We herein report two patients presenting with acute cerebellar ataxia shortly after the diagnosis of Sjögren's syndrome (SS). Two women (43- and 55-year-old) patients showed normal MRI, inflammatory cerebrospinal fluid (CSF) findings, and moderate response to immunotherapy in long-term follow-up. A broad panel of antibodies was negative for the 43-year-old patient. However, indirect immunohistochemistry showed serum/CSF antibodies with a distinctive reactivity pattern on rat brain sections. The 55-year-old patient showed anti-glutamic acid decarboxylase in serum and CSF. Five control SS patients without neurological symptoms did not have anti-neuronal antibodies. Anti-neuronal antibody investigation may contribute to the differential diagnosis of neurological involvement in SS.

BACKGROUND:Identification of individuals at increased risk for synucleinopathies is becoming more feasible with advances in biomarkers. However, the ethical and practical aspects of communicating disease risk remain unresolved, particularly across diagnostic groups and cultural contexts. OBJECTIVES:We aimed to evaluate attitudes toward disclosure of future synucleinopathy risk among individuals with isolated/idiopathic REM sleep behavior disorder (iRBD), as well as in individuals who developed Parkinson's disease (PD), or multiple system atrophy (MSA), in a large non-Western registry. METHODS:This nationwide survey study included participants from 28 movement disorders and sleep centers across Türkiye. Questionnaires assessing attitudes toward risk disclosure, additional testing, and clinical trial participation were administered face-to-face. Responses were analyzed using contingency tables and regression models. Results are reported following the Consensus-Based Checklist for Reporting of Survey Studies (CROSS) guideline. RESULTS:Among 1385 participants (1039 PD, 107 MSA, 239 iRBD), individuals with iRBD showed the highest support for risk disclosure (88.3%), exceeding PD (64.4%) and MSA (51.9%). Approval declined modestly (3-8%) when framed within the absence of disease-modifying treatment. iRBD participants were more willing for additional testing but less willing to join clinical trials (31.8%) than PD (45.3%) or MSA (48%). MSA patients expressed the greatest concern about psychological impact. Male sex had more favorable views on disclosure and trial participation, while younger and better-educated participants favored additional testing. CONCLUSIONS:Attitudes toward risk disclosure differ markedly across the synucleinopathy spectrum and demographic characteristics. Culturally informed and diagnosis-specific disclosure strategies will be essential for trial recruitment and patient-centered care.

The CHD8 gene encodes a chromatin-remodeling protein critical for neural development and transcriptional regulation. Although CHD8 mutations are classically associated with autism spectrum disorder, macrocephaly, and intellectual disability, recent reports suggest that dystonia may also be part of this spectrum. Two unrelated female patients presenting with progressive dystonia were evaluated through detailed clinical, neurological, and neuroimaging assessments. Whole exome sequencing (WES) was performed using the Twist Human Core Exome capture kit and variants were classified following American College of Medical Genetics and Genomics (ACMG) and Clingen SVI guidelines. A literature review was conducted to identify previously published CHD8 related dystonia cases. Patient 1 exhibited adult-onset segmental dystonia beginning at age 27, associated with macrocephaly and mild facial dysmorphism. Patient 2 developed generalized dystonia from adolescence, without cognitive or behavioral abnormalities. Pallidal deep brain stimulation produced marked motor improvement in Patient 1. Whole exome sequencing analyses revealed two heterozygous nonsense variants in the CHD8 gene NM_001170629.2:c.1444C>T (p.Arg482Ter) and NM_001170629.2:c.727C>T (p.Arg243Ter), respectively. Both variants were classified as likely pathogenic according to the current ACMG/ClinGen recommendations. These cases reinforce the evidence in the literature that CHD8 mutations are not only associated with neurodevelopmental disorders but may also cause isolated, adult-onset dystonia that is resistant to conventional pharmacological treatment, particularly in female patients.

Introduction:Given the global gene expression alterations associated with amyloid beta (Aβ), a hallmark of Alzheimer's disease (AD) pathology, this study aimed to investigate its potential role in modulating gene expression through the regulation of specific transcription factors (TFs). Methods:Using a combination of protein-protein interaction prediction tools and transcriptional regulatory interaction databases, we identified JUN, FOS, ATF2, ATF4, RELA, NF-κB, SMAD3, STAT1, STAT3, and SP1 as potential candidate TFs that might be involved in Aβ1-42 related pathways. We then conducted in vitro studies to demonstrate a direct effect of Aβ on these TFs and a case-control study to investigate any alterations of selected TFs in human samples. In vitro studies included HEK293 T cells treated with 0.09 µM and 10 µM Aβ1-42. The expression levels of the TFs were assessed by qRT-PCR. The mRNA expression levels of selected target transcription factors that have the highest PPI scores, namely JUN, FOS, and RELA, were also investigated in blood samples from core Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarker-confirmed AD cases and plasma ALZpath pTau217-confirmed healthy subjects. Results:In vitro studies indicated that the mRNA expression of most of the TFs was altered due to either the dose of Aβ or the period of treatments. JUN, FOS, NFKB, and SP1 mRNA expression were increased, while STAT1 and ATF2 were decreased within 24 hours of at least one dose of Aβ treatment. At 48 hours of treatment, FOS, STAT1, STAT3, ATF2, and SP1 were higher, whereas RELA, SMAD3, and NFKB were lower in Aβ-treated groups. At 72h of treatments, the ATF4 and NFKB expressions were high, whereas JUN FOS, RELA, STAT1, STAT3, ATF2, and SP1 were low in Aβ treated groups. Human samples showed that the mRNA levels of JUN and RELA were significantly higher in blood samples from AD cases compared to those from healthy individuals. Conclusion:Alterations in the expression levels of TFs in response to Aβ exposure may explain the alterations of the expression levels of genes that these TFs regulate. Given that, understanding the transcriptional effects of Aβ and its regulatory role on TFs may provide a perspective for the physiological roles of Aβ and the molecular pathways underlying AD pathogenesis.

OBJECTIVE:This study aimed to elucidate the network-level intrinsic functional connectivity (iFC) disruptions associated with Parkinson's disease (PD). By focusing on the iFC changes among the areas of the neurodegeneration pattern in the dementia stage of PD (PD-D) and by adopting a mass-univariate iFC analysis approach, the network-based statistics (NBS), we aimed to characterize the network-level dynamics along the steps of cognitive decline in PD with a high statistical sensitivity. METHODS:We conducted surface-based measurements of cortical thickness in PD-D to identify the extent of neurodegeneration, and performed iFC analyses among network nodes localized within this area by utilizing NBS across three cohorts of PD patients: those who are cognitively normal (PD-CN), those with MCI (PD-MCI), and PD-D. An additional interaction analysis was performed to assess how ACE-R scores relate to iFC alterations across cognitive stages. RESULTS:The results demonstrated that declines in iFC start during the PD-MCI stage covering the default mode (DMN), somatomotor (SMN), and dorsal attention networks (DAN), with decreased interactions between the DMN and both the SMN and DAN. As cognitive decline advances to PD-D, iFC decline in limbic and frontoparietal networks are added in addition to reduced interaction of the SMN with the two attention networks, the salience/ventral attention network and DAN. The ACE-R interaction analysis identified cognition-related subnetworks in both PD-MCI and PD-D, with positive associations between ACE-R performance and iFC strength. CONCLUSION:This study demonstrates that iFC alterations differ across cognitive stages of PD in a stage-specific and network-selective manner. While early-stage disruptions primarily involve the DMN and its interactions with attention and motor networks, later stages exhibit a more widespread disintegration. The ACE-R interaction analysis further supports this pattern, showing that lower cognitive performance is systematically associated with reduced connectivity within these same large-scale systems. Particularly striking is the evolving role of the SMN, whose progressive decoupling from attentional and executive systems points to its underestimated contribution to cognitive impairment in PD.

The thalamus is a critical subcortical hub that relays sensorimotor information and regulates higher-order cognitive processes. Accurate delineation of thalamic nuclei is essential for elucidating disease mechanisms and tracking clinical progression. In this study, we compared two segmentation approaches implemented in FreeSurfer: the conventional structural method and a joint framework that integrates diffusion tensor imaging. Magnetic resonance imaging (MRI) data from 24 healthy controls (HC), 27 patients with cognitively normal Parkinson’s disease (PD-CN), and 33 Parkinson's disease patients with mild cognitive impairment (PD-MCI) were analyzed. Segmentation methods were compared in HC to assess their effect on volume estimates. Group comparisons were then conducted separately for each method to evaluate sensitivity in detecting disease-related volumetric differences. Finally, nuclei with significant group effects in joint segmentation were tested for associations with Addenbrooke’s Cognitive Examination-Revised (ACE-R) scores. Joint segmentation yielded systematically lower thalamic volume estimates than the structural method, with significant differences across hemispheres and nuclei in HC. Group-wise analyses revealed that joint segmentation, but not structural segmentation, detected significant atrophy in the right thalamus of PD-MCI patients. At the nuclei group level, joint segmentation showed greater sensitivity, identifying bilateral anterolateral and posterior nuclei as significantly reduced in PD-MCI relative to HC. Moreover, volumes of these nuclei correlated positively with ACE-R scores. These results highlight that methodological choices critically shape the detection of thalamic pathology in PD, suggesting that incorporating diffusion MRI into segmentation may improve sensitivity to cognitively relevant subnuclear changes and support early diagnosis and disease monitoring.

Introduction:Although there are several studies on the neuroanatomical mechanisms underlying Parkinson's disease (PD)-associated cognitive impairment, the clinical usefulness of the findings from these investigations is limited. In this study, we aimed to identify magnetic resonance imaging (MRI) markers that can be practically utilized for diagnosing PD-associated cognitive impairment using a visual rating scale (VRS). Methods:Anatomical MRIs of cognitively normal (PD-CN), and PD with mild cognitive impairment (PD-MCI) patients were visually evaluated for six bilateral cortical regions. Then, hypothesis-driven cortical thickness analysis (CTA) was performed in the regions obtained from VRS. Results:As a consequence of VRS, a significant difference was found between the two groups with regards to right posterior atrophy (PA) scores (pFDR-corr = 0.042, Cohen's d= 1.06). Hypothesis-driven CTA confirmed the result of VRS by revealing cortical thinning at the precuneus and parieto-occipital sulcus junction (Max. T= 6.171, P= 0.0006, MNIx, y, z = 11.0, -62.2, 25.4). The area under the curve was 0.75, showing a good association between the PD-MCI and the right PA score. The cut-off for maximum accuracy was ≥ 2, based on the highest sum of sensitivity (0.68) and specificity (0.72). Conclusions:Our findings indicate that right PA atrophy may be helpful for clinicians in the diagnosis of PD-associated cognitive impairment.

BackgroundAmyloid-negative tau-related neurodegeneration represents a non-Alzheimer biomarker-defined profile; however, its clinical heterogeneity and prognostic relevance remain unclear within Alzheimer's disease-related frameworks.ObjectiveTo characterize the clinical spectrum and identify predictors of mortality in patients with this profile.MethodsIn this retrospective cohort study, 1280 patients evaluated at a tertiary neurology center were screened, and 130 with an amyloid-negative cerebrospinal fluid (CSF) pattern [amyloid-β (Aβ)42 normal, phosphorylated tau (pTau), and total tau (tTau) elevated] were included. Survival was assessed using Kaplan-Meier analysis, and predictors of mortality were evaluated using Cox models.ResultsThe cohort (mean age 68.8 ± 10.1 years; 45.4% female) showed heterogeneous diagnoses, mainly mild cognitive impairment and frontotemporal dementia (each 30%). Survival differed across diagnostic groups (log-rank p = 0.037), with more favorable outcomes in mild cognitive impairment. Male sex was more frequent among non-survivors (88.9% versus 45.6%, p < 0.001). Higher CSF tTau levels were associated with mortality in the joint Cox model (HR 1.003, 95% CI 1.001-1.006, p = 0.006) and faster clinical progression (r = 0.22, p = 0.011). When modeled separately, neither tTau nor pTau was independently associated with mortality; however, both became significant in opposite directions when included jointly.ConclusionsThe amyloid-negative A-T + N + profile represents a clinically heterogeneous subgroup with prognostic relevance. CSF tTau was associated with mortality and faster clinical progression, but the joint-model findings involving tTau and pTau should be interpreted cautiously as hypothesis-generating. Further studies are needed to clarify the prognostic value of tau-related biomarkers in this population.

Chronic kidney disease (CKD) is an established risk factor for Parkinson's disease (PD), but the molecular mechanisms linking these two conditions remain elusive. We performed a systems biology analysis by retrieving high-confidence gene-disease associations from DisGeNET v7.0 (PD: score ≥ 0.8, EI ≥ 0.4; CKD: score ≥ 0.6, EI ≥ 0.4) and constructing a protein-protein interaction (PPI) network via STRING v11.5 (confidence ≥ 0.700). Direct "molecular bridges" between CKD and PD proteins were identified and validated using independent databases. To corroborate biological feasibility, candidate proteins were cross-referenced with ExoCarta and Vesiclepedia databases for exosomal localization. Functional enrichment, tissue expression, and pathway analyses were conducted. Despite zero gene overlap (64 PD genes, 17 CKD genes), the PPI network showed significant convergence (81 nodes, 280 edges, PPI enrichment p < 1.0 × 10-16). Fifteen high-confidence molecular bridges were identified, including the Apolipoprotein A1 (APOA1)-α-synuclein (SNCA) interaction (combined score 0.883), which was independently validated by IntAct. Functional enrichment revealed specific association of APOA1-SNCA with "amyloid fiber formation" (false discovery rate (FDR) = 0.038). Both APOA1 and SNCA are annotated as exosome components (Kyoto Encyclopedia of Genes and Genomes (KEGG) ko04147) and were confirmed as consistent cargo in plasma, urine, and platelet-derived extracellular vesicles within proteomic databases (ExoCarta IDs: 335, 6622). Global pathway analysis highlighted inflammation, oxidative stress, and the advanced glycation end product (AGE)-receptor for AGE (RAGE) pathway. We propose an integrative model wherein CKD-induced dysregulation of APOA1 promotes α-synuclein misfolding and aggregation, and the co-packaging of these proteins into exosomes provides a plausible vehicle for kidney-to-brain propagation. This framework offers testable hypotheses and potential therapeutic targets for PD-CKD comorbidity.

BACKGROUND:Interindividual variability in motor outcomes after subthalamic nucleus deep brain stimulation (STN-DBS) in Parkinson's disease (PD) remains incompletely understood. Glymphatic-related imaging abnormalities have been reported in PD, but their relevance to neuromodulation response is unclear. OBJECTIVES:To investigate whether preoperative glymphatic function, assessed using the Diffusion Tensor Imaging along the Perivascular Space (DTI-ALPS) index, is associated with motor outcomes after STN-DBS and whether hemispheric asymmetry provides additional explanatory value. METHODS:We retrospectively evaluated 74 advanced PD patients undergoing bilateral STN-DBS with ≥6 months follow-up. Preoperative assessment included 3 T MRI-derived ALPS measures, Fazekas score, perivascular space burden, MDS-UPDRS-III, levodopa responsiveness, and metabolic markers. Primary outcome was percentage motor improvement at follow-up. Multivariable regression models assessed ALPS associations after adjustment for levodopa responsiveness and measured clinical covariates. RESULTS:Lower ALPS asymmetry index (AI) was independently associated with greater percentage motor improvement (standardized β = -0.508, p < 0.001), while greater preoperative levodopa responsiveness was also associated with improvement (β = 0.740, p < 0.001). Lower ALPS-AI was additionally associated with axial motor improvement and responder status at both ≥50% and ≥ 33% thresholds. All four principal levodopa-adjusted ALPS-AI associations remained significant after Benjamini-Hochberg correction (all pFDR≤0.0069). Mean ALPS index, Fazekas score, and perivascular space burden were not associated with motor outcomes. CONCLUSIONS:Preoperative glymphatic asymmetry was associated with motor outcomes after STN-DBS independently of levodopa responsiveness and measured clinical covariates. ALPS-derived asymmetry may capture outcome variability not reflected by conventional imaging, although prospective validation and evaluation alongside lead localization, stimulation parameters, and programming factors are required.

OBJECTIVE:Synaptic degeneration drives cognitive decline in Alzheimer's disease (AD), but synaptic biomarkers are scarce. Brain-enriched β-synuclein emerged as a synaptic damage marker. We investigated its diagnostic, prognostic, and structural correlates across the AD continuum. METHODS:In a tertiary-center cohort (n = 306), CSF β-synuclein was measured. Cognitively unimpaired (CU), AD-MCI, AD dementia (ADD), and non-AD (FTD, PD, DLB, others) groups were included. ANCOVA compared groups (age/sex adjusted); ROC assessed diagnostic performance. Multivariable regression examined 2-year MMSE decline associations. Voxel-wise interaction models evaluated β-synuclein-gray matter volume (GMV) relationships. RESULTS:CSF β-synuclein differed across groups (p < 0.001), with highest levels observed in AD-MCI and lower levels in ADD. AD-MCI levels exceeded CU/ADD. AD-MCI versus CU AUC was 0.874. Baseline β-synuclein predicted greater MMSE decline in AD-MCI (β = 0.72, p < 0.001) and ADD (β = 0.47, p = 0.017). Voxel-wise analyses revealed stage-dependent β-synuclein-GMV reversals in precentral and temporoparietal regions. CONCLUSION:CSF β-synuclein shows a stage-dependent pattern across the AD continuum, predicts cognitive decline, and dynamic structural coupling. It supports β-synuclein as a relevant synaptic biomarker in AD.

Dissecting biological pathways highlighted by Mendelian gene discovery has provided critical insights into the pathogenesis of Parkinson's disease (PD) and neurodegeneration. This approach ultimately catalyzes the identification of potential biomarkers and therapeutic targets. Here we identify PSMF1 as a gene implicated in parkinsonism and childhood neurodegeneration. We find that biallelic PSMF1 missense and loss-of-function variants co-segregate with phenotypes from early-onset PD to perinatal lethality with neurological manifestations across 18 pedigrees with 25 affected subjects, showing clear genotype-phenotype correlation. PSMF1 encodes the proteasome regulator PSMF1/hPI31, a highly conserved, ubiquitously expressed partner of the 20S proteasome and neurodegeneration-associated F-box-O 7 and valosin-containing proteins. We demonstrate that PSMF1 variants may affect proteasomal abundance and assembly, and are associated with alterations of mitochondrial membrane potential, respiration, dynamics and mitophagy in patient-derived fibroblasts. Furthermore, Drosophila and mouse models of PI31 loss of function exhibit age-dependent motor impairment, as well as brain-wide mitochondrial membrane depolarization and dopaminergic neurodegeneration in aged flies, and diffuse gliosis in mice. Collectively, our findings unequivocally link defective PSMF1/hPI31 to early-onset parkinsonism and neurodegeneration, and suggest proteasomal and mitochondrial dysfunction as pathogenic contributors.

The soluble form of the Triggering Receptor Expressed on Myeloid Cells 2 (sTREM2) is an indicator of microglial activation linked to neurodegeneration. While CSF sTREM2 shows promise as an Alzheimer’s biomarker, the relevance of plasma sTREM2 across amyloid- and tau-defined biomarker profiles and across dementia subtypes remains unclear. We therefore assessed plasma sTREM2 levels across clinical dementia diagnoses, including Alzheimer’s disease, frontotemporal dementia, dementia with Lewy bodies, posterior cortical atrophy, Parkinson’s disease with mild cognitive impairment, and normal pressure hydrocephalus, as well as across cerebrospinal fluid amyloid- and tau-defined biomarker profiles, to clarify whether plasma sTREM2 reflects disease-specific pathology or broader immune-related changes associated with neurodegenerative conditions. ELISA was used to measure the levels of plasma sTREM2 in 27 cognitively normal controls and 56 dementia patients, including those with AD, FTD, and other dementias. Patients were stratified based on clinical diagnosis and the CSF amyloid and tau status. The associations between plasma sTREM2, CSF biomarkers, and cognitive performance were investigated through correlation analyses. In the overall dementia group, plasma sTREM2 levels were significantly higher compared to the controls. The non-AD dementia group (FTD and other dementias) had significantly higher plasma sTREM2 levels compared to controls. Plasma sTREM2 concentrations were significantly higher in amyloid-negative (A−) and tau-negative (T−) patients than in controls. In the T− group, there was a positive correlation between plasma sTREM2 and CSF Aβ₁–₄₂. Our findings indicate that plasma sTREM2 may reflect peripheral immune processes, in the absence of classical AD pathology. Elevated TREM2 levels in biomarker-negative subgroups might indicate early microglial responses rather than neurodegeneration specific to a disease stage. Our findings highlight the complexity of peripheral sTREM2 and support the necessity of longitudinal studies including both CSF and plasma samples to elucidate its diagnostic value.

Introduction:Mapping the functional connectivity of brain regions became appealing in recent research in neurology. Accordingly, a growing body of evidence shows resting-state functional connectivity (rsFC) changes in neurodegenerative disorders including Parkinson's Disease (PD). As characterised by extensive and progressive dopaminergic loss in the substantia nigra, PD emerges with serious motor and non-motor dysfunctions. In the literature, the minority of PD cases have been associated with certain genetic mutations. The aim of this study was to investigate the rsFC in a group of PD patients having Parkin gene mutation. Method:Twelve PD patients with Parkin mutation (PP-PD), 12 PD patients without Parkin mutation (PN-PD) and 12 healthy controls (HC) were included in the study. All participants underwent a resting-state functional magnetic resonance imaging as well as a neuropsychological assessment and clinical examination. Results:Results indicated that PP-PD had longer disease duration, a higher rate of dyskinesia and lower scores on complex visual perception tests. The resting state networks showed that all PD (consisting of PP-PD and PN-PD) and PP-PD groups had increased functional connectivity in the frontoparietal network as compared to the HC. In addition, the PP-PD group displayed decreased functional connectivity in the dorsal attention network compared to the PN-PD. Conclusion:In conclusion, our data suggests that PD with Parkin gene mutation might be emerging with distinct resting state functional connectivity changes in the brain.

BackgroundThe data that we gathered from a protein-protein interaction (PPI) prediction tool, FpClass, and a limited number of studies indicated that the chaperones HSP90AA1, HSPA4, STUB1/CHIP might interact with amyloid-β (Aβ) and/or tau and could subsequently be co-released into the cerebrospinal fluid (CSF). Therefore, we investigated CSF levels of HSP90AA1, HSPA4, and STUB1/CHIP in Alzheimer's disease (AD), Non-AD mild cognitive impairment (Non-AD MCI), and frontotemporal dementia (FTD) cases.MethodsThe CSF levels of HSP90AA1, HSPA4, STUB/CHIP, and core AD biomarkers were determined by ELISA in AD (n = 90), Non-AD MCI (n = 27), FTD (n = 15), and subjective cognitive impairment (SCI) (n = 20) subjects.ResultsHSP90AA1 levels were significantly higher in AD cases compared to the SCI subjects. The CSF levels of STUB1/CHIP were significantly lower in AD, Non-AD MCI and FTD cases compared to the SCI subjects. STUB1/CHIP levels of FTD cases were significantly lower than all other groups. HSPA4 levels was correlated with core AD biomarkers (Aβ 1-42, p-Tau, t-Tau) regardless of disease. Non-APOE ε4 carrier FTD cases also had significantly lower STUB1/CHIP levels than other groups.ConclusionsThe STUB1/CHIP holds promise as a potential biomarker for distinguishing between SCI subjects, AD, and FTD. Furthermore, APOE might serve as an additional discriminatory factor that might be integrated with this chaperone for enhanced discrimination.

Parkinson's disease (PD) is a complex neurodegenerative disease, characterized by pronounced heterogeneity in symptoms. This study investigates the functional connectivity (FC) patterns associated with distinct symptom clusters, aiming to elucidate the heterogeneity in PD and uncover the neural mechanisms underlying its motor and cognitive symptoms. Resting-state functional MRI (rs-fMRI) data from 55 non-demented PD patients and 24 healthy controls (HC) were used to perform seed-to-seed FC analyses. A clustering algorithm was applied to the cognitive and motor scores of all PD patients to generate relatively homogeneous symptomatic subgroups. PD patients exhibited a general decrease in FC within a network comprising the sensorimotor network (SMN) and the visual network (VN) regions. Symptom-based clustering revealed three relatively homogeneous subgroups, exhibiting a gradient pattern: patients with greater motor deficits showed significant disconnection within the SMN, whereas patients with greater visuospatial deficits exhibited reduced FC in an extended subnetwork, with pronounced disconnections between the VN and SMN areas. Our study demonstrated a notable disconnection between the SMN and VN, indicating impaired visual-motor integration in PD. Stronger disconnection within the SMN was associated with greater motor dysfunction, and stronger visual-sensorimotor disconnections were associated with greater visuospatial deficits. These findings suggest that at least two separate routes of functional disconnection may be responsible for the inhomogeneous symptom distribution in PD.

This study aimed to investigate the neurocognitive deficits, structural brain alterations, and network abnormalities in individuals who had a mild SARS-CoV-2 infection, with and without brain fog, as a symptom of long COVID. A cross-sectional study was conducted involving 75 participants, categorized into three groups: 24 healthy controls (HCs), 26 COVID-19 survivors without brain fog (woFOG), and 25 with brain fog (wFOG). Neuropsychological assessments included the Free and Cued Selective Reminding Test (FCSRT) and Addenbrooke's Cognitive Examination-Revised (ACE-R). Structural and functional brain alterations were examined using voxel-based morphometry (VBM) and resting-state functional MRI (rs-fMRI). The wFOG group exhibited significant cognitive impairments, particularly in delayed free recall, attention, memory, and visuospatial skills, compared to both the woFOG and HC groups. Structural MRI analyses revealed reduced gray matter concentrations (GMC) in the left inferior temporal gyrus, left fusiform gyrus, and right orbital gyri in both COVID-19 groups relative to HCs. Additionally, the wFOG group exhibited further GMC reductions in the bilateral caudate nuclei, right putamen/pallidum, and amygdala compared to the woFOG group. rs-fMRI analyses demonstrated altered connectivity patterns in COVID-19 survivors, characterized by increased connectivity in the default mode network and visual networks, alongside decreased connectivity in the dorsal attention network. These findings indicate that even mild COVID-19 can result in persistent neurocognitive deficits, structural brain alterations, and functional network abnormalities, both in individuals with and without brain fog. The observed changes highlight the importance of long-term monitoring and targeted interventions to address potential cognitive and neurological consequences of long COVID.

Purpose of reviewApathy is one of the most prevalent and disabling symptoms of neurodegenerative disorders, yet targeted treatments remain poorly defined. In recent years, growing interest in its conceptualization and management has led to an increasing number of randomized controlled trials (RCTs) and meta-analyses addressing both pharmacological and nonpharmacological interventions.Recent findingsAmong pharmacological approaches, methylphenidate presented with early reductions in apathy with an acceptable safety profile in multiple RCTs, including a large 6-month trial. However, the sustainability of effect has not been fully achieved. Other stimulants, bupropion, and conventional Alzheimer's medications such as cholinesterase inhibitors and memantine show inconsistent or limited effects. Antidepressants and antipsychotics are not recommended for apathy, although selected agents may benefit comorbid conditions. As for the nonpharmacological interventions, evidence supports the benefits of physical exercise and the emerging promise of neuromodulation. Technology-based interventions are feasible but show variable efficacy.SummaryMethylphenidate currently represents the most studied pharmacological agent for apathy in Alzheimer's disease (AD). However, optimal management is likely to combine pharmacological and psychosocial strategies tailored to the patient context. Future studies should include pragmatic trials with apathy as a primary endpoint, long-term follow-up, and expansion beyond AD.

Dissecting biological pathways highlighted by Mendelian gene discovery has provided critical insights into the pathogenesis of Parkinson's disease (PD) and neurodegeneration. This approach ultimately catalyzes the identification of potential biomarkers and therapeutic targets. Here, we identify PSMF1 as a novel gene implicated in parkinsonism and childhood neurodegeneration. We find that biallelic PSMF1 missense and loss-of-function variants co-segregate with phenotypes from early-onset PD to perinatal lethality with neurological manifestations across 17 pedigrees with 24 affected subjects, showing clear genotype-phenotype correlation. PSMF1 encodes the proteasome regulator PSMF1/PI31, a highly conserved, ubiquitously expressed partner of the 20S proteasome and neurodegeneration-associated F-box-O 7 and valosin-containing proteins. We demonstrate that PSMF1 variants impair mitochondrial membrane potential, dynamics and mitophagy, and may affect proteasomal abundance and assembly in patient-derived fibroblasts. Furthermore, Drosophila and mouse models of PSMF1 loss of function exhibit age-dependent motor impairment, as well as brain-wide mitochondrial membrane depolarization and dopaminergic neurodegeneration in aged flies, and diffuse gliosis in mice. Collectively, our findings unequivocally link defective PSMF1 to early-onset parkinsonism and neurodegeneration, and suggest proteasomal and mitochondrial dysfunction as mechanistic contributors.