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Introduction: The aged brain frequently exhibits multiple pathologies, rather than a single hallmark pathology (pure pathology [PurP]), ranging from low/intermediate levels of additional pathology (LowP) to mixed severe pathology (mixed SevP). We investigated the frequency of PurP, LowP, and mixed SevP, and the impact of additional LowP on cognition. Methods: Data came from 670 cases from the Brains for Dementia research program. Cases were categorized into PurP, mixed SevP, or a main disease with additional LowP; 508 cases had a clinical dementia rating. Results: 69.9% of cases had LowP, 22.7% had PurP, and 7.5% had mixed SevP. Additional LowP increased the likelihood of having mild dementia versus mild cognitive impairment (MCI) by almost 20‐fold (odds ratio = 19.5). Discussion: Most aged individuals have multiple brain pathologies. The presence of one additional LowP can significantly worsen cognitive decline, increasing the risk of transitioning from MCI to dementia 20‐fold. Multimorbidity should be considered in dementia research and clinical studies. [ABSTRACT FROM AUTHOR]

Introduction: A minority of patients with sporadic early‐onset Alzheimer's disease (AD) exhibit de novo germ line mutations in the autosomal dominant genes such as APPPSEN1, or PSEN2. We hypothesized that negatively screened patients may harbor somatic variants in these genes. Methods: We applied an ultrasensitive approach based on single‐molecule molecular inversion probes followed by deep next generation sequencing of 11 genes to 100 brain and 355 blood samples from 445 sporadic patients with AD (>80% exhibited an early onset, <66 years). Results: We identified and confirmed nine somatic variants (allele fractions: 0.2%–10.8%): two APP, five SORL1, one NCSTN, and one MARK4 variants by independent amplicon‐based deep sequencing. Discussion: Two of the SORL1 variant might have contributed to the disease, the two APP variants were interpreted as likely benign and the other variants remained of unknown significance. Somatic variants in the autosomal dominant AD genes may not be a common cause of sporadic AD, including early onset cases. [ABSTRACT FROM AUTHOR]

Introduction: One characteristic of Alzheimer's disease is the formation of amyloid‐β plaques, which are typically linked to neuroinflammation and surrounded by inflammatory cells such as microglia and infiltrating immune cells. Methods: Here, we describe nonneurogenic doublecortin (DCX) positive cells, DCX being generally used as a marker for young immature neurons, at sites of amyloid‐β plaques in various transgenic amyloid mouse models and in human brains with plaque pathology. Results: The plaque‐associated DCX+ cells were not of neurogenic identity, instead most of them showed coexpression with markers for microglia (ionized calcium‐binding adapter molecule 1) and for phagocytosis (CD68 and TREM2). Another subpopulation of plaque‐associated DCX+ cells was negative for ionized calcium‐binding adapter molecule 1 but was highly positive for the pan‐leukocyte marker CD45. These hematopoietic cells were identified as CD3‐and CD8‐positive and CD4‐negative T‐cells. Discussion: Peculiarly, the DCX+/ionized calcium‐binding adapter molecule 1+ microglia and DCX+/CD8+ T‐cells were closely attached, suggesting that these two cell types are tightly interacting and that this interaction might shape plaque pathology. [ABSTRACT FROM AUTHOR]

Objective: Patients with dementia with Lewy bodies (DLB) often experience visual hallucinations, which are related to decreased quality of life for patients and increased caregiver distress. The pathologic changes that contribute to visual hallucinations are not known, but several hypotheses implicate deficient attentional processing. The superior colliculus has a role in visual attention and planning eye movements and has been directly implicated in several models of visual hallucinations. Therefore, the present study sought to identify neurodegenerative changes that may contribute to hallucinations in DLB.Methods: Postmortem superior colliculus tissue from 13 comparison, 10 DLB, and 10 Alzheimer disease (AD) cases was evaluated using quantitative neuropathologic methods.Results: α-Synuclein and tau deposition were more severe in deeper layers of the superior colliculus. DLB cases had neuronal density reductions in the stratum griseum intermedium, an important structure in directing attention toward visual targets. In contrast, neuronal density was reduced in all laminae of the superior colliculus in AD.Conclusion: These findings suggest that regions involved in directing attention toward visual targets are subject to neurodegenerative changes in DLB. Considering several hypotheses of visual hallucinations implicating dysfunctional attention toward external stimuli, these findings may provide evidence of pathologic changes that contribute to the manifestation of visual hallucinations in DLB. [ABSTRACT FROM AUTHOR]

Background: Age‐related cognitive impairment is complex and multifactorial, with numerous underlying and frequently co‐morbid pathological correlates. Given that conventional measures are imperfect predictors of cognitive impairment, improved approaches are urgently needed to identify correlated histopathological changes in an unbiased way. Methods: We used a weakly supervised deep learning algorithm, clustering‐constrained‐attention multiple‐instance learning (CLAM), on digitized whole slide images of human brain tissue sections from a group of elderly individuals without significant amyloid‐beta deposition to predict the presence or absence of cognitive impairment. The brain tissue sections were from the hippocampus and frontal cortex and were either morphologically stained with LH&E or immunohistochemically stained for hyper‐phosphorylated tau. We used attention analysis to pinpoint the underlying architectural and cellular features that the top‐performing models used for the predictions. Results: Despite noisy labels of cognition, our trained models were able to predict the presence of cognitive impairment with an accuracy that significantly beat chance, in both the morphologically stained and immunohistochemically stained whole slide images. Attention‐based analysis of the features most associated with cognitive impairment in both types of whole slide images analyzed suggests that the models identified white matter alterations in donors with cognitive impairment. Conclusions: The deep learning method for the prediction of cognitive impairment that we present, which appears to be minimally influenced by the human‐identified visually salient aspects of whole slide images, may help to discover unexpected aspects of the pathophysiology associated with cognitive impairment in the elderly. [ABSTRACT FROM AUTHOR]

Introduction Our objective was to compare the levels of three synaptic proteins involved in different steps of the synaptic transmission: Rab3A, SNAP25, and neurogranin, in three common forms of dementia: Alzheimer's disease (AD), dementia with Lewy bodies (DLB), and Parkinson's disease dementia. Methods A total of 129 postmortem human brain samples were analyzed in brain regional specific manner exploring their associations with morphologic changes and cognitive decline. Results We have observed robust changes reflecting synaptic dysfunction in all studied dementia groups. There were significant associations between the rate of cognitive decline and decreased levels of Rab3 in DLB in the inferior parietal lobe and SNAP25 in AD in the prefrontal cortex. Of particular note, synaptic proteins significantly discriminated between dementia cases and controls with over 90% sensitivity and specificity. Discussion Our findings suggest that the proposition that synaptic markers can predict cognitive decline in AD, should be extended to Lewy body diseases. [ABSTRACT FROM AUTHOR]

Background: Hallmark lesions observed Alzheimer's disease (AD) include neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau protein (HP‐T) and amyloid β plaques. Pyroglutamylated Aβ (pAβ) is a sub‐species of Aβ, and we have previously demonstrated an association between (pAβ) and HP‐T in human post‐mortem brains, and observed that pAβ predicts the severity of clinical dementia. Several studies in transgenic mouse models have demonstrated Aβ inducing HP‐T pathology and anti‐Aβ antibody treatment eliminated not only parenchymal Aβ deposits but also early stage HP‐T deposits while mature NFTs remained unaltered suggesting that Aβ ‐ HP‐T interaction takes place at an early stage of NFT development. However, these studies did not specifically look for the proportion of pAβ within Aβ and hence data on the interaction between pAβ and stages of NFT development are lacking. We now aim to investigate whether pAβ is associated with tau conformations that represent earlier stages of tangle development, measured by MC1 and CP13 antibodies in human post‐mortem tissue. Method: Tissue from frontal, temporal, parietal, occipital and entorhinal cortices from 70 post‐mortem brains (35 AD and 35 aged controls) were processed into a tissue microarray blocks for high throughput analysis, and stained for pAβ, MC1, and CP13. Percentage area of immunopositivity calculated using an automated image analysis system. Result: pAβ, MC1, and CP13 loads were higher in AD cases compared to controls in all regions (all p < 0.05). The burden of pAβ positively correlated with the burden of MC1 and CP13 in all regions (all p < 0.05). Conclusion: This study provides the first set of results from a larger screening study to determine at which point the interaction between pAβ and tau takes place. Our results suggests pAβ is associated with conformational states of tau that represent early stage tau depositions. Therefore studies investigating whether immunisation using pAβ is capable of removing early stage tau depositions, precluding excessive mature NFT tau accumulations, and attenuating cognitive decline in AD are warranted. [ABSTRACT FROM AUTHOR]

Background: Limbic‐predominant age‐related TDP‐43 encephalopathy neuropathological change (LATE‐NC) is present in approximately 57% of Alzheimer's disease (AD) cases and is associated with accelerated cognitive decline and accelerated disease progression. Hyperphosphorylated tau (HP‐τ) burden in AD is associated with cognitive deficits; it is unknown if LATE‐NC is associated with HP‐τ burden. In post‐mortem AD cases, we investigated the association between LATE‐NC and early and late HP‐τ and the impact of LATE‐NC on clinical measures of cognition. Method: 46 AD cases underwent neuropathological assessment for LATE‐NC [1] and quantitative assessment for early conformational HP‐τ (MC‐1) and intermediate/late stage HP‐τ (AT8) in the frontal, entorhinal, temporal, parietal and occipital cortices. Cognitive decline (n=20) was calculated from longitudinal mini‐Mental State Examination (MMSE; n =37). Result: 29 cases (63%) exhibited LATE‐NC (AD+). No significant differences in AT8 were revealed, however, observationally, AT8 was higher in all regions of AD+ cases. MC‐1 burden was significantly lower in the entorhinal cortex (P<0.05), and observational lower in all regions in the AD+ cases. No association between MC‐1 or AT8 with LATE‐NC score were revealed. MMSE score and cognitive decline was not significantly different between AD+ and AD‐ groups (both P>0.9) and linear regression revealed no influence of LATE‐NC on cognitive scores. Conclusion: AD+ cases exhibit lower burden of MC‐1 and higher burden of AT8 pathology indicating possible advanced progression of the disease compared to AD‐ cases. The presence of LATE‐NC is not associated with differences in cognitive scores in AD. (1) Nelson et al (2019) doi:10.1093/brain/awz099. [ABSTRACT FROM AUTHOR]

Background: Cellular senescence, the irreversible arrest of the cell cycle, is a common occurrence in ageing. Astrocytes have been shown to demonstrate a senescent phenotype, which is increased in ageing, and in Alzheimer's disease (AD) (as evidenced by p16INK4a expression). Recently, a causal link was established between p16INK4a expression and hyperphosphorylated tau (HPT) pathology in the MAPTP301SPS19 mouse model of tauopathy, where treatment with a senolytic agent removed senescent p16INK4a positive astrocytes, prevented aggregation of HPT, and preserved cognitive function, suggesting senescent astrocytes may play a role in HPT deposition observed in AD. However, data in human post‐mortem tissue from AD cases (inclusive of Aβ pathology) is lacking. Method: Frontal cortex (BA9) from 10 AD and 10 control cases were double immunolabelled for GFAP and p16INK4a. A mean number of p16INK4a positive astrocytes (identified by the presence of co‐localisations) was determined at 6 regions of interest across each section. HPT and Aβ were quantified by percentage area of immunopositivity in the same region. Result: AD cases had significantly more p16INK4a positive astrocytes compared to controls (p<0.05). We observed a positive association between number of p16INK4a positive astrocytes and HPT load in AD cases (p<0.05). No association was observed between the mean number of p16INK4a positive astrocytes and Aβ load. Conclusion: We found a positive association was found between p16INK4a positive astrocytes and HPT. This area of research warrants further investigation to determine whether the development of senolytic therapies are a viable option for the treatment of AD and other tauopathies. [ABSTRACT FROM AUTHOR]

Background: Cerebral small vessel disease (SVD) encompasses progressive fibrosis/hyalinosis of the small arteries and arterioles of the white matter (WM) resulting in ischemic WM damage. Few studies have compared SVD between different cohorts. Using a sclerotic index (SI) measurement, we quantitatively assessed vessel wall fibrosis in the frontal and parietal WM of human brains donated to brain banks in the UK and the USA. Method: 64 cases from the University of California Davis (UCD) Alzheimer's Disease Centre Biorepository and 55 cases from the Newcastle Brain and Tissue resource (NBTR) were included. Cases were neuropathological diagnosed as controls (UCD n=18; NBTR n=25), intermediate Alzheimer's disease (AD) neuropathologic change (UCD n=13; NBTR n=4), and definite AD (UCD n=33; NBTR n = 26). In the UCD cohort, 49 identified racially as White, 9 as Black African American, 3 as Chinese and 1 as Indian Asian. All cases from the NBTR identified racially as White. Using H&E sections, images of approximately eight arteries/arterioles from the frontal and parietal WM were captured and SI assessment performed. Mean SI score was calculated per region, per cases. Result: No intergroup differences in age were observed and age was not associated with SI score in either cohort. In the UCD cohort, race was not associated with neuropathological diagnosis (Chi‐sq = 8.39, p>0.211) and no differences were seen in SI scores between White and Black African Americans (p>0.69). Intergroup comparisons revealed that SI scores in both WM regions were significantly higher in the overall UCD cohort compared to the overall NBTR cohort (p>0.006) and this was consistent across controls (frontal p=0.0001; parietal p=0.045), intermediate AD neuropathological change (p=0.001), and AD (frontal p=0.001) cases. Conclusion: SVD‐associated vessel occlusion is more severe in the USA cohort from Sacramento compared to the UK cohort from Newcastle. This may reflect differences in cardiovascular disease and lifestyle of individuals enrolled in the two brain donation programmes. [ABSTRACT FROM AUTHOR]

Background: Cerebral small vessel disease (SVD) encompasses progressive fibrosis/hyalinosis of the small arteries (lipohyalinosis) and arterioles (arteriolosclerosis) of the white matter (WM) resulting in ischemic WM damage. SVD is commonly assessed using a broad semi‐quantitative (SQ) criterion. We implemented sclerotic index (SI) assessment to quantitatively assess vessel wall thickness in small arteries and arterioles separately in four regions known to exhibit WM changes. Method: The cohort consisted of 75 cases from the University of California Davis Alzheimer's Disease Centre Biorepository, neuropathological diagnosed as controls (n=18), intermediate Alzheimer's disease neuropathologic change (n=13), definite Alzheimer's disease (n=33), or cerebrovascular disease (n=11). H&E sections that included frontal and parietal WM, genu, or splenium were SQ assessed for SVD and images of small arteries (150‐800μm diameter) and arterioles (40‐150μm diameter) were captured. SI assessment was performed, and mean SI scores were calculated for arteries, arterioles, and an overall total. Result: Age was not associated with any SQ or SI measure in any region (p>0.106). SI and SQ scores of both arteries and arterioles were highly correlated in all regions (rho >0.551, p<0.0001) validating the SI method. Arteriole‐SI was significantly higher than artery‐SI in both WM regions (p<0.0001) and this was consistent cross controls and disease groups (all p<0.03). Regarding the whole cohort, frontal and parietal WM total‐SI was significantly higher than artery‐SI (P<0.0001) and significantly lower than arteriole‐SI (P<0.0001). Intragroup comparisons between frontal and parietal WM revealed no differences in artery‐ or arteriole‐SI scores (overall cohort p>0.76; subgroups p>0.112), and comparisons between genu and splenium also revealed no difference in arteriole‐SI (overall cohort p>0.41; subgroups p>0.34). Conclusion: SVD‐associated vessel fibrosis is uniform between the anterior and posterior WM. Separate assessment of arteries and arterioles should be considered given arteriolosclerosis results in more severe vessel occlusion and maybe clinically relevant to ischemic WM changes. A combined SVD assessment may lead to under‐ or overestimation of disease severity. [ABSTRACT FROM AUTHOR]

Background: Using the UK's Brains for Dementia Research (BDR) program, we investigated the frequency of neuropathological dementia diagnosis, the proportion of pure, mixed or concomitant pathologies and the pathological substrates for cognitive impairment. Method: All cases (n = 673) underwent standardised neuropathological assessment outlined in [1]. Cases were classed as 'pure', 'mixed' or 'concomitant'. 473 cases had clinical dementia rating (CDR) scores: binary linear regression was employed to estimate the odds of increasing CDR score due to the presence of pathologies and multiple pathologies. Result: 142 cases (21.1%) were diagnosed as controls and 531 fulfilled the criteria for a neurodegenerative disease: Alzheimer's disease (n = 221) > Lewy body disease (n = 65) > vascular dementia (n = 50). Only 23.5% were classified as 'pure', 63.1% as 'concomitant' and 13.4% as 'mixed'. 147 (28.9%) had no cognitive impairment and 301 had dementia. Higher burdens of hyperphosphorylated‐ τ (Hpτ), amyloid‐β and α‐synuclein burden had a three‐fold increase on the risk of being demented (OR = <3.4; 95% CI 2.1, 5.5). Regarding the conversion from mild cognitive impairment to dementia, Hpτ had a two‐fold increase on risk (OR = 1.75; 95% CI 1.16, 2.6) and the presence of multiple pathologies had a nine‐fold increase on risk (OR = 8.8; 95% CI 3.19, 24.3). Conclusion: The majority of the BDR cohort contains multiple pathologies. Increasing burden of Hpτ and multiple pathologies greatly increases the odds of dementia. (1) Francis et al, (2018) DOI 10.3233/JAD‐180699. [ABSTRACT FROM AUTHOR]

Background: We have previously shown that the pathogenesis of parietal white matter lesions (WML) seen in Alzheimer's disease (AD) can be associated with degenerative loss as a result of Wallerian degeneration activated by hyperphosphorylated tau (HPτ) [1]. In a subset of these cases, we investigated the the pathological composition and aetiology of WML from the frontal region. Method: Frontal WML from 40 post‐mortem brains (AD, n=19; controls, n=21) were quantitative assessed for WML severity, axonal loss and demyelination, as well cortical measures of HPτ, amyloid‐beta (Aβ) and WM‐small vessel disease (SVD) score. Biochemical assessment included the Wallerian degeneration‐associated protease calpain and the ratio of myelin‐associated glycoprotein (MAG) and proteolipid protein (PLP) as a measure of hypoperfusion. Result: No significant difference was revealed in WML severity between controls and AD. WML severity was associated with axonal and myelin loss in AD (both P<0.02), but only myelin loss in controls (P<0.0001). WML severity correlated with WM‐SVD score in both controls (P<0.0001) and AD (P <0.05); no association between WML severity and HPτ was revealed in the AD group. Calpain was increased in AD but this was not significant, and calpain correlated with Aβ (P<0.05). No significant difference was seen in MAG:PLP between AD and controls. Conclusion: Frontal WML in AD are likely influenced by both ischemic and degenerative mechanisms in contrast to the posterior WM that has a prominent degenerative influence. This study highlights important regional differences in the pathogenesis of WML that may be diagnostically relevant. (1) McAleese et al (2017) DOI 10.1007/s00401‐017‐1738‐2 [ABSTRACT FROM AUTHOR]

Background: In addition to the well‐established risk associated with the APOE locus, there has been considerable success in identifying additional genetic variants associated with Alzheimer's disease (AD). Individually these variants confer only a small increase on an individual's overall risk; however, combined into a polygenic risk score (PRS), they represent a powerful tool in genetic epidemiology for the investigation of correlates of high genetic risk. We investigated the clinical and neuropathological outcomes associated with high PRS for AD in the Brains for Dementia Research (BDR) cohort. Method: 693 individuals in the BDR cohort with high quality genetic data and neuropathology measurements, including staging assessments (Braak and Thal) and established diagnostic criteria were included in this study. PRS were calculated for each individual as the number of genetic risk alleles, weighted by the log odds ratio, using the results of the largest available GWAS of AD. Statistical analysis was performed using regression models whilst controlling for age at death, sex and brain bank. Result: We report statistically significant associations between APOE genotype and Braak neurofibrillary tangle stage, a measure of tauopathy, and Thal stage, a measure of Aβ plaque propagation. We also found significant associations between AD PRS and multiple measures of neuropathology (Braak stage, Thal stage, Lewy body stage, and severe cerebral amyloid angiopathy). In order to determine if APOE and AD PRS represent independent predictors of tauopathy (Braak stage) and b‐amyloidosis (Thal stage), we performed a joint analysis finding that APOE and PRS combine in an additive manner to influence both measures of neuropathology. Conclusion: The results from this study characterise how genetic risk for AD influence both the clinical and pathological features of dementia and increases our understanding of the interaction between APOE status and other genetic risk factors. [ABSTRACT FROM AUTHOR]

Background: Senile plaques frequently contain pyroglutamate amyloid β (Aβ‐pE(3)), a N‐terminally truncated Aβ species that is more closely linked to Alzheimer's Disease (AD) compared to other Aβ species. Tau protein is highly phosphorylated at several residues in AD, specifically tau protein phosphorylated (ptau) at Ser202/Thr205 is known to be increased in AD. First studies suggest that the two pathologies of plaques and tau phosphorylation might be linked to each other. Method: To evaluate if Aβ‐pE(3) and ptau Ser202/Thr205 levels correlate in human and transgenic AD mouse models we analyzed human cortical and hippocampal brain tissue of different Braak stages as well as murine brain tissue of two transgenic mouse models for levels of Aβ‐pE(3) and ptau Ser202/Thr205 and correlated the data. Result: Our results show that Aβ‐pE(3) formation increases already at early Braak stages while ptau Ser202/Thr205 mostly increases at later stages. Further analyses revealed strong correlations between the two pathologies in the temporal, frontal, cingulate and occipital cortex. However, correlation in the hippocampus was weaker. Evaluation of murine transgenic brain tissue demonstrated a slow but steady increase of Aβ‐pE(3) from 6 to 12 months of age in the cortex and hippocampus of APPSL mice and a very early and strong Aβ‐pE(3) increase in 5xFAD mice. ptau Ser202/Thr205 levels increased at the age of 9 months in APPSL mice and already at 6 months in 5xFAD mice. Conclusion: Our results show that Aβ‐pE(3) and ptau Ser202/Thr205 levels strongly correlate in human as well as murine brain tissues, suggesting that tau phosphorylation might be amplified by Aβ‐pE(3). [ABSTRACT FROM AUTHOR]

Background: Lewy body diseases (LBD) are characterised by Lewy body pathology, cell loss and mitochondrial dysfunction, but the overlap between these three features is not well understood. We have explored the hypothesis that neurodegeneration in LBD is the result of energy failure in cells with high energy demands, such as cortical fast‐spiking interneurons and cholinergic basal forebrain neurons, irrespective of Lewy body accumulation. Method: We obtained post‐mortem substantia innominata, prefrontal cortex and inferior temporal cortex brain tissue from LBD cases, controls, and disease‐control groups (Alzheimer's disease and/or mitochondrial disease cases). We conducted stereological analysis of fast‐spiking interneurons, pyramidal neurons and cholinergic neurons; neuropathological analysis of alpha‐synuclein, amyloid‐beta and tau; and immunofluorescent quantification of NDUFB8 (Complex I) and COX4 (Complex IV) normalised to mitochondrial mass. Result: Despite not developing Lewy bodies, we observed a 40% reduction in density of fast‐spiking interneurons, whilst pyramidal neurons that are vulnerable to Lewy bodies had preserved populations. Changes in cell density were not related to any neuropathological feature. Preliminary data suggests Complex I reductions relative to VDAC1 in fast‐spiking interneurons and cholinergic nbM neurons, with more variable changes in Complex IV expression. Conclusion: The present findings demonstrate loss of a cell population that does not develop Lewy bodies alongside preservation of proximal Lewy body‐bearing neurons. This challenges the hypothesis that neurodegeneration in LBD results from Lewy body pathology. Our preliminary findings indicate that mitochondrial impairments in cells with high reliance on energy production may more closely relate to neurodegeneration in LBD than Lewy body formation. [ABSTRACT FROM AUTHOR]

Background: Inflammation is usually terminated by resolution, mediated by pro‐resolving mediators including Annexin A1 (AnxA1) which is known to be involved in granulocyte trafficking as well as efferocytosis of apoptotic neutrophils. Failure in resolution may lead to chronic inflammation, which has been considered a pathological hallmark of neurodegenerative diseases. We investigated the expression levels of AnxA1 in post‐mortem brain tissues and their correlation with pathological burden in dementia. Method: Protein levels of AnxA1 were measured in post‐mortem parietal cortices (Brodmann area BA40) as well as frontal cortices (BA9) of well characterized Parkinson disease dementia (PDD), dementia with Lewy bodies (DLB), Alzheimer's disease (AD) patients and healthy controls via immunoblotting. Amyloid and cytokines were quantified via ELISA and Luminex respectively. Result: In BA40, expression of cleaved (33 kDa) AnxA1 was found to be elevated in DLB and AD as compared to controls. While cleaved AnxA1 (33 kDa) showed an increasing trend in BA9, the increase was not significant. In our cohort of patients with dementia, levels of cleaved AnxA1 was also positively correlated with ratio of soluble amyloid‐β42/40. In addition, as AnxA1 activation has been shown to increase production of anti‐inflammatory markers such as IL10 and IL13. We measured IL10 and IL13 and found positive correlations with AnxA1. Conclusion: Our results suggest that elevation of AnxA1 in DLB and AD may be a compensatory response to the increased inflammation in neurodegenerative diseases, in an attempt to resolve inflammation. Previous in vitro and in vivo research also revealed elevated AnxA1 in 5XFAD mice models and in vitro AnxA1 treatment reduced pro‐inflammatory and increased anti‐inflammatory cytokines. Our results demonstrate that similar associations are observed in post‐mortem samples and suggest that AnxA1 may play a similar role in humans. [ABSTRACT FROM AUTHOR]

Background: Many studies have provided strong evidence to support JNK3 isoform‐specific involvement in several processes underlying Alzheimer's Disease (AD) pathogenesis including dysfunction of synaptic plasticity and cognition, phosphorylation of tau and amyloidogenic processing of the amyloid precursor protein. Moreover, the tissue‐specific expression of JNK3 primarily in the brain suggests a potential pivotal role of JNK3 in the central nervous system. Method: Using immunoblotting, JNK3 levels were measured in the post‐mortem parietal lobe cortex (Brodmann Area 40) of a cohort of longitudinally assessed Alzheimer's Disease (AD), Lewy Body Dementia (LBD), and healthy control patients. Although LBD brains are mainly characterized by the presence of α‐synuclein‐containing lewy bodies, It has been shown that LBD brains exhibit a substantial degree of AD pathologies, including amyloid plaques and neurofibrillary tangles particularly in cortex regions associated with higher cognitive functions. We investigated the association between levels of JNK3 and several neuropathological measures too. Result: We found a significant decrease in JNK3 levels in all dementia groups compared to control. Our results also showed that levels of JNK3 were significantly associated with amyloid plaque (AP) and neurofibrillary tangle (NFT) pathology scores but not lewy body (LB) scores. Conclusion: Our results suggest a possible compensatory mechanism to maintain levels of JNK3 to protect against further pathological damage. It was suggested that this compensatory effect is the brain's adaptive means in response to pathological insults, to aid in dampening further damage during disease progression, and that these compensatory changes usually comes into play in the 'latent' phase of disease progression. In addition, JNK3 is likely to be involved in AD‐related processes but not in mechanisms that are associated with driving the formation of α‐synuclein pathological aggregates. The role of JNK3 in LBD could be in relation to common pathogenic pathways that underlie all dementia. [ABSTRACT FROM AUTHOR]