson Disease; Lewy Bodies; Arteriolosclerosis; Independent Living; Parkinsonian Disorders; Cerebrovascular Disorders; Atherosclerosis; Infarction
PubMed: 37438127
DOI: 10.1212/WNL.0000000000207497 -
Journal Der Deutschen Dermatologischen... Nov 2023Diagnostic work-up of leg ulcers is time- and cost-intensive. This study aimed at evaluating ulcer location as a diagnostic criterium and providing a diagnostic...
BACKGROUND
Diagnostic work-up of leg ulcers is time- and cost-intensive. This study aimed at evaluating ulcer location as a diagnostic criterium and providing a diagnostic algorithm to facilitate differential diagnosis.
PATIENTS AND METHODS
The study consisted of 277 patients with lower leg ulcers. The following five groups were defined: Venous leg ulcer, arterial ulcers, mixed ulcer, arteriolosclerosis, and vasculitis. Using computational surface rendering, predilection sites of different ulcer types were evaluated. The results were integrated in a multinomial logistic regression model to calculate the likelihood of a specific diagnosis depending on location, age, bilateral involvement, and ulcer count. Additionally, neural network image analysis was performed.
RESULTS
The majority of venous ulcers extended to the medial malleolar region. Arterial ulcers were most frequently located on the dorsal aspect of the forefoot. Arteriolosclerotic ulcers were distinctly localized at the middle third of the lower leg. Vasculitic ulcers appeared to be randomly distributed and were markedly smaller, multilocular and bilateral. The multinomial logistic regression model showed an overall satisfactory performance with an estimated accuracy of 0.68 on unseen data.
CONCLUSIONS
The presented algorithm based on ulcer location may serve as a basic tool to narrow down potential diagnoses and guide further diagnostic work-up.
Topics: Humans; Ulcer; Leg Ulcer; Varicose Ulcer; Leg; Algorithms
PubMed: 37658661
DOI: 10.1111/ddg.15192