Cognitive trajectories preluding the onset of different dementia entities: a descriptive longitudinal study using the NACC database.

OBJECTIVE: To describe the 10-year preclinical cognitive trajectories of older, non-demented individuals towards the onset of the four most prevalent types of dementia, i.e., Alzheimer's disease(AD), Lewy body(LBD), vascular(VD) and frontotemporal dementia(FTD). METHODS: Our analysis focused on data from older (≥ 60years) NACC (National Alzheimer's Coordinating Center) participants. Four distinct presymptomatic dementia groups (AD-LBD-VD-FTD) and a comparison group of cognitively unimpaired(CU) participants were formed. Comprehensive cognitive assessments involving verbal episodic memory, semantic verbal fluency, confrontation naming, mental processing speed - attention and executive function - cognitive flexibility were conducted at baseline and on an approximately yearly basis. Descriptive analyses (adjusted general linear models) were performed to determine and compare the yearly cognitive scores of each group throughout the follow-up. Exploratory analyses were conducted to estimate the rates of cognitive decline. RESULTS: There were 3343 participants who developed AD, 247 LBD, 108 FTD, 155 VD and 3398 composed the CU group. Participants with AD performed worse on episodic memory than those with VD and LBD for about 3 to 4 years prior to dementia onset (the FTD group documented an intermediate course). Presymptomatic verbal fluency and confrontation naming trajectories differentiated quite well between the FTD group and the remaining dementia entities. Participants with incident LBD and VD performed worse than those with AD on executive functions and mental processing speed-attention since about 5 years prior to the onset of dementia, and worse than those with FTD more proximally to the diagnosis of the disorder. CONCLUSIONS: Heterogeneous cognitive trajectories characterize the presymptomatic courses of the most prevalent dementia entities.

Phase 2A Learnings Incorporated into RewinD-LB, a Phase 2B Clinical Trial of Neflamapimod in Dementia with Lewy Bodies.

BACKGROUND: In an exploratory 91-participant phase 2a clinical trial (AscenD-LB, NCT04001517) in dementia with Lewy bodies (DLB), neflamapimod showed improvement over placebo on multiple clinical endpoints. To confirm those results, a phase 2b clinical study (RewinD-LB, NCT05869669 ) that is similar to AscenD-LB has been initiated. OBJECTIVES: To optimize the choice of patient population, primary endpoint, and biomarker evaluations in RewinD-LB. DESIGN: Evaluation of the efficacy results from AscenD-LB, the main results of which, and a re-analysis after stratification for absence or presence of AD co-pathology (assessed by plasma ptau181), have been published. In addition, the MRI data from a prior phase 2a clinical trial in Early Alzheimer's disease (AD), were reviewed. SETTING: 22 clinical sites in the US and 2 in the Netherlands. PARTICIPANTS: Probable DLB by consensus criteria and abnormal dopamine uptake by DaTscan™ (Ioflupane I123 SPECT). INTERVENTION: Neflamapimod 40mg capsules or matching placebo capsules, twice-a-day (BID) or three-times-a-day (TID), for 16 weeks. MEASUREMENTS: 6-test Neuropsychological Test Battery (NTB) assessing attention and executive function, Clinical Dementia Rating Sum-of-Boxes (CDR-SB), Timed Up and Go (TUG), International Shopping List Test (ISLT). RESULTS: Within AscenD-LB, patients without evidence of AD co-pathology exhibited a neflamapimod treatment effect that was greater than that in the overall population and substantial (cohen's d effect size vs. placebo ≥ for CDR-SB, TUG, Attention and ISLT-recognition). In addition, the CDR-SB and TUG performed better than the cognitive tests to demonstrate neflamapimod treatment effect in comparison to placebo. Further, clinical trial simulations indicate with 160-patients (randomized 1:1), RewinD-LB conducted in patients without AD co-pathology has >95% (approaching 100%) statistical power to detect significant improvement over placebo on the CDR-SB. Preliminary evidence of positive treatment effects on beta functional connectivity by EEG and basal forebrain atrophy by MRI were obtained in AscenD-LB and the Early AD study, respectively. CONCLUSION: In addition to use of a single dose regimen of neflamapimod (40mg TID), key distinctions between phase 2b and phase 2a include RewinD-LB (1) excluding patients with AD co-pathology, (2) having CDR-SB as the primary endpoint, and (3) having MRI studies to evaluate effects on basal forebrain atrophy.

Ligand Profiling as a Diagnostic Tool to Differentiate Patient-Derived α-Synuclein Polymorphs.

Amyloid fibrils are characteristic of many neurodegenerative diseases, including Alzheimer's and Parkinson's diseases. While different diseases may have fibrils formed of the same protein, the supramolecular morphology of these fibrils is disease-specific. Here, a method is reported to distinguish eight morphologically distinct amyloid fibrils based on differences in ligand binding properties. Eight fibrillar polymorphs of α-synuclein (αSyn) were investigated: five generated de novo using recombinant αSyn and three generated using protein misfolding cyclic amplification (PMCA) of recombinant αSyn seeded with brain homogenates from deceased patients diagnosed with Parkinson's disease (PD), multiple system atrophy (MSA), and dementia with Lewy bodies (DLB). Fluorescence binding assays were carried out for each fibril using a toolkit of six different ligands. The fibril samples were separated into five categories based on a binary classification of whether they bound specific ligands or not. Quantitative binding measurements then allowed every fibrillar polymorph to be uniquely identified, and the PMCA fibrils derived from PD, MSA, and DLB patients could be unambiguously distinguished. This approach constitutes a novel and operationally simple method to differentiate amyloid fibril morphologies and to identify disease states using PMCA fibrils obtained by seeding with patient samples.

Neuroinflammation is associated with Alzheimer's disease co-pathology in dementia with Lewy bodies.

BACKGROUND: Neuroinflammation and Alzheimer's disease (AD) co-pathology may contribute to disease progression and severity in dementia with Lewy bodies (DLB). This study aims to clarify whether a different pattern of neuroinflammation, such as alteration in microglial and astroglial morphology and distribution, is present in DLB cases with and without AD co-pathology. METHODS: The morphology and load (% area of immunopositivity) of total (Iba1) and reactive microglia (CD68 and HLA-DR), reactive astrocytes (GFAP) and proteinopathies of alpha-synuclein (KM51/pser129), amyloid-beta (6 F/3D) and p-tau (AT8) were assessed in a cohort of mixed DLB + AD (n = 35), pure DLB (n = 15), pure AD (n = 16) and control (n = 11) donors in limbic and neocortical brain regions using immunostaining, quantitative image analysis and confocal microscopy. Regional and group differences were estimated using a linear mixed model analysis. RESULTS: Morphologically, reactive and amoeboid microglia were common in mixed DLB + AD, while homeostatic microglia with a small soma and thin processes were observed in pure DLB cases. A higher density of swollen astrocytes was observed in pure AD cases, but not in mixed DLB + AD or pure DLB cases. Mixed DLB + AD had higher CD68-loads in the amygdala and parahippocampal gyrus than pure DLB cases, but did not differ in astrocytic loads. Pure AD showed higher Iba1-loads in the CA1 and CA2, higher CD68-loads in the CA2 and subiculum, and a higher astrocytic load in the CA1-4 and subiculum than mixed DLB + AD cases. In mixed DLB + AD cases, microglial load associated strongly with amyloid-beta (Iba1, CD68 and HLA-DR), and p-tau (CD68 and HLA-DR), and minimally with alpha-synuclein load (CD68). In addition, the highest microglial activity was found in the amygdala and CA2, and astroglial load in the CA4. Confocal microscopy demonstrated co-localization of large amoeboid microglia with neuritic and classic-cored plaques of amyloid-beta and p-tau in mixed DLB + AD cases. CONCLUSIONS: In conclusion, microglial activation in DLB was largely associated with AD co-pathology, while astrocytic response in DLB was not. In addition, microglial activity was high in limbic regions, with prevalent AD pathology. Our study provides novel insights into the molecular neuropathology of DLB, highlighting the importance of microglial activation in mixed DLB + AD.

The Body, the Brain, the Environment, and Parkinson's Disease.

The brain- and body-first models of Lewy body disorders predict that aggregated alpha-synuclein pathology usually begins in either the olfactory system or the enteric nervous system. In both scenarios the pathology seems to arise in structures that are closely connected to the outside world. Environmental toxicants, including certain pesticides, industrial chemicals, and air pollution are therefore plausible trigger mechanisms for Parkinson's disease and dementia with Lewy bodies. Here, we propose that toxicants inhaled through the nose can lead to pathological changes in alpha-synuclein in the olfactory system that subsequently spread and give rise to a brain-first subtype of Lewy body disease. Similarly, ingested toxicants can pass through the gut and cause alpha-synuclein pathology that then extends via parasympathetic and sympathetic pathways to ultimately produce a body-first subtype. The resulting spread can be tracked by the development of symptoms, clinical assessments, in vivo imaging, and ultimately pathological examination. The integration of environmental exposures into the brain-first and body-first models generates testable hypotheses, including on the prevalence of the clinical conditions, their future incidence, imaging patterns, and pathological signatures. The proposed link, though, has limitations and leaves many questions unanswered, such as the role of the skin, the influence of the microbiome, and the effects of ongoing exposures. Despite these limitations, the interaction of exogenous factors with the nose and the gut may explain many of the mysteries of Parkinson's disease and open the door toward the ultimate goal -prevention.

Parkinson's Disease and Dementia with Lewy Bodies: One and the Same.

The question whether Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB) are expressions of the same underlying disease has been vigorously debated for decades. The recently proposed biological definitions of Lewy body disease, which do not assign any particular importance to the dopamine system over other degenerating neurotransmitter systems, has once more brought the discussion about different types of Lewy body disease to the forefront. Here, we briefly compare PDD and DLB in terms of their symptoms, imaging findings, and neuropathology, ultimately finding them to be indistinguishable. We then present a conceptual framework to demonstrate how one can view different clinical syndromes as manifestations of a shared underlying Lewy body disease. Early Parkinson's disease, isolated RBD, pure autonomic failure and other autonomic symptoms, and perhaps even psychiatric symptoms, represent diverse manifestations of the initial clinical stages of Lewy body disease. They are characterized by heterogeneous and comparatively limited neuronal dysfunction and damage. In contrast, Lewy body dementia, an encompassing term for both PDD and DLB, represents a more uniform and advanced stage of the disease. Patients in this category display extensive and severe Lewy pathology, frequently accompanied by co-existing pathologies, as well as multi-system neuronal dysfunction and degeneration. Thus, we propose that Lewy body disease should be viewed as a single encompassing disease entity. Phenotypic variance is caused by the presence of individual risk factors, disease mechanisms, and co-pathologies. Distinct subtypes of Lewy body disease can therefore be defined by subtype-specific disease mechanisms or biomarkers.

Psychosis in Neurodegenerative Dementias: A Systematic Comparative Review.

Background: Psychosis, characterized by delusions and/or hallucinations, is frequently observed during the progression of Alzheimer's disease (AD) and other neurodegenerative dementias (ND) (i.e., dementia with Lewy bodies (DLB), and frontotemporal dementia (FTD)) and cause diagnostic and management difficulties. Objective: This review aims at presenting a concise and up-to-date overview of psychotic symptoms that occur in patients with ND with a comparative approach. Methods: A systematic review was conducted following the PRISMA guidelines. 98 original studies investigating psychosis phenotypes in neurodegenerative dementias were identified (40 cohort studies, 57 case reports). Results: Psychosis is a frequently observed phenomenon during the course of ND, with reported prevalence ranging from 22.5% to 54.1% in AD, 55.9% to 73.9% in DLB, and 18% to 42% in FTD. Throughout all stages of these diseases, noticeable patterns emerge depending on their underlying causes. Misidentification delusions (16.6-78.3%) and visual hallucinations (50-69.6%) are frequently observed in DLB, while paranoid ideas and somatic preoccupations seem to be particularly common in AD and FTD, (respectively 9.1-60.3% and 3.10-41.5%). Limited data were found regarding psychosis in the early stages of these disorders. Conclusions: Literature data suggest that different ND are associated with noticeable variations in psychotic phenotypes, reflecting disease-specific tendencies. Further studies focusing on the early stages of these disorders are necessary to enhance our understanding of early psychotic manifestations associated with ND and help in differential diagnosis issues.

Exploring Psychosis in Neurodegenerative Dementia: Connecting Symptoms to Neurobiology.

The following commentary discusses a review by Cressot et al. entitled: 'Psychosis in Neurodegenerative Dementias: A Systematic Comparative Review'. The authors describe the epidemiology and phenomenology of psychosis across neurodegenerative dementias. Dementia with Lewy bodies had the highest reported prevalence of psychosis at 74% followed by Alzheimer's disease, 54% and frontotemporal degeneration, 42%. Detailed characterization of psychosis shows differences in the types of hallucinations and delusions by dementia type. These findings suggest that different types of dementia related pathology are associated with high rates of psychosis with more specific symptom profiles than previously appreciated. Understanding the differences and variety of psychotic experiences across dementia types may have diagnostic and therapeutic implications for treating hallucinations and delusions in populations suffering from neurodegenerative diseases.

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.

Revisiting the relevance of Hirano bodies in neurodegenerative diseases.

AIMS: Hirano bodies (HBs) are eosinophilic pathological structures with two morphological phenotypes commonly found in the hippocampal CA1 region in Alzheimer's disease (AD). This study evaluated the prevalence and distribution of HBs in AD and other neurodegenerative diseases. METHODS: This cross-sectional study systematically evaluated HBs in a cohort of 193 cases with major neurodegenerative diseases, including AD (n = 91), Lewy body disease (LBD, n = 87), progressive supranuclear palsy (PSP, n = 36), multiple system atrophy (MSA, n = 14) and controls (n = 26). The prevalence, number and morphology of HBs in the stratum lacunosum (HBL) and CA1 pyramidal cell layer were examined. In addition, we investigated the presence of HBs in five additional hippocampal subregions. RESULTS: The morphological types of HBs in CA1 were divided into three, including a newly discovered type, and were evaluated separately, with their morphology confirmed in three dimensions: (1) classic rod-shaped HB (CHB), (2) balloon-shaped HB (BHB) and the newly described (3) string-shaped HB (SHB). The prevalence of each HB type differed between disease groups: Compared with controls, for CHB in AD, AD + LBD, PSP and corticobasal degeneration, for BHB in AD + LBD and PSP, and SHB in AD + LBD and PSP were significantly increased. Regression analysis showed that CHBs were independently associated with higher Braak NFT stage, BHBs with LBD and TDP-43 pathology, SHBs with higher Braak NFT stage, PSP and argyrophilic grain disease and HBLs with MSA. CONCLUSIONS: This study demonstrates that HBs are associated with diverse neurodegenerative diseases and shows that morphological types appear distinctively in various conditions.

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.

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.

Who am I with my Lewy bodies? The insula as a core region of the self-concept networks.

BACKGROUND: Dementia with Lewy bodies (DLB) is characterized by insular atrophy, which occurs at the early stage of the disease. Damage to the insula has been associated with disorders reflecting impairments of the most fundamental components of the self, such as anosognosia, which is a frequently reported symptom in patients with Lewy bodies (LB). The purpose of this study was to investigate modifications of the self-concept (SC), another component of the self, and to identify neuroanatomical correlates, in prodromal to mild DLB. METHODS: Twenty patients with prodromal to mild DLB were selected to participate in this exploratory study along with 20 healthy control subjects matched in terms of age, gender, and level of education. The Twenty Statements Test (TST) was used to assess the SC. Behavioral performances were compared between LB patients and control subjects. Three-dimensional magnetic resonance images (MRI) were acquired for all participants and correlational analyses were performed using voxel-based morphometry (VBM) in whole brain and using a mask for the insula. RESULTS: The behavioral results on the TST showed significantly impaired performances in LB patients in comparison with control subjects (p < .0001). Correlational analyses using VBM revealed positive correlations between the TST and grey matter volume within insular cortex, right supplementary motor area, bilateral inferior temporal gyri, right inferior frontal gyrus, and left lingual gyrus, using a threshold of p = .001 uncorrected, including total intracranial volume (TIV), age, and MMSE as nuisance covariates. Additionally, correlational analysis using a mask for the insula revealed positive correlation with grey matter volume within bilateral insular cortex, using a threshold of p = .005. CONCLUSIONS: The behavioral results confirm the existence of SC impairments in LB patients from the prodromal stage of the disease, compared to matched healthy controls. As we expected, VBM analyses revealed involvement of the insula, among that of other brain regions, already known to be involved in other self-components. While this study is exploratory, our findings provide important insights regarding the involvement of the insula within the self, confirming the insula as a core region of the self-networks, including for high-order self-representations such as the SC.

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.

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.

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.

Sensitive detection of pathological seeds of α-synuclein, tau and prion protein on solid surfaces.

Prions or prion-like aggregates such as those composed of PrP, α-synuclein, and tau are key features of proteinopathies such as prion, Parkinson's and Alzheimer's diseases, respectively. Their presence on solid surfaces may be biohazardous under some circumstances. PrP prions bound to solids are detectable by ultrasensitive real-time quaking-induced conversion (RT-QuIC) assays if the solids can be immersed in assay wells or the prions transferred to pads. Here we show that prion-like seeds can remain detectable on steel wires for at least a year, or even after enzymatic cleaning and sterilization. We also show that contamination of larger objects with pathological seeds of α-synuclein, tau, and PrP can be detected by simply assaying a sampling medium that has been transiently applied to the surface. Human α-synuclein seeds in dementia with Lewy bodies brain tissue were detected by α-synuclein RT-QuIC after drying of tissue dilutions with concentrations as low as 10-6 onto stainless steel. Tau RT-QuIC detected tau seeding activity on steel exposed to Alzheimer's disease brain tissue diluted as much as a billion fold. Prion RT-QuIC assays detected seeding activity on plates exposed to brain dilutions as extreme as 10-5-10-8 from prion-affected humans, sheep, cattle and cervids. Sampling medium collected from surgical instruments used in necropsies of sporadic Creutzfeldt-Jakob disease-infected transgenic mice was positive down to 10-6 dilution. Sensitivity for prion detection was not sacrificed by omitting the recombinant PrP substrate from the sampling medium during its application to a surface and subsequent storage as long as the substrate was added prior to performing the assay reaction. Our findings demonstrate practical prototypic surface RT-QuIC protocols for the highly sensitive detection of pathologic seeds of α-synuclein, tau, and PrP on solid objects.

Mapping brain metabolism, connectivity and neurotransmitters topography in early and late onset dementia with lewy bodies.

INTRODUCTION: Early-onset dementia with Lewy bodies (EO-DLB) is associated with rapid cognitive decline and severe neuropsychiatric symptoms at onset. METHODS: Using FDG-PET imaging for 62 patients (21 EO-DLB, 41 LO (late-onset)-DLB), we explored brain hypometabolism, and metabolic connectivity in the whole-brain network and resting-state networks (RSNs). We also evaluated the spatial association between brain hypometabolism and neurotransmitter pathways topography. RESULTS: Direct comparisons between the two clinical subgroups showed that EO-DLB was characterized by a lower metabolism in posterior cingulate/precuneus and occipital cortex. Metabolic connectivity analysis revealed significant alterations in posterior regions in both EO-DLB and LO-DLB. The EO-DLB, however, showed more severe loss of connectivity between occipital and parietal nodes and hyperconnectivity between frontal and cerebellar nodes. Spatial topography association analysis indicated significant correlations between neurotransmitter maps (i.e. acetylcholine, GABA, serotonin, dopamine) and brain hypometabolism in both EO and LO-DLB, with significantly higher metabolic correlation in the presynaptic serotonergic system for EO-DLB, supporting its major dysfunction. CONCLUSIONS: Our study revealed greater brain hypometabolism and loss of connectivity in posterior brain region in EO- than LO-DLB. Serotonergic mapping emerges as a relevant factor for further investigation addressing clinical differences between DLB subtypes.

The cingulate island sign in a mixed memory clinical cohort: Prevalence and diagnostic accuracy.

INTRODUCTION: Visual rating of the cingulate island sign (CIS) on [18F]fluorodeoxyglucose ([18F]FDG) positron emission tomography (PET) has a high specificity for dementia with Lewy bodies (DLB) in selected cohorts such as DLB versus Alzheimer's disease (AD). In a mixed memory clinical population this study aimed to uncover the prevalence of CIS, the diagnostic accuracy for DLB, and the relationship between CIS and disease severity. METHODS: CIS on [18F]FDG-PET was retrospectively assessed with the visual CIS rating scale (CISRs) in 1000 patients with a syndrome diagnosis of mild cognitive impairment (MCI) or dementia with no restrictions in etiological diagnosis. RESULTS: In this cohort 24.3 % had a CISRs score ≥1 and 3.5 % had a CISRs score = 4. The prevalence of a CISRs score ≥1 was highest in DLB (74.0 %, n = 57). A CISRs score ≥1 was present in at least 9 % in other diagnostic groups. The prevalence of CIS across disease severities showed no statistically significant difference (p = 0.23). To differentiate DLB from non-DLB the optimal cut-off was a CISRs score ≥1 (balanced accuracy = 77.1 %) in MCI/mild dementia and a CISRs score ≥2 (balanced accuracy = 80.6 %) in moderate/severe dementia. The positive predictive value of a CISRs score = 4 for DLB was 57.7 % in MCI/mild dementia and 33.3 % in moderate/severe dementia. CONCLUSION: The CISRs is useful in differentiating DLB from other etiologies in a mixed memory clinical population. Balanced accuracy and positive predictive value may vary across disease severities in the population studied.