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: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.

BACKGROUND:Early onset parkinsonism caused by F-box only protein7 (FBXO7) pathogenic variants is a rare autosomal recessive disorder presenting with a combination of parkinsonism, pyramidal signs, dystonia, cognitive impairment, and psychiatric features. Although previous case reports have mentioned neuroimaging findings, there is no comprehensive study characterizing the radiological spectrum of FBXO7 pathogenic variants. CASES:Ten patients from seven families followed at two tertiary centers in Turkey were included. The cohort included six males and four females with a mean onset age of 21.1 years. Frontal atrophy was the most common MRI finding, followed by global cortical and cerebellar atrophy. One patient showed iron accumulation in the pallidum, and two exhibited severe dopaminergic deficit on DaTSCAN. LITERATURE REVIEW:Pathogenic variants in the FBXO7 gene have been identified in diverse populations over the past 15 years, contributing to a broader understanding of clinical and radiological spectrum. Global cortical atrophy has emerged as the most frequently reported neuroimaging finding in FBXO7-related parkinsonism. CONCLUSIONS:FBXO7 pathogenic variants are associated with heterogeneous neuroimaging findings. Frontal and global cortical atrophy are common, while iron deposition and DaTSCAN abnormalities offer additional diagnostic clues. Larger, longitudinal studies are necessary to establish specific imaging biomarkers for FBXO7-related neurodegeneration.

Objective: Neuroinflammation is involved in the pathology of Alzheimer's disease (AD). Peripheral levels of various inflammatory cytokines are altered during AD pathogenesis. This study aimed to examine the role of peripheral inflammation in AD pathogenesis by measuring serum levels and gene expression of specific inflammatory cytokines in AD patients. Therefore, we analyzed serum interleukin-6 (IL-6) and transforming growth factor-beta 1 (TGF-beta 1) levels and mRNA expressions of IL-6 and tumor necrosis factor-alpha (TNF-alpha) in peripheral blood mononuclear cells of AD patients and controls. Materials and Methods: We quantitatively assessed serum IL-6 and TGF-beta 1 levels in 25 AD patients and 33 age-matched controls using enzymelinked immunosorbent assay. In addition, we evaluated the mRNA expressions of IL-6 and TNF-alpha in peripheral blood mononuclear cells from 31 AD patients and their respective controls (n=30) via quantitative real-time polymerase chain reaction. Results: AD patients tended to have higher serum IL-6 and TGF-beta 1 levels compared to the controls, but the difference was not statistically significant. IL-6 and TNF-alpha mRNA expression was significantly downregulated in AD patients compared to the controls (p=0.000 and p=0.004; respectively). Serum IL-6 and TGF-beta 1 levels were negatively correlated with age in AD patients (p=0.025, r=-0.467 and p=0.035, r=-0.431; respectively). Conclusion: The outcomes of this study suggest a disruption in the peripheral immune response in individuals with AD. The observed decreased expression of cytokine genes in peripheral leukocytes may indicate a contributory mechanism through which peripheral cytokines influence AD pathogenesis.

Objective: Neuroinflammation is involved in the pathology of Alzheimer's disease (AD). Peripheral levels of various inflammatory cytokines are altered during AD pathogenesis. This study aimed to examine the role of peripheral inflammation in AD pathogenesis by measuring serum levels and gene expression of specific inflammatory cytokines in AD patients. Therefore, we analyzed serum interleukin-6 (IL-6) and transforming growth factor-beta 1 (TGF-β1) levels and mRNA expressions of IL-6 and tumor necrosis factor-alpha (TNF-α) in peripheral blood mononuclear cells of AD patients and controls. Materials and Methods: We quantitatively assessed serum IL-6 and TGF-β1 levels in 25 AD patients and 33 age-matched controls using enzymelinked immunosorbent assay. In addition, we evaluated the mRNA expressions of IL-6 and TNF-α in peripheral blood mononuclear cells from 31 AD patients and their respective controls (n=30) via quantitative real-time polymerase chain reaction. Results: AD patients tended to have higher serum IL-6 and TGF-β1 levels compared to the controls, but the difference was not statistically significant. IL-6 and TNF-α mRNA expression was significantly downregulated in AD patients compared to the controls (p=0.000 and p=0.004; respectively). Serum IL-6 and TGF-β1 levels were negatively correlated with age in AD patients (p=0.025, r=-0.467 and p=0.035, r=-0.431; respectively). Conclusion: The outcomes of this study suggest a disruption in the peripheral immune response in individuals with AD. The observed decreased expression of cytokine genes in peripheral leukocytes may indicate a contributory mechanism through which peripheral cytokines influence AD pathogenesis.

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

BackgroundDystonia is one of the most common movement disorders. To date, the genetic causes of dystonia in populations of European descent have been extensively studied. However, other populations, particularly those from the Middle East, have not been adequately studied. The purpose of this study is to discover the genetic basis of dystonia in a clinically and genetically well-characterised dystonia cohort from Turkey, which harbours poorly studied populations.MethodsExome sequencing analysis was performed in 42 Turkish dystonia families. Using co-expression network (CEN) analysis, identified candidate genes were interrogated for the networks including known dystonia-associated genes and genes further associated with the protein-protein interaction, animal model-based characteristics and clinical findings.ResultsWe identified potentially disease-causing variants in the established dystonia genes (PRKRA, SGCE, KMT2B, SLC2A1, GCH1, THAP1, HPCA, TSPOAP1, AOPEP; n=11 families (26%)), in the uncommon forms of dystonia-associated genes (PCCB, CACNA1A, ALDH5A1, PRKN; n=4 families (10%)) and in the candidate genes prioritised based on the pathogenicity of the variants and CEN-based analyses (n=11 families (21%)). The diagnostic yield was found to be 36%. Several pathways and gene ontologies implicated in immune system, transcription, metabolic pathways, endosomal-lysosomal and neurodevelopmental mechanisms were over-represented in our CEN analysis.ConclusionsHere, using a structured approach, we have characterised a clinically and genetically well-defined dystonia cohort from Turkey, where dystonia has not been widely studied, and provided an uncovered genetic basis, which will facilitate diagnostic dystonia research.

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.

The anti-inflammatory adipokine intelectin-1, which is encoded by the ITLN1 gene, is hypothesized to be linked to the pathogenesis of type 2 diabetes (T2DM) and obesity. The purpose of this study was to examine the effect of the ITLN1 gene polymorphism rs2274907 on obesity and T2DM in Turkish adults. The impact of genotype on lipid profiles and serum intelectin levels in the obese and diabetes groups was also investigated. Randomly selected 2266 adults (mean age, 55.0 ± 11.7 years; 51.2

Abstract Objectives Estrogen receptor 1 (ESR1) gene polymorphisms are associated with Alzheimer's disease (AD) and ESR1 mRNA transcription is affected by polymorphisms in the first intronic region of the gene. ESR1 PvuII rs2234693 (NM 000125.3:c.453-397T > C) and XbaI rs9340799 (NM 000125.3:c.453-351A > G) polymorphisms have been shown to be associated with AD. In this study, we sought to determine the association of PvuII and XbaI polymorphisms with AD. We also examined whether PvuII and XbaI polymorphisms affect disease susceptibility by influencing ESR1 mRNA expression. Methods Genotyping was performed in 424 AD patients and 302 controls. The polymerase chain reaction and restriction enzyme digestion was used to determine the prevalence of the ESR1 polymorphisms. ESR1 mRNA expression was analyzed in blood cells of 85 patients and 53 age-matched controls by quantitative real-time polymerase chain reaction. Results Our results showed no significant difference in genotype and allele frequencies of ESR1 PvuII and XbaI polymorphisms between patients and controls but frequencies of the PvuII C and XbaI G alleles were significantly higher in patients with the APOE ε4 allele. ESR1 mRNA levels were significantly lower in AD patients compared with controls (p = 0.001). XbaI A allele is significantly associated with lower ESR1 mRNA levels (p = 0.044) and this association remained significant after adjusting for age, gender and APOE ε4 carrier status (p = 0.035). Conclusion Our study showed that the distribution of PvuII and XbaI alleles were associated with the APOE ε4 allele. The XbaI polymorphism may be associated with a higher risk of AD by altering ESR1 mRNA levels.

Objective: Estrogen receptor 1 (ESR1) polymorphisms are associated with Alzheimer's disease (AD) and polymorphisms in the first intronic region of the gene are known to affect ESR1 mRNA transcription. The first intronic region of the ESR1 contains two polymorphisms that have received the most attention: PvuII rs2234693 (NM 000125.3:c.453-397T>C) and XbaI rs9340799 (NM 000125.3:c.453-351A>G). Both polymorphisms have been shown to be associated with AD, but consistent findings across populations have not been established. This study aimed to determine whether ESR1 PvuII and XbaI polymorphisms are associated with the disease in a cohort of Turkish AD patients. Whether PvuII and XbaI polymorphisms affect disease susceptibility by influencing ESR1 mRNA expression was also examined. Materials and Methods: Genotyping was performed in 424 patients with AD (mean age: 64.5 +/- 11.1 yrs) and 302 controls (mean age: 56.4 +/- 13.0 yrs). The polymerase chain reaction (PCR) and restriction enzyme digestion methods were used to determine the prevalence of the ESR1 PvuII and XbaI polymorphisms. The ESR1 mRNA expression was analyzed in the peripheral blood cells of 85 patients and 53 age-matched controls using quantitative real-time PCR. Results: No significant difference in genotype and allele frequencies of ESR1 PvuII and XbaI polymorphisms between the patients and controls was found. However, the frequencies of the PvuII C and XbaI G alleles were significantly higher in the patients with the apolipoprotein-E (APOE) 64 allele. The ESR1 mRNA levels were significantly lower in the patients with AD compared with the controls (P = 0.001). The XbaI A allele was significantly associated with lower ESR1 mRNA levels (P = 0.044) and this association remained significant even after adjusting for confounders such as age, gender and APOE 64 carrier status (P = 0.035). Conclusion: This study demonstrated that the distribution of PvuII and XbaI alleles is associated with the APOE 64 allele. The XbaI polymorphism may be associated with a risk of AD ESR1 mRNA levels.

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.

Leukodystrophies broadly affect the brain white matter. As such, diseases including cerebral autosomal dominant/ recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL/CARASIL) are included in this group. NOTCH3 and HTRA1 variants are a known cause of CADASIL and CARASIL, respectively. Studies have reported NOTCH3 variants in Alzheimer’s disease, and heterozygous HTRA1 variants in cerebral small vessel disease. Therefore, there is growing evidence of leukodystrophy gene variants in neurodegenerative diseases. We screened a whole-exome sequenced Turkish dementia cohort for rare variants in a panel of leukodystrophy genes. Where familial samples were available, we tested for segregation. We also consulted the exome data available from the Turkish Variome to gauge a better estimate of population frequency for candidate variants. We identified rare variants in leukodystrophy genes in individuals from this Turkish dementia cohort. Variants in NOTCH3 include a known pathogenic gain-of-cysteine variant in a family presenting with CADASIL (NOTCH3 p.Arg133Cys); a novel loss-of-cysteine variant (NOTCH3 p.Cys65Tyr) in an atypic dementia case, and a novel cysteine-sparing missense variant (NOTCH3 p.Ala818Thr) in a family with Alzheimer’s disease and mild cognitive impairment. Considering the increased consanguinity of the Turkish population we were expecting to identify bi-allelic variants in HTRA1 with potential roles in disease. Instead, NOTCH3 presented a higher burden of variability, including known and novel variants expected to be involved in disease.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and retinal vasculopathy with cerebral leukodystrophy and systemic manifestations (RVCL-S) are the most common forms of rare monogenic early-onset cerebral small vessel disease and share clinical, and, to different extents, neuroradiological and neuropathological features. However, whether CADASIL and RVCL-S overlapping phenotype may be explained by shared genetic risk or causative factors such as TREX1 coding variants remains poorly understood. To investigate this intriguing hypothesis, we used exome sequencing to screen TREX1 protein-coding variability in a large multi-ethnic cohort of 180 early-onset independent familial and apparently sporadic CADASIL-like Caucasian patients from the USA, Portugal, Finland, Serbia and Turkey. We report 2 very rare and likely pathogenic TREX1 mutations: a loss of function mutation (p.Ala129fs) clustering in the catalytic domain, in an apparently sporadic 46-year-old patient from the USA and a missense mutation (p.Tyr305Cys) in the well conserved C-terminal region, in a 57-year-old patient with positive family history from Serbia. In concert with recent findings, our study expands the clinical spectrum of diseases associated with TREX1 mutations.

Objective: Mutations in the Presenilin-1 (PSEN1) gene have been associated with early-onset familial Alzheimer disease (AD) and these mutations usually exhibit full penetrance.However, the p.E318G variant located at exon 9 of PSEN1 is an exception.This variant is also seen in non-demented controls other than patients with AD suggesting that it may be a rare polymorphism or a mutation with low penetrance.In addition, results from studies conducted in different populations investigating the role of p.E318G variant in AD were conflicting.In this study, we aimed to determine the frequency of the PSEN1 p.E318G variant and APOE genotypes in a Turkish cohort and to investigate whether they were associated with the risk of AD. Materials and Methods:The study included 217 patients with familial AD, 153 patients with sporadic AD, and 402 controls.The PSEN1 p.E318G and APOE genotypes were determined using real-time polymerase chain reaction with hydrolysis probes.Results: The p.E318G variant was found in five patients with familial AD, three patients with sporadic AD, and 11 control subjects.There was no significant difference in the distribution of the p.E318G variant between patients and controls in familial and sporadic forms.APOE ε4 allele carriers had an increased risk for AD compared with non-carriers both in familial [odds ratio (OR): 3.67, 95% confidence interval (CI): (2.69-4.99);p<0.001] and sporadic cases [OR: 2.91, 95% CI: (2.06-4.10);p<0.001].No significant difference was found in the distribution of the p.E318G variant with either the absence or presence of the APOE ε4 allele.Conclusion: Our results showed that PSEN1 p.E318G variation, either alone or together with the APOE ε4 allele, is not associated with AD risk in Turkish patients with AD.However, the APOE ε4 allele constitutes a significant risk factor for AD both in familial and sporadic forms.

Recently, several genome-wide association studies identified PHACTR1 as key locus for five diverse vascular disorders: coronary artery disease, migraine, fibromuscular dysplasia, cervical artery dissection and hypertension. Although these represent significant risk factors or comorbidities for ischemic stroke, PHACTR1 role in brain small vessel ischemic disease and ischemic stroke most important survival mechanism, such as the recruitment of brain collateral arteries like posterior communicating arteries (PcomAs), remains unknown. Therefore, we applied exome and genome sequencing in a multi-ethnic cohort of 180 early-onset independent familial and apparently sporadic brain small vessel ischemic disease and CADASIL-like Caucasian patients from US, Portugal, Finland, Serbia and Turkey and in 2 C57BL/6J stroke mouse models (bilateral common carotid artery stenosis [BCCAS] and middle cerebral artery occlusion [MCAO]), characterized by different degrees of PcomAs patency. We report 3 very rare coding variants in the small vessel ischemic disease-CADASIL-like cohort (p.Glu198Gln, p.Arg204Gly, p.Val251Leu) and a stop-gain mutation (p.Gln273*) in one MCAO mouse. These coding variants do not cluster in PHACTR1 known pathogenic domains and are not likely to play a critical role in small vessel ischemic disease or brain collateral circulation. We also exclude the possibility that copy number variants (CNVs) or a variant enrichment in Phactr1 may be associated with PcomA recruitment in BCCAS mice or linked to diverse vascular traits (cerebral blood flow pre-surgery, PcomA size, leptomeningeal microcollateral length and junction density during brain hypoperfusion) in C57BL/6J mice, respectively. Genetic variability in PHACTR1 is not likely to be a common susceptibility factor influencing small vessel ischemic disease in patients and PcomA recruitment in C57BL/6J mice. Nonetheless, rare variants in PHACTR1 RPEL domains may influence the stroke outcome and are worth investigating in a larger cohort of small vessel ischemic disease patients, different ischemic stroke subtypes and with functional studies.

Objective: The etiology of Alzheimer's disease (AD) is affected via oxidative stress. Antioxidant enzymes are extremely important in preventing reactive oxygen species (ROS) causing damage in the cell. The changes in expression levels of oxidant and antioxidant genes are key factors in cell response to oxidative stress. As a result, this study investigated the change in expression levels of specific oxidative stress related genes (solute carrier family 7 member 11 (SLC7A11), glutathione peroxidase 4 (GPX4), catalase (CAT) and acylcoa synthetase long chain family member 4 (ACSL4)) in peripheral blood of AD patients. Materials and Methods: Quantitative reverse-transcription polymerase chain reaction (qRT-PCR) was used to assess the expression levels of oxidative stress-related genes in 25 AD patients and 22 controls, and the findings were statistically evaluated. Results: SLC7A11, GPX4, CAT, and ACSL4 gene expression levels did not vary significantly between AD patients and controls. The results also showed significant negative correlation between age of onset and ACSL4 expression. Conclusion: This is the first study that evaluated mRNA expression levels of SLC7A11, GPX4 and ACSL4 genes in AD. The results suggested that the peripheral blood expression of above-mentioned genes did not alter in AD. However, due to the small number of subjects, this findings are preliminary and should be validated with a larger number of subjects.

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.

Diseases caused by homozygous variants are more prevalent in consanguineous populations where regions of homozygosity (ROHs) spanning the genome are extended. The same diseases are comparatively rarer in outbred populations, and thus identifying pathogenic variants is more challenging without much larger cohorts. It has been previously shown that the genomic segment harboring the disease gene is located within the longest ROH more often than expected. We utilize both whole genome genotyping and whole exome sequencing data to identify ROHs and candidate variants causing or contributing to the risk of disease in a consanguineous Turkish dementia cohort. Patient diagnoses in this cohort include Alzheimer’s disease, frontotemporal dementia and mild cognitive impairment. Previous studies in consanguineous families from this cohort have identified novel rare biallelic variants in TREM2 as the cause of an atypical frontotemporal dementia phenotype. Additional heterozygous variants in this gene have since been recognized as risk factors for neurodegenerative diseases, most prominently the p.R47H variant is now well established as one of the most significant genetic risk factors for Alzheimer’s disease. In this study, we detected homozygous variants within ROHs, in both known neurodegenerative disease-causing genes, and in novel genes which have been previously implicated in other, rare diseases. These results are important for considering both potential dose-effects and pleiotropy, respectively. To the best of our knowledge, this is the largest study on the Turkish dementia population which utilizes such extended ROHs to identify rare homozygous variants.