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.

There is compelling evidence that mitochondrial dysfunction may be crucial in the pathophysiology of Alzheimer’s disease (AD) and Parkinson’s disease (PD). SUL-238 is a novel, investigational small molecule which improves mitochondrial function in animal models. Its oral administration (partially) restores AD-associated changes in protein expression in an AD mouse model and results in a significant reduction in amyloid plaque size/accumulation, enhancement of synaptic transmission and improved memory performance. These findings indicate that modulating mitochondrial metabolism by SUL-238 may provide a promising approach for treatment of AD. This was a single, oral ascending dose (SAD) Phase 1, first-in-human, randomized, double-blind, placebo-controlled study conducted in healthy adults (ClinicalTrials.gov identifier, NCT06277492). Part 1 included 6 cohorts (50, 100, 250, 500, 1000 and 2000 mg orally, n=23). In part 2, pharmacokinetics (PK) of a single 1000 mg oral dose was investigated in 10 healthy adults. In Part 2B, food effect was assessed using a randomized, single oral 2000 mg dose, two-treatment, two-period, crossover design (n=20). The primary objectives were assessment of safety, tolerability, and PK. Cerebrospinal fluid (CSF)-to-plasma concentration percentage was determined in the SAD and food effect parts. There were no adverse effects (AEs) that precluded dose escalation, AE rates were comparable between participants receiving SUL-238 and placebo. All AEs were mild or moderate in severity. Mean t 1/2 ranged between 0.86-3.80 hours and mean T max ranged between 0.50-1.39 hours. Under fed condition there was a 50% reduction in C max and a 60% reduction in AUC 0-inf as compared to fasting condition. The mean CSF-to-plasma percentages at 2- and 8-hours post-dose were 21.1% and 74.2%, respectively. In this Phase 1, first-in-human, healthy volunteer study, 50-2000 mg single oral doses of SUL-238 were safe and well-tolerated, while demonstrating a favourable PK profile, and a high CSF penetration.

Oromandibular dystonia and laryngospasm are defined as paraneoplastic syndromes of anti-Ri antibody. Herein, we report a 50-year-old woman admitted to the outpatient clinic with cervical contraction, speech and gait disturbance, and mental deterioration persisting for one year. She was diagnosed with undifferentiated nasopharyngeal carcinoma during further examination for two years of tinnitus and underwent radiotherapy. Her neurological symptoms started six months after radiotherapy. During this period, she underwent a tracheostomy due to a sudden laryngospasm. Anti-Ri antibody was positive in the paraneoplastic antibody screening. Her cervical dystonia and mental deterioration partially improved with intravenous pulse steroid and immunoglobulin therapies. However, the patient deceased due to aspiration pneumonia after six months. This rare clinical presentation, characterized by cervical dystonia, laryngospasm, spastic quadriparesis, and mental deterioration, should be considered anti-Ri antibody-associated paraneoplastic syndrome for patients with nasopharyngeal carcinoma.

BACKGROUND:There is compelling evidence that mitochondrial dysfunction may be crucial in the pathophysiology of Alzheimer's disease (AD) and Parkinson's disease (PD). SUL-238 is a novel, investigational small molecule which improves mitochondrial function in animal models. Its oral administration (partially) restores AD-associated changes in protein expression in an AD mouse model and results in a significant reduction in amyloid plaque size/accumulation, enhancement of synaptic transmission and improved memory performance. These findings indicate that modulating mitochondrial metabolism by SUL-238 may provide a promising approach for treatment of AD. METHOD:This was a single, oral ascending dose (SAD) Phase 1, first-in-human, randomized, double-blind, placebo-controlled study conducted in healthy adults (ClinicalTrials.gov identifier, NCT06277492). Part 1 included 6 cohorts (50, 100, 250, 500, 1000 and 2000 mg orally, n=23). In part 2, pharmacokinetics (PK) of a single 1000 mg oral dose was investigated in 10 healthy adults. In Part 2B, food effect was assessed using a randomized, single oral 2000 mg dose, two-treatment, two-period, crossover design (n=20). The primary objectives were assessment of safety, tolerability, and PK. Cerebrospinal fluid (CSF)-to-plasma concentration percentage was determined in the SAD and food effect parts. RESULT:There were no adverse effects (AEs) that precluded dose escalation, AE rates were comparable between participants receiving SUL-238 and placebo. All AEs were mild or moderate in severity. Mean t1/2 ranged between 0.86-3.80 hours and mean Tmax ranged between 0.50-1.39 hours. Under fed condition there was a 50% reduction in Cmax and a 60% reduction in AUC0-inf as compared to fasting condition. The mean CSF-to-plasma percentages at 2- and 8-hours post-dose were 21.1% and 74.2%, respectively. CONCLUSION:In this Phase 1, first-in-human, healthy volunteer study, 50-2000 mg single oral doses of SUL-238 were safe and well-tolerated, while demonstrating a favourable PK profile, and a high CSF penetration.

Background Neurodegeneration with brain iron accumulation (NBIA) comprises a genetically and clinically heterogeneous group of rare neurological disorders characterized particularly by iron accumulation in the basal ganglia. To date, 15 genes have been associated with NBIA. Among them, WDR45, linked to beta-propeller protein-associated neurodegeneration (BPAN), represents the only X-linked dominant subtype of NBIA. Herein, clinical, electrophysiological, and neuroimaging evaluations were used to broaden the understanding of BPAN in a newly reported case series.Methods This study included 10 individuals with BPAN, categorized into three age groups. WDR45 variant data retrieved from next-generation sequencing or Sanger sequencing were reviewed and reassessed. Comprehensive clinical evaluations including magnetic resonance imaging (MRI), fluorodeoxyglucose positron emission tomography (FDG-PET), and video electroencephalographic monitoring were conducted.Results The clinical manifestations were highly heterogeneous, with cognitive impairment being a consistent finding among the patients, with variable severity. The associated WDR45 variants are likely to exert loss-of-function effects. Electroencephalogram (EEG) abnormalities included age-dependent background slowing and epileptiform discharges. MRI indicated a characteristic pattern, while two patients lacked these typical findings. FDG-PET imaging demonstrated hypometabolism extending beyond cerebral structures, with predominant cerebellar and pontine involvement in pediatric patients and frontoparietal hypometabolism in adults.Conclusions This study contributes further to our understanding of the heterogeneous clinical spectrum of BPAN. Genotype-phenotype correlation in BPAN remains unclear due to the absence of sufficiently large cohorts in the literature, including the present study. Nevertheless, even within this small sample, the phenotypic heterogeneity observed among individuals harboring the same genotype highlights the biological complexity of the disease. Neuroimaging findings may reflect progressive and widespread neurological involvement in an age-dependent pattern, whereas EEG data suggest that epilepsy severity tends to decrease after adolescence.

INTRODUCTION:Diagnosing Alzheimer's disease (AD) is challenging due to overlapping symptoms with other dementias and the invasiveness of current biomarkers. This study introduces the NULISA platform, a novel proteomics technology, to evaluate diagnostic accuracy of known biomarkers and uncover novel biomarkers underlying different dementias. METHODS:We analyzed plasma and cerebrospinal fluid (CSF) samples from 248 participants diagnosed with Alzheimer's disease (AD), dementia with Lewy bodies (DLB), frontotemporal dementia (FTD), and mild cognitive impairment (MCI). Plasma biomarkers were evaluated using regression models, receiver operating characteristics curve (ROC) analysis, and pathway enrichment. RESULTS:Plasma phosphorylated Tau217 (pTau217) demonstrated the highest diagnostic accuracy for AD, DLB, and FTD (area under the curve [AUCs]: 0.9, 0.84, and 0.79, respectively). CXCL1 (fractalkine), synaptosomal-associated protein 25 (SNAP25), triggering receptor expressed on myeloid cells 1 (TREM1), β-synuclein, and tyrosine kinase (TEK) are expressed differently in DLB and FTD than AD. Ingenuity pathway analyses revealed astrocytic, synaptic, and inflammatory pathways as shared and distinct mechanisms across these dementia types. CONCLUSION:Our findings establish plasma pTau217 as a robust diagnostic marker. This study provides new plasma biomarkers for differential diagnosis of dementias with a noninvasive method. HIGHLIGHTS:Plasma pTau217 showed high diagnostic accuracy for AD, DLB, and FTD. CXCL1, SNAP25, TREM1, β-synuclein, and TEK are novel markers distinguishing other dementias from AD. Noninvasive plasma biomarkers enable diagnosis and differentiation of dementias.

Alzheimer's disease (AD) diagnosis is challenging due to overlapping symptoms with other dementias. Current diagnostic methods are invasive and costly, highlighting the need for accessible biomarkers. This study investigates the diagnostic performance and pathophysiological implications of a novel plasma biomarker panel in a mixed dementia cohort, aiming to enhance diagnosis and elucidate underlying pathogenic mechanisms. 120 plasma biomarkers were analyzed using the NULISA platform in a well-characterized mixt dementia. CSF biomarkers were measured via ELISA. Statistical analyses employed ANOVA, and Kruskal-Wallis tests for group comparisons. Spearman correlations assessed relationships between CSF and plasma biomarkers. Diagnostic accuracy was evaluated using regression models and ROC curves. Feature importance and selection were performed using random forest analysis. Protein interactions assessed with GO enrichment analysis. We evaluated 248 subjects (130 females, 118 males) with 117 AD, 50 MCI, 39 FTD, 25 DLB, and 17 other dementias. Plasma pTau were significantly elevated in AD compared to other groups, and in DLB compared to MCI. Plasma Aβ42 was highest in DLB, while NfL was highest in FTD. Plasma GFAP was highest in AD and elevated in DLB compared to MCI and FTD. Plasma pTau levels showed a negative correlation with CSF Aβ42 and a positive correlation with CSF pTau in the entire cohort. CSF and plasma NfL levels were also highly correlated. These correlations were stronger in DLB and amyloid-positive MCI groups but weaker or absent in the AD group. Plasma pTau, GFAP, and NfL were negatively correlated with MMSE in AD, while GFAP showed a negative correlation with MMSE in FTD and DLB. Plasma pTau217 demonstrated the best diagnostic accuracy for AD, DLB, FTD diagnosis and CSF amyloid positivity (AUCs 0.9, 0.84, 0.79, and 0.87, respectively). pTau181, pTau217, pTau231, total-tau and GFAP had lower odds in DLB and FTD compared to AD. AGRN, CXCL1, SCNB, TEK, and UCHL1 had higher odds in DLB compared to AD. SNAP25 had lower odds ratio in FTD compared to AD and DLB. pTau181, pTau217, pTau231, GFAP, MAPT, SNAP25 and PGF is related to AD progression. Random forest analysis incorporating all plasma biomarkers, age, and gender yielded an AUCs of 0.85 for AD, 0.84 for FTD, and 0.75 for DLB. Refining the model by including biomarkers identified as significant in regression model improved performance, resulting in AUCs of 0.88 for AD, 0.87 for FTD, and 0.81 for DLB. This demonstrates potential for enhancing diagnostic accuracy through targeted biomarker panel refinement. ### Competing Interest Statement HZ has served at scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, Alzinova, ALZpath, Amylyx, Annexon, Apellis, Artery Therapeutics, AZTherapies, Cognito Therapeutics, CogRx, Denali, Eisai, LabCorp, Merry Life, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Quanterix, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures sponsored by Alzecure, BioArctic, Biogen, Cellectricon, Fujirebio, Lilly, Novo Nordisk, Roche, and WebMD, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). AJH has consulted for Quanterix and Lilly. ### Funding Statement The study is supported by the Scientific and Technological Research Council of Turkey TUBITAK (Project No. 22AG017 APYOK2. Grant Recipient: Erdinc Dursun). HZ is a Wallenberg Scholar and a Distinguished Professor at the Swedish Research Council supported by grants from the Swedish Research Council (#2023 00356 #2022 01018 and #2019 02397) the European Unions Horizon Europe research and innovation programme under grant agreement No 101053962 Swedish State Support for Clinical Research (#ALFGBG 71320) the Alzheimer Drug Discovery Foundation (ADDF) USA (#201809 2016862) the AD Strategic Fund and the Alzheimer's Association (#ADSF 21 831376 C #ADSF 21 831381 C #ADSF 21 831377 C and #ADSF 24 1284328 C) the European Partnership on Metrology co-financed from the European Unions Horizon Europe Research and Innovation Programme and by the Participating States (NEuroBioStand #22HLT07) the Bluefield Project Cure Alzheimers Fund the Olav Thon Foundation the Erling Persson Family Foundation Familjen Ronstroms Stiftelse Stiftelsen for Gamla Tjanarinnor Hjarnfonden Sweden (#FO2022 0270) the European Unions Horizon 2020 research and innovation programme under the Marie Sklodowska Curie grant agreement No 860197 (MIRIADE) the European Union Joint Programme Neurodegenerative Disease Research (JPND2021 00694) the National Institute for Health and Care Research University College London Hospitals Biomedical Research Centre and the UK Dementia Research Institute at UCL (UKDRI 1003). J.H. D.A.S. and U.Y. are supported by the UK Dementia Research Institute [award numbers UK DRI 1009] through UK DRI Ltd principally funded by the Medical Research Council. J.H. M.S. and D.A.S. are supported by the Dolby Foundation and by the National Institute for Health Research University College London Hospitals Biomedical Research Centre. J.H. also received funding from Cure Alzheimers Fund. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Istanbul University Ethics Committee (approval number 2023/1191, granted 22/06/2023). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors

Valosin-containing protein ( VCP ) mutations are causative for multisystem proteinopathy, a disease characterized by variable phenotypes including inclusion body myopathy, Paget’s disease of bone, and frontotemporal dementia. More recent reports identified VCP variants as the cause of other neurodegenerative diseases, such as Parkinson’s disease and vacuolar tauopathy. We screened a Turkish dementia cohort for VCP variants in order to assess their role as the cause of disease in this population. One hundred and forty six Turkish dementia patients were examined clinically and were analyzed for VCP coding variants using whole-exome sequencing. Familial samples were collected and analyzed in order to test for segregation of candidate variants. We identified a heterozygous missense VCP p.Ile216Met variant segregating with disease in a family where the proband was diagnosed with prodromal dementia with Lewy bodies. Our report potentially extends the spectrum of phenotypes attributed to VCP mutations to include prodromal dementia with Lewy bodies.

Introduction: Anticholinergic burden may be an important risk factor for the cognitive impairment. Especially in polypharmacy, even drugs with low anticholinergic effects may contribute to a significant anticholinergic burden. The drugs with anticholinergic effects are used in treatment of motor and nonmotor symptoms of Parkinson's disease (PD). Therefore, it is important to screen for polypharmacy and anticholinergic burden in PD patients with mild cognitive impairment (MCI). Methods: This cross-sectional study was conducted with 58 patients with PD. PD-MCI was diagnosed according to MDS Level 2 Comprehensive Assessment. Cognitive performance (attention - working memory, executive functions, language, memory, and visuospatial functions) of patients was evaluated. The anticholinergic burden was scored by Anticholinergic Cognitive Burden (ACB) Scale, Anticholinergic Risk Scale (ARS), and Anticholinergic Drug Scale (ADS). Results: There was no significant difference in anticholinergic burden between PD-MCI and PD-normal cognition. A significant concordance was observed between ACB, ARS, and ADS scores (p < 0.001; Kendall's W = 0.653). While the variable predicting anticholinergic burden was the total number of drugs for ACB and ADS scales, it was the number of antiparkinson drugs for ARS scale. Conclusion: Patients with PD are at high risk for polypharmacy and anticholinergic burden. Anticholinergic burden should be considered in the selection of drugs, especially for comorbidities in patients with PD. No significant correlation was found between the cognition and anticholinergic burden in patients with PD-MCI. Although the risk scores of antiparkinson and other drugs were different among the 3 scales, significant concordance was observed between scales.

INTRODUCTION:The key feature that distinguishes mild cognitive impairment (MCI) from dementia is the absence of significant functional decline because of cognitive impairment. In Parkinson's disease patients (PD) with MCI (PD-MCI), the effect of cognitive impairment on complex instrumental daily activities, such as medication management, is not well established.METHOD:26 patients with PD-MCI (diagnosed to Level 2 Movement Disorders Society diagnostic criteria) and 32 idiopathic PD patients without cognitive impairment participated in the study. A detailed neuropsychological testing battery (including tests for attention and working memory, executive functions, language, visuospatial functions, episodic memory) and various prospective memory tasks were applied to the patients. Medication taking behaviors were evaluated using two different methods based on the performance (medication management ability assessment) and self-reporting (adherence scale).RESULTS:The PD-MCI group obtained significantly lower scores in medication management assessment and made more mistakes on following prescription instructions (e.g., they took more or less tablets and did not use medications as instructed with regard to meal times). Cognitive areas predicting success in medication management performance were language, event-based prospective memory and visuospatial functions. There was no significant difference between the two groups' self-reporting of adherence.CONCLUSION:Mild cognitive impairment in patients with PD adversely affects medication management. Diagnosing MCI in PD is important to ensure that the appropriate measures can be taken to provide support and improve the medication management process. Adherence assessments based on self-reporting may not provide reliable and sensitive information in patients with PD-MCI.

Introduction:In patients with Parkinson's disease (PD), low cerebrospinal fluid (CSF) amyloid beta 1-42 (Ab42) at baseline is the most consistent CSF biomarker as a risk factor for developing dementia. Low CSF Ab42 is, however, a typical hallmark of Alzheimer's disease (AD). Hence, low CSF Ab42 in patients with PD may indicate presence of comorbid AD pathology and may predict a more AD-like cognitive profile when they develop dementia. Our study aimed to investigate if low CSF Ab42 at baseline is associated with a more AD-like cognitive profile in PD patients with dementia. Methods:In a prospectively followed-up, population-based cohort of newly diagnosed PD patients, we compared the cognitive profile of dementia in those with a low CSF Ab42 level at baseline with that of patients who had normal levels at the time when they developed dementia. Four different cognitive domain z-scores (memory, attention, executive, visuospatial) were calculated. Patients were subdivided into three tertiles or categorized dichotomously based on the baseline CSF Ab42 levels as measured by electrochemiluminescence and ELISA. Results:During 10-year follow-up, 37 patients met the inclusion criteria. Memory domain composite z-scores, memory subtest z-scores, and the difference between long-delay free recall versus recognition scores were not significantly different between the groups. Composite z-scores of visuospatial functions significantly differed between the tertiles, which was not significant after Bonferroni correction. In the dichotomous group analysis, z-scores of visuospatial functions significantly differed between the two groups. The other cognitive domain z-scores were not significantly different. Conclusions:In patients with PD dementia, low CSF Ab42 level at baseline is not associated with a specific cognitive profile.

BACKGROUND:Biallelic pathogenic variants in the SCARB2 gene have been associated with action myoclonus-renal failure (AMRF) syndrome. Even though SCARB2 associated phenotype has been reported to include typical neurological characteristics, depending on the localization and the feature of the pathogenic variants, clinical course and the presentations have been shown to differ.CASE PRESENTATION:Whole exome sequencing (WES) analysis revealed a homozygous truncating variant (p.N45MfsX88) in SCARB2 gene in the index case, and subsequent sanger sequencing analysis validated the variant in all affected family members from a Turkish family with the clinical characteristics associated with AMRF and related disorders. Intrafamilial clinical heterogeneity with common features including dysarthria, tremor and proteinuria, and distinct features such as peripheral neuropathy (PNP), myoclonus and seizures between the affected cases, was observed in the family. In-depth literature review enabled the detailed investigation of the reported variants associated with AMRF and suggested that while the type of the variant did not have a major impact on the course of the clinical characteristics, only the C terminal localization of the pathogenic variant significantly affected the clinical presentation, particularly the age at onset (AO) of the disease.CONCLUSIONS:In this study we showed that biallelic SCARB2 pathogenic variants might cause a spectrum of common and distinct features associated with AMRF. Of those features while the common features include myoclonus (100%), ataxia (96%), tonic clonic seizures (82%), dysarthria (68%), tremor (65%), and renal impairment (62%), the uncommon features involve PNP (17%), hearing loss (6.8%), and cognitive impairment (13.7%). AO has been found to be significantly higher in the carriers of the p.G462DfsX34 pathogenic variant. SCARB2 pathogenic variants have not been only implicated in AMRF but also in the pathogenesis of Parkinson's disease (PD) and Gaucher disease (GD), suggesting the importance of genetic and functional studies in the clinical and the diagnostic settings. Given the proven role of SCARB2 gene in the pathogenesis of AMRF, PD and GD with a wide spectrum of clinical symptoms, investigation of the possible modifiers, such as progranulin and HSP7, has a great importance.

Nasu–Hakola disease (NHD) is a rare, autosomal recessive disorder characterized by skeletal and neurological symptoms. Behavioral symptoms with cognitive impairment may mimic the behavioral variant of frontotemporal dementia (bvFTD) and other early‐onset dementias. Our patients were analyzed and the literature was reviewed to delineate neurological and neuroimaging findings suggestive of NHD.

INTRODUCTION:Missense variants and multiplications of the alpha-synuclein gene (SNCA) are established as rare causes of autosomal dominant forms of Parkinson's Disease (PD). METHODS:Two families of Turkish origins with PD were studied; the SNCA coding region was analyzed by Sanger sequencing, and by whole exome sequencing (WES) in the index patient of the first and the second family, respectively. Co-segregation studies and haplotype analysis across the SNCA locus were carried out. Functional studies included in vitro thioflavin-T aggregation assay and in silico structural modelling of the alpha-synuclein (α-syn) protein. RESULTS:We identified a novel heterozygous SNCA variant, c.215C > T (p.Thr72Met), segregating with PD in a total of four members in the two families. A shared haplotype across the SNCA locus was found among variant carriers, suggestive of a common ancestor. We next showed that the Thr72Met α-syn displays enhanced aggregation in-vitro, compared to the wild-type species. In silico analysis of a tetrameric α-syn structural model revealed that Threonine 72 lies in the tetrameric interface, and substitution with the much larger methionine residue could potentially destabilize the tetramer. CONCLUSION:We present clinical, genetic, and functional data supporting a causative role of the SNCA c.215C > T (p.Thr72Met) variant in familial PD. Testing for this variant in patients with PD, especially of Turkish origin, might detect additional carriers. Further functional analyses might offer new insights into the shared biochemical properties of the PD-causing SNCA missense variants, and how they lead to neurodegeneration.

Introduction: The majority of Parkinson's disease (PD) ensue late-onset with a complex spectrum of environmental and genetic risk factors. Awareness of genetic causes in patients with PD is essential for genetic counseling and future genotype-oriented therapeutic developments. Methods: Large pathogenic changes in eight PD-related genes and small pathogenic sequence variants in 22 PDrelated genes were investigated simultaneously in 82 PD patients from 79 families where clinical evaluations were performed. The phenotypic characteristics of the patients with molecular changes were examined for genotype-phenotype relations. Results: Pathogenic variants in SNCA, PRKN, DJ-1, FBXO7, and GBA genes were determined in 25 patients from 24 families (24/79, 30%). Associated variants were found in PRKN in 14, SNCA in three, FBXO7 in two, and DJ-1 in one patient. A novel homozygous deletion (c.491delT, p.(V164Dfs*13) (SCV001733595)) leading to protein truncation in the PRKN gene was identified in two patients from the same family. Furthermore, heterozygous GBA gene variants were detected in five patients from different families. Conclusion: It has been shown that the most common cause of genetically transmitted PD is the PRKN gene, while LRRK2 does not play an essential role in this selected population. It has been suggested that even if the autosomal recessive inheritance is expected, genes with autosomal dominant effects such as SNCA should not be overlooked and suggested for investigation. Our study is also the first for evaluating the pathogenic GBA variants' frequency in PD patients from Turkey.

INTRODUCTION:The most prominent risk factor of Alzheimer's disease (AD) is aging. Aging also influences the physical appearance. Our clinical experience suggests that patients with AD may appear younger than their actual age. Based on this empirical observation, we set forth to test the hypothesis with human and computer-based estimation systems.METHOD:We compared 50 early-stage AD patients with 50 age and sex-matched controls. Facial images of all subjects were recorded using a video camera with high resolution, frontal view, and clear lighting. Subjects were recorded during natural conversations while performing Mini-Mental State Examination, including spontaneous smiles in addition to static images. The images were used for age estimation by 2 methods: (1) computer-based age estimation; (2) human-based age estimation. Computer-based system used a state-of-the-art deep convolutional neural network classifier to process the facial images contained in a single-video session and performed frame-based age estimation. Individuals who estimated the age by visual inspection of video sequences were chosen following a pilot selection phase. The mean error (ME) of estimations was the main end point of this study.RESULTS:There was no statistically significant difference between the ME scores for AD patients and healthy controls (p = 0.33); however, the difference was in favor of younger estimation of the AD group. The average ME score for AD patients was lower than that for healthy controls in computer-based estimation system, indicating that AD patients were on average estimated to be younger than their actual age as compared to controls. This difference was statistically significant (p = 0.007).CONCLUSION:There was a tendency for humans to estimate AD patients younger, and computer-based estimations showed that AD patients were estimated to be younger than their real age as compared to controls. The underlying mechanisms for this observation are unclear.

BACKGROUND:There is evidence that alterations in functional connectivity (FC) of the striatocortical circuits may appear before the onset of clinical symptoms of Parkinson's disease (PD). OBJECTIVE:The aim of this study was to investigate FC of the striatocortical circuitry in asymptomatic carriers of heterozygous glucocerebrosidase (GBA) mutations, which pose a significant risk for developing PD. METHODS:Twenty-one parents of confirmed Gaucher disease patients who were carrying heterozygous GBA mutations and 18 healthy individuals matched for age and gender were included. GBA mutation analysis was performed in all participants. Clinical evaluation included neurological examination, Mini Mental State Examination, and UPDRS Part III. Structural and functional MRI data of 18 asymptomatic GBA mutation carriers (asGBAmc) and 17 healthy controls (HC) were available. FC was analyzed with seed-based approach. RESULTS:Eleven asymptomatic mutation carriers had heterozygous p.L483P mutation, 6 subjects heterozygous p.N409S mutation and 1 subject heterozygous p.R392G mutation in GBA gene. Mini-Mental State Examination mean score was 28.77 (±1.16) and 29.64 (±0.70) in asGBAmc and HC groups, respectively (p = 0.012). Significant increased connectivityConclusion:Our results suggest that alterations in striatocortical FC can be detected in asymptomatic heterozygous GBA mutation carriers who are at risk of developing PD. These findings may provide insight into network changes during the asymptomatic phase of PD.

Wilson’s disease (WD) is an autosomal recessive genetic disorder of copper metabolism, and WD patients can present with neurologic symptoms. We aimed to report the general characteristics and prognosis of a Turkish series of WD patients with neurological manifestations. A total of 12,352 patients were screened from the patient database, and 53 WD patients were included. Patients were classified based on the predominant neurological syndrome type including tremor, dystonia, parkinsonism, or discrete neurological signs and were classified as having “good outcome,” “stable,” and “poor outcome” according to their treatment response. There were 32 male and 21 female patients, aged 20–66 years. The mean follow-up was 11.3 ± 4.56 years. Sixty-two percent of patients presented predominantly with neurological symptoms. Neurological WD diagnosis was established after a mean time delay of 2.3 years from the WD diagnosis. The most common neurological manifestation was dystonia, followed by tremor and parkinsonism. Fifteen patients had a family history of WD. Consanguinity was present in 20 patients. Patients were treated with D-penicillamine, trientine, zinc salts, or their combinations. Besides the main treatments, 41 patients were on symptomatic treatment for neurologic symptoms. Thirty-six patients had a “good outcome,” five patients were stable, and six patients had “poor outcome.” Post-chelation neurological worsening was observed in 11 patients. WD should be considered in differential diagnosis in any patient with unexplained neurologic symptoms. Early diagnosis is important, and appropriate treatment should be promptly initiated to prevent progressive and irreversible damage, with good prognosis and stable disease in the majority of the patients with treatment compliance.