Neuropathological Changes Research Articles

Neighborhood disadvantage reduces cognitive reserve independent of neuropathologic change.

Individuals in socioeconomically disadvantaged neighborhoods exhibit increased risk for impaired cognitive function. Whether this association relates to the major dementia-related neuropathologies is unknown. This cross-sectional study included 469 autopsy cases from 2011 to 2023. The relationships between neighborhood disadvantage measured by Area Deprivation Index (ADI) percentiles categorized into tertiles, cognition evaluated by the last Mini-Mental State Examination (MMSE) scores before death, and 10 dementia-associated proteinopathies and cerebrovascular disease were assessed using regression analyses. Higher ADI was significantly associated with lower MMSE score. This was mitigated by increasing years of education. ADI was not associated with an increase in dementia-associated neuropathologic change. Moreover, the significant association between ADI and cognition remained even after controlling for changes in major dementia-associated proteinopathies or cerebrovascular disease. Neighborhood disadvantage appears to be associated with decreased cognitive reserve. This association is modified by education but is independent of the major dementia-associated neuropathologies.

Association of PM2.5 Exposure and Alzheimer Disease Pathology in Brain Bank Donors-Effect Modification by APOE Genotype.

Fine particulate matter (PM2.5) exposure has been found to be associated with Alzheimer disease (AD) and is hypothesized to cause inflammation and oxidative stress in the brain, contributing to neuropathology. The APOE gene, a major genetic risk factor of AD, has been hypothesized to modify the association between PM2.5 and AD. However, little prior research exists to support these hypotheses. This study investigates the association between traffic-related PM2.5 and AD hallmark pathology, including effect modification by APOE genotype, in an autopsy cohort. A cross-sectional study was conducted using brain tissue donors enrolled in the Emory Goizueta AD Research Center who died before 2020 (n = 224). Donors were assessed for AD pathology including the Braak stage, Consortium to Establish a Registry for AD (CERAD) score, and combined AD neuropathologic change (ABC) score. Traffic-related PM2.5 concentrations were modeled for the metro-Atlanta area during 2002-2019 with a spatial resolution of 200-250 m. One-year, 3-year, and 5-year average PM2.5 concentrations before death were matched to participants' home address. We assessed the association between traffic-related PM2.5 and AD hallmark pathology and effect modification by APOE genotype, using adjusted ordinal logistic regression models. Among the 224 participants, the mean age of death was 76 years, and 57% had at least 1 APOE ε4 copy. Traffic-related PM2.5 was significantly associated with the CERAD score for the 1-year exposure window (odds ratio [OR] 1.92; 95% CI 1.12-3.30) and the 3-year exposure window (OR 1.87; 95% CI 1.01-3.17). PM2.5 was also associated with higher Braak stage and ABC score albeit nonsignificantly. The strongest associations between PM2.5 and neuropathology markers were among those without APOE ε4 alleles (e.g., for the CERAD score and 1-year exposure window, OR 2.31; 95% CI 1.36-3.94), though interaction between PM2.5 and APOE genotype was not statistically significant. Our study found traffic-related PM2.5 exposure was associated with the CERAD score in an autopsy cohort, contributing to epidemiologic evidence that PM2.5 affects β-amyloid deposition in the brain. This association was particularly strong among donors without APOE ε4 alleles. Future studies should further investigate the biological mechanisms behind this association.

MCC950 Attenuates Microglial NLRP3-Mediated Chronic Neuroinflammation and Memory Impairment in a Rat Model of Repeated Low-Level Blast Exposure.

Blast-induced traumatic brain injury is typically regarded as a signature medical concern for military personnel who are exposed to explosive devices in active combat zones. However, soldiers as well as law enforcement personnel may be repeatedly exposed to low-level blasts during training sessions with heavy weaponries as part of combat readiness. Service personnel who sustain neurotrauma from repeated low-level blast (rLLB) exposure do not display overt pathological symptoms immediately but rather develop mild symptoms including cognitive impairments, attention deficits, mood changes, irritability, and sleep disturbances over time. Recently, we developed a rat model of rLLB by applying controlled low-level blast pressures (≤ 70 kPa) repeated five times successively to mimic the pressures experienced by service members. Using this model, we assessed anxiety-like symptoms, motor coordination, and short-term memory as a function of time. We also investigated the role of the NLRP3 inflammasome, a complex involved in chronic microglial activation and pro-inflammatory cytokine interleukin (IL)-1β release, in rLLB-induced neuroinflammation. NLRP3 and caspase-1 protein expression, microglial activation, and IL-1β release were examined as factors likely contributing to these neurobehavioral changes. Animals exposed to rLLB displayed acute and chronic short-term memory impairments and chronic anxiety-like symptoms accompanied by increased microglial activation, NLRP3 expression, and IL-1β release. Treatment with MCC950, an NLRP3 inflammasome complex inhibitor, suppressed microglial activation, reduced NLRP3 expression and IL-1β release, and improved short-term memory deficits after rLLB exposure. Collectively, this study demonstrates that rLLB induces chronic neurobehavioral and neuropathological changes by increasing NLRP3 inflammasome protein expression followed by cytokine IL-1β release.

Investigating neuropathological changes and underlying neurobiological mechanisms in the early stages of primary blast-induced traumatic brain injury: Insights from a rat model

The utilization of explosives and chemicals has resulted in a rise in blast-induced traumatic brain injury (bTBI) in recent times. However, there is a dearth of diagnostic biomarkers and therapeutic targets for bTBI due to a limited understanding of biological mechanisms, particularly in the early stages. The objective of this study was to examine the early neuropathological characteristics and underlying biological mechanisms of primary bTBI. A total of 83 Sprague Dawley rats were employed, with their heads subjected to a blast shockwave of peak overpressure ranging from 172 to 421 kPa in the GI, GII, and GIII groups within a closed shock tube, while the body was shielded. Neuromotor dysfunctions, morphological changes, and neuropathological alterations were detected through modified neurologic severity scores, brain water content analysis, MRI scans, histological, TUNEL, and caspase-3 immunohistochemical staining. In addition, label-free quantitative (LFQ)-proteomics was utilized to investigate the biological mechanisms associated with the observed neuropathology. Notably, no evident damage was discernible in the GII and GI groups, whereas mild brain injury was observed in the GIII group. Neuropathological features of bTBI were characterized by morphologic changes, including neuronal injury and apoptosis, cerebral edema, and cerebrovascular injury in the shockwave's path. Subsequently, 3153 proteins were identified and quantified in the GIII group, with subsequent enriched neurological responses consistent with pathological findings. Further analysis revealed that signaling pathways such as relaxin signaling, hippo signaling, gap junction, chemokine signaling, and sphingolipid signaling, as well as hub proteins including Prkacb, Adcy5, and various G-protein subunits (Gnai2, Gnai3, Gnao1, Gnb1, Gnb2, Gnb4, and Gnb5), were closely associated with the observed neuropathology. The expression of hub proteins was confirmed via Western blotting. Accordingly, this study proposes signaling pathways and key proteins that exhibit sensitivity to brain injury and are correlated with the early pathologies of bTBI. Furthermore, it highlights the significance of G-protein subunits in bTBI pathophysiology, thereby establishing a theoretical foundation for early diagnosis and treatment strategies for primary bTBI.

Clinically approved immunomodulators ameliorate behavioral changes in a mouse model of hereditary spastic paraplegia type 11.

We have previously demonstrated that neuroinflammation by the adaptive immune system acts as a robust and targetable disease amplifier in a mouse model of Spastic Paraplegia, type 11 (SPG11), a complicated form of Hereditary Spastic Paraplegia (HSP). While we identified an impact of neuroinflammation on distinct neuropathological changes and gait performance, neuropsychological features, typical and clinically highly relevant symptoms of complicated HSPs, were not addressed. Here we show that the corresponding SPG11 mouse model shows distinct behavioral abnormalities, particularly related to social behavior thus partially reflecting the neuropsychological changes in patients. We provide evidence that some behavioral abnormalities can be mitigated by genetic inactivation of the adaptive immune system. Translating this into a clinically applicable approach, we show that treatment with the established immunomodulators fingolimod or teriflunomide significantly attenuates distinct behavioral abnormalities, with the most striking effect on social behavior. This study links neuroinflammation to behavioral abnormalities in a mouse model of SPG11 and may thus pave the way for using immunomodulators as a treatment approach for SPG11 and possibly other complicated forms of HSP with neuropsychological involvement.

Regional AT-8 reactive tau species correlate with intracellular Aβ levels in cases of low AD neuropathologic change

The amyloid cascade hypothesis states that Aβ aggregates induce pathological changes in tau, leading to neurofibrillary tangles (NFTs) and cell death. A caveat with this hypothesis is the spatio-temporal divide between plaques and NFTs. This has been addressed by the inclusion of soluble Aβ and tau species in the revised amyloid cascade hypothesis. Nevertheless, despite the potential for non-plaque Aβ to contribute to tau pathology, few studies have examined relative correlative strengths between total Aβ, plaque Aβ and intracellular Aβ with tau pathology within a single tissue cohort. Employing frozen and fixed frontal cortex grey and white matter tissue from non-AD controls (Con; n = 39) and Alzheimer’s disease (AD) cases (n = 21), biochemical and immunohistochemical (IHC) measures of Aβ and AT-8 phosphorylated tau were assessed. Biochemical native-state dot blots from crude tissue lysates demonstrated robust correlations between total Aβ and AT-8 tau, when considered as a combined cohort (Con and AD) and when as Con and AD cases, separately. In contrast, no associations between Aβ plaques and AT-8 were reported when using IHC measurements in either Con or AD cases. However, when intracellular Aβ was measured via the Aβ specific antibody MOAB-2, a correlative relationship with AT-8 tau was reported in non-AD controls but not in AD cases. Collectively the data suggests that accumulating intracellular Aβ may influence AT-8 pathology, early in AD-related neuropathological change. Despite the lower levels of phospho-tau and Aβ in controls, the robust correlative relationships observed suggest a physiological association of Aβ production and tau phosphorylation, which may be modified during disease. This study is supportive of a revised amyloid cascade hypothesis and demonstrates regional associative relationships between tau pathology and intracellular Aβ, but not extracellular Aβ plaques.

Neuropathologic Burden and Dementia in Nonagenarians and Centenarians: Comparison of 2 Community-Based Cohorts

The aim of this study was to compare 2 large clinicopathologic cohorts of participants aged 90+ and to determine whether the association between neuropathologic burden and dementia in these older groups differs substantially from those seen in younger-old adults. Autopsied participants from The 90+ Study and Adult Changes in Thought (ACT) Study community-based cohort studies were evaluated for dementia-associated neuropathologic changes. Associations between neuropathologic variables and dementia were assessed using logistic or linear regression, and the weighted population attributable fraction (PAF) per type of neuropathologic change was estimated. The 90+ Study participants (n = 414) were older (mean age at death = 97.7 years) and had higher amyloid/tau burden than ACT <90 (n = 418) (mean age at death = 83.5 years) and ACT 90+ (n = 401) (mean age at death = 94.2 years) participants. The ACT 90+ cohort had significantly higher rates of limbic-predominant age-related TDP-43 encephalopathy (LATE-NC), microvascular brain injury (μVBI), and total neuropathologic burden. Independent associations between individual neuropathologic lesions and odds of dementia were similar between all 3 groups, with the exception of μVBI, which was associated with increased dementia risk in the ACT <90 group only (odds ratio 1.5, 95% CI 1.2-1.8, p < 0.001). Weighted PAF scores indicated that eliminating μVBI, although more prevalent in ACT 90+ participants, would have little effect on dementia. Conversely, eliminating μVBI in ACT <90 could theoretically reduce dementia at a similar rate to that of AD neuropathologic change (weighted PAF = 6.1%, 95% CI 3.8-8.4, p = 0.001). Furthermore, reducing LATE-NC in The 90+ Study could potentially reduce dementia to a greater degree (weighted PAF = 5.1%, 95% CI 3.0-7.3, p = 0.001) than either ACT cohort (weighted PAFs = 1.69, 95% CI 0.4-2.7). Our results suggest that specific neuropathologic features may differ in their effect on dementia among nonagenarians and centenarians from cohorts with different selection criteria and study design. Furthermore, microvascular lesions seem to have a more significant effect on dementia in younger compared with older participants. The results from this study demonstrate that different populations may require distinct dementia interventions, underscoring the need for disease-specific biomarkers.

Differential DNA methylation in the brain as potential mediator of the association between traffic-related PM2.5 and neuropathology markers of Alzheimer's disease.

Growing evidence indicates that fine particulate matter (PM2.5) is a risk factor for Alzheimer's disease (AD), but the underlying mechanisms have been insufficiently investigated. We hypothesized differential DNA methylation (DNAm) in brain tissue as a potential mediator of this association. We assessed genome-wide DNAm (Illumina EPIC BeadChips) in prefrontal cortex tissue and three AD-related neuropathological markers (Braak stage, CERAD, ABC score) for 159 donors, and estimated donors' residential traffic-related PM2.5 exposure 1, 3, and 5 years prior to death. We used a combination of the Meet-in-the-Middle approach, high-dimensional mediation analysis, and causal mediation analysis to identify potential mediating CpGs. PM2.5 was significantly associated with differential DNAm at cg25433380 and cg10495669. Twenty-four CpG sites were identified as mediators of the association between PM2.5 exposure and neuropathology markers, several located in genes related to neuroinflammation. Our findings suggest differential DNAm related to neuroinflammation mediates the association between traffic-related PM2.5 and AD. First study to evaluate the potential mediation effect of DNA methylation for the association between PM2.5 exposure and neuropathological changes of Alzheimer's disease. Study was based on brain tissues rarely investigated in previous air pollution research. Cg10495669, assigned to RBCK1 gene playing a role in inflammation, was associated consistently with 1-year, 3-year, and 5-year traffic-related PM2.5 exposures prior to death. Meet-in-the-middle approach and high-dimensional mediation analysis were used simultaneously to increase the potential of identifying the differentially methylated CpGs. Differential DNAm related to neuroinflammation was found to mediate the association between traffic-related PM2.5 and Alzheimer's disease.

Cryptic exon inclusion is a molecular signature of LATE-NC in aging brains

The aggregation, mislocalization, and phosphorylation of TDP-43 are pathologic hallmarks of several neurodegenerative diseases and provide a defining criterion for the neuropathologic diagnosis of Limbic-predominant Age-related TDP-43 Encephalopathy (LATE). LATE neuropathologic changes (LATE-NC) are often comorbid with other neurodegenerative pathologies including Alzheimer’s disease neuropathologic changes (ADNC). We examined whether TDP-43 regulated cryptic exons accumulate in the hippocampus of neuropathologically confirmed LATE-NC cases. We found that several cryptic RNAs are robustly expressed in LATE-NC cases with or without comorbid ADNC and correlate with pTDP-43 abundance; however, the accumulation of cryptic RNAs is more robust in LATE-NC with comorbid ADNC. Additionally, cryptic RNAs can robustly distinguish LATE-NC from healthy controls and AD cases. These findings expand our current understanding and provide novel potential biomarkers for LATE pathogenesis.

Abstract TP306: Anemia Causes Hematoma Expansion, Cerebral Hypoxia-Driven Microglial Activation, and Early Mortality in Mice With Intracerebral Hemorrhage

Anemic intracerebral hemorrhage (ICH) patients are observed to have poor clinical outcomes with increased risk of hematoma expansion (HE) and impaired cerebral oxygenation. To assess whether anemia causes these observations, we assessed neuroimaging evidence of HE and neuropathological changes of hypoxia and blood brain barrier (BBB) dysfunction in anemic vs non-anemic mice with ICH. Anemia was generated in 3 month old female C57/BL6 mice using iron-deficient chow. Age and sex-matched controls were fed iron-replete control diet. Anemia was verified using modified Drabkin assays. Collagenase was used to induce ICH. ICH volume and HE were quantified using serial T2-weighed MRI at 1, 4, and 24 hours after ICH. Early 24 hour mortality was recorded. After the last MRI, surviving mice were euthanized by intracardiac perfusion and the brain was processed for histological analysis of vascular permeability (IgG), microglia number and activation (Iba1 and CD68), and response to hypoxia (HIF1α). Statistical analyses were performed using two-tailed ANOVA. Compared to controls, anemic mice displayed larger final ICH lesion volumes (anemia: 7.7 mm 3 vs control: 6.1 mm 3 ), greater HE at 24 hours (anemia: 111.4% vs control: 23.6%) and increased early mortality (anemia: 30% vs control: 0%). Histological analyses revealed that, while microglial activation and BBB permeability to serum IgGs in control mice were restricted to the ipsilateral hemisphere and mostly localized perilesionally, anemic mice had increased immune infiltration and increased BBB permeability in both hemispheres. Similarly, non-ICH anemic mice showed increased and widespread immune cell infiltration and increased BBB permeability compared to non-ICH control mice, suggesting that consistently low hemoglobin concentrations may increase cerebrovascular susceptibility to injury.Future studies will be needed to further clarify cellular and molecular mechanisms driving our findings and whether anemia can be a treatable target to improve ICH outcomes.

Amelioration of the brain structural connectivity is accompanied with changes of gut microbiota in a tuberous sclerosis complex mouse model

Tuberous sclerosis complex (TSC) is a genetic disease that causes benign tumors and dysfunctions in many organs, including the brain. Aside from the brain malformations, many individuals with TSC exhibit neuropsychiatric symptoms. Among these symptoms, autism spectrum disorder (ASD) is one of the most common co-morbidities, affecting up to 60% of the population. Past neuroimaging studies strongly suggested that the impairments in brain connectivity contribute to ASD, whether or not TSC-related. Specifically, the tract-based diffusion tensor imaging (DTI) analysis provides information on the fiber integrity and has been used to study the neuropathological changes in the white matter of TSC patients with ASD symptoms. In our previous study, curcumin, a diet-derived mTOR inhibitor has been shown to effectively mitigate learning and memory deficits and anxiety-like behavior in Tsc2+/− mice via inhibiting astroglial proliferation. Recently, gut microbiota, which is greatly influenced by the diet, has been considered to play an important role in regulating several components of the central nervous system, including glial functions. In this study, we showed that the abnormal social behavior in the Tsc2+/− mice can be ameliorated by the dietary curcumin treatment. Second, using tract-based DTI analysis, we found that the Tsc2+/− mice exhibited altered fractional anisotropy, axial and radial diffusivities of axonal bundles connecting the prefrontal cortex, nucleus accumbens, hypothalamus, and amygdala, indicating a decreased brain network. Third, the dietary curcumin treatment improved the DTI metrics, in accordance with changes in the gut microbiota composition. At the bacterial phylum level, we showed that the abundances of Actinobacteria, Verrucomicrobia, and Tenericutes were significantly correlated with the DTI metrics FA, AD, and RD, respectively. Finally, we revealed that the expression of myelin-associated proteins, myelin bassic protein (MBP) and proteolipid protein (PLP) was increased after the treatment. Overall, we showed a strong correlation between structural connectivity alterations and social behavioral deficits, as well as the diet-dependent changes in gut microbiota composition.

Neem Leaf Supplement Ameliorates Depressive Like Behaviour in Alzheimer’s Disease Model in Adult Male Wistar Rats

Aim of the Study: Currently, reports linked neuropathological changes in Alzheimer’s Disease (AD) to be a risk factor in depression. There is a need to develop natural therapeutics, with strong antioxidant property like Neem leaf, to avert AD’s neuropathological and behavioural changes using animal model induced by neurotoxin aluminium chloride. This study is aimed at ascertaining depressive like disorders in AD model while evaluating mechanism through which Neem averts AD neurodegeneration in the fronto-cerebellar cortex and possible depressive like behaviour. Methodology: Twenty (20) adult male Wistar rats used were grouped (n=5) viz: control group (A), neurodegenerative model given aluminium (B), 200mg/kg Neem leaf supplement (C) and 200mg/kg Neem leaf treated AD model (D). Neurobehavioural changes for reward memory and depressive like behaviour were evaluated using Y-maze (open arm reward test) and the tail suspension test (TST). The frontal and cerebellar cortices were excised, fixed and processed for Haematoxylin and Eosin stain (H and E), Cresyl fast violet (CFV) stain for Nissl bodies and astrocytes immunohistochemistry using glial fibrillary acidic protein (GFAP). Behavioural test data were analyzed using ANOVA and test for significance done @ p&lt;0.05. Results: Aluminum induced neurodegeneration similar to AD pathology characterized by loss of neurons, chromatolysis, proliferation of astrocytes and decline in cognitive function in addition to exhibiting depressive like behaviour seen in a decrease number of reward arm entries, increase in time spent to reach reward arm and immobility time in the TST attributed to loss of cognitive function relative to loss of neurons integrity in the fronto-cerebellar cortex. However, neem leaf supplementation mitigates against AD model neuropathological and neurobehavioural presentations resulting in an improved neurocognition, neuron survival or repair, decline in astrocytes proliferation and decline in depressive like behavior as compared to Aluminum induced AD model. Conclusion: Neem leaf alleviates depressive like behaviour associated with neurocognitive impairment through the interaction between neuron-astrocytes to protect neurons against aluminum induced neuroinflamamation and strengthens neural circuit for cognitive function.

Association between white matter hyperintensities and altered cerebral blood flow in maintenance hemodialysis patients: a longitudinal study

ObjectivesTo explore changes in cerebral blood flow (CBF) and white matter in hemodialysis patients.MethodsThirty-three hemodialysis patients who underwent two brain MRI at an interval of three years and 33 age- and sex-matched healthy controls (HC) underwent structural and arterial spin-labeling MRI examinations. Intergroup differences in CBF in the gray matter, white matter, and whole matter, and regional white matter hyperintensities (WMH) were analyzed. Based on the changes in CBF between the baseline and follow-up groups, the hemodialysis patients were divided into two subgroups: an increased CBF group and a decreased CBF group. Differences in CBF and WMH between the subgroups and HC were analyzed.ResultsPatients undergoing hemodialysis exhibited increased cerebral watershed (CW) WMH, deep WMH, and periventricular WMH (P < 0.01). The CBF of patients with decreased CBF was higher than that of HC at baseline (,P < 0.01) and lower than that of HC at follow-up (P < 0.01). Compared with the increased CBF group, obvious development of deep WMH was found in the decreased CBF group for the gray matter, white matter, and whole matter (P < 0.01).ConclusionsWMH in hemodialysis patients were distributed in the deep white matter, periventricular white matter and CW, and progressed with the extension of hemodialysis duration. CBF in hemodialysis patients could manifest as both increased and decreased, and WMH in patients with decreased CBF developed severely with prolongation of hemodialysis duration.Advances in knowledgeThese findings provide a basis for exploring neuropathological changes of hemodialysis patients.

Examining the New Consensus Criteria for Traumatic Encephalopathy Syndrome in Community-Dwelling Older Adults.

In 2021, an expert panel of clinician-scientists published the first consensus research diagnostic criteria for traumatic encephalopathy syndrome (TES), a clinical condition thought to be associated with chronic traumatic encephalopathy neuropathological change. This study evaluated the TES criteria in older adults and assessed associations between TES criteria and a history of repetitive head impacts. This cross-sectional, survey-based study examined the symptoms of TES, previous repetitive head impacts, and a variety of current health difficulties. To meet symptom criteria for TES, participants had to report progressive changes with memory, executive functioning, and/or neurobehavioral dysregulation. To meet the criterion for substantial exposure to repetitive head impacts via contact sports, participants reported at least 5 years of contact sport exposure (with 2+ years in high school or beyond). A sample of 507 older adults (mean age = 70.0 years, 65% women) completed the survey and 26.2% endorsed having one or more of the progressive core clinical features of TES. Those who had a significant history of contact sport exposure were not significantly more likely to meet TES criteria compared with those who did not (31.3% vs. 25.3%, p = 0.46). In a binary logistic regression predicting TES status, current depression or anxiety (odds ratio [OR] = 12.55; 95% confidence interval [CI] = 4.43-35.51), history of psychiatric disorders (OR = 2.07, 95% CI = 1.22-3.49), male sex (OR = 1.87), and sleep problems (OR = 1.71, 95% CI = 1.01-2.91) were associated with meeting TES criteria. The sport exposure criterion, age, and current pain were not significantly associated with TES status (ps > 0.05). A significant minority of participants with no history of neurotrauma endorsed symptoms consistent with TES (22.0% of men and 19.8% of women). Nearly 80% of neurotrauma naïve participants with clinically significant anxiety/depression met criteria for TES. In summary, approximately one in four older adults met the symptom criteria for TES, many of whom had no history of repetitive neurotrauma. Mental health problems and sleep issues were associated with TES, whereas having a history of repetitive head impacts in contact sports was not. These data suggest that the new consensus diagnostic criteria for TES may have low specificity and may carry a higher risk of misdiagnosing those with other physical and mental health conditions as having TES.

Tau maturation in the clinicopathological spectrum of Lewy body and Alzheimer's disease.

Alzheimer's disease neuropathologic change and alpha-synucleinopathy commonly co-exist and contribute to the clinical heterogeneity of dementia. Here, we examined tau epitopes marking various stages of tangle maturation to test the hypotheses that tau maturation is more strongly associated with beta-amyloid compared to alpha-synuclein, and within the context of mixed pathology, mature tau is linked to Alzheimer's disease clinical phenotype and negatively associated with Lewy body dementia. We used digital histology to measure percent area-occupied by pathology in cortical regions among individuals with pure Alzheimer's disease neuropathologic change, pure alpha-synucleinopathy, and a co-pathology group with both Alzheimer's and alpha-synuclein pathologic diagnoses. Multiple tau monoclonal antibodies were used to detect early (AT8, MC1) and mature (TauC3) epitopes of tangle progression. We used linear/logistic regression to compare groups and test the association between pathologies and clinical features. There were lower levels of tau pathology (β = 1.86-2.96, p < 0.001) across all tau antibodies in the co-pathology group compared to the pure Alzheimer's pathology group. Among individuals with alpha-synucleinopathy, higher alpha-synuclein was associated with greater early tau (AT8 β = 1.37, p < 0.001; MC1 β = 1.2, p < 0.001) but not mature tau (TauC3 p = 0.18), whereas mature tau was associated with beta-amyloid (β = 0.21, p = 0.01). Finally, lower tau, particularly TauC3 pathology, was associated with lower frequency of both core clinical features and categorical clinical diagnosis of dementia with Lewy bodies. Mature tau may be more closely related to beta-amyloidosis than alpha-synucleinopathy, and pathophysiological processes of tangle maturation may influence the clinical features of dementia in mixed Lewy-Alzheimer's pathology.

Pathologic correlates of aging-related tau astrogliopathy: ARTAG is associated with LATE-NC and cerebrovascular pathologies, but not with ADNC

Age-related tau astrogliopathy (ARTAG) is detectable in the brains of over one-third of autopsied persons beyond age 80, but the pathoetiology of ARTAG is poorly understood. Insights can be gained by analyzing risk factors and comorbid pathologies. Here we addressed the question of which prevalent co-pathologies are observed with increased frequency in brains with ARTAG. The study sample was the National Alzheimer's Coordinating Center (NACC) data set, derived from multiple Alzheimer's disease research centers (ADRCs) in the United States. Data from persons with unusual conditions (e.g. frontotemporal dementia) were excluded leaving 504 individual autopsied research participants, clustering from 20 different ADRCs, autopsied since 2020; ARTAG was reported in 222 (44.0%) of included participants. As has been shown previously, ARTAG was increasingly frequent with older age and in males. The presence and severity of other common subtypes of pathology that were previously linked to dementia were analyzed, stratifying for the presence of ARTAG. In logistical regression-based statistical models that included age and sex as covariates, ARTAG was relatively more likely to be found in brains with limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC), and in brains with comorbid cerebrovascular pathology (arteriolosclerosis and/or brain infarcts). However, ARTAG was not associated with severe Alzheimer's disease neuropathologic change (ADNC), or primary age-related tauopathy (PART). In a subset analysis of 167 participants with neurocognitive testing data, there was a marginal trend for ARTAG pathology to be associated with cognitive impairment as assessed with MMSE scores (P = 0.07, adjusting for age, sex, interval between final clinic visit and death, and ADNC severity). A limitation of the study was that there were missing data about ARTAG pathologies, with incomplete operationalization of ARTAG according to anatomic region and pathologic subtypes (e.g., thorn-shaped or granular-fuzzy astrocytes). In summary, ARTAG was not associated with ADNC, whereas prior observations about ARTAG occurring with increased frequency in aging, males, and brains with LATE-NC were replicated. It remains to be determined whether the increased frequency of ARTAG in brains with comorbid cerebrovascular pathology is related to local infarctions or neuroinflammatory signaling, or with some other set of correlated factors including blood-brain barrier dysfunction.

The influence of limbic-predominant age-related TDP-43 encephalopathy on argyrophilic grain disease: A voxel-based morphometry analysis of pathologically confirmed cases

BackgroundThe influence of limbic-predominant age-related TAR DNA-binding protein of 43 kDa encephalopathy neuropathological change (LATE-NC) on structural alterations in argyrophilic grain disease (AGD) have not been documented. This study aimed to investigate the morphological impact of LATE-NC on AGD through voxel-based morphometry (VBM) technique. Materials and methodsFifteen individuals with pathologically verified AGD, comprising 6 with LATE-NC (comorbid AGD [cAGD]) and 9 without LATE-NC (pure AGD [pAGD]), along with 10 healthy controls (HC) were enrolled. Whole-brain 3D-T1-weighted images were captured and preprocessed utilizing the Computational Anatomy Toolbox 12. VBM was employed to compare gray matter volume among (i) pAGD and HC, (ii) cAGD and HC, and (iii) pAGD and cAGD. ResultsIn comparison to HC, the pAGD group exhibited slightly asymmetric gray matter volume loss, particularly in the ambient gyrus, amygdala, hippocampus, anterior cingulate gyrus, and insula. Alternatively, the cAGD group exhibited greater gray matter volume loss, with a predominant focus on the inferolateral regions encompassing the ambient gyrus, amygdala, hippocampus, and the inferior temporal area, including the anterior temporal pole. The atrophy of the bilateral anterior temporal pole and right inferior temporal gyrus persisted when contrasting the pAGD and cAGD groups. ConclusionComorbidity with LATE-NC is linked to different atrophic distribution, particularly affecting the inferolateral regions in AGD. Consequently, the consideration of comorbid LATE-NC is crucial in individuals with AGD exhibiting more widespread temporal atrophy.

A circRNA ceRNA network involved in cognitive dysfunction after chronic cerebral hypoperfusion.

Chronic Cerebral Hypoperfusion (CCH) is associated with cognitive dysfunction, the underlying mechanisms of which remain elusive, hindering the development of effective therapeutic approaches. In this study, we employed an established CCH animal model to delve into neuropathological alterations like oxidative stress, inflammation, neurotransmitter synthesis deficits, and other morphological alterations. Our findings revealed that while the number of neurons remained unchanged, there was a significant reduction in neuronal fibers post-CCH, as evidenced by microtubule-associated protein 2 (MAP2) staining. Moreover, myelin basic protein (MBP) staining showed exacerbated demyelination of neuronal fibers. Furthermore, we observed increased neuroinflammation, proliferation, and activation of astrocytes and microglia, as well as synaptic loss and microglial-mediated synapse engulfment post-CCH. Utilizing RNA sequencing, differential expression analysis displayed alterations in both mRNAs and circRNAs. Following gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses, both showed significant enrichment in immunological and inflammation-related terms and pathways. Importantly, the differentially expressed circular RNAs (DE circRNAs) exhibited a notable coexpression pattern with DE mRNAs. The ternary circRNA-miRNA-mRNA competing endogenous RNAs (ceRNA) network was constructed, and subsequent analysis reiterated the significance of neuroimmunological and neuroinflammatory dysfunction in CCH-induced neuropathological changes and cognitive dysfunction. This study underscores the potential role of circRNAs in these processes, suggesting them as promising therapeutic targets to mitigate the detrimental effects of CCH.

TDP-43 and Alzheimer's Disease Pathology in the Brain of a Harbor Porpoise Exposed to the Cyanobacterial Toxin BMAA.

Cetaceans are well-regarded as sentinels for toxin exposure. Emerging studies suggest that cetaceans can also develop neuropathological changes associated with neurodegenerative disease. The occurrence of neuropathology makes cetaceans an ideal species for examining the impact of marine toxins on the brain across the lifespan. Here, we describe TAR DNA-binding protein 43 (TDP-43) proteinopathy and Alzheimer's disease (AD) neuropathological changes in a beached harbor porpoise (Phocoena phocoena) that was exposed to a toxin produced by cyanobacteria called β-N-methylamino-L-alanine (BMAA). We found pathogenic TDP-43 cytoplasmic inclusions in neurons throughout the cerebral cortex, midbrain and brainstem. P62/sequestosome-1, responsible for the autophagy of misfolded proteins, was observed in the amygdala, hippocampus and frontal cortex. Genes implicated in AD and TDP-43 neuropathology such as APP and TARDBP were expressed in the brain. AD neuropathological changes such as amyloid-β plaques, neurofibrillary tangles, granulovacuolar degeneration and Hirano bodies were present in the hippocampus. These findings further support the development of progressive neurodegenerative disease in cetaceans and a potential causative link to cyanobacterial toxins. Climate change, nutrient pollution and industrial waste are increasing the frequency of harmful cyanobacterial blooms. Cyanotoxins like BMAA that are associated with neurodegenerative disease pose an increasing public health risk.

Age and beta amyloid deposition impact gait speed, stride length, and gait smoothness while transitioning from an even to an uneven walking surface in older adults

BackgroundCapturing a measure of movement quality during a complex walking task may indicate the earliest signs of detrimental changes to the brain due to beta amyloid (Aβ) deposition and be a potential differentiator of older adults at elevated and low risk of developing Alzheimer's disease. This study aimed to determine: 1) age-related differences in gait speed, stride length, and gait smoothness while transitioning from an even to an uneven walking surface, by comparing young adults (YA) and older adults (OA), and 2) if gait speed, stride length, and gait smoothness in OA while transitioning from an even to an uneven walking surface is influenced by the amount of Aβ deposition present in an OA's brain. MethodsParticipants included 56 OA (>70 years of age) and 29 YA (25–35 years of age). In OA, Aβ deposition in the brain was quantified by PET imaging. All participants completed a series of cognitive assessments, a functional mobility assessment, and self-report questionnaires. Then participants performed two sets of walking trials on a custom-built walkway containing a mixture of even and uneven surface sections, including three trials with a grass uneven surface and three trials with a rocks uneven surface. Gait data were recorded using a wireless inertial measurement unit system. Stride length, gait speed, and gait smoothness (i.e., log dimensionless lumbar jerk) in the anteroposterior (AP), mediolateral (ML), and vertical (VT) directions were calculated for each stride. Outcomes were retained for five stride locations immediately surrounding the surface transition. ResultsOA exhibited slower gait (Grass: p < 0.001; Rocks: p = 0.006), shorter strides (Grass: p < 0.001; Rocks: p = 0.008), and smoother gait (Grass AP: p < 0.001; Rocks AP: p = 0.002; Rocks ML: p = 0.02) than YA, but they also exhibited greater reductions in gait speed and stride length than YA while transitioning to the uneven grass and rocks surfaces. Within the OA group, those with greater Aβ deposition exhibited decreases in smoothness with age (Grass AP: p = 0.02; Rocks AP: p = 0.03; Grass ML: p = 0.04; Rocks ML: p = 0.03), while those with lower Aβ deposition exhibited increasing smoothness with age (Grass AP: p = 0.01; Rocks AP: p = 0.02; Grass ML: p = 0.08; Rocks ML: p = 0.07). Better functional mobility was associated with less smooth gait (Grass ML: p = 0.02; Rocks ML: p = 0.05) and with less variable gait smoothness (Grass and Rocks AP: both p = 0.04) in the OA group. ConclusionThese results suggest that, relative to YA, OA may be adopting more cautious, compensatory gait strategies to maintain smoothness when approaching surface transitions. However, OA with greater Aβ deposition may have limited ability to adopt compensatory gait strategies to increase the smoothness of their walking as they get older because of neuropathological changes altering the sensory integration process and causing worse dynamic balance (i.e., jerkier gait). Functional mobility, in addition to age and Aβ deposition, may be an important factor of whether or not an OA chooses to employ compensatory strategies to prioritize smoothness while walking and what type of compensatory strategy an OA chooses.