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Background: Altered brain energy metabolism is implicated in Alzheimer disease (AD). Limited and conflicting studies on brain pH changes, indicative of metabolic alterations associated with neural activity, warrant a comprehensive investigation into their relevance in this neurodegenerative condition. Furthermore, the relationship between these pH changes and established AD neuropathological evaluations, such as Braak staging, remains unexplored., Methods: We conducted quantitative meta-analyses on postmortem brain and cerebrospinal fluid pH in patients with AD and non-AD controls using publicly available demographic data. We collected raw pH data from studies in the NCBI GEO, PubMed, and Google Scholar databases., Results: Our analysis of 20 datasets (723 patient samples and 524 control samples) using a random-effects model showed a significant decrease in brain and cerebrospinal fluid pH in patients compared with controls (Hedges' g = -0.57, P < .0001). This decrease remained significant after considering postmortem interval, age at death, and sex. Notably, pH levels were negatively correlated with Braak stage, indicated by the random-effects model of correlation coefficients from 15 datasets (292 patient samples and 159 control samples) (adjusted r = -0.26, P < .0001). Furthermore, brain pH enhanced the discriminative power of the APOEε4 allele, the most prevalent risk gene for AD, in distinguishing patients from controls in a meta-analysis of 4 combined datasets (95 patient samples and 87 control samples)., Conclusions: The significant decrease in brain pH in AD underlines its potential role in disease progression and diagnosis. This decrease, potentially reflecting neural hyperexcitation, could enhance our understanding of neurodegenerative pathology and aid in developing diagnostic strategies., (© The Author(s) 2024. Published by Oxford University Press on behalf of CINP.)

Pharmacological phosphodiesterase 4D (PDE4D) inhibition shows therapeutic potential to restore memory function in Alzheimer's disease (AD), but will likely evoke adverse side effects. As PDE4D encodes multiple isoforms, targeting specific isoforms may improve treatment efficacy and safety. Here, we investigated whether PDE4D isoform expression and PDE4D DNA methylation is affected in AD and whether expression changes are associated with severity of pathology and cognitive impairment. In post-mortem temporal lobe brain material from AD patients (n = 42) and age-matched controls (n = 40), we measured PDE4D isoform expression and PDE4D DNA (hydroxy)methylation using quantitative polymerase chain reaction and Illumina 450k Beadarrays, respectively. Linear regression revealed increased PDE4D1, -D3, -D5, and -D8 expression in AD with concurrent (hydroxy)methylation changes in associated promoter regions. Moreover, increased PDE4D1 and -D3 expression was associated with higherplaque and tau pathology levels, higher Braak stages, and progressed cognitive impairment. Future studies should indicate functional roles of specific PDE4D isoforms and the efficacy and safety of their selective inhibition to restore memory function in AD., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

In Parkinson's disease (PD), neuronal alpha-synuclein aggregates are distributed throughout the nervous system, including the brain, spinal cord, sympathetic ganglia, submandibular gland, enteric nervous system, cardiac and pelvic plexuses, adrenal medulla, and skin. Thus, PD is a progressive multiorgan disease clinically associated with various motor and nonmotor symptoms. The earliest PD-related lesions appear to develop in the olfactory bulb, dorsal vagal nucleus, and possibly also the peripheral autonomic nervous system. The brain is closely connected with the enteric nervous system via axons of the efferent fibers of the dorsal nucleus of vagal nerve. Anatomical connections also exist between the olfactory bulb and brainstem. Accumulating evidence from experimental studies indicates that transneuronal propagation of misfolded alpha-synuclein is involved in the progression of PD. However, it cannot be ruled out that alpha-synuclein pathology in PD is multicentric in origin. Based on pathological findings from studies on human materials, the present review will update the progression pattern of alpha-synuclein pathology in PD., (© 2020 Japanese Society of Neuropathology.)

The presence of Alzheimer's disease (AD)-related neuropathology among cognitively normal individuals has been well documented. It has been proposed that these individuals may represent a pre-clinical AD population. Previous studies have demonstrated a negative association between the presence of both amyloid-β (Aβ) plaques and neurofibrillary tangles with ante-mortem cognitive performance, a relationship which is likely influenced by a number of factors including age and APOE ɛ4 carrier status. The present study determined whether the presence of neuritic plaques (NPs) and diffuse plaques (DPs) are associated with performance in a number of cognitive domains after accounting for APOE ɛ4 carrier status and neurofibrillary tangle presence in a cohort of 123 older participants from the Rush Religious Order Study who died with a premortem clinical diagnosis of no cognitive impairment (NCI). After adjusting for age at death, education, gender, Braak stage, and APOE ɛ4 carrier status, the presence of NPs was associated with lower performance in the cognitive domains of Global Cognition (p = 0.002), Episodic Memory (p = 0.03), Semantic Memory (p = 0.009), and Visuospatial performance (p = 0.006), while DPs showed no association with any cognitive domain examined. These results suggest that decreases in cognition in elderly NCI individuals are associated with an increase in NPs and not DPs when age at death, education, gender, APOE ɛ4 status, and Braak stage are taken into consideration.

Alterations in calcium homeostasis are widely reported to contribute to synaptic degeneration and neuronal loss in Alzheimer's disease. Elevated cytosolic calcium concentrations lead to activation of the calcium-sensitive cysteine protease, calpain, which has a number of substrates known to be abnormally regulated in disease. Analysis of human brain has shown that calpain activity is elevated in AD compared to controls, and that calpain-mediated proteolysis regulates the activity of important disease-associated proteins including the tau kinases cyclin-dependent kinase 5 and glycogen kinase synthase-3. Here, we sought to investigate the likely temporal association between these changes during the development of sporadic AD using Braak staged post-mortem brain. Quantification of protein amounts in these tissues showed increased activity of calpain-1 from Braak stage III onwards in comparison to controls, extending previous findings that calpain-1 is upregulated at end-stage disease, and suggesting that activation of calcium-sensitive signalling pathways are sustained from early stages of disease development. Increases in calpain-1 activity were associated with elevated activity of the endogenous calpain inhibitor, calpastatin, itself a known calpain substrate. Activation of the tau kinases, glycogen-kinase synthase-3 and cyclin-dependent kinase 5 were also found to occur in Braak stage II-III brain, and these preceded global elevations in tau phosphorylation and the loss of post-synaptic markers. In addition, we identified transient increases in total amyloid precursor protein and pre-synaptic markers in Braak stage II-III brain, that were lost by end stage Alzheimer's disease, that may be indicative of endogenous compensatory responses to the initial stages of neurodegeneration. These findings provide insight into the molecular events that underpin the progression of Alzheimer's disease, and further highlight the rationale for investigating novel treatment strategies that are based on preventing abnormal calcium homeostasis or blocking increases in the activity of calpain or important calpain substrates.

Alzheimer's disease is characterized by the presence of amyloid-β and tau deposition in the brain, hippocampal atrophy and increased rates of hippocampal atrophy over time. Another protein, TAR DNA binding protein 43 (TDP-43) has been identified in up to 75% of cases of Alzheimer's disease. TDP-43, tau and amyloid-β have all been linked to hippocampal atrophy. TDP-43 and tau have also been linked to hippocampal atrophy in cases of primary age-related tauopathy, a pathological entity with features that strongly overlap with those of Alzheimer's disease. At present, it is unclear whether and how TDP-43 and tau are associated with early or late hippocampal atrophy in Alzheimer's disease and primary age-related tauopathy, whether either protein is also associated with faster rates of atrophy of other brain regions and whether there is evidence for protein-associated acceleration/deceleration of atrophy rates. We therefore aimed to model how these proteins, particularly TDP-43, influence non-linear trajectories of hippocampal and neocortical atrophy in Alzheimer's disease and primary age-related tauopathy. In this longitudinal retrospective study, 557 autopsied cases with Alzheimer's disease neuropathological changes with 1638 ante-mortem volumetric head MRI scans spanning 1.0-16.8 years of disease duration prior to death were analysed. TDP-43 and Braak neurofibrillary tangle pathological staging schemes were constructed, and hippocampal and neocortical (inferior temporal and middle frontal) brain volumes determined using longitudinal FreeSurfer. Bayesian bivariate-outcome hierarchical models were utilized to estimate associations between proteins and volume, early rate of atrophy and acceleration in atrophy rates across brain regions. High TDP-43 stage was associated with smaller cross-sectional brain volumes, faster rates of brain atrophy and acceleration of atrophy rates, more than a decade prior to death, with deceleration occurring closer to death. Stronger associations were observed with hippocampus compared to temporal and frontal neocortex. Conversely, low TDP-43 stage was associated with slower early rates but later acceleration. This later acceleration was associated with high Braak neurofibrillary tangle stage. Somewhat similar, but less striking, findings were observed between TDP-43 and neocortical rates. Braak stage appeared to have stronger associations with neocortex compared to TDP-43. The association between TDP-43 and brain atrophy occurred slightly later in time (∼3 years) in cases of primary age-related tauopathy compared to Alzheimer's disease. The results suggest that TDP-43 and tau have different contributions to acceleration and deceleration of brain atrophy rates over time in both Alzheimer's disease and primary age-related tauopathy. [ABSTRACT FROM AUTHOR]

Although mutations within the TREM2 gene have been robustly associated with Alzheimer's disease, it is not known whether alterations in the regulation of this gene are also involved in pathogenesis. Here, we present data demonstrating increased DNA methylation in the superior temporal gyrus in Alzheimer's disease brain at a CpG site located 289 bp upstream of the transcription start site of the TREM2 gene in 3 independent study cohorts using 2 different technologies (Illumina Infinium 450K methylation beadchip and pyrosequencing). A meta-analysis across all 3 cohorts reveals consistent AD-associated hypermethylation ( p = 3.47E-08). This study highlights that extending genetic studies of TREM2 in AD to investigate epigenetic changes may nominate additional mechanisms by which disruption to this gene increases risk. [ABSTRACT FROM AUTHOR]

Introduction: Deposition of abnormally phosphorylated tau (phospho-tau) occurs in Alzheimer's disease but also with brain ageing. The Braak staging scheme focused on neurofibrillary tangles, butabundant p-tau is also present in neuropil threads, and a recent scheme has been proposed by theBrainNet Europe consortium for staging tau pathology based on neuropil threads. We determined therelationship of threads to tangles, and the value of staging for threads in an unselected population-representative ageing brain cohort. We also determined the prevalence of astroglial tau pathologies, and their relationship to neuronal tau. Phospho-tau pathology was determined by immunohistochemistry (AT8 antibody) in the MRC-CFAS neuropathology cohort. Neuropil threads were staged using the BrainNet Europe protocol for tau pathology, and compared with Braak tangle stages. Astroglial tau pathology was assessed in neo-cortical, mesial temporal and subcortical areas. Results: Cases conformed well to the hierarchical neuropil threads staging of the BrainNet Europe protocol and correlated strongly with Braak staging (r=0.84, p < 0.001). Based on the areas under the receiver operator curves (AUC), incorporating either threads or tangle staging significantly improved dementia case identification to a similar degree over age alone (Braak stage χ² (1)=10.1, p=0.002; BNE stage χ² (1)=9.7, p=0.002). Thorn-shaped astrocytes, present in 40 % of cases, were most common in mesial temporal lobe, then brainstem, and were associated with subpial tau-positive neurites (mesial temporal: χ² (1)=61.3, p < 0.001; brainstem: χ² (1)=47.9, p < 0.001). Adding thorn astrocytes did not improve dementia prediction (AUC: χ² (1)=0.77, p=0.381), but there was a weak relationship between numbers of areas involved and staging for threads or tangles (r=0.17, p=0.023). Neuropil threads develop hierarchically in parallel with neurofibrillary tangles. Conclusions: The BrainNet Europe staging protocol is straightforward to apply, and offers similar predictive value for dementia to Braak tangle staging. Astroglial tauopathy, particularly thorn shaped astrocyte formation, does not relate to dementia status, but the association with phospho-tau neurites may suggest a pathogenic relationship to neuronal tau pathology. [ABSTRACT FROM AUTHOR]

The aim of this study was to determine whether the TAR DNA-binding protein of 43 kDa (TDP-43) has any independent effect on the clinical and neuroimaging features typically ascribed to Alzheimer's disease (AD) pathology, and whether TDP-43 pathology could help shed light on the phenomenon of resilient cognition in AD. Three-hundred and forty-two subjects pathologically diagnosed with AD were screened for the presence, burden and distribution of TDP-43. All had been classified as cognitively impaired or normal, prior to death. Atlas-based parcellation and voxel-based morphometry were used to assess regional atrophy on MRI. Regression models controlling for age at death, apolipoprotein ε4 and other AD-related pathologies were utilized to explore associations between TDP-43 and cognition or brain atrophy, stratified by Braak stage. In addition, we determined whether the effects of TDP-43 were mediated by hippocampal sclerosis. One-hundred and ninety-five (57 %) cases were TDP-positive. After accounting for age, apolipoprotein ε4 and other pathologies, TDP-43 had a strong effect on cognition, memory loss and medial temporal atrophy in AD. These effects were not mediated by hippocampal sclerosis. TDP-positive subjects were 10× more likely to be cognitively impaired at death compared to TDP-negative subjects. Greater cognitive impairment and medial temporal atrophy were associated with greater TDP-43 burden and more extensive TDP-43 distribution. TDP-43 is an important factor in the manifestation of the clinico-imaging features of AD. TDP-43 also appears to be able to overpower what has been termed resilient brain aging. TDP-43 therefore should be considered a potential therapeutic target for the treatment of AD. [ABSTRACT FROM AUTHOR]