Single-nucleus multi-omics of Parkinson's disease reveals a glutamatergic neuronal subtype susceptible to gene dysregulation via alteration of transcriptional networks.

The genetic architecture of Parkinson's disease (PD) is complex and multiple brain cell subtypes are involved in the neuropathological progression of the disease. Here we aimed to advance our understanding of PD genetic complexity at a cell subtype precision level. Using parallel single-nucleus (sn)RNA-seq and snATAC-seq analyses we simultaneously profiled the transcriptomic and chromatin accessibility landscapes in temporal cortex tissues from 12 PD compared to 12 control subjects at a granular single cell resolution. An integrative bioinformatic pipeline was developed and applied for the analyses of these snMulti-omics datasets. The results identified a subpopulation of cortical glutamatergic excitatory neurons with remarkably altered gene expression in PD, including differentially-expressed genes within PD risk loci identified in genome-wide association studies (GWAS). This was the only neuronal subtype showing significant and robust overexpression of SNCA. Further characterization of this neuronal-subpopulation showed upregulation of specific pathways related to axon guidance, neurite outgrowth and post-synaptic structure, and downregulated pathways involved in presynaptic organization and calcium response. Additionally, we characterized the roles of three molecular mechanisms in governing PD-associated cell subtype-specific dysregulation of gene expression: (1) changes in cis-regulatory element accessibility to transcriptional machinery; (2) changes in the abundance of master transcriptional regulators, including YY1, SP3, and KLF16; (3) candidate regulatory variants in high linkage disequilibrium with PD-GWAS genomic variants impacting transcription factor binding affinities. To our knowledge, this study is the first and the most comprehensive interrogation of the multi-omics landscape of PD at a cell-subtype resolution. Our findings provide new insights into a precise glutamatergic neuronal cell subtype, causal genes, and non-coding regulatory variants underlying the neuropathological progression of PD, paving the way for the development of cell- and gene-targeted therapeutics to halt disease progression as well as genetic biomarkers for early preclinical diagnosis.

Decoding frontotemporal and cell-type-specific vulnerabilities to neuropsychiatric disorders and psychoactive drugs.

Frontotemporal lobe abnormalities are linked to neuropsychiatric disorders and cognition, but the role of cellular heterogeneity between temporal lobe (TL) and frontal lobe (FL) in the vulnerability to genetic risk factors remains to be elucidated. We integrated single-nucleus transcriptome analysis in 'fresh' human FL and TL with genetic susceptibility, gene dysregulation in neuropsychiatric disease and psychoactive drug response data. We show how intrinsic differences between TL and FL contribute to the vulnerability of specific cell types to both genetic risk factors and psychoactive drugs. Neuronal populations, specifically PVALB neurons, were most highly vulnerable to genetic risk factors for psychiatric disease. These psychiatric disease-associated genes were mostly upregulated in the TL, and dysregulated in the brain of patients with obsessive-compulsive disorder, bipolar disorder and schizophrenia. Among these genes, GRIN2A and SLC12A5, implicated in schizophrenia and bipolar disorder, were significantly upregulated in TL PVALB neurons and in psychiatric disease patients' brain. PVALB neurons from the TL were twofold more vulnerable to psychoactive drugs than to genetic risk factors, showing the influence and specificity of frontotemporal lobe differences on cell vulnerabilities. These studies provide a cell type resolved map of the impact of brain regional differences on cell type vulnerabilities in neuropsychiatric disorders.

Postmortem imaging reveals patterns of medial temporal lobe vulnerability to tau pathology in Alzheimer's disease.

Our current understanding of the spread and neurodegenerative effects of tau neurofibrillary tangles (NFTs) within the medial temporal lobe (MTL) during the early stages of Alzheimer's Disease (AD) is limited by the presence of confounding non-AD pathologies and the two-dimensional (2-D) nature of conventional histology studies. Here, we combine ex vivo MRI and serial histological imaging from 25 human MTL specimens to present a detailed, 3-D characterization of quantitative NFT burden measures in the space of a high-resolution, ex vivo atlas with cytoarchitecturally-defined subregion labels, that can be used to inform future in vivo neuroimaging studies. Average maps show a clear anterior to poster gradient in NFT distribution and a precise, spatial pattern with highest levels of NFTs found not just within the transentorhinal region but also the cornu ammonis (CA1) subfield. Additionally, we identify granular MTL regions where measures of neurodegeneration are likely to be linked to NFTs specifically, and thus potentially more sensitive as early AD biomarkers.

Tau propagation in the brain olfactory circuits is associated with smell perception changes in aging.

The direct access of olfactory afferents to memory-related cortical systems has inspired theories about the role of the olfactory pathways in the development of cortical neurodegeneration in Alzheimer's disease (AD). In this study, we used baseline olfactory identification measures with longitudinal flortaucipir and PiB PET, diffusion MRI of 89 cognitively normal older adults (73.82 ± 8.44 years; 56% females), and a transcriptomic data atlas to investigate the spatiotemporal spreading and genetic vulnerabilities of AD-related pathology aggregates in the olfactory system. We find that odor identification deficits are predominantly associated with tau accumulation in key areas of the olfactory pathway, with a particularly strong predictive power for longitudinal tau progression. We observe that tau spreads from the medial temporal lobe structures toward the olfactory system, not the reverse. Moreover, we observed a genetic background of odor perception-related genes that might confer vulnerability to tau accumulation along the olfactory system.

Associations Between Self and Study Partner Report of Cognitive Decline With Regional Tau in a Multicohort Study.

BACKGROUND AND OBJECTIVES: Self-reported cognitive decline is an early behavioral manifestation of Alzheimer disease (AD) at the preclinical stage, often believed to precede concerns reported by a study partner. Previous work shows cross-sectional associations with ß-amyloid (Aß) status and self-reported and study partner-reported cognitive decline, but less is known about their associations with tau deposition, particularly among those with preclinical AD. METHODS: This cross-sectional study included participants from the Anti-Amyloid Treatment in Asymptomatic AD/Longitudinal Evaluation of Amyloid Risk and Neurodegeneration studies (N = 444) and the Harvard Aging Brain Study and affiliated studies (N = 231), which resulted in a cognitively unimpaired (CU) sample of individuals with both nonelevated (Aß-) and elevated Aß (Aß+). All participants and study partners completed the Cognitive Function Index (CFI). Two regional tau composites were derived by averaging flortaucipir PET uptake in the medial temporal lobe (MTL) and neocortex (NEO). Global Aß PET was measured in Centiloids (CLs) with Aß+ >26 CL. We conducted multiple linear regression analyses to test associations between tau PET and CFI, covarying for amyloid, age, sex, education, and cohort. We also controlled for objective cognitive performance, measured using the Preclinical Alzheimer Cognitive Composite (PACC). RESULTS: Across 675 CU participants (age = 72.3 ± 6.6 years, female = 59%, Aß+ = 60%), greater tau was associated with greater self-CFI (MTL: ß = 0.28 [0.12, 0.44], p < 0.001, and NEO: ß = 0.26 [0.09, 0.42], p = 0.002) and study partner CFI (MTL: ß = 0.28 [0.14, 0.41], p < 0.001, and NEO: ß = 0.31 [0.17, 0.44], p < 0.001). Significant associations between both CFI measures and MTL/NEO tau PET were driven by Aß+. Continuous Aß showed an independent effect on CFI in addition to MTL and NEO tau for both self-CFI and study partner CFI. Self-CFI (ß = 0.01 [0.001, 0.02], p = 0.03), study partner CFI (ß = 0.01 [0.003, 0.02], p = 0.01), and the PACC (ß = -0.02 [-0.03, -0.01], p < 0.001) were independently associated with MTL tau, but for NEO tau, PACC (ß = -0.02 [-0.03, -0.01], p < 0.001) and study partner report (ß = 0.01 [0.004, 0.02], p = 0.002) were associated, but not self-CFI (ß = 0.01 [-0.001, 0.02], p = 0.10). DISCUSSION: Both self-report and study partner report showed associations with tau in addition to Aß. Additionally, self-report and study partner report were associated with tau above and beyond performance on a neuropsychological composite. Stratification analyses by Aß status indicate that associations between self-reported and study partner-reported cognitive concerns with regional tau are driven by those at the preclinical stage of AD, suggesting that both are useful to collect on the early AD continuum.

Temporal tau asymmetry spectrum influences divergent behavior and language patterns in Alzheimer's disease.

Understanding the psychiatric symptoms of Alzheimer s disease (AD) is crucial for advancing precision medicine and therapeutic strategies. The relationship between AD behavioral symptoms and asymmetry in spatial tau PET patterns is not well-known. Braak tau progression implicates the temporal lobes early. However, the clinical and pathological implications of temporal tau laterality remain unexplored. This cross-sectional study investigated the correlation between temporal tau PET asymmetry and behavior assessed using the neuropsychiatric inventory and composite scores for memory, executive function, and language, using data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset. In the entire cohort, continuous right and left temporal tau contributions to behavior and cognition were evaluated, controlling for age, sex, education, and tau burden on the contralateral side. Additionally, a temporal tau laterality index was calculated to define "asymmetry-extreme" groups (individuals with laterality indices greater than two standard deviations from the mean). 695 individuals (age = 73.9 ± 7.6 years, 372 (53.5 %) females) were included, comprising 281 (40%) cognitively unimpaired (CU) amyloid negative, 185 (27%) CU amyloid positive, and 229 (33%) impaired (CI) amyloid positive participants. In the full cohort analysis, right temporal tau was associated with worse behavior (B = 8.14, p-value = 0.007), and left temporal tau was associated with worse language (B = 1.4, p-value < 0.001). Categorization into asymmetry-extreme groups revealed 20 right- and 27 left-asymmetric participants. Within these extreme groups, there was additional heterogeneity along the anterior-posterior dimension. Asymmetrical tau burden is associated with distinct behavioral and cognitive profiles. Wide multi-cultural implementation of social cognition measures is needed to understand right-sided asymmetry in AD.

Availability of individual proteins for quantitative analysis in postmortem brains preserved in two different brain banks.

AIM: Postmortem brain research is necessary for elucidating the pathology of schizophrenia; an increasing number of studies require a combination of suitable tissue samples preserved at multiple brain banks. In this study, we examined whether a comparative study of protein expression levels can be conducted using postmortem brain samples preserved in different facilities. METHODS: We compared the demographic factors of postmortem brain samples preserved in two institutions and measured and compared the expression levels of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and glial fibrillary acidic protein (GFAP) in the prefrontal cortex and superior temporal gyrus. GAPDH is generally used as a loading control for western blotting, and GFAP is considered as an astrocyte marker in the brain. RESULTS: We found significant differences between the two institutions in postmortem interval, age at death, and preservation time. To reduce the effects of these differences on our measurements, the parameters were set as covariates in our analyses of covariance. Subsequently, no differences in GAPDH and GFAP expression were found between institutions. CONCLUSIONS: When studies are conducted using brain samples preserved in different brain banks, differences in demographic factors should be carefully considered and taken into account by statistical methods to minimize their impact as much as possible. Since there was no significant difference in the protein expression levels of GAPDH and GFAP in either region between the two institutions that preserved the postmortem brains, we concluded that it is possible to perform protein quantitative analysis assuming that there is no effect of difference between two institutions.

Mediterranean diet protects against a neuroinflammatory cortical transcriptome: Associations with brain volumetrics, peripheral inflammation, social isolation, and anxiety in nonhuman primates (Macaca fascicularis).

Mediterranean diets may be neuroprotective and prevent cognitive decline relative to Western diets; however, the underlying biology is poorly understood. We assessed the effects of Western versus Mediterranean-like diets on RNAseq-generated transcriptional profiles in lateral temporal cortex and their relationships with longitudinal changes in neuroanatomy, circulating monocyte gene expression, and observations of social isolation and anxiety in 38 socially-housed, middle-aged female cynomolgus macaques (Macaca fascicularis). Diet resulted in differential expression of seven transcripts (FDR < 0.05). Cyclin dependent kinase 14 (CDK14), a proinflammatory regulator, was lower in the Mediterranean group. The remaining six transcripts [i.e., "lunatic fringe" (LFNG), mannose receptor C type 2 (MRC2), solute carrier family 3 member 2 (SLCA32), butyrophilin subfamily 2 member A1 (BTN2A1), katanin regulatory subunit B1 (KATNB1), and transmembrane protein 268 (TMEM268)] were higher in cortex of the Mediterranean group and generally associated with anti-inflammatory/neuroprotective pathways. KATNB1 encodes a subcomponent of katanin, important in maintaining microtubule homeostasis. BTN2A1 is involved in immunomodulation of γδ T-cells which have anti-neuroinflammatory and neuroprotective effects. CDK14, LFNG, MRC2, and SLCA32 are associated with inflammatory pathways. The latter four differentially expressed cortex transcripts were associated with peripheral monocyte transcript levels, neuroanatomical changes determined by MRI, and with social isolation and anxiety. These results provide important insights into the potential mechanistic processes linking diet, peripheral and central inflammation, and behavior. Collectively, our results provide evidence that, relative to Western diets, Mediterranean diets confer protection against peripheral and central inflammation which is reflected in preserved brain structure and socioemotional behavior. Ultimately, such protective effects may confer resilience to the development of neuropathology and associated disease.

Spatiotemporal patterns of locus coeruleus integrity predict cortical tau and cognition.

Autopsy studies indicated that the locus coeruleus (LC) accumulates hyperphosphorylated tau before allocortical regions in Alzheimer's disease. By combining in vivo longitudinal magnetic resonance imaging measures of LC integrity, tau positron emission tomography imaging and cognition with autopsy data and transcriptomic information, we examined whether LC changes precede allocortical tau deposition and whether specific genetic features underlie LC's selective vulnerability to tau. We found that LC integrity changes preceded medial temporal lobe tau accumulation, and together these processes were associated with lower cognitive performance. Common gene expression profiles between LC-medial temporal lobe-limbic regions map to biological functions in protein transport regulation. These findings advance our understanding of the spatiotemporal patterns of initial tau spreading from the LC and LC's selective vulnerability to Alzheimer's disease pathology. LC integrity measures can be a promising indicator for identifying the time window when individuals are at risk of disease progression and underscore the importance of interventions mitigating initial tau spread.

Alteration of medial temporal lobe metabolism related to Alzheimer's disease and dementia with lewy bodies.

BACKGROUND: Association of medial temporal lobe (MTL) metabolism with Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) has not been evaluated considering their mixed disease (MD). METHODS: 131 patients with AD, 133 with DLB, 122 with MD, and 28 normal controls (NCs) underwent neuropsychological tests, assessments for parkinsonism, cognitive fluctuation (CF), and visual hallucinations (VH), and 18F-fluorodeoxyglucose PET to quantify MTL metabolism in the amygdala, hippocampus, and entorhinal cortex. The effects of AD and DLB on MTL metabolism were evaluated using general linear models (GLMs). Associations between MTL metabolism, cognition, and clinical features were evaluated using GLMs or logistic regression models separately performed for the AD spectrum (NC + AD + MD), DLB spectrum (NC + DLB + MD), and disease groups (AD + DLB + MD). Covariates included age, sex, and education. RESULTS: AD was associated with hippocampal/entorhinal hypometabolism, whereas DLB was associated with relative amygdalar/hippocampal hypermetabolism. Relative MTL hypermetabolism was associated with lower attention/visuospatial/executive scores and severe parkinsonism in both the AD and DLB spectra and disease groups. Left hippocampal/entorhinal hypometabolism was associated with lower verbal memory scores, whereas right hippocampal hypometabolism was associated with lower visual memory scores in both the AD spectrum and disease groups. Relative MTL hypermetabolism was associated with an increased risk of CF and VH in the disease group, and relative amygdalar hypermetabolism was associated with an increased risk of VH in the DLB spectrum. CONCLUSIONS: Entorhinal-hippocampal hypometabolism and relative amygdala-hippocampal hypermetabolism could be characteristics of AD- and DLB-related neurodegeneration, respectively.

Alzheimer's Disease-associated Region-specific Decrease of Vesicular Glutamate Transporter Immunoreactivity inthe Medial Temporal Lobe and Superior Temporal Gyrus.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder for which there are very limited treatment options. Dysfunction of the excitatory neurotransmitter system is thought to play a major role in the pathogenesis of this condition. Vesicular glutamate transporters (VGLUTs) are key to controlling the quantal release of glutamate. Thus, expressional changes in disease can have implications for aberrant neuronal activity, raising the possibility of a therapeutic target. There is no information regarding the expression of VGLUTs in the human medial temporal lobe in AD, one of the earliest and most severely affected brain regions. This study aimed to quantify and compare the layer-specific expression of VGLUT1 and VGLUT2 between control and AD cases in the hippocampus, subiculum, entorhinal cortex, and superior temporal gyrus. Free-floating fluorescent immunohistochemistry was used to label VGLUT1 and VGLUT2 in the hippocampus, subiculum, entorhinal cortex, and superior temporal gyrus. Sections were imaged using laser-scanning confocal microscopy and transporter densitometric analysis was performed. VGLUT1 density was not significantly different in AD tissue, except lower staining density observed in the dentate gyrus stratum moleculare (p = 0.0051). VGLUT2 expression was not altered in the hippocampus and entorhinal cortex of AD cases but was significantly lower in the subiculum (p = 0.015) and superior temporal gyrus (p = 0.0023). This study indicates a regionally specific vulnerability of VGLUT1 and VGLUT2 expression in the medial temporal lobe and superior temporal gyrus in AD. However, the causes and functional consequences of these disturbances need to be further explored to assess VGLUT1 and VGLUT2 as viable therapeutic targets.

TAF15 amyloid filaments in frontotemporal lobar degeneration.

Frontotemporal lobar degeneration (FTLD) causes frontotemporal dementia (FTD), the most common form of dementia after Alzheimer's disease, and is often also associated with motor disorders1. The pathological hallmarks of FTLD are neuronal inclusions of specific, abnormally assembled proteins2. In the majority of cases the inclusions contain amyloid filament assemblies of TAR DNA-binding protein 43 (TDP-43) or tau, with distinct filament structures characterizing different FTLD subtypes3,4. The presence of amyloid filaments and their identities and structures in the remaining approximately 10% of FTLD cases are unknown but are widely believed to be composed of the protein fused in sarcoma (FUS, also known as translocated in liposarcoma). As such, these cases are commonly referred to as FTLD-FUS. Here we used cryogenic electron microscopy (cryo-EM) to determine the structures of amyloid filaments extracted from the prefrontal and temporal cortices of four individuals with FTLD-FUS. Surprisingly, we found abundant amyloid filaments of the FUS homologue TATA-binding protein-associated factor 15 (TAF15, also known as TATA-binding protein-associated factor 2N) rather than of FUS itself. The filament fold is formed from residues 7-99 in the low-complexity domain (LCD) of TAF15 and was identical between individuals. Furthermore, we found TAF15 filaments with the same fold in the motor cortex and brainstem of two of the individuals, both showing upper and lower motor neuron pathology. The formation of TAF15 amyloid filaments with a characteristic fold in FTLD establishes TAF15 proteinopathy in neurodegenerative disease. The structure of TAF15 amyloid filaments provides a basis for the development of model systems of neurodegenerative disease, as well as for the design of diagnostic and therapeutic tools targeting TAF15 proteinopathy.

Metabolic connectivity as a predictor of surgical outcome in mesial temporal lobe epilepsy.

OBJECTIVE: The study investigated metabolic connectivity (MC) differences between patients with unilateral drug-resistant mesial temporal lobe epilepsy (MTLE) with hippocampal sclerosis (HS) and healthy controls (HCs), based on [18 F]-fluorodeoxyglucose (FDG)-PET data. We focused on the MC changes dependent on the lateralization of the epileptogenic lobe and on correlations with postoperative outcomes. METHODS: FDG-PET scans of 47 patients with unilateral MTLE with histopathologically proven HS and 25 HC were included in the study. All the patients underwent a standard anterior temporal lobectomy and were more than 2 years after the surgery. MC changes were compared between the two HS groups (left HS, right HS) and HC. Differences between the metabolic network of seizure-free and non-seizure-free patients after surgery were depicted afterward. Network changes were correlated with clinical characteristics. RESULTS: The study showed widespread metabolic network changes in the HS patients as compared to HC. The changes were more extensive in the right HS than in the left HS. Unfavorable surgical outcomes were found in patients with decreased MC within the network including both the lesional and contralesional hippocampus, ipsilesional frontal operculum, and contralesional insula. Favorable outcomes correlated with decreased MC within the network involving both orbitofrontal cortices and the ipsilesional temporal lobe. SIGNIFICANCE: There are major differences in the metabolic networks of left and right HS, with more extensive changes in right HS. The changes within the metabolic network could help predict surgical outcomes in patients with HS. MC may identify patients with potentially unfavorable outcomes and direct them to a more detailed presurgical evaluation. PLAIN LANGUAGE SUMMARY: Metabolic connectivity is a promising method for metabolic network mapping. Metabolic networks in mesial temporal lobe epilepsy are dependent on lateralization of the epileptogenic lobe and could predict surgical outcomes.

Evaluation of the diagnostic utility on 1.5T and 3.0T 1H magnetic resonance spectroscopy for temporal lobe epilepsy.

BACKGROUND: 1H magnetic resonance spectroscopy (1H-MRS) can be used to study neurological disorders because it can be utilized to examine the concentrations of related metabolites. However, the diagnostic utility of different field strengths for temporal lobe epilepsy (TLE) remains unclear. The purpose of this study is to make quantitative comparisons of metabolites of TLE at 1.5T and 3.0T and evaluate their efficacy. METHODS: Our retrospective collections included the single-voxel 1H-MRS of 23 TLE patients and 17 healthy control volunteers (HCs) with a 1.5T scanner, as well as 29 TLE patients and 17 HCs with a 3.0T scanner. Particularly, HCs were involved both the scans with 1.5T and 3.0T scanners, respectively. The metabolites, including the N-acetylaspartate (NAA), creatine (Cr), and choline (Cho), were measured in the left or right temporal pole of brain. To analyze the ratio of brain metabolites, including NAA/Cr, NAA/Cho, NAA/(Cho + Cr) and Cho/Cr, four controlled experiments were designed to evaluate the diagnostic utility of TLE on 1.5T and 3.0T MRS, included: (1) 1.5T TLE group vs. 1.5T HCs by the Mann-Whitney U Test, (2) 3.0T TLE group vs. 3.0T HCs by the Mann-Whitney U Test, (3) the power analysis for the 1.5T and 3.0T scanner, and (4) 3.0T HCs vs. 1.5T HCs by Paired T-Test. RESULTS: Three metabolite ratios (NAA/Cr, NAA/Cho, and NAA/(Cho + Cr) showed the same statistical difference (p < 0.05) in distinguishing the TLE from HCs in the bilateral temporal poles when using 1.5T or 3.0T scanners. Similarly, the power analysis demonstrated that four metabolite ratios (NAA/Cr, NAA/Cho, NAA/(Cho + Cr), Cho/Cr) had similar distinction abilities between 1.5T and 3.0T scanner, denoting both 1.5T and 3.0T scanners were provided with similar sensitivities and reproducibilities for metabolites detection. Moreover, the metabolite ratios of the same healthy volunteers were not statistically different between 1.5T and 3.0T scanners, except for NAA/Cho (p < 0.05). CONCLUSIONS: 1.5T and 3.0T scanners may have comparable diagnostic potential when 1H-MRS was used to diagnose patients with TLE.

Interindividual variation in human cortical cell type abundance and expression.

Single-cell transcriptomic studies have identified a conserved set of neocortical cell types from small postmortem cohorts. We extended these efforts by assessing cell type variation across 75 adult individuals undergoing epilepsy and tumor surgeries. Nearly all nuclei map to one of 125 robust cell types identified in the middle temporal gyrus. However, we found interindividual variance in abundances and gene expression signatures, particularly in deep-layer glutamatergic neurons and microglia. A minority of donor variance is explainable by age, sex, ancestry, disease state, and cell state. Genomic variation was associated with expression of 150 to 250 genes for most cell types. This characterization of cellular variation provides a baseline for cell typing in health and disease.

Morphological connectivity differences in Alzheimer's disease correlate with gene transcription and cell-type.

Alzheimer's disease (AD) is one of the most prevalent forms of dementia in older individuals. Convergent evidence suggests structural connectome abnormalities in specific brain regions are linked to AD progression. The biological basis underpinnings of these connectome changes, however, have remained elusive. We utilized an individual regional mean connectivity strength (RMCS) derived from a regional radiomics similarity network to capture altered morphological connectivity in 1654 participants (605 normal controls, 766 mild cognitive impairment [MCI], and 283 AD). Then, we also explored the biological basis behind these morphological changes through gene enrichment analysis and cell-specific analysis. We found that RMCS probes of the hippocampus and medial temporal lobe were significantly altered in AD and MCI, with these differences being spatially related to the expression of AD-risk genes. In addition, gene enrichment analysis revealed that the modulation of chemical synaptic transmission is the most relevant biological process associated with the altered RMCS in AD. Notably, neuronal cells were found to be the most pertinent cells in the altered RMCS. Our findings shed light on understanding the biological basis of structural connectome changes in AD, which may ultimately lead to more effective diagnostic and therapeutic strategies for this devastating disease.

Expression of Cytoskeletal Proteins (GFAP, Vimentin), Proapoptotic Protein (Caspase-3) and Protective Protein (S100) in the Epileptic Focus in Adults and Children with Drug-Resistant Temporal Lobe Epilepsy Associated with Focal Cortical Dysplasia.

The European Commission of the International League Against Epilepsy (ILAE) has identified glial mechanisms of seizures and epileptogenesis as top research priorities. The aim of our study was to conduct a comparative analysis of the expression levels of cytoskeletal proteins (glial fibrillar acidic protein (GFAP) and vimentin), protective protein S100, and proapoptotic caspase-3 protein in patients with drug-resistant epilepsy (DRE) associated with focal cortical dysplasia (FCD). We aimed to investigate how the expression levels of these proteins depend on age (both in children and adults), gender, and disease duration, using immunohistochemistry. Nonparametric statistical methods were employed for data analysis. In the epileptic focus area of the cortex and white matter in patients with FCD-associated temporal lobe DRE, a higher level of expression of these proteins was observed. Age and gender differences were found for vimentin and S100. In the early stages of disease development, there was a compensatory sequential increase in the expression of cytoskeletal and protective proteins. In patients with DRE, depending on the disease duration, patterns of development of neurodegeneration were noted, which is accompanied by apoptosis of gliocytes. These results provide insights into epilepsy mechanisms and may contribute to improving diagnostic and treatment approaches.

Differences in whole-brain metabolism are associated with the expression of genes related to neurovascular unit integrity and synaptic plasticity in temporal lobe epilepsy.

PURPOSE: Temporal lobe epilepsy (TLE) is a common, polygenic epilepsy syndrome that involves glucose hypometabolism in the epileptogenic zone. However, the transcriptional and cellular signatures underlying the metabolism in TLE remain unclear. METHODS: In this retrospective study, 2-[18F]-fluoro-2-deoxy-D-glucose ([18F]FDG) positron emission tomography (PET) scans of TLE patients (n = 104) who underwent anterior temporal lobectomy were consecutively collected between 2016 and 2021. The transcriptional profiles of TLE risk genes across the brain were identified by the gene expression analyses from six TLE patients and twelve postmortem donors (six from the Allen Human Brain Atlas). Integrating the neuroimaging and transcriptomic data, we examined the relationship between the expression of TLE-associated genes and metabolic alterations in TLE. Furthermore, we performed functional enrichment analyses of the genes with higher weight in partial least squares regression using Metascape. RESULTS: A total of 104 patients with TLE (mean age 29 ± 9 years, 50% male) and 30 healthy controls (HCs) (mean age 31 ± 6 years, 53% male) were enrolled. Compared to that of HCs, patients with TLE showed hypometabolism in the temporal lobes and adjacent structures but hypermetabolism in the thalamus and basal ganglia. The cortical map of inter-group differences in cerebral metabolism was spatially correlated with the expression of a weighted combination of genes enriched in ontology terms and pathways related to neurovascular unit (NVU) integrity and synaptic plasticity. DISCUSSION: Our findings, combined with the analysis of neuroimaging and transcriptional data, suggest that genes related to NVU integrity and synaptic plasticity may drive alterations to brain metabolism that mediate the genetic risk of TLE.

Medial Temporal Lobe Tau Aggregation Relates to Divergent Cognitive and Emotional Empathy Abilities in Alzheimer's Disease.

BACKGROUND: In Alzheimer's disease (AD), the gradual accumulation of amyloid-ß (Aß) and tau proteins may underlie alterations in empathy. OBJECTIVE: To assess whether tau aggregation in the medial temporal lobes related to differences in cognitive empathy (the ability to take others' perspectives) and emotional empathy (the ability to experience others' feelings) in AD. METHODS: Older adults (n = 105) completed molecular Aß positron emission tomography (PET) scans. Sixty-eight of the participants (35 women) were Aß positive and symptomatic with diagnoses of mild cognitive impairment, dementia of the Alzheimer's type, logopenic variant primary progressive aphasia, or posterior cortical atrophy. The remaining 37 (22 women) were asymptomatic Aß negative healthy older controls. Using the Interpersonal Reactivity Index, we compared current levels of informant-rated cognitive empathy (Perspective-Taking subscale) and emotional empathy (Empathic Concern subscale) in the Aß positive and negative participants. The Aß positive participants also underwent molecular tau-PET scans, which were used to investigate whether regional tau burden in the bilateral medial temporal lobes related to empathy. RESULTS: Aß positive participants had lower perspective-taking and higher empathic concern than Aß negative healthy controls. Medial temporal tau aggregation in the Aß positive participants had divergent associations with cognitive and emotional empathy. Whereas greater tau burden in the amygdala predicted lower perspective-taking, greater tau burden in the entorhinal cortex predicted greater empathic concern. Tau burden in the parahippocampal cortex did not predict either form of empathy. CONCLUSIONS: Across AD clinical syndromes, medial temporal lobe tau aggregation is associated with lower perspective-taking yet higher empathic concern.

A heterozygous splicing variant IVS9-7A > T in intron 9 of the MAPT gene in a patient with right-temporal variant frontotemporal dementia with atypical 4 repeat tauopathy.

Right temporal variant frontotemporal dementia, also called right-predominant semantic dementia, often has an unclear position within the framework of the updated diagnostic criteria for behavioral variant frontotemporal dementia or primary progressive aphasia. Recent studies have suggested that this population may be clinically, neuropathologically, and genetically distinct from those with behavioral variant frontotemporal dementia or left-predominant typical semantic variant primary progressive aphasia. Here we describe a Japanese case of right temporal variant frontotemporal dementia with novel heterozygous MAPT mutation Adenine to Thymidine in intervening sequence (IVS) 9 at position -7 from 3' splicing site of intron 9/exon 10 boundary (MAPT IVS9-7A > T). Postmortem neuropathological analysis revealed a predominant accumulation of 4 repeat tau, especially in the temporal lobe, amygdala, and substantia nigra, but lacked astrocytic plaques or tufted astrocytes. Immunoelectron microscopy of the tau filaments extracted from the brain revealed a ribbon-like structure. Moreover, a cellular MAPT splicing assay confirmed that this novel variant promoted the inclusion of exon 10, resulting in the predominant production of 4 repeat tau. These data strongly suggest that the MAPT IVS9-7 A > T variant found in our case is a novel mutation that stimulates the inclusion of exon 10 through alternative splicing of MAPT transcript and causes predominant 4 repeat tauopathy which clinically presents as right temporal variant frontotemporal dementia.