Ageing-Related Neurodegeneration and Cognitive Decline.

Neuropathological assessment was conducted on 1630 subjects, representing 5% of all the deceased that had been sent to the morgue of Uppsala University Hospital during a 15-year-long period. Among the 1630 subjects, 1610 were ≥41 years of age (range 41 to 102 years). Overall, hyperphosphorylated (HP) τ was observed in the brains of 98% of the 1610 subjects, and amyloid ß-protein (Aß) in the brains of 64%. The most common alteration observed was Alzheimer disease neuropathologic change (ADNC) (56%), followed by primary age-related tauopathy (PART) in 26% of the subjects. In 16% of the subjects, HPτ was limited to the locus coeruleus. In 14 subjects (<1%), no altered proteins were observed. In 3 subjects, only Aß was observed, and in 17, HPτ was observed in a distribution other than that seen in ADNC/PART. The transactive DNA-binding protein 43 (TDP43) associated with limbic-predominant age-related TDP encephalopathy (LATE) was observed in 565 (35%) subjects and α-synuclein (αS) pathology, i.e., Lewy body disease (LBD) or multi system atrophy (MSA) was observed in the brains of 21% of the subjects. A total of 39% of subjects with ADNC, 59% of subjects with PART, and 81% of subjects with HPτ limited to the locus coeruleus lacked concomitant pathologies, i.e., LATE-NC or LBD-NC. Of the 293 (18% of the 1610 subjects) subjects with dementia, 81% exhibited a high or intermediate level of ADNC. In 84% of all individuals with dementia, various degrees of concomitant alterations were observed; i.e., MIXED-NC was a common cause of dementia. A high or intermediate level of PART was observed in 10 subjects with dementia (3%), i.e., tangle-predominant dementia. No subjects exhibited only vascular NC (VNC), but in 17 subjects, severe VNC might have contributed to cognitive decline. Age-related tau astrogliopathy (ARTAG) was observed in 37% of the 1610 subjects and in 53% of those with dementia.

Characterization of monoamine oxidase-B (MAO-B) as a biomarker of reactive astrogliosis in Alzheimer's disease and related dementias.

Reactive astrogliosis accompanies the two neuropathological hallmarks of Alzheimer's disease (AD)-Aß plaques and neurofibrillary tangles-and parallels neurodegeneration in AD and AD-related dementias (ADRD). Thus, there is growing interest in developing imaging and fluid biomarkers of reactive astrogliosis for AD/ADRD diagnosis and prognostication. Monoamine oxidase-B (MAO-B) is emerging as a target for PET imaging radiotracers of reactive astrogliosis. However, a thorough characterization of MAO-B expression in postmortem control and AD/ADRD brains is lacking. We sought to: (1) identify the primary cell type(s) expressing MAO-B in control and AD brains; (2) quantify MAO-B immunoreactivity in multiple brain regions of control and AD donors as a proxy for PET radiotracer uptake; (3) correlate MAO-B level with local AD neuropathological changes, reactive glia, and cortical atrophy; (4) determine whether the MAOB rs1799836 SNP genotype impacts MAO-B expression level; (5) compare MAO-B immunoreactivity across AD/ADRD, including Lewy body diseases (LBD) and frontotemporal lobar degenerations with tau (FTLD-Tau) and TDP-43 (FTLD-TDP). We found that MAO-B is mainly expressed by subpial and perivascular cortical astrocytes as well as by fibrous white matter astrocytes in control brains, whereas in AD brains, MAO-B is significantly upregulated by both cortical reactive astrocytes and white matter astrocytes across temporal, frontal, and occipital lobes. By contrast, MAO-B expression level was unchanged and lowest in cerebellum. Cortical MAO-B expression was independently associated with cortical atrophy and local measures of reactive astrocytes and microglia, and significantly increased in reactive astrocytes surrounding Thioflavin-S+ dense-core Aß plaques. MAO-B expression was not affected by the MAOB rs1799836 SNP genotype. MAO-B expression was also significantly increased in the frontal cortex and white matter of donors with corticobasal degeneration, Pick's disease, and FTLD-TDP, but not in LBD or progressive supranuclear palsy. These findings support ongoing efforts to develop MAO-B-based PET radiotracers to image reactive astrogliosis in AD/ADRD.

Altered TFEB subcellular localization in nigral neurons of subjects with incidental, sporadic and GBA-related Lewy body diseases.

Transcription factor EB (TFEB) is a master regulator of genes involved in the maintenance of autophagic and lysosomal homeostasis, processes which have been implicated in the pathogenesis of GBA-related and sporadic Parkinson's disease (PD), and dementia with Lewy bodies (DLB). TFEB activation results in its translocation from the cytosol to the nucleus. Here, we investigated TFEB subcellular localization and its relation to intracellular alpha-synuclein (aSyn) accumulation in post-mortem human brain of individuals with either incidental Lewy body disease (iLBD), GBA-related PD/DLB (GBA-PD/DLB) or sporadic PD/DLB (sPD/DLB), compared to control subjects. We analyzed nigral dopaminergic neurons using high-resolution confocal and stimulated emission depletion (STED) microscopy and semi-quantitatively scored the TFEB subcellular localization patterns. We observed reduced nuclear TFEB immunoreactivity in PD/DLB patients compared to controls, both in sporadic and GBA-related cases, as well as in iLBD cases. Nuclear depletion of TFEB was more pronounced in neurons with Ser129-phosphorylated (pSer129) aSyn accumulation in all groups. Importantly, we observed previously-unidentified TFEB-immunopositive perinuclear clusters in human dopaminergic neurons, which localized at the Golgi apparatus. These TFEB clusters were more frequently observed and more severe in iLBD, sPD/DLB and GBA-PD/DLB compared to controls, particularly in pSer129 aSyn-positive neurons, but also in neurons lacking detectable aSyn accumulation. In aSyn-negative cells, cytoplasmic TFEB clusters were more frequently observed in GBA-PD/DLB and iLBD patients, and correlated with reduced GBA enzymatic activity as well as increased Braak LB stage. Altered TFEB distribution was accompanied by a reduction in overall mRNA expression levels of selected TFEB-regulated genes, indicating a possible early dysfunction of lysosomal regulation. Overall, we observed cytoplasmic TFEB retention and accumulation at the Golgi in cells without apparent pSer129 aSyn accumulation in iLBD and PD/DLB patients. This suggests potential TFEB impairment at the early stages of cellular disease and underscores TFEB as a promising therapeutic target for synucleinopathies.

Disease and brain region specific immune response profiles in neurodegenerative diseases with pure and mixed protein pathologies.

The disease-specific accumulation of pathological proteins has long been the major focus of research in neurodegenerative diseases (ND), including Alzheimer's disease (AD) and related dementias (RD), but the recent identification of a multitude of genetic risk factors for ND in immune-associated genes highlights the importance of immune processes in disease pathogenesis and progression. Studies in animal models have characterized the local immune response to disease-specific proteins in AD and ADRD, but due to the complexity of disease processes and the co-existence of multiple protein pathologies in human donor brains, the precise role of immune processes in ND is far from understood. To better characterize the interplay between different extracellular and intracellular protein pathologies and the brain's intrinsic immune system in ND, we set out to comprehensively profile the local immune response in postmortem brain samples of individuals with "pure" beta-Amyloid and tau pathology (AD), "pure" α-Synuclein pathology in Lewy body diseases (LBD), as well as cases with Alzheimer's disease neuropathological changes (ADNC) and Lewy body pathology (MIX). Combining immunohistochemical profiling of microglia and digital image analysis, along with deep immunophenotyping using gene expression profiling on the NanoString nCounter® platform and digital spatial profiling on the NanoString GeoMx® platform we identified a robust immune activation signature in AD brain samples. This signature is maintained in persons with mixed pathologies, irrespective of co-existence of AD pathology and Lewy body (LB) pathology, while LBD brain samples with "pure" LB pathology exhibit an attenuated and distinct immune signature. Our studies highlight disease- and brain region-specific immune response profiles to intracellular and extracellular protein pathologies and further underscore the complexity of neuroimmune interactions in ND.

α-Synuclein triggers cofilin pathology and dendritic spine impairment via a PrPC-CCR5 dependent pathway.

Cognitive dysfunction and dementia are critical symptoms of Lewy Body dementias (LBD). Specifically, alpha-synuclein (αSyn) accumulation in the hippocampus leading to synaptic dysfunction is linked to cognitive deficits in LBD. Here, we investigated the pathological impact of αSyn on hippocampal neurons. We report that either αSyn overexpression or αSyn pre-formed fibrils (PFFs) treatment triggers the formation of cofilin-actin rods, synapse disruptors, in cultured hippocampal neurons and in the hippocampus of synucleinopathy mouse models and of LBD patients. In vivo, cofilin pathology is present concomitantly with synaptic impairment and cognitive dysfunction. Rods generation prompted by αSyn involves the co-action of the cellular prion protein (PrPC) and the chemokine receptor 5 (CCR5). Importantly, we show that CCR5 inhibition, with a clinically relevant peptide antagonist, reverts dendritic spine impairment promoted by αSyn. Collectively, we detail the cellular and molecular mechanism through which αSyn disrupts hippocampal synaptic structure and we identify CCR5 as a novel therapeutic target to prevent synaptic impairment and cognitive dysfunction in LBD.

Skin Biopsy Detection of Phosphorylated α-Synuclein in Patients With Synucleinopathies.

Importance: Finding a reliable diagnostic biomarker for the disorders collectively known as synucleinopathies (Parkinson disease [PD], dementia with Lewy bodies [DLB], multiple system atrophy [MSA], and pure autonomic failure [PAF]) is an urgent unmet need. Immunohistochemical detection of cutaneous phosphorylated α-synuclein may be a sensitive and specific clinical test for the diagnosis of synucleinopathies. Objective: To evaluate the positivity rate of cutaneous α-synuclein deposition in patients with PD, DLB, MSA, and PAF. Design, Setting, and Participants: This blinded, 30-site, cross-sectional study of academic and community-based neurology practices conducted from February 2021 through March 2023 included patients aged 40 to 99 years with a clinical diagnosis of PD, DLB, MSA, or PAF based on clinical consensus criteria and confirmed by an expert review panel and control participants aged 40 to 99 years with no history of examination findings or symptoms suggestive of a synucleinopathy or neurodegenerative disease. All participants completed detailed neurologic examinations and disease-specific questionnaires and underwent skin biopsy for detection of phosphorylated α-synuclein. An expert review panel blinded to pathologic data determined the final participant diagnosis. Exposure: Skin biopsy for detection of phosphorylated α-synuclein. Main Outcomes: Rates of detection of cutaneous α-synuclein in patients with PD, MSA, DLB, and PAF and controls without synucleinopathy. Results: Of 428 enrolled participants, 343 were included in the primary analysis (mean [SD] age, 69.5 [9.1] years; 175 [51.0%] male); 223 met the consensus criteria for a synucleinopathy and 120 met criteria as controls after expert panel review. The proportions of individuals with cutaneous phosphorylated α-synuclein detected by skin biopsy were 92.7% (89 of 96) with PD, 98.2% (54 of 55) with MSA, 96.0% (48 of 50) with DLB, and 100% (22 of 22) with PAF; 3.3% (4 of 120) of controls had cutaneous phosphorylated α-synuclein detected. Conclusions and Relevance: In this cross-sectional study, a high proportion of individuals meeting clinical consensus criteria for PD, DLB, MSA, and PAF had phosphorylated α-synuclein detected by skin biopsy. Further research is needed in unselected clinical populations to externally validate the findings and fully characterize the potential role of skin biopsy detection of phosphorylated α-synuclein in clinical care.

Altered structural and functional connectivity in Posterior Cortical Atrophy and Dementia with Lewy bodies.

Posterior cortical atrophy (PCA) and dementia with Lewy bodies (DLB) show distinct atrophy and overlapping hypometabolism profiles, but it is unknown how disruptions in structural and functional connectivity compare between these disorders and whether breakdowns in connectivity relate to either atrophy or hypometabolism. Thirty amyloid-positive PCA patients, 24 amyloid-negative DLB patients and 30 amyloid-negative cognitively unimpaired (CU) healthy individuals were recruited at Mayo Clinic, Rochester, MN, and underwent a 3T head MRI, including structural MRI, resting state functional MRI (rsfMRI) and diffusion tensor imaging (DTI) sequences, as well as [18F] fluorodeoxyglucose (FDG) PET. We assessed functional connectivity within and between 12 brain networks using rsfMRI and the CONN functional connectivity toolbox and calculated regional DTI metrics using the Johns Hopkins atlas. Multivariate linear-regression models corrected for multiple comparisons and adjusted for age and sex compared DTI metrics and within-network and between-network functional connectivity across groups. Regional gray-matter volumes and FDG-PET standard uptake value ratios (SUVRs) were calculated and analyzed at the voxel-level using SPM12. We used univariate linear-regression models to investigate the relationship between connectivity measures, gray-matter volume, and FDG-PET SUVR. On DTI, PCA showed degeneration in occipito-parietal white matter, posterior thalamic radiations, splenium of the corpus collosum and sagittal stratum compared to DLB and CU, with greater degeneration in the temporal white matter and the fornix compared to CU. We observed no white-matter degeneration in DLB compared to CU. On rsfMRI, reduced within-network connectivity was present in dorsal and ventral default mode networks (DMN) and the dorsal-attention network in PCA compared to DLB and CU, with reduced within-network connectivity in the visual and sensorimotor networks compared to CU. DLB showed reduced connectivity in the cerebellar network compared to CU. Between-network analysis showed increased connectivity in both cerebellar-to-sensorimotor and cerebellar-to-dorsal attention network connectivity in PCA and DLB. PCA showed reduced anterior DMN-to-cerebellar and dorsal attention-to-sensorimotor connectivity, while DLB showed reduced posterior DMN-to-sensorimotor connectivity compared to CU. PCA showed reduced dorsal DMN-to-visual connectivity compared to DLB. The multimodal analysis revealed weak associations between functional connectivity and volume in PCA, and between functional connectivity and metabolism in DLB. These findings suggest that PCA and DLB have unique connectivity alterations, with PCA showing more widespread disruptions in both structural and functional connectivity; yet some overlap was observed with both disorders showing increased connectivity from the cerebellum.

Association of Anticholinergic Drug Burden With Cognitive and Functional Decline Over Time in Dementia With Lewy Bodies: 1-Year Follow-Up Study.

BACKGROUND: The purpose of this study was to investigate the relationship between anticholinergic burden (ACB), and cognitive and functional alterations in patients with dementia of Lewy bodies (DLB) during a 1-year follow-up period. METHODS: This cohort study included patients diagnosed with DLB admitted to a tertiary geriatric outpatient clinic. Cognition, functional performance, and nutritional status were assessed at baseline, 6 months, and 12 months during the follow-up period. The ACB was evaluated, and participants were grouped as ACB ≥1 and ACB=0. RESULTS: A total of 112 patients with DLB (mean age, 79.3 ± 6.8 years; 50.9% female) were included. The mean number of medications was 5.1 ± 4, 56.9% of participants had polypharmacy, and 55.2% had an anticholinergic drug burden. Individuals with ACB ≥1 had lower instrumental activities of daily living (IADL) scores at baseline than those with ACB=0 (P=0.014). The Barthel index and Lawton-Brody IADL scores significantly decreased in the ACB ≥1 group on repetitive measurements over time, whereas only the Lawton-Brody IADL scores worsened in the ACB=0 group (all P<0.001). There were no significant differences in cognitive scores and Mini-Mental State Examination subdomains between the groups. The dependent variable repetitive test revealed a significant deterioration in the orientation subdomain in the ACB ≥1 group over time (P=0.001). Multivariable regression models showed no significant effect of ACB score on cognitive and functional impairment. CONCLUSION: Our study provides evidence that the use of anticholinergic drugs in this vulnerable population may potentially increase the morbidity by adversely affecting functional status and cognitive orientation.

Differences in the treatment needs of patients with dementia with Lewy bodies and their caregivers and differences in their physicians' awareness of those treatment needs according to the clinical department visited by the patients: a subanalysis of an observational survey study.

BACKGROUND: We investigated whether the treatment needs of patients with dementia with Lewy bodies (DLB) and their caregivers, along with their attending physicians' perception of those treatment needs, differ according to the clinical department visited by the patients. METHODS: This was a subanalysis of a multicenter, cross-sectional, observational survey study. Data from the main study were classified according to the clinical department visited by the patient: psychiatric group (P-group), geriatric internal medicine group (G-group), and neurology group (N-group). The treatment needs of patients and caregivers were defined as "the symptom that causes them the most distress", and the frequency of each answer was tabulated. RESULTS: This subanalysis included 134, 65, and 49 patient-caregiver pairs in the P-, G-, and N-groups, respectively. Statistically significant differences in patient background characteristics such as patient age; initial symptom domains; use of cholinesterase inhibitors, levodopa, antipsychotics, and Yokukansan; and total scores of the Mini-Mental State Examination, Neuropsychiatric Inventory-12, and Movement Disorder Society-Unified Parkinson's Disease Rating Scale Parts II and III were shown among the three subgroups. While there were no differences in patients' treatment needs among the subgroups, residual analysis showed that in the N-group, parkinsonism was more of a problem than other symptom domains (p = 0.001). There were significant differences in caregivers' treatment needs among the three subgroups (p < 0.001). The patient-physician concordance rates for the symptom domains that caused patients the most distress were: P-group, 42.9% (kappa coefficient [κ] = 0.264); G-group, 33.3% (κ = 0.135), and N-group, 67.6% (κ = 0.484). The caregiver-physician concordance rates for the symptom domains that caused the caregivers the most distress were: P-group, 54.8% (κ = 0.351), G-group, 50.0% (κ = 0.244), and N-group, 47.4% (κ = 0.170). CONCLUSION: This subanalysis revealed differences in the treatment needs of patients with DLB and their caregivers according to the clinical department they attended. There might be a lack of awareness of those treatment needs by the attending physicians, regardless of their specialty. TRIAL REGISTRATION: UMIN Clinical Trials Registry UMIN000041844.

Markers for the detection of Lewy body disease versus Alzheimer's disease in mild cognitive impairment: a systematic review and meta-analysis.

BACKGROUND: Mild cognitive impairment (MCI) may evolve into dementia. Early recognition of possible evolution to Alzheimer's disease (AD) and dementia with Lewy Bodies (DLB) is of importance, but actual diagnostic criteria have some limitations. In this systematic review and meta-analysis, we aimed to find the most accurate markers that can discriminate patients with DLB versus AD, in MCI stage. METHODS: We searched several databases up to 17 August 2023 including studies comparing markers that may distinguish DLB-MCI from AD-MCI. We reported data regarding sensitivity, specificity, and the area under the curves (AUCs) with their 95% confidence intervals (CIs). RESULTS: Among 2219 articles initially screened, eight case-control studies and one cohort study were included for a total of 832 outpatients with MCI. The accuracy of cerebrospinal fluid (CSF) markers was the highest among the markers considered (AUC > 0.90 for the CSF markers), with the AUC of CSF Aß42/Aß40 of 0.94. The accuracy for clinical symptom scales was very good (AUC = 0.93), as evaluated in three studies. Although limited to one study, the accuracy of FDG-PET (cingulate island sign ratio) was very good (AUC = 0.95) in discriminating DLB from AD in MCI, while the accuracy of SPECT markers and EEG frequencies was variable. CONCLUSIONS: Few studies have assessed the accuracy of biomarkers and clinical tools to distinguish DLB from AD at the MCI stage. While results are promising for CSF markers, FDG-PET and clinical symptoms scales, more studies, particularly with a prospective design, are needed to evaluate their accuracy and clinical usefulness. CLINICAL TRIAL REGISTRATION: Prospero (CRD42023422600).

Role of GBA variants in Lewy body disease neuropathology.

Rare and common GBA variants are risk factors for both Parkinson's disease (PD) and dementia with Lewy bodies (DLB). However, the degree to which GBA variants are associated with neuropathological features in Lewy body disease (LBD) is unknown. Herein, we assessed 943 LBD cases and examined associations of 15 different neuropathological outcomes with common and rare GBA variants. Neuropathological outcomes included LBD subtype, presence of a high likelihood of clinical DLB (per consensus guidelines), LB counts in five cortical regions, tyrosine hydroxylase immunoreactivity in the dorsolateral and ventromedial putamen, ventrolateral substantia nigra neuronal loss, Braak neurofibrillary tangle (NFT) stage, Thal amyloid phase, phospho-ubiquitin (pS65-Ub) level, TDP-43 pathology, and vascular disease. Sequencing of GBA exons revealed a total of 42 different variants (4 common [MAF > 0.5%], 38 rare [MAF < 0.5%]) in our series, and 165 cases (17.5%) had a copy of the minor allele for ≥ 1 variant. In analysis of common variants, p.L483P was associated with a lower Braak NFT stage (OR = 0.10, P < 0.001). In gene-burden analysis, presence of the minor allele for any GBA variant was associated with increased odds of a high likelihood of DLB (OR = 2.00, P < 0.001), a lower Braak NFT stage (OR = 0.48, P < 0.001), a lower Thal amyloid phase (OR = 0.55, P < 0.001), and a lower pS65-Ub level (ß: -0.37, P < 0.001). Subgroup analysis revealed that GBA variants were most common in LBD cases with a combination of transitional/diffuse LBD and Braak NFT stage 0-II or Thal amyloid phase 0-1, and correspondingly that the aforementioned associations of GBA gene-burden with a decreased Braak NFT stage and Thal amyloid phase were observed only in transitional or diffuse LBD cases. Our results indicate that in LBD, GBA variants occur most frequently in cases with greater LB pathology and low AD pathology, further informing disease-risk associations of GBA in PD, PD dementia, and DLB.

Molecular Behavior of α-Synuclein Is Associated with Membrane Transport, Lipid Metabolism, and Ubiquitin-Proteasome Pathways in Lewy Body Disease.

Lewy body diseases (LBDs) feature α-synuclein (α-syn)-containing Lewy bodies, with misfolded α-syn potentially propagating as seeds. Using a seeding amplification assay, we previously reported distinct α-syn seeding in LBD cases based on the area under seeding curves. This study revealed that LBD cases showing different α-syn seeding kinetics have distinct proteomics profiles, emphasizing disruptions in mitochondria and lipid metabolism in high-seeder cases. Though the mechanisms underlying LBD development are intricate, the factors influencing α-syn seeding activity remain elusive. To address this and complement our previous findings, we conducted targeted transcriptome analyses in the substantia nigra using the nanoString nCounter assay together with histopathological evaluations in high (n = 4) and low (n = 3) nigral α-syn seeders. Neuropathological findings (particularly the substantia nigra) were consistent between these groups and were characterized by neocortical LBD associated with Alzheimer's disease neuropathologic change. Among the 1811 genes assessed, we identified the top 20 upregulated and downregulated genes and pathways in α-syn high seeders compared with low seeders. Notably, alterations were observed in genes and pathways related to transmembrane transporters, lipid metabolism, and the ubiquitin-proteasome system in the high α-syn seeders. In conclusion, our findings suggest that the molecular behavior of α-syn is the driving force in the neurodegenerative process affecting the substantia nigra through these identified pathways. These insights highlight their potential as therapeutic targets for attenuating LBD progression.

Age-Related Pathology in Corticobasal Degeneration.

Elderly human brains are vulnerable to multiple proteinopathies, although each protein has a different transmission pathway. Tau-immunoreactive astrocytes are well-known in elderly brains. In contrast, astrocytic plaques, a hallmark in corticobasal degeneration (CBD), rarely occur in aging and neurodegenerative disease other than CBD. To elucidate the clinicopathological correlation of aging-related pathology in CBD, we examined 21 pathologically proven CBD cases in our institute (12 males and 9 females, with a mean age of death 70.6 years). All CBD cases showed grains and neurofibrillary tangles (NFTs). Fifteen cases (71.4%) showed beta-amyloid deposition such as senile plaques or cerebral amyloid angiopathy. Three cases (14.3%) had Lewy body pathology. One case was classified as amygdala-predominant Lewy body disease, although no cases met the pathological criteria for Alzheimer's disease. Five cases (23.8%) displayed Limbic-predominant and age-related TDP-43 encephalopathy (LATE). NFTs, grains, and TDP-43-positive neuronal inclusions were widely distributed throughout the limbic system of CBD patients, but their densities were low. CBD might a have similar cell vulnerability and transmission pathway to that of multiple proteinopathy in aging brains.

Fractal Analysis in Neurodegenerative Diseases.

Neurodegenerative diseases are defined by progressive nervous system dysfunction and death of neurons. The abnormal conformation and assembly of proteins is suggested to be the most probable cause for many of these neurodegenerative disorders, leading to the accumulation of abnormally aggregated proteins, for example, amyloid ß (Aß) (Alzheimer's disease and vascular dementia), tau protein (Alzheimer's disease and frontotemporal lobar degeneration), α-synuclein (Parkinson's disease and Lewy body dementia), polyglutamine expansion diseases (Huntington disease), or prion proteins (Creutzfeldt-Jakob disease). An aberrant gain-of-function mechanism toward excessive intraparenchymal accumulation thus represents a common pathogenic denominator in all these proteinopathies. Moreover, depending upon the predominant brain area involvement, these different neurodegenerative diseases lead to either movement disorders or dementia syndromes, although the underlying mechanism(s) can sometimes be very similar, and on other occasions, clinically similar syndromes can have quite distinct pathologies. Non-Euclidean image analysis approaches such as fractal dimension (FD) analysis have been applied extensively in quantifying highly variable morphopathological patterns, as well as many other connected biological processes; however, their application to understand and link abnormal proteinaceous depositions to other clinical and pathological features composing these syndromes is yet to be clarified. Thus, this short review aims to present the most important applications of FD in investigating the clinical-pathological spectrum of neurodegenerative diseases.

Disentangling and quantifying the relative cognitive impact of concurrent mixed neurodegenerative pathologies.

Neurodegenerative pathologies such as Alzheimer disease neuropathologic change (ADNC), Lewy body disease (LBD), limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC), and cerebrovascular disease (CVD) frequently coexist, but little is known about the exact contribution of each pathology to cognitive decline and dementia in subjects with mixed pathologies. We explored the relative cognitive impact of concurrent common and rare neurodegenerative pathologies employing multivariate logistic regression analysis adjusted for age, gender, and level of education. We analyzed a cohort of 6,262 subjects from the National Alzheimer's Coordinating Center database, ranging from 0 to 6 comorbid neuropathologic findings per individual, where 95.7% of individuals had at least 1 neurodegenerative finding at autopsy and 75.5% had at least 2 neurodegenerative findings. We identified which neuropathologic entities correlate most frequently with one another and demonstrated that the total number of pathologies per individual was directly correlated with cognitive performance as assessed by Clinical Dementia Rating (CDR®) and Mini-Mental State Examination (MMSE). We show that ADNC, LBD, LATE-NC, CVD, hippocampal sclerosis, Pick disease, and FTLD-TDP significantly impact overall cognition as independent variables. More specifically, ADNC significantly affected all assessed cognitive domains, LBD affected attention, processing speed, and language, LATE-NC primarily affected tests related to logical memory and language, while CVD and other less common pathologies (including Pick disease, progressive supranuclear palsy, and corticobasal degeneration) had more variable neurocognitive effects. Additionally, ADNC, LBD, and higher numbers of comorbid neuropathologies were associated with the presence of at least one APOE ε4 allele, and ADNC and higher numbers of neuropathologies were inversely correlated with APOE ε2 alleles. Understanding the mechanisms by which individual and concomitant neuropathologies affect cognition and the degree to which each contributes is an imperative step in the development of biomarkers and disease-modifying therapeutics, particularly as these medical interventions become more targeted and personalized.

Spatial transcriptomics reveals molecular dysfunction associated with cortical Lewy pathology.

A key hallmark of Parkinson's disease (PD) is Lewy pathology. Composed of α-synuclein, Lewy pathology is found both in dopaminergic neurons that modulate motor function, and cortical regions that control cognitive function. Recent work has established the molecular identity of dopaminergic neurons susceptible to death, but little is known about cortical neurons susceptible to Lewy pathology or molecular changes induced by aggregates. In the current study, we use spatial transcriptomics to capture whole transcriptome signatures from cortical neurons with α-synuclein pathology compared to neurons without pathology. We find, both in PD and related PD dementia, dementia with Lewy bodies and in the pre-formed fibril α-synucleinopathy mouse model, that specific classes of excitatory neurons are vulnerable to developing Lewy pathology. Further, we identify conserved gene expression changes in aggregate-bearing neurons that we designate the Lewy-associated molecular dysfunction from aggregates (LAMDA) signature. Neurons with aggregates downregulate synaptic, mitochondrial, ubiquitin-proteasome, endo-lysosomal, and cytoskeletal genes and upregulate DNA repair and complement/cytokine genes. Our results identify neurons vulnerable to Lewy pathology in the PD cortex and describe a conserved signature of molecular dysfunction in both mice and humans.

Structure of alpha-synuclein fibrils derived from human Lewy body dementia tissue.

The defining feature of Parkinson disease (PD) and Lewy body dementia (LBD) is the accumulation of alpha-synuclein (Asyn) fibrils in Lewy bodies and Lewy neurites. Here we develop and validate a method to amplify Asyn fibrils extracted from LBD postmortem tissue samples and use solid state nuclear magnetic resonance (SSNMR) studies to determine atomic resolution structure. Amplified LBD Asyn fibrils comprise a mixture of single protofilament and two protofilament fibrils with very low twist. The protofilament fold is highly similar to the fold determined by a recent cryo-electron microscopy study for a minority population of twisted single protofilament fibrils extracted from LBD tissue. These results expand the structural characterization of LBD Asyn fibrils and approaches for studying disease mechanisms, imaging agents and therapeutics targeting Asyn.

Lower oddball event-related EEG delta and theta responses in patients with dementia due to Parkinson's and Lewy body than Alzheimer's disease.

Oddball task-related EEG delta and theta responses are associated with frontal executive functions, which are significantly impaired in patients with dementia due to Parkinson's disease (PDD) and Lewy bodies (DLB). The present study investigated the oddball task-related EEG delta and theta responses in patients with PDD, DLB, and Alzheimer's disease dementia (ADD). During visual and auditory oddball paradigms, EEG activity was recorded in 20 ADD, 17 DLB, 20 PDD, and 20 healthy (HC) older adults. Event-related EEG power spectrum and phase-locking analysis were performed at the delta (1-4 Hz) and theta (4-7 Hz) frequency bands for target and nontarget stimuli. Compared to the HC persons, dementia groups showed lower frontal and central delta and theta power and phase-locking associated with task performance and neuropsychological test scores. Notably, this effect was more significant in the PDD and DLB than in the ADD. In conclusion, oddball task-related frontal and central EEG delta and theta responses may reflect frontal supramodal executive dysfunctions in PDD and DLB patients.

LRP10 and α-synuclein transmission in Lewy body diseases.

Autosomal dominant variants in LRP10 have been identified in patients with Lewy body diseases (LBDs), including Parkinson's disease (PD), Parkinson's disease-dementia (PDD), and dementia with Lewy bodies (DLB). Nevertheless, there is little mechanistic insight into the role of LRP10 in disease pathogenesis. In the brains of control individuals, LRP10 is typically expressed in non-neuronal cells like astrocytes and neurovasculature, but in idiopathic and genetic cases of PD, PDD, and DLB, it is also present in α-synuclein-positive neuronal Lewy bodies. These observations raise the questions of what leads to the accumulation of LRP10 in Lewy bodies and whether a possible interaction between LRP10 and α-synuclein plays a role in disease pathogenesis. Here, we demonstrate that wild-type LRP10 is secreted via extracellular vesicles (EVs) and can be internalised via clathrin-dependent endocytosis. Additionally, we show that LRP10 secretion is highly sensitive to autophagy inhibition, which induces the formation of atypical LRP10 vesicular structures in neurons in human-induced pluripotent stem cells (iPSC)-derived brain organoids. Furthermore, we show that LRP10 overexpression leads to a strong induction of monomeric α-synuclein secretion, together with time-dependent, stress-sensitive changes in intracellular α-synuclein levels. Interestingly, patient-derived astrocytes carrying the c.1424 + 5G > A LRP10 variant secrete aberrant high-molecular-weight species of LRP10 in EV-free media fractions. Finally, we show that this truncated patient-derived LRP10 protein species (LRP10splice) binds to wild-type LRP10, reduces LRP10 wild-type levels, and antagonises the effect of LRP10 on α-synuclein levels and distribution. Together, this work provides initial evidence for a possible functional role of LRP10 in LBDs by modulating intra- and extracellular α-synuclein levels, and pathogenic mechanisms linked to the disease-associated c.1424 + 5G > A LRP10 variant, pointing towards potentially important disease mechanisms in LBDs.