Başar Bilgiç

Using Exome Sequencing to Reveal Mutations in TREM2 Presenting as a Frontotemporal Dementia–like Syndrome Without Bone Involvement

OBJECTIVE To identify new genes and risk factors associated with frontotemporal dementia (FTD). Several genes and loci have been associated with different forms of FTD, but a large number of families with dementia do not harbor mutations in these genes. DESIGN Whole-exome sequencing and whole-genome genotyping were performed in all patients. Genetic variants obtained from whole-exome sequencing were integrated with the data obtained from whole-genome genotyping. SETTING Database of the Behavioral Neurology Outpatient Clinic of the Department of Neurology, Istanbul Faculty of Medicine, Istanbul, Turkey. PATIENTS Forty-four Turkish patients with an FTD-like clinical diagnosis were included in the study. Relatives were screened when appropriate. MAIN OUTCOME MEASURE Mutations in the triggering receptor expressed on myeloid cells 2 gene (TREM2). RESULTS In 3 probands with FTD-like disease, we identified different homozygous mutations in TREM2 that had previously been associated with polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL). None of these 3 patients had a typical clinical presentation of PLOSL: they presented with behavioral change and subsequent cognitive impairment and motor features but without any bone cysts or bone-associated phenotypes. Imaging showed white matter abnormalities as well as frontal atrophy in all 3 patients. CONCLUSIONS Our results show that TREM2 is responsible for an unexpectedly high number of dementia cases in our cohort, suggesting that this gene should be taken into account when mutations in other dementia genes are excluded. Even for complex syndromes such as dementia, exome sequencing has proven to be a rapid and cost-effective tool to identify genetic mutations, allowing for the association of clinical phenotypes with unexpected molecular underpinnings.

Loss of VPS13C Function in Autosomal-Recessive Parkinsonism Causes Mitochondrial Dysfunction and Increases PINK1/Parkin-Dependent Mitophagy

Autosomal-recessive early-onset parkinsonism is clinically and genetically heterogeneous. The genetic causes of approximately 50% of autosomal-recessive early-onset forms of Parkinson disease (PD) remain to be elucidated. Homozygozity mapping and exome sequencing in 62 isolated individuals with early-onset parkinsonism and confirmed consanguinity followed by data mining in the exomes of 1,348 PD-affected individuals identified, in three isolated subjects, homozygous or compound heterozygous truncating mutations in vacuolar protein sorting 13C (VPS13C). VPS13C mutations are associated with a distinct form of early-onset parkinsonism characterized by rapid and severe disease progression and early cognitive decline; the pathological features were striking and reminiscent of diffuse Lewy body disease. In cell models, VPS13C partly localized to the outer membrane of mitochondria. Silencing of VPS13C was associated with lower mitochondrial membrane potential, mitochondrial fragmentation, increased respiration rates, exacerbated PINK1/Parkin-dependent mitophagy, and transcriptional upregulation of PARK2 in response to mitochondrial damage. This work suggests that loss of function of VPS13C is a cause of autosomal-recessive early-onset parkinsonism with a distinctive phenotype of rapid and severe progression.

The interleukin 1 alpha, interleukin 1 beta, interleukin 6 and alpha-2-macroglobulin serum levels in patients with early or late onset Alzheimer's disease, mild cognitive impairment or Parkinson's disease

Alzheimers disease (EOAD, LOAD), mild cognitive impairment (MCI), Parkinsons disease (PD) and healthy controls were included to determine the serum interleukin-1s (IL-1α, IL-1β), IL-6 and alpha-2-macroglobulin (α2M) levels using ELISA. IL-6 might be a significant contributor to the inflammatory response in LOAD. The MCI data indicate that IL-1s, α2M and BDNF are somehow related, and this relationship might allow MCI patients to be more similar to the healthy controls. A correlation analysis of multiple biomarkers in different neurodegenerative disorders might be more useful than determining the levels of a single cytokine in a single disorder.

Exome sequencing reveals an unexpected genetic cause of disease: NOTCH3 mutation in a Turkish family with Alzheimer's disease

Alzheimers disease (AD) is a genetically complex disorder for which the definite diagnosis is only accomplished postmortem. Mutations in 3 genes (APP, PSEN1, and PSEN2) are known to cause AD, but a large number of familial cases do not harbor mutations in these genes and several unidentified genes that contain disease-causing mutations are thought to exist. We performed whole exome sequencing in a Turkish patient clinically diagnosed with Alzheimers disease from a consanguineous family with a complex history of neurological and immunological disorders and identified a mutation in NOTCH3 (p.R1231C), previously described as causing cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Complete screening of NOTCH3 in a cohort of 95 early onset AD cases and 95 controls did not reveal any additional pathogenic mutations. Although the complex history of disease in this family precluded us to establish segregation of the mutation found with disease, our results show that exome sequencing is a rapid, cost-effective and comprehensive tool to detect genetic mutations, allowing for the identification of unexpected genetic causes of clinical phenotypes. As etiological based therapeutics become more common, this method will be key in diagnosing and treating disease.

A novel compound heterozygous mutation in TREM2 found in a Turkish frontotemporal dementia-like family

Triggering receptor expressed on myeloid cells 2 (TREM2) homozygous mutations cause Nasu-Hakola disease, an early-onset recessive form of dementia preceded by bone cysts and fractures. The same type of mutations has recently been shown to cause frontotemporal dementia (FTD) without the presence of any bone phenotype. Here, we further confirm the association of TREM2 mutations with FTD-like phenotypes by reporting the first compound heterozygous mutation in a Turkish family.

The Prevalence of Dementia in an Urban Turkish Population

A cross-sectional, population-based, 2-stage prevalence study was conducted in a sample of 1019 community-dwelling persons over the age of 70 years living in Istanbul. In the first phase, participants were screened with the Mini-Mental State Examination for evidence of cognitive impairment. In the second phase, 79% of those who screened positive (n = 322) and 9% of screen-negatives (n = 63) underwent a standardized diagnostic workup. Diagnosis of dementia and Alzheimers disease (AD) was made according to established criteria. Ninety-three cases of dementia were identified, 58 of whom were diagnosed with probable AD. Based on these numbers, the prevalence rates of probable AD and dementia were calculated to be 11.0% (95% CI, 7.0% to 15.0%) and 20.0% (95% CI, 14.0% to 26.0%), respectively, in this population. Prevalence rates of dementia and AD in Istanbul, Turkey, are comparable with those seen in the Western world.

Risk factors for Alzheimer disease: a population-based case-control study in Istanbul, Turkey.

The objective is to study risk factors for Alzheimer disease (AD) in Istanbul, Turkey. This is a population-based case-control study. We screened people over age 70 in the community for cognitive impairment. The screen positives and a proportion of screen negatives underwent neurologic examination in the second phase. Cases were 57 “probable” AD patients and controls were 127 cognitively normal individuals identified by neurologic examination. Odds ratios (OR) were calculated using multivariate logistic regression analysis. Having a university/college degree had a protective effect on AD risk (OR = 0.10, 95% confidence interval [CI] = 0.02–0.50). Exposure to occupational electromagnetic field had an OR of 4.02 (95% CI = 1.02–15.78). Use of electricity for residential heating also showed elevated risk (OR = 2.77, 95% CI = 1.12–6.85). Our results suggest that having a higher education is protective from AD and that electromagnetic field exposure at work or at home is a significant risk factor.

BDNF, TNFα, HSP90, CFH, and IL-10 Serum Levels in Patients with Early or Late Onset Alzheimer's Disease or Mild Cognitive Impairment

Identifying early-detection biomarkers have become an increasingly important approach in the treatment and prevention of Alzheimers disease (AD). In this study, we investigated the potential of brain-derived neurotrophic factor (BDNF), complement factor H (CFH), tumor necrosis factor-α (TNFα), interleukin 10 (IL-10), and heat shock protein 90 (Hsp90) as serum biomarkers for AD in a cohort of the Turkish population because they have been suggested to be associated with AD. Serum BDNF, CFH, TNFα, IL-10, and Hsp90 levels in three groups of patients, early-onset AD (EOAD; age of onset < 65; n = 22), late-onset AD (LOAD; age of onset > 65; n = 54), and mild cognitive impairment (MCI) (n = 30), were compared with age-matched healthy controls (age < 65, n = 18 and age > 65; n = 32) using ELISA. The serum BDNF levels significantly decreased and TNFα levels significantly increased in the EOAD and LOAD groups compared to the age-matched healthy controls. There was a correlation between serum TNFα and IL-10 levels in the LOAD and healthy control groups. Serum CFH levels in the LOAD and MCI patients were significantly decreased compared with controls. Serum Hsp90 levels in the EOAD, LOAD, and MCI patients were significantly decreased compared with controls. The protein misfolding, the inflammatory response, and decreased neurotrophic factor synthesis are all suggested to be related to AD type brain pathology, and our results indicate these alterations might be traced from serum samples. For accurate early diagnosis of AD, it is important to determine a profile of alterations in multiple biomarkers in large-scale population studies.

The distinct genetic pattern of ALS in Turkey and novel mutations

The frequency of amyotrophic lateral sclerosis (ALS) mutations has been extensively investigated in several populations; however, a systematic analysis in Turkish cases has not been reported so far. In this study, we screened 477 ALS patients for mutations, including 116 familial ALS patients from 82 families and 361 sporadic ALS (sALS) cases. Patients were genotyped for C9orf72 (18.3%), SOD1 (12.2%), FUS (5%), TARDBP (3.7%), and UBQLN2 (2.4%) gene mutations, which together account for approximately 40% of familial ALS in Turkey. No SOD1 mutations were detected in sALS patients; however, C9orf72 (3.1%) and UBQLN2 (0.6%) explained 3.7% of sALS in the population. Exome sequencing revealed mutations in OPTN, SPG11, DJ1, PLEKHG5, SYNE1, TRPM7, and SQSTM1 genes, many of them novel. The spectrum of mutations reflect both the distinct genetic background and the heterogeneous nature of the Turkish ALS population.

Cognitive impairment and dementia in Parkinson's disease: practical issues and management.

Cognitive impairment and dementia pose particular challenges in the management of patients with Parkinsons disease (PD). Decision‐making capacity can render patients vulnerable in a way that requires careful ethical considerations by clinicians with respect to medical decision making, research participation, and public safety. Clinicians should discuss how future decisions will be made as early in the disease course as possible. Because of cognitive, visual, and motor impairments, PD may be associated with unsafe driving, leading to early driving cessation in many. DBS of the STN and, to a lesser degree, globus pallidus interna (GPi) has consistently been associated with decreased verbal fluency, but significant global cognitive decline is usually not observed in patients who undergo rigorous selection. There are some observations suggesting lesser cognitive decline in GPi DBS than STN DBS, but further research is required. Management of PD dementia (PDD) patients involves both pharmacological and nonpharmacological measures. Patients with PDD should be offered treatment with a cholinesterase inhibitor taking into account expected benefits and potential risks. Treatment with neuroleptics may be necessary to treat psychosis; classical neuroleptics, as well as risperidone and olanzapine, should be avoided. Quetiapine might be considered first‐line treatment because it does not need special monitoring, although the strongest evidence for efficacy exists for clozapine. Evidence from randomized, controlled studies in the PDD population is lacking; selective serotonin reuptake inhibitors or serotonin‐norepinephrine reuptake inhibitors may be used to treat depressive features. Clonazepam or melatonin may be useful in the treatment of rapid eye movement behavior disorder.