Parkinson's Disease With Dementia Research Articles

Analysis of cognitive dysfunction in Parkinson's disease using voxel based morphometry and radiomics.

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.

Hypoperfusion in Alzheimer's Disease-Prone Regions and Dementia Conversion in Parkinson's Disease.

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 18F-N-(3-fluoropropyl)-2β-carboxymethoxy-3β-(4-iodophenyl) nortropane (18F-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 18F-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 18F-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 18F-FP-CIT PET can be a useful biomarker for predicting early dementia conversion in patients with PD.

Development and characterization of a non-human primate model of disseminated synucleinopathy.

The presence of a widespread cortical synucleinopathy is the main neuropathological hallmark underlying clinical entities such as Parkinson's disease with dementia (PDD) and dementia with Lewy bodies (DLB). There currently is a pressing need for the development of non-human primate (NHPs) models of PDD and DLB to further overcome existing limitations in drug discovery. Here we took advantage of a retrogradely-spreading adeno-associated viral vector serotype 9 coding for the alpha-synuclein A53T mutated gene (AAV9-SynA53T) to induce a widespread synucleinopathy of cortical and subcortical territories innervating the putamen. Four weeks post-AAV deliveries animals were sacrificed and a comprehensive biodistribution study was conducted, comprising the quantification of neurons expressing alpha-synuclein, rostrocaudal distribution and their specific location. Intraputaminal deliveries of AAV9-SynA53T lead to a disseminated synucleinopathy throughout ipsi- and contralateral cerebral cortices, together with transduced neurons located in the ipsilateral caudal intralaminar nuclei and in the substantia nigra pars compacta (leading to thalamostriatal and nigrostriatal projections, respectively). Cortical afferent systems were found to be the main contributors to putaminal afferents (superior frontal and precentral gyri in particular). Obtained data extends current models of synucleinopathies in NHPs, providing a reproducible platform enabling the adequate implementation of end-stage preclinical screening of new drugs targeting alpha-synuclein.

The relationship between major depressive disorder and dementia: A bidirectional two-sample Mendelian randomization study

BackgroundMajor depressive disorder (MDD) and dementia psychiatric and neurological diseases that are clinically widespread, but whether there is a causal link between them is still unclear. In this study, bidirectional two-sample Mendelian randomization (MR) was used to investigate the potential causal relationship between MDD and dementia via a genome-wide association study (GWAS) database, containing samples from the European population. MethodWe collected data on MDD and common clinical dementia subtypes from GWAS, including Alzheimer's disease (AD), frontotemporal dementia (FTD), dementia with Lewy bodies (DLB), Parkinson's disease with dementia (PDD), and vascular dementia (VaD). A series of bidirectional two-sample MR studies and correlation sensitivity analysis were carried out. ResultsIn the study of the effect of MDD on dementia subtypes, no causal relationship was found between MDD and dementia subtypes other than VaD, inverse variance weighted (IVW) method: odds ratio (OR), 2.131; 95 % confidence interval (CI), 1.249–3.639, P = 0.006; MDD-AD: OR, 1.000; 95 % CI, 0.999–1.001, P = 0.537; MDD-FTD: OR, 1.476; 95 % CI, 0.471–4.627, P = 0.505; MDD-PDD: OR, 0.592; 95 % CI, 0.204–1.718, P = 0.335; MR–Egger method: MDD-DLB: OR, 0.582; 95 % CI, 0.021–15.962, P = 0.751. In reverse MR analyses, no dementia subtype was found to be a risk factor for MDD. LimitationsThe results of this study may not be generalizable to non-European populations. ConclusionMDD was identified as a potential risk factor for VaD, but no dementia subtype was found to be a risk factor for MDD. These results suggest a new avenue for the prevention of VaD.

Plasma miR-203a-3p as a Novel Predictor of Dementia in Patients with Parkinson's Disease.

The early detection of cognitive decline in Parkinson's disease is important for providing drug therapy and non-pharmacological management. The circulating microRNAs present in plasma are promising biomarkers of PD with dementia (PDD) due to their critical roles in synaptic plasticity and the regulation of neurodegeneration-associated proteins. In this study, we aimed to identify plasma microRNAs that may differentiate PD with or without cognitive impairment. Global microRNA expression was obtained from a discovery set of 123 participants who were divided into four groups, namely normal controls (HC), PD with no dementia (PDND), PD with mild cognitive impairment (PD-MCI), and PDD, using next-generation sequencing. The BOLD selector was used for microRNA candidate selection. Six miRNAs, namely miR-203a-3p, miR-626, miR-662, miR-3182, miR-4274, and miR-4295, were clustered as potential candidates for use in identifying PDND from PD-MCI. Another independent cohort of 120 participants was further recruited in a validation step in order to detect candidate microRNAs via droplet digital PCR (ddPCR), which was used for its high sensitivity in detecting low miRNA concentrations. Our results show that the ratio of miR-203a-3p/miR-16-5p, in which miR-16-5p was used as a reference control miRNA, was significantly increased in PDD compared to that seen in PD-MCI and PDND individually, and was negatively correlated with the MoCA scores (r = -0.237, p = 0.024) in patients with PD. However, there was no significant difference in the ratio of miR-203a-3p/miR-16-5p between HC and PDND, PD-MCI, or PDD individually. The ROC curve of the logistic regression model, factoring in the variables of age, the ratio of miR-203a-3p/miR-16-5p, and the UPDRS III score, demonstrated an AUC of 0.883. Our findings suggest that the ratio of miR-203a-3p/miR-16-5p, used with age and motor score, could be a predictor of dementia among PD patients.

[Investigation of the Relationship Between Akkermansia Genomic Diversity in Gut Microbiota and Parkinson's Disease Dementia].

Although it is known that the relative abundance of Akkermansia, a bacterial genus commonly associated with health, increases in the gut microbiota of Parkinson's disease (PD) patients, the exact reason for this increase remains unclear. This study was aimed to identify potential changes in Akkermansia within the gut microbiota of PD patients in Türkiye. For this purpose, shotgun metagenomics and a novel Akkermansia genus-specific amplicon sequencing technique was used to investigate the presence of specific Akkermansia strains associated with cognitive impairment (CI) stages in PD and to examine potential genes within these strains. In this context, four gut microbiota samples from Türkiye -three PD with dementia (PDD) and one healthy control without CI (HC)- were analyzed by shotgun metagenomics and metagenome-assembled genomes assigned to Akkermansia genus were reconstructed. Then, a custom database was created by combining these genomes with the Akkermansia genomes in public databases and next generation sequencing (NGS) compatible primers specific to the genus Akkermansia were designed using this database. After optimization of amplification and library preparation steps for genus-specific next generation sequencing, gut microbiota samples from 64 PD patients [32 PDD and 32 PD with mild CI (PD-MCI)] and 26 HCs were analyzed by genus-specific amplicon sequencing. The results revealed the presence of seven strains assigned to Akkermansia muciniphila in gut microbiota samples, two of which showed significant distribution differences (p< 0.05) between demented (PDD) and non-demented groups (PD-MCI, HC). When gene contents of the detected Akkermansia genomes were examined through comparative genomic analysis, the presence of 12 genes only in Akkermansia genomes specific to non-demented groups were predicted. The annotations of these genes showed that they were not reported before with unknown functions. In this study, for the first time, gut microbiota samples from PD patients in Türkiye were analyzed using shotgun metagenomics, a novel genus-specific amplicon sequencing method was developed specifically for the analysis of Akkermansia genus, and then Akkermansia strains and genes potentially associated with CI stages in PD were identified using this method. The results underscore that investigating the species or strain level differences could help better understanding of the changes associated with PD in the human gut microbiota.

Distinct tau and alpha-synuclein molecular signatures in Alzheimer’s disease with and without Lewy bodies and Parkinson’s disease with dementia

Alpha-synuclein (aSyn) pathology is present in approximately 50% of Alzheimer’s disease (AD) cases at autopsy and might impact the age-of-onset and disease progression in AD. Here, we aimed to determine whether tau and aSyn profiles differ between AD cases with Lewy bodies (AD-LB), pure AD and Parkinson’s disease with dementia (PDD) cases using epitope-, post-translational modification- (PTM) and isoform-specific tau and aSyn antibody panels spanning from the N- to C-terminus. We included the middle temporal gyrus (MTG) and amygdala (AMY) of clinically diagnosed and pathologically confirmed cases and performed dot blotting, western blotting and immunohistochemistry combined with quantitative and morphological analyses. All investigated phospho-tau (pTau) species, except pT181, were upregulated in AD-LB and AD cases compared to PDD and control cases, but no significant differences were observed between AD-LB and AD subjects. In addition, tau antibodies targeting the proline-rich regions and C-terminus showed preferential binding to AD-LB and AD brain homogenates. Antibodies targeting C-terminal aSyn epitopes and pS129 aSyn showed stronger binding to AD-LB and PDD cases compared to AD and control cases. Two pTau species (pS198 and pS396) were specifically detected in the soluble protein fractions of AD-LB and AD subjects, indicative of early involvement of these PTMs in the multimerization process of tau. Other phospho-variants for both tau (pT212/S214, pT231 and pS422) and aSyn (pS129) were only detected in the insoluble protein fraction of AD-LB/AD and AD-LB/PDD cases, respectively. aSyn load was higher in the AMY of AD-LB cases compared to PDD cases, suggesting aggravated aSyn pathology under the presence of AD pathology, while tau load was similar between AD-LB and AD cases. Co-localization of pTau and aSyn could be observed within astrocytes of AD-LB cases within the MTG. These findings highlight a unique pathological signature for AD-LB cases compared to pure AD and PDD cases.

Regional differences in synaptic degeneration are linked to alpha-synuclein burden and axonal damage in Parkinson’s disease and dementia with Lewy bodies

Regional differences in synaptic degeneration may underlie differences in clinical presentation and neuropathological disease progression in Parkinson’s Disease (PD) and Dementia with Lewy bodies (DLB). Here, we mapped and quantified synaptic degeneration in cortical brain regions in PD, PD with dementia (PDD) and DLB, and assessed whether regional differences in synaptic loss are linked to axonal degeneration and neuropathological burden. We included a total of 47 brain donors, 9 PD, 12 PDD, 6 DLB and 20 non-neurological controls. Synaptophysin+ and SV2A+ puncta were quantified in eight cortical regions using a high throughput microscopy approach. Neurofilament light chain (NfL) immunoreactivity, Lewy body (LB) density, phosphorylated-tau and amyloid-β load were also quantified. Group differences in synaptic density, and associations with neuropathological markers and Clinical Dementia Rating (CDR) scores, were investigated using linear mixed models. We found significantly decreased synaptophysin and SV2A densities in the cortex of PD, PDD and DLB cases compared to controls. Specifically, synaptic density was decreased in cortical regions affected at Braak α-synuclein stage 5 in PD (middle temporal gyrus, anterior cingulate and insula), and was additionally decreased in cortical regions affected at Braak α-synuclein stage 4 in PDD and DLB compared to controls (entorhinal cortex, parahippocampal gyrus and fusiform gyrus). Synaptic loss associated with higher NfL immunoreactivity and LB density. Global synaptophysin loss associated with longer disease duration and higher CDR scores. Synaptic neurodegeneration occurred in temporal, cingulate and insular cortices in PD, as well as in parahippocampal regions in PDD and DLB. In addition, synaptic loss was linked to axonal damage and severe α-synuclein burden. These results, together with the association between synaptic loss and disease progression and cognitive impairment, indicate that regional synaptic loss may underlie clinical differences between PD and PDD/DLB. Our results might provide useful information for the interpretation of synaptic biomarkers in vivo.

Highly tunable bimane-based fluorescent probes: design, synthesis, and application as a selective amyloid binding dye.

Small molecule fluorescent probes are indispensable tools for a broad range of biological applications. Despite many probes being available, there is still a need for probes where photophysical properties and biological selectivity can be tuned as desired. Here, we report the rational design and synthesis of a palette of fluorescent probes based on the underexplored bimane scaffold. The newly developed probes with varied electronic properties show tunable absorption and emission in the visible region with large Stokes shifts. Probes featuring electron-donating groups exhibit rotor effects that are sensitive to polarity and viscosity by "intramolecular charge transfer" (ICT) and twisted intramolecular charge transfer (TICT) mechanisms, respectively. These properties enable their application as "turn-on" fluorescent probes to detect fibrillar aggregates of the α-synuclein (αS) protein that are a hallmark of Parkinson's disease (PD). One probe shows selective binding to αS fibrils relative to soluble proteins in cell lysates and amyloid fibrils of tau and amyloid-β. Finally, we demonstrate the diagnostic potential of the probe in selectively detecting αS fibrils amplified from PD with dementia (PDD) patient samples.

Structural changes in the retina and serum HMGB1 levels are associated with decreased cognitive function in patients with Parkinson's disease

BackgroundCognitive impairment is a serious nonmotor symptom in patients with Parkinson's disease (PD). Currently, there are few studies investigating the relationship of serum markers and retinal structural changes with cognitive function in PD. ObjectiveTo investigate the relationship between retinal structural changes, serum high mobility group box-1 (HMGB1) levels and cognitive function and motor symptoms in PD patients. MethodsEighty-nine participants, including 47 PD patients and 42 healthy subjects, were enrolled. PD patients were divided into Parkinson's disease with normal cognitive (PD-NC), Parkinson's disease with mild cognitive impairment (PD-MCI), and Parkinson's disease with dementia (PDD) groups. The motor and nonmotor symptoms of PD patients were evaluated with clinical scale. Serum HMGB1 levels were detected by enzyme-linked immunosorbent assay (ELISA), and ganglion cell-inner plexiform layer complex (GCIPL) thickness changes in the macula were quantitatively analyzed by swept source optical coherence tomography (SS-OCT) in all patients. ResultsCompared with the control group, the macular GCIPL (t = −2.308, P = 0.023) was thinner and serum HMGB1 (z = −2.285, P = 0.022) was increased in PD patients. Macular GCIPL thickness in patients with PD-MCI and PDD were significantly lower than that in PD-NC patients, but there were no significant difference between the PD-MCI and PDD groups. Serum HMGB1 levels in patients with PD-MCI and PDD were significantly higher than those in PD-NC patients, and serum HMGB1 levels in PDD patients were higher than those in PD-MCI patients. Correlation analysis showed that serum HMGB1 levels in PD patients were positively correlated with disease duration, HY stage, UPDRS-I score, UPDRS-III score, and UPDRS total score and negatively correlated with MOCA score. Macular GCIPL thickness was negatively correlated with HY stage and positively correlated with MOCA score, and macular GCIPL thickness was negatively correlated with serum HMGB1 level. Logistic regression analysis showed that elevated serum HMGB1 level, thinner macular GCIPL thickness, and higher HY stage were independent risk factors for Parkinson's disease with cognitive impairment (PD-CI). The areas under the receiver operating characteristic curve (AUC) for the serum HMGB1 level and macular GCIPL thickness-based diagnosis of PD-MCI, PDD and PD-CI based on in patients with PD were 0.786 and 0.825, 0.915 and 0.856, 0.852 and 0.841, respectively. The AUC for the diagnosis of PD-MCI, PDD and PD-CI with serum HMGB1 level and GCIPL thickness combined were 0.869, 0.967 and 0.916, respectively. ConclusionThe macular GCIPL thickness and serum HMGB1 level are potential markers of cognitive impairment in PD patients, and their combination can significantly improve the accuracy of the diagnosis of cognitive impairment in PD.

T1w/T2w MRI ratio brain signature across degenerative syndromes and their cognitive impairment continuum and mixed presentations

AbstractBackgroundWe aimed to investigate the ratio’s signature in diverse clinically‐defined neurodegenerative syndromes and their cognitive impairment continuum. Our hypothesis was that higher cognitive impairment would be associated with lower cortical T1w/T2w ratio in all clinical subtypes.MethodWe used standardized MRI data obtained from participants in the COMPASS‐ND study of the Canadian Consortium on Neurodegeneration in Aging. T1w images were resampled down to T2w resolution; after co‐registration, intensities were standardized between 1‐100 and the ratio computed. Brain segmentation was then performed using FreeSurfer 6.0 on T1w images with the Desikan‐Killiany‐Tourville and default subcortical atlases. Participants included 109 cognitively intact elderly (CIE), 131 subjective cognitive decline (SCD), 252 mild cognitive impairment (MCI), 113 vascular‐MCI (V‐MCI), 55 mixed vascular‐Alzheimer’s dementia (V‐AD), 76 Alzheimer’s disease (AD), 21 Lewy‐body dementia (LBD), 33 fronto‐temporal‐dementia (FTD), 77 Parkinson’s disease (PD), 35 PD‐MCI and nine PD with dementia (PDD). Since the between‐vendor distributions differed (Fig1), Z scores were computed separately for each scanner vendor (GE, Philips, or Siemens) with CIE as a reference group. ANCOVA with age as covariate and FDR correction were conducted between each group and CIE.ResultNo significant effect of age was observed. Compared to CIE, significantly higher T1w/T2w ratios were observed in SCD for most of the brain (57/86 regions), in MCI for six frontal areas only, while decline was observed in AD throughout the brain (Fig1). V‐MCI showed lower ratios in subcortical areas only while V‐AD had pronounced lower ratios in subcortical areas as well as in 11 cortical areas. PD had marked lower ratios throughout the brain with the exception of an intact corpus callosum (Fig2). Contrariwise, FTD only displayed a lower ratio in the corpus callosum whereas PD‐MCI and LBD did not show any significant difference with CIE.ConclusionWe observed clear distinct patterns of T1w/T2w ratios for SCD, MCI, AD and PD groups. Since this ratio does not seem specific to a neural biological substrate, the meaning of these differences remains to be determined. Nevertheless, these results suggest that simple MRI measures such as the T1w/T2w ratio can highlight underlying mechanisms in various neurodegenerative processes.

Proteomic comparison between CSF samples and CSF‐derived EVs from patients with Alzheimer’s disease, Parkinson’s disease and Lewy Body dementia

AbstractBackgroundExtracellular vesicles (EVs) have recently been considered as a potential biomarker source for a variety of diseases, including neurodegenerative disorders. EVs are important mediators of intercellular communication due to their capacity to transfer genetic material, lipids and proteins. By means of their communication role, interesting biomarkers are often enriched in EVs compared to total biofluid. In this study, this hypothesis is tested as untargeted proteomics is performed on both CSF samples and CSF‐derived EV samples from the same cohort with different dementia diseases.MethodCSF samples were collected from 297 patients (with Alzheimer’s disease (AD), Parkinson’s disease (PD), PD with cognitive deficit (PDCD), PD with dementia (PDD), Lewy Body dementia (LBD)) and healthy controls (HC). Furthermore, EVs were obtained from 500µL of the same CSF samples, isolated by SmartSEC HT. Total protein quantification was measured using absorbance at 280nm for CSF samples, and by fluorescence (NanoOrangeTM) for CSF‐derived EV samples. For both types of sample, LC‐MS/MS based proteomics analyses were performed.ResultTotal protein quantification showed multiple significant differences between all groups, both in CSF samples and in CSF‐derived EV samples. In both types of sample, PDCD group showed the highest protein concentration after normalization. In regard to LC‐MS/MS results, a first analysis resulted in a total of 3036 identified proteins (1564 protein groups) for the CSF samples, and 6627 proteins (3360 protein groups) for the CSF‐derived EV samples. The current analyses show four statistically differentially expressed proteins between CSF‐derived EV samples from HC and AD, AD and PD, LBD and PDCD. By the time of AAIC2023, also CSF samples will be analysed and a comparison will be drawn between both types of sample.ConclusionAs more in‐depth proteomic analyses will be performed by AAIC2023, a definite conclusion will be given at the conference. For now, already differences in total protein concentration were observed between the different disease groups and LC‐MS/MS of CSF‐derived EV samples resulted in four statistically differentially expressed proteins.

Causal relationship between psoriasis vulgaris and dementia: Insights from Mendelian randomization analysis.

Many clinical studies have demonstrated a correlation between psoriasis vulgaris and dementia, yet this correlation remains controversial. Our study employed the Mendelian randomization (MR) method to investigate the causal relationship between psoriasis vulgaris and dementia. Data were obtained from the summary statistics of the genome-wide association studies from IEU-OpenGWAS project database. In univariate Mendelian randomization (UVMR) analysis, psoriasis vulgaris was used as exposure. Alzheimer disease (AD), vascular dementia (VaD), dementia with Lewy bodies (DLB), Parkinson's disease with dementia (PDD) and frontotemporal dementia (FTD) served as the outcomes. In multivariate Mendelian randomization (MVMR) analysis, VaD served as the outcome. The first MVMR analysis used psoriasis vulgaris, mean platelet volume (MPV), platelet distribution width (PDW) and platelet count (PLT) as exposures. The second MVMR analysis used psoriasis vulgaris, vitamin D level and 25 hydroxyvitamin D level as exposures. The main analysis employed the inverse variance weighted method, and the outcomes were evaluated by odds ratio (OR) and 95% confidence interval (95% CI). In UVMR analysis, the results depicted that psoriasis vulgaris was associated with VaD (OR: 0.903, 95% CI: 0.818-0.996, p = 0.041). The results revealed insignificant associations between psoriasis vulgaris and other dementia types. After adjusting the effects of MPV, PDW and PLT in MVMR analysis, the association between psoriasis vulgaris and VaD was no longer significant (p = 0.164). Similarly, after adjusting the effects of vitamin D level and 25 hydroxyvitamin D level in MVMR analysis, the association between psoriasis vulgaris and VaD was also no longer significant (p = 0.533). Our study suggests that psoriasis vulgaris may potentially decrease VaD incidence. However, the causal association between psoriasis vulgaris and VaD may be impeded by platelet-related indices, vitamin D level and 25 hydroxyvitamin D level.

Navigating the Gene Co-Expression Network and Drug Repurposing Opportunities for Brain Disorders Associated with Neurocognitive Impairment.

Neurocognitive impairment refers to a spectrum of disorders characterized by a decline in cognitive functions such as memory, attention, and problem-solving, which are often linked to structural or functional abnormalities in the brain. While its exact etiology remains elusive, genetic factors play a pivotal role in disease onset and progression. This study aimed to identify highly correlated gene clusters (modules) and key hub genes shared across neurocognition-impairing diseases, including Alzheimer's disease (AD), Parkinson's disease with dementia (PDD), HIV-associated neurocognitive disorders (HAND), and glioma. Herein, the microarray datasets AD (GSE5281), HAND (GSE35864), glioma (GSE15824), and PD (GSE7621) were used to perform Weighted Gene Co-expression Network Analysis (WGCNA) to identify highly preserved modules across the studied brain diseases. Through gene set enrichment analysis, the shared modules were found to point towards processes including neuronal transcriptional dysregulation, neuroinflammation, protein aggregation, and mitochondrial dysfunction, hallmarks of many neurocognitive disorders. These modules were used in constructing protein-protein interaction networks to identify hub genes shared across the diseases of interest. These hub genes were found to play pivotal roles in processes including protein homeostasis, cell cycle regulation, energy metabolism, and signaling, all associated with brain and CNS diseases, and were explored for their drug repurposing experiments. Drug repurposing based on gene signatures highlighted drugs including Dorzolamide and Oxybuprocaine, which were found to modulate the expression of the hub genes in play and may have therapeutic implications in neurocognitive disorders. While both drugs have traditionally been used for other medical purposes, our study underscores the potential of a combined WGCNA and drug repurposing strategy for searching for new avenues in the simultaneous treatment of different diseases that have similarities in gene co-expression networks.

Pareidolias are a function of visuoperceptual impairment.

Pareidolias, or the misperception of ambiguous stimuli as meaningful objects, are complex visual illusions thought to be phenomenologically similar to Visual Hallucination (VH). VH are a major predictor of dementia in Parkinson's Disease (PD) and are included as a core clinical feature in Dementia with Lewy Bodies (DLB). A newly developed Noise Pareidolia Test (NPT) was proposed as a possible surrogate marker for VH in DLB patients as increased pareidolic responses correlated with informant-corroborated accounts of VH. This association could, however, be mediated by visuoperceptual impairment. To understand the drivers of performance on the NPT, we contrasted performances in patient groups that varied both in terms of visuoperceptual ability and rates of VH. N = 43 patients were studied of whom n = 13 had DLB or PD with Dementia (PDD); n = 13 had PD; n = 12 had typical, memory-onset Alzheimer's Disease (tAD); and n = 5 had Posterior Cortical Atrophy (PCA) due to Alzheimer's disease. All patient groups reported pareidolias. Within the Lewy body disorders (PD, DLB, PDD), there was no significant difference in pareidolic response rates between hallucinating and non-hallucinating patients. Visuoperceptual deficits and pareidolic responses were most frequent in the PCA group-none of whom reported VH. Regression analyses in the entire patient cohort indicated that pareidolias were strongly predicted by visuoperceptual impairment but not by the presence of VH. These findings suggest that pareidolias reflect the underlying visuoperceptual impairment of Lewy body disorders, rather than being a direct marker for VH.

Nigral Pathology Contributes to Microstructural Integrity of Striatal and Frontal Tracts in Parkinson's Disease.

Motor and cognitive impairment in Parkinson's disease (PD) is associated with dopaminergic dysfunction that stems from substantia nigra (SN) degeneration and concomitant α-synuclein accumulation. Diffusion magnetic resonance imaging (MRI) can detect microstructural alterations of the SN and its tracts to (sub)cortical regions, but their pathological sensitivity is still poorly understood. To unravel the pathological substrate(s) underlying microstructural alterations of SN, and its tracts to the dorsal striatum and dorsolateral prefrontal cortex (DLPFC) in PD. Combining post-mortem in situ MRI and histopathology, T1-weighted and diffusion MRI, and neuropathological samples of nine PD, six PD with dementia (PDD), five dementia with Lewy bodies (DLB), and 10 control donors were collected. From diffusion MRI, mean diffusivity (MD) and fractional anisotropy (FA) were derived from the SN, and tracts between the SN and caudate nucleus, putamen, and DLPFC. Phosphorylated-Ser129-α-synuclein and tyrosine hydroxylase immunohistochemistry was included to quantify nigral Lewy pathology and dopaminergic degeneration, respectively. Compared to controls, PD and PDD/DLB showed increased MD of the SN and SN-DLPFC tract, as well as increased FA of the SN-caudate nucleus tract. Both PD and PDD/DLB showed nigral Lewy pathology and dopaminergic loss compared to controls. Increased MD of the SN and FA of SN-caudate nucleus tract were associated with SN dopaminergic loss. Whereas increased MD of the SN-DLPFC tract was associated with increased SN Lewy neurite load. In PD and PDD/DLB, diffusion MRI captures microstructural alterations of the SN and tracts to the dorsal striatum and DLPFC, which differentially associates with SN dopaminergic degeneration and Lewy neurite pathology. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Striatal dopamine transporter binding differs between dementia with Lewy bodies and Parkinson’s disease with dementia

123I-ioflupane single-photon emission computed tomography (SPECT) is a highly sensitive and established neuroimaging technique for parkinsonian syndromes (PS). However, differentiating PS by visual inspection or analysis of regions of interest is challenging. To date, image analysis has not been able to differentiate dementia with Lewy bodies (DLB) from Parkinson's disease with dementia (PDD). This study aimed to differentiate PS based on the characteristics of striatal dopamine transporter (DAT) binding using voxel-based analysis. We acquired 123I-ioflupane SPECT data from patients with DLB (n = 30), Parkinson's disease (PD; n = 122), PDD (n = 19), multiple system atrophy with predominant parkinsonism (MSA-P; n = 18), and progressive supranuclear palsy (PSP; n = 45). DAT binding was reduced in the posterior striatum of patients with PD and PDD, whereas it was similar in MSA-P, PSP, and DLB. Hippocampal atrophy, visually evaluated by cerebral magnetic resonance imaging, did not affect striatal DAT binding in DLB. DAT binding in the anterior striatum was inversely correlated with the severity of parkinsonism in PD and PDD but not in DLB. Thus, the appearance of striatal DAT binding might indicate different pathological processes in DLB and PDD.

Classification of Parkinson’s disease with dementia using phase locking factor of event-related oscillations to visual and auditory stimuli

Objective. In the last decades, machine learning approaches have been widely used to distinguish Parkinson’s disease (PD) and many other neuropsychiatric diseases. They also speed up the clinicians and facilitate decision-making for several conditions with similar clinical symptoms. The current study attempts to detect PD with dementia (PDD) by event-related oscillations (EROs) during cognitive processing in two modalities, i.e. auditory and visual. Approach. The study was conducted to discriminate PDD from healthy controls (HC) using event-related phase-locking factors in slow frequency ranges (delta and theta) during visual and auditory cognitive tasks. Seventeen PDD and nineteen HC were included in the study, and linear discriminant analysis was used as a classifier. During classification analysis, multiple settings were implemented by using different sets of channels (overall, fronto-central and temporo-parieto-occipital (TPO) region), frequency bands (delta-theta combined, delta, theta, and low theta), and time of interests (0.1–0.7 s, 0.1–0.5 s and 0.1–0.3 s for delta, delta-theta combined; 0.1–0.4 s for theta and low theta) for spatial-spectral-temporal searchlight procedure. Main results. The classification performance results of the current study revealed that if visual stimuli are applied to PDD, the delta and theta phase-locking factor over fronto-central region have a remarkable contribution to detecting the disease, whereas if auditory stimuli are applied, the phase-locking factor in low theta over TPO and in a wider range of frequency (1–7 Hz) over the fronto-central region classify HC and PDD with better performances. Significance. These findings show that the delta and theta phase-locking factor of EROs during visual and auditory stimuli has valuable contributions to detecting PDD.

The role of plasma cortisol in dementia, epilepsy, and multiple sclerosis: A Mendelian randomization study.

Many clinical studies have shown a correlation between plasma cortisol and neurological disorders. This study explored the causal relationship between plasma cortisol and dementia, epilepsy and multiple sclerosis based on Mendelian randomization (MR) method. Data were taken from the summary statistics of a genome-wide association study, FinnGen consortium and United Kingdom Biobank. Dementia, epilepsy, and multiple sclerosis were used as outcomes, and genetic variants associated with plasma cortisol were used as instrumental variables. The main analysis was performed using the inverse variance weighted method, and the results were assessed according to the odds ratio (OR) and 95% confidence interval. Heterogeneity tests, pleiotropy tests, and leave-one-out method were conducted to evaluate the stability and accuracy of the results. In two-sample MR analysis, the inverse variance weighted method showed that plasma cortisol was associated with Alzheimer's disease (AD) [odds ratio (95% confidence interval) = 0.99 (0.98-1.00), P = 0.025], vascular dementia (VaD) [odds ratio (95% confidence interval) = 2.02 (1.00-4.05), P = 0.049)], Parkinson's disease with dementia (PDD) [odds ratio (95% confidence interval) = 0.24 (0.07-0.82), P = 0.023] and epilepsy [odds ratio (95% confidence interval) = 2.00 (1.03-3.91), P = 0.042]. There were no statistically significant associations between plasma cortisol and dementia with Lewy bodies (DLB), frontotemporal dementia (FTD) and multiple sclerosis. This study demonstrates that plasma cortisol increase the incidence rates of epilepsy and VaD and decrease the incidence rates of AD and PDD. Monitoring plasma cortisol concentrations in clinical practice can help prevent diseases, such as AD, PDD, VaD and epilepsy.

Neurofilament light chain is increased in the parahippocampal cortex and associates with pathological hallmarks in Parkinson’s disease dementia

BackgroundIncreased neurofilament levels in biofluids are commonly used as a proxy for neurodegeneration in several neurodegenerative disorders. In this study, we aimed to investigate the distribution of neurofilaments in the cerebral cortex of Parkinson’s disease (PD), PD with dementia (PDD) and dementia with Lewy bodies (DLB) donors, and its association with pathology load and MRI measures of atrophy and diffusivity.MethodsUsing a within-subject post-mortem MRI-pathology approach, we included 9 PD, 12 PDD/DLB and 18 age-matched control donors. Cortical thickness and mean diffusivity (MD) metrics were extracted respectively from 3DT1 and DTI at 3T in-situ MRI. After autopsy, pathological hallmarks (pSer129-αSyn, p-tau and amyloid-β load) together with neurofilament light-chain (NfL) and phosphorylated-neurofilament medium- and heavy-chain (p-NfM/H) immunoreactivity were quantified in seven cortical regions, and studied in detail with confocal-laser scanning microscopy. The correlations between MRI and pathological measures were studied using linear mixed models.ResultsCompared to controls, p-NfM/H immunoreactivity was increased in all cortical regions in PD and PDD/DLB, whereas NfL immunoreactivity was increased in the parahippocampal and entorhinal cortex in PDD/DLB. NfL-positive neurons showed degenerative morphological features and axonal fragmentation. The increased p-NfM/H correlated with p-tau load, and NfL correlated with pSer129-αSyn but more strongly with p-tau load in PDD/DLB. Lastly, neurofilament immunoreactivity correlated with cortical thinning in PD and with increased cortical MD in PDD/DLB.ConclusionsTaken together, increased neurofilament immunoreactivity suggests underlying axonal injury and neurofilament accumulation in morphologically altered neurons with increased pathological burden. Importantly, we demonstrate that such neurofilament markers at least partly explain MRI measures that are associated with the neurodegenerative process.