Hasmet Hanagasi

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.

Early-onset L-dopa-responsive Parkinsonism with pyramidal signs due to ATP13A2, PLA2G6, FBXO7 and Spatacsin mutations

Seven autosomal recessive genes associated with juvenile and young‐onset Levodopa‐responsive parkinsonism have been identified. Mutations in PRKN, DJ‐1, and PINK1 are associated with a rather pure parkinsonian phenotype, and have a more benign course with sustained treatment response and absence of dementia. On the other hand, Kufor‐Rakeb syndrome has additional signs, which distinguish it clearly from Parkinsons disease including supranuclear vertical gaze palsy, myoclonic jerks, pyramidal signs, and cognitive impairment. Neurodegeneration with brain iron accumulation type I (Hallervorden‐Spatz syndrome) due to mutations in PANK2 gene may share similar features with Kufor‐Rakeb syndrome. Mutations in three other genes, PLA2G6 (PARK14), FBXO7 (PARK15), and Spatacsin (SPG11) also produce clinical similar phenotypes in that they presented with rapidly progressive parkinsonism, initially responsive to Levodopa treatment but later, developed additional features including cognitive decline and loss of Levodopa responsiveness. Here, using homozygosity mapping and sequence analysis in families with complex parkinsonisms, we identified genetic defects in the ATP13A2 (1 family), PLA2G6 (1 family) FBXO7 (2 families), and SPG11 (1 family). The genetic heterogeneity was surprising given their initially common clinical features. On careful review, we found the FBXO7 cases to have a phenotype more similar to PRKN gene associated parkinsonism. The ATP13A2 and PLA2G6 cases were more seriously disabled with additional swallowing problems, dystonic features, severe in some, and usually pyramidal involvement including pyramidal weakness. These data suggest that these four genes account for many cases of Levodopa responsive parkinsonism with pyramidal signs cases formerly categorized clinically as pallido‐pyramidal syndrome.

Cognitive impairment in amyotrophic lateral sclerosis: evidence from neuropsychological investigation and event-related potentials

The presence of subclinical cognitive impairment in patients with amyotrophic lateral sclerosis (ALS) is investigated using neuropsychological assessment and event-related potential recordings (ERP). An extensive battery of neuropsychological tests assessing the domains of attention, memory, language, visuo-spatial and executive functions were administered to 20 non-demented patients with sporadic ALS and 13 age- and education-matched healthy control subjects. Mismatch negativity (MMN), P3b, P3a (novelty P300) and contingent negative variation (CNV) were recorded. ALS patients were significantly impaired in tests of working memory, sustained attention, response inhibition, naming, verbal fluency and complex visuo-spatial processing. The memory impairment seemed to be secondary to deficits in forming learning strategies and retrieval. In ERP recordings, P3a and P3b amplitudes of ALS patients were lower compared with the controls, P3a latencies were significantly longer and mean CNV amplitudes were higher. These results indicate subclinical impairment of cognitive functions in patients with ALS. The pattern of cognitive impairment suggests the dysfunction of the frontal network.

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.

The effects of rasagiline on cognitive deficits in Parkinson's disease patients without dementia: A randomized, double-blind, placebo-controlled, multicenter study

Cognitive impairment can occur at all stages of Parkinsons disease. Rasagiline is a selective monoamine oxidase type‐B inhibitor that enhances central dopaminergic transmission. Dopamine is thought to be involved in certain cognitive processes such as working memory. We assessed the effects of rasagiline on cognitive deficits in cognitively impaired, nondemented patients with Parkinsons disease. This was a randomized, double‐blind, placebo‐controlled prospective study. Patients with Parkinsons disease receiving stable dopaminergic treatment were assigned to receive rasagiline 1 mg/day or placebo for 3 months. Patients were eligible if they had impairment in 2 of 4 cognitive domains (attention, executive functions, memory, visuospatial functions) in the screening neuropsychological tests, yet did not fulfill criteria for Parkinsons disease dementia. Fifty‐five patients were randomized; 48 patients completed the study. Patients in the rasagiline group showed significant improvement in digit span–backward compared with the placebo group (P = .04), with trends favoring rasagiline in digit span total and digit‐ordering tests. Verbal fluency total score showed a significant difference in favor of rasagiline (P = .038), with trends favoring rasagiline in semantic fluency test and Stroop spontaneous corrections. The composite cognitive domain Z scores revealed a significant difference in favor of rasagiline compared with placebo in the attentional Z score (P < .005). There were no significant differences between the 2 groups in the other cognitive tests or cognitive domain Z scores. The monoamine oxidase type‐B inhibitor rasagiline may exert beneficial effects on certain aspects of attention and executive functions in nondemented patients with Parkinsons disease with cognitive impairment.

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.

Pain is common in Parkinson's disease

OBJECTIVE AND BACKGROUND Patients with Parkinsons disease may present with severe or intractable pain, which can be more distressing than the motor disability. The aim of this prospective study was to assess the prevalence of pain and underlying causes in patients with idiopathic Parkinsons disease. PATIENTS AND METHODS Ninety-six patients (42 female, 54 men) were interviewed and pain was assessed using patient descriptions, Visual Analog Scale (VAS) and Leeds Assessment of Neuropathic Symptoms and Signs (LANSS). Stait Trait Anxiety Inventory (STAI-TX 1 and 2) and Beck Depression Scale were also administered. RESULTS Pain as the first symptom of PD was seen in 3 patients (2.8%), 63 (64.9%) out of 96 patients reported pain. Pain types included musculoskeletal type of different etiologies (28 patients, 44.4%), radicular or neuropathic pain (7 patients, 11.1%), pain secondary to dystonia (12 patients, 19.1%) and central pain (8 patients, 12.7%). Eight patients (12.7%) described more than one type of pain. Pain did not correlate with sex, duration of disease, disease stage, use of dopamine agonists and levodopa, years of levodopa treatment and current levodopa dosage, depression, anxiety, sleep disturbances, age at onset of PD or history of disease in first-degree relatives. Akathisia seemed to be correlated with presence of pain (p<0.02). CONCLUSIONS Our results suggest that pain is one of the most common non-motor symptoms in patients with PD. In order to identify the appropriate treatment strategy, it is essential to identify the underlying etiology.

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.