Hakan Gurvit

TREM2 mutations implicated in neurodegeneration impair cell surface transport and phagocytosis

Loss of TREM2 function impairs phagocytosis and correlates with decreased soluble TREM2 in biological fluids of patients with neurodegenerative disorders. TREM2 and Neurodegeneration Little is known about how risk factors facilitate initiation and propagation of neurodegenerative disorders. Rare mutations in TREM2 increase the risk for several neurodegenerative disorders including Alzheimer’s disease (AD), Parkinson’s disease, and frontotemporal dementia (FTD). Kleinberger et al. now show that mutations associated with neurodegenerative diseases interfere with TREM2 function by preventing its maturation, transport to the cell surface, and shedding. Expression of mutant TREM2 led to reduced phagocytic activity by different cell types, suggesting that removal of cellular debris by, for example, microglia in the brain might be affected in patients with TREM2 mutations. In a patient with FTD-like syndrome carrying a homozygous TREM2 mutation, no soluble TREM2 was detected in the cerebrospinal fluid (CSF) and plasma. Patients with sporadic FTD and AD showed slightly reduced concentrations of soluble TREM2 in their CSF. Although much further testing and validation are needed, soluble TREM2 might be useful as a marker of neurodegeneration. Genetic variants in the triggering receptor expressed on myeloid cells 2 (TREM2) have been linked to Nasu-Hakola disease, Alzheimer’s disease (AD), Parkinson’s disease, amyotrophic lateral sclerosis, frontotemporal dementia (FTD), and FTD-like syndrome without bone involvement. TREM2 is an innate immune receptor preferentially expressed by microglia and is involved in inflammation and phagocytosis. Whether and how TREM2 missense mutations affect TREM2 function is unclear. We report that missense mutations associated with FTD and FTD-like syndrome reduce TREM2 maturation, abolish shedding by ADAM proteases, and impair the phagocytic activity of TREM2-expressing cells. As a consequence of reduced shedding, TREM2 is virtually absent in the cerebrospinal fluid (CSF) and plasma of a patient with FTD-like syndrome. A decrease in soluble TREM2 was also observed in the CSF of patients with AD and FTD, further suggesting that reduced TREM2 function may contribute to increased risk for two neurodegenerative disorders.

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.

EFNS-ENS Guidelines on the diagnosis and management of disorders associated with dementia

The last version of the EFNS dementia guidelines is from 2007. In 2010, the revised guidelines for Alzheimers disease (AD) were published. The current guidelines involve the revision of the dementia syndromes outside of AD, notably vascular cognitive impairment, frontotemporal lobar degeneration, dementia with Lewy bodies, corticobasal syndrome, progressive supranuclear palsy, Parkinsons disease dementia, Huntingtons disease, prion diseases, normal‐pressure hydrocephalus, limbic encephalitis and other toxic and metabolic disorders. The aim is to present a peer‐reviewed evidence‐based statement for the guidance of practice for clinical neurologists, geriatricians, psychiatrists and other specialist physicians responsible for the care of patients with dementing disorders. It represents a statement of minimum desirable standards for practice guidance.

Comparative analysis of event-related potentials during Go/NoGo and CPT: Decomposition of electrophysiological markers of response inhibition and sustained attention

Neuropsychological tests target specific cognitive functions; however, numerous cognitive subcomponents are involved in each test. The aim of this study was to decompose the components of two frontal executive function tests, Go/NoGo (GNG) and cued continuous performance task (CPT), by analyzing event-related potentials (ERPs) of 24 subjects both in time and time-frequency domains. In the time domain, P1, N1, P2, N2 and P3 peak amplitudes and latencies and mean amplitudes of 100 ms time windows of the post-P3 time period were measured. For GNG, the N1 amplitude and for both GNG and CPT N2 amplitudes were significantly higher in the NoGo condition compared with the Go condition. P3 had a central maximum in the NoGo conditions of both paradigms in contrast to a parietal maximum in the Go conditions. All peaks except P1 and mean amplitudes of the post-P3 period were more positive in CPT compared to those of GNG. N1, N2 and P3 latencies were longer for the NoGo condition than the Go condition in the CPT. In time-frequency analyses, the NoGo condition evoked higher theta coefficients than the Go condition, whereas the CPT and GNG paradigms differed mainly in the delta band. These results suggest that theta component reflects response inhibition in both GNG and CPT, whereas delta component reflects the more demanding sustained attention requirement of the CPT. The latency prolongation observed with the NoGo condition of the CPT paradigm was thought to be due to perseverance/inhibition conflict enhanced by the primer stimuli in CPT.

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.