NEWS FROM THE WORLD- Sex differences in the prevalence of genetic mutations in FTD and ALS A meta-analysis

ABSTRACT

Objective: To conduct a meta-analysis that investigates sex differences in the prevalence of mutations in the 3 most common genes that cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD)—chromosome 9 open reading frame 72 (C9orf72), progranulin (GRN), or microtubule-associated protein tau (MAPT)—in patients clinically diagnosed with these conditions.

Methods: MEDLINE, EMBASE, and PsycINFO databases were searched (inception to June 30, 2016). Studies of patients with FTD or ALS that reported the number of men and women with and without mutations of interest were selected. Female to male pooled risk ratios (RR) and 95% confidence intervals (CI) for each mutation were calculated using random-effects models.

Results: Thirty-two articles reporting 12,784 patients with ALS (including 1,244 C9orf72 mutation carriers) revealed a higher prevalence of female patients with C9orf72-related ALS (RR 1.16, 95% CI 1.04–1.29). Twenty-three articles reporting 5,320 patients with FTD (including 488 C9orf72 mutation carriers) revealed no sex differences in C9orf72-related FTD (RR 0.95, 95% CI 0.81–1.12). Thirty-six articles reporting 3,857 patients with FTD (including 369 GRNmutation carriers) revealed a higher prevalence of female patients with GRN-related FTD (RR 1.33, 95% CI 1.09–1.62). Finally, 21 articles reporting 2,377 patients with FTD (including 215 MAPT mutation carriers) revealed no sex difference in MAPT-related FTD (RR 1.21, 95% CI 0.95–1.55).

Conclusions: Higher female prevalence of C9orf72 hexanucleotide repeat expansions in ALS and GRN mutations in FTD suggest that sex-related risk factors might moderate C9orf72 and GRN-mediated phenotypic expression.

Neurology 2017

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MicroRNA-137 and microRNA-195* inhibit vasculogenesis in brain arteriovenous malformations

Abstract

Objective

Brain arteriovenous malformations (AVMs) are the most common cause of nontraumatic intracerebral hemorrhage in young adults. The genesis of brain AVM remains enigmatic. We investigated microRNA (miRNA) expression and its contribution to the pathogenesis of brain AVMs.

Methods

We used a large-scale miRNA analysis of 16 samples including AVMs, hemangioblastoma, and controls to identify a distinct AVM miRNA signature. AVM smooth muscle cells (AVMSMCs) were isolated and identified by flow cytometry and immunohistochemistry, and candidate miRNAs were then tested in these cells. Migration, tube formation, and CCK-8–induced proliferation assays were used to test the effect of the miRNAs on phenotypic properties of AVMSMCs. A quantitative proteomics approach was used to identify protein expression changes in AVMSMCs treated with miRNA mimics.

Results

A distinct AVM miRNA signature comprising a large portion of lowly expressed miRNAs was identified. Among these miRNAs, miR-137 and miR-195* levels were significantly decreased in AVMs and constituent AVMSMCs. Experimentally elevating the level of these microRNAs inhibited AVMSMC migration, tube formation, and survival in vitro and the formation of vascular rings in vivo. Proteomics showed the protein expression signature of AVMSMCs and identified downstream proteins regulated by miR-137 and miR-195* that were key signaling proteins involved in vessel development.

Interpretation

Our results indicate that miR-137 and miR-195* act as vasculogenic suppressors in AVMs by altering phenotypic properties of AVMSMCs, and that the absence of miR-137 and miR-195* expression leads to abnormal vasculogenesis. 

Ann Neurol 2017

Brain imaging tests for chronic pain: medical, legal and ethical issues and recommendations

Chronic pain is the greatest source of disability globally and claims related to chronic pain feature in many insurance and medico-legal cases. Brain imaging (for example, functional MRI, PET, EEG and magnetoencephalography) is widely considered to have potential for diagnosis, prognostication, and prediction of treatment outcome in patients with chronic pain. In this Consensus Statement, a presidential task force of the International Association for the Study of Pain examines the capabilities of brain imaging in the diagnosis of chronic pain, and the ethical and legal implications of its use in this way. The task force emphasizes that the use of brain imaging in this context is in a discovery phase, but has the potential to increase our understanding of the neural underpinnings of chronic pain, inform the development of therapeutic agents, and predict treatment outcomes for use in personalized pain management. The task force proposes standards of evidence that must be satisfied before any brain imaging measure can be considered suitable for clinical or legal purposes. The admissibility of such evidence in legal cases also strongly depends on laws that vary between jurisdictions. For these reasons, the task force concludes that the use of brain imaging findings to support or dispute a claim of chronic pain — effectively as a pain lie detector — is not warranted, but that imaging should be used to further our understanding of the mechanisms underlying pain.

Nature Reviews Neurology 2017

Tuberculous meningitis

Tuberculosis remains a global health problem, with an estimated 10.4 million cases and 1.8 million deaths resulting from the disease in 2015. The most lethal and disabling form of tuberculosis is tuberculous meningitis (TBM), for which more than 100,000 new cases are estimated to occur per year. In patients who are co-infected with HIV-1, TBM has a mortality approaching 50%. Study of TBM pathogenesis is hampered by a lack of experimental models that recapitulate all the features of the human disease. Diagnosis of TBM is often delayed by the insensitive and lengthy culture technique required for disease confirmation. Antibiotic regimens for TBM are based on those used to treat pulmonary tuberculosis, which probably results in suboptimal drug levels in the cerebrospinal fluid, owing to poor blood–brain barrier penetrance. The role of adjunctive anti-inflammatory, host-directed therapies — including corticosteroids, aspirin and thalidomide — has not been extensively explored. To address this deficit, two expert meetings were held in 2009 and 2015 to share findings and define research priorities. This Review summarizes historical and current research into TBM and identifies important gaps in our knowledge. We will discuss advances in the understanding of inflammation in TBM and its potential modulation; vascular and hypoxia-mediated tissue injury; the role of intensified antibiotic treatment; and the importance of rapid and accurate diagnostics and supportive care in TBM.

Nature Reviews Neurology 2017

Trends in Dementia Incidence in a Birth Cohort Analysis of the Einstein Aging Study

Abstract

Importance  Trends in dementia incidence rates have important implications for planning and prevention. To better understand incidence trends over time requires separation of age and cohort effects, and few prior studies have used this approach.

Objectives  To examine trends in dementia incidence and concomitant trends in cardiovascular comorbidities among individuals aged 70 years or older who were enrolled in the Einstein Aging Study between 1993 and 2015.

Design, Setting, and Participants  In this birth cohort analysis of all-cause dementia incidence in persons enrolled in the Einstein Aging Study from October 20, 1993, through November 17, 2015, a systematically recruited, population-based sample of 1348 participants from Bronx County, New York, who were 70 years or older without dementia at enrollment and at least one annual follow-up was studied. Poisson regression was used to model dementia incidence as a function of age, sex, educational level, race, and birth cohort, with profile likelihood used to identify the timing of significant increases or decreases in incidence.

Exposures  Birth year and age.

Main Outcomes and Measures  Incident dementia defined by consensus case conference based on annual, standardized neuropsychological and neurologic examination findings, using criteria from the DSM-IV.

Results  Among 1348 individuals (mean [SD] baseline age, 78.5 [5.4] years; 830 [61.6%] female; 915 [67.9%] non-Hispanic white), 150 incident dementia cases developed during 5932 person-years (mean [SD] follow-up, 4.4 [3.4] years). Dementia incidence decreased in successive birth cohorts. Incidence per 100 person-years was 5.09 in birth cohorts before 1920, 3.11 in the 1920 through 1924 birth cohorts, 1.73 in the 1925 through 1929 birth cohorts, and 0.23 in cohorts born after 1929. Change point analyses identified a significant decrease in dementia incidence among those born after July 1929 (95% CI, June 1929 to January 1930). The relative rate for birth cohorts before July 1929 vs after was 0.13 (95% CI, 0.04-0.41). Prevalence of stroke and myocardial infarction decreased across successive birth cohorts, whereas diabetes prevalence increased. Adjustment for these cardiovascular comorbidities did not explain the decreased dementia incidence rates for more recent birth cohorts.

Conclusions and Relevance  Analyses confirm decreasing dementia incidence in this population-based sample. Whether decreasing incidence will contribute to reduced burden of dementia given the aging of the population is not known.

JAMA Neurology 2017

Neurological Complications Associated With Anti–Programmed Death 1 (PD-1) Antibodies

Abstract

Importance  Neurological complications are an increasingly recognized consequence of the use of anti–programmed death 1 (PD-1) antibodies in the treatment of solid-organ tumors, with an estimated frequency of 4.2%. To date, the clinical spectrum and optimum treatment approach are not established.

Objective  To investigate the frequency, clinical spectrum, and optimum treatment approach to neurological complications associated with anti–PD-1 therapy.

Design, Setting, and Participants  This single-center, retrospective cohort study was conducted from either September or December 2014 (the approval dates of the study drugs by the US Food and Drug Administration) to May 19, 2016. All patients receiving anti–PD-1 monoclonal antibodies were identified using the Mayo Cancer Pharmacy Database. Patients with development of neurological symptoms within 12 months of anti–PD-1 therapy were included. Patients with neurological complications directly attributable to metastatic disease or other concurrent cancer-related treatments were excluded.

Main Outcomes and Measures  Clinical and pathological characteristics, time to development of neurological symptoms, and modified Rankin Scale (mRS) score.

Results  Among 347 patients treated with anti–PD1 monoclonal antibodies (pembrolizumab or nivolumab), 10 (2.9%) developed subacute onset of neurological complications. Seven patients were receiving pembrolizumab, and 3 patients were receiving nivolumab. The patients included 8 men and 2 women. Their median age was 71 years (age range, 31-78 years). Neurological complications occurred after a median of 5.5 (range, 1-20) cycles of anti–PD-1 inhibitors. Complications included myopathy (n = 2), varied neuropathies (n = 4), cerebellar ataxia (n = 1), autoimmune retinopathy (n = 1), bilateral internuclear ophthalmoplegia (n = 1), and headache (n = 1). Peripheral neuropathies included axonal and demyelinating polyradiculoneuropathies (n = 2), length-dependent neuropathies (n = 1), and asymmetric vasculitic neuropathy (n = 1). The time to maximum symptom severity varied from 1 day to more than 3 months. The median mRS score was 2.5 (range, 1-5), indicating mild to moderate disability. Five patients experienced other systemic immune-mediated complications, including hypothyroidism (n = 3), colitis (n = 2), and hepatitis (n = 1). Treatment with anti–PD-1 antibodies was discontinued in all patients. Treatment included corticosteroids (n = 7), intravenous immunoglobulin (n = 3), and plasma exchange (n = 1). Nine patients improved, with a median mRS score of 2 (range, 0-6). One patient with severe necrotizing myopathy died.

Conclusions and Relevance  Neurological adverse events associated with anti–PD-1 therapy have a diverse phenotype, with more frequent neuromuscular complications. Although rare, they will likely be encountered with increasing frequency as anti–PD-1 therapy expands to other cancers. The time of onset is unpredictable, and evolution may be rapid and life-threatening. Prompt recognition and discontinuation of anti–PD-1 therapy is recommended. In some cases, immune rescue treatment may be required.

JAMA Neurology 2017

Mutations of AKT3 are associated with a wide spectrum of developmental disorders including extreme megalencephaly

Abstract

Mutations of genes within the phosphatidylinositol-3-kinase (PI3K)-AKT-MTOR pathway are well known causes of brain overgrowth (megalencephaly) as well as segmental cortical dysplasia (such as hemimegalencephaly, focal cortical dysplasia and polymicrogyria). Mutations of the AKT3 gene have been reported in a few individuals with brain malformations, to date. Therefore, our understanding regarding the clinical and molecular spectrum associated with mutations of this critical gene is limited, with no clear genotype–phenotype correlations. We sought to further delineate this spectrum, study levels of mosaicism and identify genotype–phenotype correlations of AKT3-related disorders. We performed targeted sequencing of AKT3 on individuals with these phenotypes by molecular inversion probes and/or Sanger sequencing to determine the type and level of mosaicism of mutations. We analysed all clinical and brain imaging data of mutation-positive individuals including neuropathological analysis in one instance. We performed ex vivo kinase assays on AKT3 engineered with the patient mutations and examined the phospholipid binding profile of pleckstrin homology domain localizing mutations. We identified 14 new individuals with AKT3mutations with several phenotypes dependent on the type of mutation and level of mosaicism. Our comprehensive clinical characterization, and review of all previously published patients, broadly segregates individuals with AKT3 mutations into two groups: patients with highly asymmetric cortical dysplasia caused by the common p.E17K mutation, and patients with constitutional AKT3 mutations exhibiting more variable phenotypes including bilateral cortical malformations, polymicrogyria, periventricular nodular heterotopia and diffuse megalencephaly without cortical dysplasia. All mutations increased kinase activity, and pleckstrin homology domain mutants exhibited enhanced phospholipid binding. Overall, our study shows that activating mutations of the critical AKT3 gene are associated with a wide spectrum of brain involvement ranging from focal or segmental brain malformations (such as hemimegalencephaly and polymicrogyria) predominantly due to mosaic AKT3 mutations, to diffuse bilateral cortical malformations, megalencephaly and heterotopia due to constitutional AKT3 mutations. We also provide the first detailed neuropathological examination of a child with extreme megalencephaly due to a constitutional AKT3 mutation. This child has one of the largest documented paediatric brain sizes, to our knowledge. Finally, our data show that constitutional AKT3mutations are associated with megalencephaly, with or without autism, similar to PTEN-related disorders. Recognition of this broad clinical and molecular spectrum of AKT3 mutations is important for providing early diagnosis and appropriate management of affected individuals, and will facilitate targeted design of future human clinical trials using PI3K-AKT pathway inhibitors.

Brain 2017