Parkinson's Disease With Dementia Research Articles

The abnormal accumulation of alpha-Synuclein (αSyn) within neurons is a hallmark of synucleinopathies, such as Parkinson's disease (PD), and could stem from impaired protein degradation. Genetic, in vitro, and post-mortem studies have suggested that lysosomal dysfunction and impaired proteolytic activity play important roles in the pathogenesis of PD. Lysosomes have been proposed as key sites for αSyn degradation, but direct evidence of the lysosomal localization of endogenous αSyn in the human brain is limited. This study aimed to investigate the localization of αSyn proteoforms, including different post-translational modifications (PTMs), within lysosomes of post-mortem human nigral neurons. We analyzed formalin-fixed, paraffin-embedded brain tissue from donors diagnosed with PD, PD with Dementia (PDD) or incidental Lewy body disease (iLBD). Substantia nigra sections were assessed using an extensive panel of αSyn-specific antibodies, including PTM-specific antibodies, and selected lysosomal markers via multiplex immunofluorescence, confocal and stimulated emission depletion (STED) microscopy. Here, we demonstrate widespread accumulation of αSyn within lysosomes in nigral dopaminergic neuron somas of donors with PD/PDD and iLBD. This lysosomal αSyn appeared morphologically distinct from cytosolic inclusions such as Lewy bodies (LBs) and related macro-aggregates, and was present both in cells with and without these larger αSyn deposits. When present, macro-aggregates were consistently accompanied by ring-shaped lysosomal structures. Compared to other neuronal morphologies, lysosomal αSyn was the most frequent morphology at early Braak stages (1–4), with a decline at later stages (5–6). Interestingly, lysosomal αSyn was detected solely by targeting the N-terminus or the NAC domain of αSyn, and not with antibodies targeting Serine 129-phosphorylated αSyn or other epitopes at the C-terminus (CT), suggesting that lysosome-associated αSyn lacks the CT. Our findings reveal two co-existing pools of neuronal somatic αSyn: a CT-negative lysosome-associated form, and a primarily non-lysosomal CT-positive form. Overall, we provide direct evidence of lysosomal involvement in cellular αSyn metabolism in post-mortem human PD brain.Supplementary InformationThe online version contains supplementary material available at 10.1186/s13024-025-00884-3.

Autophagy activation ameliorates cognitive deficits and alpha-synuclein pathology in an adeno-associated viral vector mediated rat model of Lewy body disorders.

Cognitive function, psychobehavioral symptoms, and MRI features in patients with non-demented Parkinson's disease, Parkinson's disease with dementia, and dementia with Lewy bodies.

Community-based surveys conducted in Japan investigating the prevalence of dementia and its underlying causes revealed that dementia of Alzheimer's type (DAT) is the most common, followed by vascular dementia (VaD), dementia with Lewy bodies (DLB), mixed dementia, and other conditions including frontotemporal lobar degeneration (FTLD). Accurate differential diagnosis of these disorders requires clarification of their clinical characteristics. The initial symptoms of DAT typically include recent memory loss, episodic memory impairment, and temporal disorientation. Behavioral and psychological symptoms often observed in DAT include delusions of theft, "saving appearance" responses, and head-turning signs. Vascular dementia develops in association with cerebrovascular disease and frequently exhibits a stepwise progression. DLB is characterized by core clinical features such as cognitive fluctuations, visual hallucinations, parkinsonism, and REM sleep behavior disorder. Diagnostic tools such as 123Iodine-metaiodobenzylguanidine (MIBG) myocardial scintigraphy and dopamine transporter (DAT) imaging may aid in diagnosis. In Parkinson's disease with dementia (PDD), cognitive impairment appears more than one year after the onset of parkinsonism. FTLD involves degeneration of the frontal and temporal lobes, leading to prominent changes in personality, behavior, and language function. Several subtypes of FTLD exist depending on the affected brain region, including the behavioral variant of frontotemporal dementia, semantic dementia, and progressive non-fluent aphasia. Idiopathic normal-pressure hydrocephalus (iNPH) is characterized by gait disturbance, urinary incontinence, and dementia, resulting from an abnormal accumulation of cerebrospinal fluid. Pathologically confirmed cases of DLB and progressive supranuclear palsy (PSP) may occasionally present with symptoms resembling iNPH.

Dementia is a syndrome of impaired brain function in which cognitive functions such as memory, language, attention, direction, and judgment are impaired, affecting or interfering with daily functioning. As dementia becomes more widespread, it is crucial to investigate the underlying mechanisms that contribute to cognitive decline. C-C chemokine receptor 5 (CCR5) has been extensively researched for its role in immune responses and function as a co-receptor in HIV infection. Current research indicates that CCR5, which acts as a regulator of synaptic plasticity, is involved in modulating various forms of learning and memory. Most studies suggest that CCR5 generally has a detrimental effect on diseases associated with dementia. This review seeks to deliver an extensive analysis of CCR5's role in cognitive processes by summarizing existing literature from both animal and human studies. It will cover the involvement of CCR5 in standard learning and memory functions, as well as in various types of dementia. The review will specifically address conditions such as HIV-related neurocognitive impairment (HAND), Alzheimer's disease (AD), stroke, vascular dementia, multiple sclerosis (MS), frontotemporal dementia (FTD), dementia with Lewy bodies (DLB), and Parkinson's disease with dementia (PDD). Based on the fact that CCR5 plays a contributing role in many diseases that cause dementia, this review also proposed CCR5 inhibition as a possible target for alleviating and ameliorating dementia.

ABSTRACTThe age‐associated neurodegenerative disorder, Lewy body dementia (LBD), encompasses neuropsychiatric symptom‐overlapping Dementia with Lewy bodies (DLB) and Parkinson's Disease with Dementia (PDD). We characterised how differential mitochondrial DNA (mtDNA) profiles contribute to neurotype‐specific neurodegeneration and thereby clinicopathological heterogeneity, between LBD's syndromes. We further characterised key nuclear‐encoding genes' recalibrations in response to such mtDNA changes. In post‐mortem ‘single‐cell’ acetylcholine‐ and noradrenaline‐producing neurons, respectively of the pedunculopontine nucleus (PPN) and locus coeruleus (LC) from DLB, PDD and neurological‐control brains, we quantified ‘major arc’‐locating mtDNA deletions (mtDels) and ‐copy number (mtCN), and measured mRNA levels of nuclear‐encoding genes regulating mtDNA maintenance, ‐biogenesis and mitophagy. DLB cases' OXPHOS defect instigating mtDel burden was higher in both neurotypes than PDD. In DLB, mtCN was reduced for both neurotypes, but PDD cases revealed mtDNA depletion in LC‐noradrenergic neurons only. DLB patients' shorter survival correlated with PPN‐cholinergic neurons' mtDel levels, inversely with wild‐type mtCN, implying that such neurons' inability to maintain sufficient wild‐type mtDNA content drive DLBs' rapid psycho‐cognitive manifestations. Contrastingly, PDD's longer disease duration allowed compensation against mtDels' clonal expansion in PPN‐cholinergic neurons. Moreover, PDD induced mRNA depletion of a mitochondrial genome maintenance gene in PPN‐cholinergic neurons, whilst LC‐noradrenergic neurons displayed reduced expression of a mitophagy regulating gene. Here we identify mitochondrial genome maintenance and mitophagy pathway enrichment as therapeutic targets to offset defective mtDNA within pontine cholinergic and noradrenergic neurons of PDD patients. The pronounced LBD subtype‐related mitochondria‐nuclear genetic differences question the consensus that pathology converges at disease end‐stage, calling for LBD subtype and neurotype‐specific therapeutics.

BackgroundThe hippocampus is highly affected in neurodegenerative diseases, including Alzheimer’s disease (AD) and Parkinson’s disease (PD). The relationship between neuropathology and atrophy in hippocampal subfields is complex due to differences in the selective neuronal vulnerability to distinct protein aggregates that underlie cognitive impairment. The aim of the current study was to investigate the relation between hippocampal subfield volumes, neuropathological burden (amyloid-β, p-tau and α-synuclein) and cognitive performance in AD, PD and control brain donors, using a cross-disease and within-subject post-mortem in situ MRI and neuropathology approach.MethodsA total of 60 brain donors, including 14 non-neurological controls, 27 AD and 19 PD, underwent post-mortem in situ MRI. From 3D-T1 images hippocampal subfield and entorhinal cortex volumes were derived using FreeSurfer-based subfield segmentation. Hippocampal tissue was obtained at subsequent autopsy, fixed and immunostained for amyloid-β, p-tau and pSer129-αSyn. Immunoreactivity in hippocampal subfields was quantified as area% load using QuPath. Clinical Dementia Rating scores were extracted from the clinical files when available.ResultsAD showed atrophy and increased p-tau, but not amyloid-β, burden in the CA1, subiculum and entorhinal cortex compared to controls, however MRI and neuropathology did not correlate. Controls and PD had similar hippocampal subfield volumes and pathology load. In PD, p-tau pathology, rather than pSer129-αSyn, was associated with lower total hippocampal volume (r=-0.68, p = 0.045), predominantly in PD with dementia (PDD) (r=-0.99, p = 0.013). Cross-disease, volume loss of the subiculum (r=-0.68, p = 0.001) and entorhinal cortex (r=-0.73, p = 0.004) strongly associated with cognitive impairment. Moreover, p-tau pathology had the strongest effect on subfield atrophy, most pronounced in the subiculum (β=-0.570, p < 0.001), but could only explain 22–44% of the volumetric variance.ConclusionsEven though p-tau was the strongest predictor of hippocampal subfield atrophy, AD-pathology (p-tau and amyloid-β) only partially accounted for volumetric differences in hippocampal subfields, highlighting the significance of other pathologies or mechanisms. The increased sensitivity of subicular and entorhinal cortical atrophy compared to total hippocampal atrophy highlights the potential clinical value of incorporating hippocampal subfield atrophy in monitoring disease progression.

White matter hyperintensity tissue property spatial variations as a function of cognitive status in Parkinson's disease.

Acoustic prosodic parameters associated with Parkinson's disease cognitive impairment.

Resting-state electroencephalographic rhythms depend on sex in patients with dementia due to Parkinson's and Lewy Body diseases: An exploratory study.

Parkinson's disease with dementia (PDD) severely affects the quality of life of patients with Parkinson's disease (PD) in the later stages. Recently, PD patients with diabetes were found to have a higher risk of cognitive decline and developing dementia with a faster progression, but the underlying mechanism remains unclear. Diabetes-related white matter damage may partially explain the mechanism by which diabetes participates in PDD. Seventy PD patients were included. PD patients underwent diffusion tensor imaging from The Second Affiliated Hospital of Chongqing Medical University were collected and were divided into four groups: PD with diabetes without dementia, PD with dementia without diabetes, PD without dementia and diabetes. Tract-based spatial statistics analysis and region-of-interest-based analysis were performed. Factorial analysis with diabetes and dementia taken as the main effects was performed, and the differences between the white matter fibers of PD patients from the four groups were also analyzed. The interaction between diabetes and dementia in the damage of white matter in PD patients was also analyzed. We found that both diabetes and dementia were found to be related to the damage in internal capsule, corona radiata, and thalamic radiation of the PD patients. There is an interaction between diabetes and dementia in the white matter damage of PD patients. Both diabetes and dementia were found to be related to the damage in internal capsule, corona radiata, and thalamic radiation of the PD patients. Diabetes may participate in cognitive decline in PD patients via damaging cognition-related white matter tracts.

Abstract BackgroundGlial fibrillary acidic protein (GFAP) is a marker of cerebral astrogliosis and occasionally elevated in patients with dementia. GFAP in cerebrospinal fluid (CSF), is routinely requested in referrals to neurochemistry laboratories; however, its ability to differentiate dementias and diagnostic capability is unclear. Our aim was to elucidate this, using two large datasets.MethodFirst, GFAP data measured since 2015 was retrieved from the database of the Clinical Neurochemistry Laboratory at the Sahlgrenska University hospital. We then cross‐referenced with the Swedish dementia registry (SveDem). Here, information on ten different diagnoses such as early onset AD (EAD [&lt;65 years]), late onset AD (LAD [≥65 years]), Parkinson disease with dementia (PDD), vascular dementia (VaD) and frontotemporal dementia (FTD), each with specific diagnostic criteria, were retrieved.The GFAP data was log10‐transformed, followed by an analysis of covariance (ANCOVA) and a subsequent post‐hoc Tukey’s test, with GFAP as dependent variable, diagnosis as independent variable and sex and age as covariates.ResultIn total, 1912 individuals (mean [SD] age, 71.9 [8.2] years; 52% male), were included. Lower log10‐transformed GFAP concentrations were seen in PDD (mean [SD], 2.68, [0.28] pg/mL), than in EAD, LAD, VaD and FTD; here, mean concentrations of 2.76 (0.24), 2.89 (0.23), 2.89 (0.32) and 2.76 (0.25) pg/mL were observed, respectively.In the post hoc analysis, GFAP differentiated VaD from EAD (p&lt;0.001). PDD concentrations were significantly different from VaD (p&lt;0.001) and LAD (p&lt;0.001). Further, it also differentiated FTD from VaD (p=0.006) and LAD (p=0.001).ConclusionCSF GFAP could on a group level help differentiate VaD from EAD, FTD and PDD. Also, it could differentiate PDD from LAD. These results bear potential clinical relevance, where clinicians in some uncertain cases could use this marker as a differential tool.

Abstract BackgroundThe Parkinson's disease (PD) cognition‐related covariance pattern (PDCP) was derived from network analysis of metabolic positron emission tomography (PET). The expression score is a feasible imaging biomarker that correlates with neuropsychological test performance. Graph analysis within specific networks characterizes brain function, particularly in terms of assortativity, which reflects the tendency to connect to nodes with similar degree values. However, PDCP assortativity is unclear.MethodsA total of 102 patients with PD underwent neuropsychological testing and [18F]‐fluorodeoxyglucose PET. Patients scoring less than 130 on the Dementia Rating Scale‐2 (DRS‐2) were classified as having PD with dementia (PDD). PD with mild cognitive impairment in single or multiple functions (sMCI or mMCI) was defined as having one (sMCI) or two or more (mMCI) of the following criteria: DRS‐2 subscore (Attention &lt; 35, Initiation/Perseveration &lt; 35, Construction &lt; 6, Conceptualization &lt; 35, Memory &lt; 24), Wisconsin Card Sorting Test &lt; 13 (executive), Hooper Visual Organization Test &lt; 30 (visuospatial), and Boston Naming Test &lt; 48 (language). The others were defined as having normal cognition (PD‐NC). We identified 35 anatomical regions of interest (ROIs) as nodes corresponding to the PDCP network. The pairwise correlation at each node of normalized metabolic activity derived from FDG‐PET data was calculated in each group by 100 bootstrapping iterations. The assortativity coefficient was calculated as the Pearson correlation coefficient of degrees between connected node pairs. Group differences were tested by repeated measures analysis of variance as group and threshold coefficients.ResultsThere were 22 PD‐NC, 24 sMCI, 31 mMCI, and 25 PDD. Demographic data are shown in Table 1. PDCP assortativity showed no significant differences between PD‐NC and sMCI (P = 0.23). However, it was increased in mMCI and PDD compared to PD‐NC and sMCI (P &lt; 0.01). In addition, it was higher in PDD than in mMCI (P &lt; 0.001) (Figure 1).ConclusionsAssortativity in the PDCP network is a potential predictor of the transition from MCI to dementia in PD patients. Furthermore, patients with cognitive impairment in multiple functions are at risk of developing dementia.

Abstract BackgroundAstrocytes are specialized glial cells that play crucial roles in the brain by providing metabolic and trophic support for the neurons. They become reactive (activated) and heterogeneously respond to neuropathology such as injuries and neurodegenerative diseases (NDs). High‐throughput single‐nucleus (snRNA‐seq) RNA sequencing has enabled a profound understanding of cell type heterogeneity. However, the number of astrocyte subpopulations in different regions of the brain, and the similarities and differences among these subpopulations in healthy and disease conditions are not clear.MethodWe performed uniform data analysis using the same algorithm and parameters on astrocytes from postmortem human brain single‐nucleus RNA‐sequencing (snRNA‐seq) data obtained from eight datasets with seven different brain regions of normal control subjects and subjects with different NDs including Alzheimer’s disease (AD), dementia with Lewy body disease (DLBD), Parkinson’s disease (PD), Parkinson’s disease with dementia (PDD), Huntingtin disease (HD), or Nasu‐Hakola disease (NHD). We identified astrocyte subpopulations and systematically compared astrocyte subpopulations and defined their common marker gene set across seven brain regions in six disease conditions. We conducted functional enrichment pathway analysis on the marker genes to understand the putative contribution of these subpopulations to NDs including across different brain regions.ResultWe identified 3‐6 distinct astrocyte subpopulations by examining the expression of conserved marker genes across all the different datasets. Two subpopulations were shared across all the NDs and brain regions, representing homeostatic (Ast‐0) and activated transcriptional states (Ast‐1 and Ast‐2), while the other subpopulations are unique to different datasets. Functional enrichment analysis revealed distinct and shared pathways among astrocyte subpopulations across all brain regions.ConclusionWe identified astrocyte subpopulations shared across all the brain regions and disease conditions with shared molecular marker genes but also regional‐ or disease‐specific gene expression features. We also observed disease‐ or brain region‐specific astrocyte subpopulations. These results suggest that regional differences in astrocyte subpopulations or gene expression could underly regional differences in brain susceptibility to different neurodegenerative diseases.

Introduction: The aim was to examine the differences in electroencephalography (EEG) findings by visual and automated quantitative analyses between Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) and Parkinson's disease with dementia (PDD). Methods: EEG data of 20 patients with AD and 24 with DLB/PDD (12 DLB and 12 PDD) were retrospectively analyzed. Based on the awake EEG, the posterior dominant rhythm frequency and proportion of patients who showed intermittent focal and diffuse slow waves (IDS) were visually and automatically compared between the AD and DLB/PDD groups. Results: On visual analysis, patients with DLB/PDD showed a lower PDR frequency than patients with AD. In patients with PDR <8 Hz and occipital slow waves or patients with PDR <8 Hz and IDS, DLB/PDD was highly suspected (PPV 100%) and AD was unlikely (PPV 0%). On automatic analysis, the findings of the PDR were similar to those on visual analysis. Comparisons between visual and automatic analysis showed an overlap in the focal slow wave commonly detected by both methods in 10 of 44 patients, and concordant presence or absence of IDS in 29 of 43 patients. With respect to PDR <8 Hz and the combination of PDR <8 Hz and IDS, PPV and NPV in DLB/PDD and AD were not different between visual and automatic analysis. Conclusions: As the noninvasive, widely available clinical tool of low expense, visual analysis of EEG findings provided highly sufficient information to delineate different brain dysfunction in AD and DLB/PDD, and automatic EEG analysis could support visual analysis especially about PD.

Introduction: There is limited understanding of body mass index (BMI) and serum albumin levels in patients with dementia. This study aimed to investigate the association between BMI, serum albumin levels, and dementia in patients with Alzheimer’s disease (AD), dementia with Lewy bodies (DLB), and Parkinson’s disease with dementia (PDD). Methods: A total of 336 patients with dementia (173 with AD, 112 with DLB, 51 with PDD) and 220 healthy controls were recruited. Pearson and Spearman correlation analyses were performed to examine the relationships between BMI or serum albumin and MMSE scores, as well as neuropathological markers. Logistic regression models were used to analyze the data, adjusting for confounding variables. Results: Using the highest BMI quartile (≥26.04 kg/m2) and serum albumin quartile (≥41.21 g/L) as reference groups, the lowest BMI quartile (<21.91 kg/m2) was significantly associated with AD (p < 0.001) and DLB (p = 0.003). The lowest serum albumin quartile (≤37.60 g/L) was independently associated with DLB (p < 0.001) and AD (p = 0.006). In AD patients, BMI was associated with Aβ1–42 and p-Tau181 in cerebrospinal fluid after controlling for confounders, while serum albumin was correlated with T-Tau and T-tau/Aβ1–42 (p < 0.05). Conclusion: Decreased serum albumin and BMI levels are associated with DLB and AD in dementia patients. Although no correlation was found between BMI or serum albumin and MMSE scores, there was a significant association with AD cerebrospinal fluid pathologic markers.

Advanced qEEG analyses discriminate between dementia subtypes

Parkinson’s disease with dementia (PDD) is a neurological disorder that clinically and neuropathologically overlaps with Parkinson’s disease (PD) and Alzheimer’s disease (AD). Although it is assumed that alpha-synuclein (α\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\mathrm{\\alpha }$$\\end{document}-Syn), amyloid beta (Aβ\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\upbeta$$\\end{document}), and the protein Tau might synergistically induce cholinergic neuronal degeneration, presently the pathological mechanism of PDD remains unclear. Therefore, it is essential to delve into the cellular and molecular aspects of this neurological entity to identify potential targets for prevention and treatment strategies. Cholinergic-like neurons (ChLNs) were exposed to rotenone (ROT, 10μ\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\upmu$$\\end{document}M) for 24 h. ROT provokes loss of ΔΨm\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\Delta \\mathrm{\\Psi m}$$\\end{document}, generation of reactive oxygen species (ROS), phosphorylation of leucine-rich repeated kinase 2 (LRRK2 at Ser935) concomitantly with phosphorylation of α\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\mathrm{\\alpha }$$\\end{document} -synuclein (α\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\mathrm{\\alpha }$$\\end{document}-Syn, Ser129), induces accumulation of intracellular Aβ\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\upbeta$$\\end{document} (iAβ\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\upbeta$$\\end{document}), oxidized DJ-1 (Cys106), as well as phosphorylation of TAU (Ser202/Thr205), increases the phosphorylation of c-JUN (Ser63/Ser73), and increases expression of proapoptotic proteins TP53, PUMA, and cleaved caspase 3 (CC3) in ChLNs. These neuropathological features resemble those reproduced in presenilin 1 (PSEN1) E280A ChLNs. Interestingly, anti-oxidant and anti-amyloid cannabidiol (CBD), JNK inhibitor SP600125 (SP), TP53 inhibitor pifithrin-α\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\mathrm{ \\alpha }$$\\end{document} (PFT), and LRRK2 kinase inhibitor PF-06447475 (PF475) significantly diminish ROT-induced oxidative stress (OS), proteinaceous, and cell death markers in ChLNs compared to naïve ChLNs. In conclusion, ROT induces p-α\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\mathrm{ \\alpha }$$\\end{document} -Syn, iAβ\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\upbeta$$\\end{document}, p-Tau, and cell death in ChLNs, recapitulating the neuropathology findings in PDD. Our report provides an excellent in vitro model to test for potential therapeutic strategies against PDD. Our data suggest that ROT induces a neuropathologic phenotype in ChLNs similar to that caused by the mutation PSEN1 E280A.

Cognitive impairment in Parkinson's disease (PD) is associated with changes in the brain anatomical structures. The objective of this study, is to identify the atrophy patterns based on the severity of cognitive decline and evaluate the disease progression. In this study, gray matter alterations are analysed in 135 PD subjects under 3 cognitive domains (91 Cognitively normal PD (NC-PD), 25 PD with Mild Cognitive Impairment (PD-MCI) and 19 PD with Dementia (PD-D)) by comparing them with 58 Healthy Control (HC) subjects. Voxel Based Morphometry (VBM) is used to segment the gray matter regions in magnetic resonance images and analyse the atrophy patterns statistically. Significant patterns of gray matter variations observed in the middle temporal and medial frontal region differentiate between HC and PD subject groups based on the severity of cognitive decline. Abnormalities in gray matter is substantiated through radiomic features extracted from the significant gray matter clusters. Significant radiomic features of the clusters are able to differentiate between the HC and PD-D subjects with an accuracy of 81.82%. Higher atrophy levels identified in PD-D subjects compared to NC-PD and PD-MCI group enables early diagnosis and treatment procedures. The combined and comprehensive analysis of gray matter alterations through VBM and radiomic features gives better assessment of cognitive impairment in PD.

Although early detection of individuals at risk of dementia conversion is important in patients with Parkinson's disease (PD), there is still no consensus on neuroimaging biomarkers for predicting future cognitive decline. We aimed to investigate whether cerebral perfusion patterns on early-phase 18 F-N-(3-fluoropropyl)-2β-carboxymethoxy-3β-(4-iodophenyl) nortropane ( 18 F-FP-CIT) PET have the potential to serve as a neuroimaging predictor for early dementia conversion in patients with PD. In this retrospective analysis, we enrolled 187 patients with newly diagnosed PD who underwent dual-phase 18 F-FP-CIT PET at initial assessment and serial cognitive assessments during the follow-up period (>5 years). Patients with PD were classified into 2 groups: the PD with dementia (PDD)-high-risk (PDD-H; n = 47) and the PDD-low-risk (PDD-L; n = 140) groups according to dementia conversion within 5 years of PD diagnosis. We explored between-group differences in the regional uptake in the early-phase 18 F-FP-CIT PET images. We additionally performed a linear discriminant analysis to develop a prediction model for early PDD conversion. The PDD-H group exhibited hypoperfusion in Alzheimer's disease (AD)-prone regions (inferomedial temporal and posterior cingulate cortices, and insula) compared with the PDD-L group. A prediction model using regional uptake in the right entorhinal cortex, left amygdala, and left isthmus cingulate cortex could optimally distinguish the PDD-H group from the PDD-L group. Regional hypoperfusion in the AD-prone regions on early-phase 18 F-FP-CIT PET can be a useful biomarker for predicting early dementia conversion in patients with PD.