Neuroinflammatory component of gray matter pathology in multiple sclerosis

Abstract

Objective

In multiple sclerosis (MS), using simultaneous magnetic resonance–positron emission tomography (MR-PET) imaging with 11C-PBR28, we quantified expression of the 18kDa translocator protein (TSPO), a marker of activated microglia/macrophages, in cortex, cortical lesions, deep gray matter (GM), white matter (WM) lesions, and normal-appearing WM (NAWM) to investigate the in vivo pathological and clinical relevance of neuroinflammation.

Methods

Fifteen secondary-progressive MS (SPMS) patients, 12 relapsing–remitting MS (RRMS) patients, and 14 matched healthy controls underwent 11C-PBR28 MR-PET. MS subjects underwent 7T -weighted imaging for cortical lesion segmentation, and neurological and cognitive evaluation. 11C-PBR28 binding was measured using normalized 60- to 90-minute standardized uptake values and volume of distribution ratios.

Results

Relative to controls, MS subjects exhibited abnormally high 11C-PBR28 binding across the brain, the greatest increases being in cortex and cortical lesions, thalamus, hippocampus, and NAWM. MS WM lesions showed relatively modest TSPO increases. With the exception of cortical lesions, where TSPO expression was similar, 11C-PBR28 uptake across the brain was greater in SPMS than in RRMS. In MS, increased 11C-PBR28 binding in cortex, deep GM, and NAWM correlated with neurological disability and impaired cognitive performance; cortical thinning correlated with increased thalamic TSPO levels.

Interpretation

In MS, neuroinflammation is present in the cortex, cortical lesions, deep GM, and NAWM, is closely linked to poor clinical outcome, and is at least partly linked to neurodegeneration. Distinct inflammatory-mediated factors may underlie accumulation of cortical and WM lesions. Quantification of TSPO levels in MS could prove to be a sensitive tool for evaluating in vivo the inflammatory component of GM pathology, particularly in cortical lesions. 

Ann Neurol 2016

Risk of Pregnancy-Associated Stroke Across Age Groups in New York State

Key Points

Question  Does pregnancy increase stroke risk in older women of childbearing age?

Findings  In this population-based study in New York State, age-stratified incidence risk ratios were calculated to determine the stroke risk during pregnancy or post partum, compared with stroke risk in similarly aged nonpregnant women. Stroke risk was more than doubled in women aged 12 to 24 years and increased significantly by 60% in women 25 to 34 years during pregnancy or post partum; there was no difference in stroke risk in women 35 years or older.

Meaning  Pregnancy does not increase stroke risk in older women but does increase stroke risk in younger women.

Abstract

Importance  Older age is associated with increased risk of pregnancy-associated stroke (PAS). Data are limited on age-specific incidence ratios of PAS compared with stroke risk in nonpregnant women.

Objectives  To assess the risk of stroke by age group in pregnant and postpartum women compared with their nonpregnant contemporaries and to compare risk factors across age groups in the exposed (pregnant/postpartum) and unexposed (nonpregnant) populations.

Design, Setting, and Participants  International Classification of Diseases, Ninth Revision, billing codes from the calendar year 2003-2012 New York State Department of Health inpatient database and population data were used to identify all women aged 12 to 55 years with cerebrovascular events, including transient ischemic attack, ischemic and hemorrhagic stroke, cerebral venous thrombosis, and nonspecified PAS. The cumulative incidence of PAS per 100 000 pregnant/postpartum women vs nonpregnancy-associated stroke (NPAS) per 100 000 women in age cohorts of 24 years or younger, 25 to 34, 35 to 44, and 45 years or older was calculated. Risk factors between groups were compared using logistic regression models. The study included data from calendar years 2003 through 2012. Data analysis was performed from July 11, 2015, to July 16, 2016.

Exposures  Pregnancy, including the postpartum period up to 6 weeks after delivery.

Main Outcomes and Measures  Incidence risk ratios (IRRs) for stroke per age cohort, defined as cumulative risk of stroke in the exposed population divided by cumulative risk of stroke in the unexposed population, were determined, and stroke risk factors and mortality were compared between populations.

Results  There were 19 146 women hospitalized with stroke during the study period; 797 of the women were pregnant/post partum. The overall median (interquartile range) age of the women was 31 (25-35) years in those with PAS and 48 (41-52) years in those with NPAS. The incidence of PAS in women aged 12 to 24 years was 14 events per 100 000 pregnant/postpartum women vs NPAS incidence of 6.4 per 100 000 nonpregnant women (IRR, 2.2; 95% CI, 1.9-2.6); for ages 25 to 34 years, 21.2 per 100 000 vs 13.5 per 100 000 (IRR, 1.6; 95% CI, 1.4-1.7); for ages 35 to 44 years, 33 per 100 000 vs 31 per 100 000 (IRR, 1.1; 95% CI, 0.9-1.2); and for ages 45 to 55 years, 46.9 per 100 000 vs 73.7 per 100 000 (IRR, 0.6; 95% CI, 0.3-1.4). PAS accounted for 18% of strokes in women younger than 35 years vs 1.4% of strokes in women aged 35 to 55 years. Women in the NPAS group vs the PAS group had more vascular risk factors, including chronic hypertension (age <35 years: 437 [15.7%] vs 60 [9.8%], P < .001; age 35-55 years: 7573 [48.6%] vs 36 [19.3%], P < .001), diabetes (age <35 years: 103 [3.7%] vs 9 [1.5%], P = .002; age 35-55 years: 2618 [16.8%] vs 12 [6.4%], P < .001), and active smoking (age <35 years: 315 [11.3%] vs 29 [4.8%], P < .001; age 35-55 years: 2789 [17.9%] vs 10 [5.3%], P < .001); and had higher mortality (age <35 years: 288 [11.3%] vs 37 [6.5%], P < .001; age 35-55 years: 2121 [13.4%] vs 14 [6.1%], P < .001).

Conclusions and Relevance  Younger women, but not older women, have an increased stroke risk during pregnancy and post partum compared with their nonpregnant contemporaries. These results suggest that pregnancy does not increase the risk of stroke in older women.

JAMA Neurology 2016

Analysis of Mutations in AARS2 in a Series of CSF1R-Negative Patients With Adult-Onset Leukoencephalopathy With Axonal Spheroids and Pigmented Glia

Key Points

Question  What is the genetic cause of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) in patients with typical features who are negative for mutations in the CSF1R(colony-stimulating factor 1) gene?

Findings  In this case series study, using focused exome sequencing, bilallelic mutations in the AARS2(alanyl-transfer [t]RNA synthetase 2) gene were identified in 5 patients with typical clinical, radiologic, and pathologic features of ALSP. Frameshifting and splice site mutations were common.

Meaning  Screening the AARS2 gene should be considered in all patients with adult-onset leukodystrophy with clinical or radiologic features suggesting ALSP.

Abstract

Importance  Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a frequent cause of adult-onset leukodystrophy known to be caused by autosomal dominant mutations in the CSF1R (colony-stimulating factor 1) gene. The discovery that CSF1R mutations cause ALSP led to more accurate prognosis and genetic counseling for these patients in addition to increased interest in microglia as a target in neurodegeneration. However, it has been known since the discovery of the CSF1R gene that there are patients with typical clinical and radiologic evidence of ALSP who do not carry pathogenic CSF1R mutations. These patients include those in whom the pathognomonic features of axonal spheroids and pigmented microglia have been found. Achieving a genetic diagnosis in these patients is important to our understanding of this disorder.

Objective  To genetically characterize a group of patients with typical features of ALSP who do not carry CSF1R mutations.

Design, Settings, and Participants  In this case series study, 5 patients from 4 families were identified with clinical, radiologic, or pathologic features of ALSP in whom CSF1R mutations had been excluded previously by sequencing. Data were collected between May 2014 and September 2015 and analyzed between September 2015 and February 2016.

Main Outcomes and Measures  Focused exome sequencing was used to identify candidate variants. Family studies, long-range polymerase chain reaction with cloning, and complementary DNA sequencing were used to confirm pathogenicity.

Results  Of these 5 patients, 4 were men (80%); mean age at onset of ALSP was 29 years (range, 15-44 years). Biallelic mutations in the alanyl-transfer (t)RNA synthetase 2 (AARS2) gene were found in all 5 patients. Frameshifting and splice site mutations were common, found in 4 of 5 patients, and sequencing of complementary DNA from affected patients confirmed that the variants were loss of function. All patients presented in adulthood with prominent cognitive, neuropsychiatric, and upper motor neuron signs. Magnetic resonance imaging in all patients demonstrated a symmetric leukoencephalopathy with punctate regions of restricted diffusion, typical of ALSP. In 1 patient, brain biopsy demonstrated axonal spheroids and pigmented microglia, which are the pathognomonic signs of ALSP.

Conclusions and Relevance  This work indicates that mutations in the tRNA synthetase AARS2 gene cause a recessive form of ALSP. The CSF1R and AARS2 proteins have different cellular functions but overlap in a final common pathway of neurodegeneration. This work points to novel targets for research and will lead to improved diagnostic rates in patients with adult-onset leukoencephalopathy.

JAMA Neurology 2016

Association Between Dietary Intake and Function in Amyotrophic Lateral Sclerosis

Key Points

Question  What is the association between nutrient intake and amyotrophic lateral sclerosis function and respiratory function at diagnosis?

Findings  In this cross-sectional analysis of a multicenter cohort of 302 patients with amyotrophic lateral sclerosis, antioxidants, carotenes, fruits, and vegetables were associated with higher amyotrophic lateral sclerosis function at baseline.

Meaning  Nutritional care of the patient with amyotrophic lateral sclerosis should include promotion of foods high in antioxidants and carotenes, including fruits and vegetables.

Abstract

Importance  There is growing interest in the role of nutrition in the pathogenesis and progression of amyotrophic lateral sclerosis (ALS).

Objective  To evaluate the associations between nutrients, individually and in groups, and ALS function and respiratory function at diagnosis.

Design, Setting, and Participants  A cross-sectional baseline analysis of the Amyotrophic Lateral Sclerosis Multicenter Cohort Study of Oxidative Stress study was conducted from March 14, 2008, to February 27, 2013, at 16 ALS clinics throughout the United States among 302 patients with ALS symptom duration of 18 months or less.

Exposures  Nutrient intake, measured using a modified Block Food Frequency Questionnaire (FFQ).

Main Outcomes and Measures  Amyotrophic lateral sclerosis function, measured using the ALS Functional Rating Scale–Revised (ALSFRS-R), and respiratory function, measured using percentage of predicted forced vital capacity (FVC).

Results  Baseline data were available on 302 patients with ALS (median age, 63.2 years [interquartile range, 55.5-68.0 years]; 178 men and 124 women). Regression analysis of nutrients found that higher intakes of antioxidants and carotenes from vegetables were associated with higher ALSFRS-R scores or percentage FVC. Empirically weighted indices using the weighted quantile sum regression method of “good” micronutrients and “good” food groups were positively associated with ALSFRS-R scores (β [SE], 2.7 [0.69] and 2.9 [0.9], respectively) and percentage FVC (β [SE], 12.1 [2.8] and 11.5 [3.4], respectively) (all P < .001). Positive and significant associations with ALSFRS-R scores (β [SE], 1.5 [0.61]; P = .02) and percentage FVC (β [SE], 5.2 [2.2]; P = .02) for selected vitamins were found in exploratory analyses.

Conclusions and Relevance  Antioxidants, carotenes, fruits, and vegetables were associated with higher ALS function at baseline by regression of nutrient indices and weighted quantile sum regression analysis. We also demonstrated the usefulness of the weighted quantile sum regression method in the evaluation of diet. Those responsible for nutritional care of the patient with ALS should consider promoting fruit and vegetable intake since they are high in antioxidants and carotenes.

Progressive multiple sclerosis: from pathogenic mechanisms to treatment

During the past decades, better understanding of relapsing-remitting multiple sclerosis disease mechanisms have led to the development of several disease-modifying therapies, reducing relapse rates and severity, through immune system modulation or suppression. In contrast, current therapeutic options for progressive multiple sclerosis remain comparatively disappointing and challenging. One possible explanation is a lack of understanding of pathogenic mechanisms driving progressive multiple sclerosis. Furthermore, diagnosis is usually retrospective, based on history of gradual neurological worsening with or without occasional relapses, minor remissions or plateaus. In addition, imaging methods as well as biomarkers are not well established. Magnetic resonance imaging studies in progressive multiple sclerosis show decreased blood–brain barrier permeability, probably reflecting compartmentalization of inflammation behind a relatively intact blood–brain barrier. Interestingly, a spectrum of inflammatory cell types infiltrates the leptomeninges during subpial cortical demyelination. Indeed, recent magnetic resonance imaging studies show leptomeningeal contrast enhancement in subjects with progressive multiple sclerosis, possibly representing an in vivo marker of inflammation associated to subpial demyelination. Treatments for progressive disease depend on underlying mechanisms causing central nervous system damage. Immunity sheltered behind an intact blood–brain barrier, energy failure, and membrane channel dysfunction may be key processes in progressive disease. Interfering with these mechanisms may provide neuroprotection and prevent disability progression, while potentially restoring activity and conduction along damaged axons by repairing myelin. Although most previous clinical trials in progressive multiple sclerosis have yielded disappointing results, important lessons have been learnt, improving the design of novel ones. This review discusses mechanisms involved in progressive multiple sclerosis, correlations between histopathology and magnetic resonance imaging studies, along with possible new therapeutic approaches.

Brain 2016

Refining duration and frequency thresholds of restless legs syndrome diagnosis criteria

ABSTRACT

Objective: This study assesses the prevalence of restless legs syndrome (RLS) using DSM-5 criteria and determines what is the most appropriate threshold for the frequency and duration of RLS symptoms.

Methods: The Sleep-EVAL knowledge base system queried the interviewed subjects on life, sleeping habits, and health. Questions on sleep and mental and organic disorders (DSM-5, ICD-10) were also asked. A representative sample of 19,136 noninstitutionalized individuals older than 18 years living in the United States was interviewed through a cross-sectional telephone survey. The participation rate was 83.2%.

Results: The prevalence of the 4 leg symptoms describing RLS occurring at least 1 d/wk varied between 5.7% and 12.3%. When the frequency was set to at least 3 d/wk, the prevalence dropped and varied between 1.8% and 4.5% for the 4 leg symptoms. Higher frequency of leg symptoms was associated with greater distress and impairment with a marked increase at 3 d/wk. Symptoms were mostly chronic, lasting for more than 3 months in about 97% of the cases. The prevalence of RLS according to DSM-5 was 1.6% (95% confidence interval 1.4%–1.8%) when frequency was set at 3 d/wk. Stricter criteria for frequency of restless legs symptoms resulted in a reduction of prevalence of the disorder. The prevalence was further reduced when clinical impact was taken into consideration.

Conclusions: In order to avoid inflation of case rates and to identify patients in whom treatment is truly warranted, using a more conservative threshold of 3 times or greater per week appears the most appropriate.

Neurology 2016

Increased risk for clinical onset of myasthenia gravis during the postpartum period

ABSTRACT

Objective: To study the risk of clinical onset of myasthenia gravis (MG) in pregnancy and during the first 6 months postpartum because an association between pregnancy or the postpartum period and the onset of autoimmune MG is widely assumed but not proven.

Methods: The design was a cross-sectional population-based cohort study of 2 MG cohorts (Norway and the Netherlands) with 1,038 healthy controls from Norway. Data were obtained on 246 women with MG (age at onset 15–45 years). Data on pregnancy, hormonal factors, and clinical symptoms were collected by a previously validated environmental MG questionnaire. Relative risk of MG onset before, during, and after pregnancy was calculated by multinomial logistic regression for Norwegian women reaching 45 years of age, adjusted for the observed distribution of person-years in the corresponding control group.

Results: Of the included women with MG, 13 (11.5%) of the Dutch and 24 (18.0%) of the Norwegian patients had their first myasthenia symptoms during the pregnancy or postpartum period. The postpartum period was confirmed to be significantly associated with the onset of symptoms of MG in Norwegian women with MG (relative risk 5.5, 95% confidence interval 2.6–11.6). The risk was highest after the first childbirth.

Conclusions: Women have a high-risk period for the onset of clinical symptoms of MG in the postpartum period, in particular after the first childbirth. Future studies should aim at elucidating the role of the hormonal-immunological-genetic interaction in the pathogenesis of MG.

Neurology 2016

Expanding the phenotype of BICD2 mutations toward skeletal muscle involvement

ABSTRACT

Objective: To expand the spectrum of bicaudal D, Drosophila, homologue 2 (BICD2) gene–related diseases, which so far includes autosomal dominant spinal muscular atrophy with lower extremity predominance 2 and hereditary spastic paraplegia due to mutations in the BICD2 gene.

Methods: We analyzed 2 independent German families with clinical, genetic, and muscle MRI studies. In both index patients, muscle histopathologic studies were performed. Transfection studies were carried out to analyze the functional consequences of the disease-causing mutations.

Results: We identified the mutations p.Ser107Leu and p.Thr703Met in the BICD2 gene in the 2 families, respectively. In contrast to other patients carrying the same mutations, our patients present features of a myopathy with slow progression. Immunofluorescence studies and immunoelectron microscopy showed striking impairment of Golgi integrity, vesicle pathology, and abnormal BICD2 accumulation either within the nuclei (p.Ser107Leu) or in the perinuclear region (p.Thr703Met). Transfection studies confirmed BICD2 aggregation in different subcellular locations.

Conclusions: Our findings extend the phenotypic spectrum of BICD2-associated disorders by features of a chronic myopathy and show a pathomechanism of BICD2 defects in skeletal muscle.

Neurology 2016

In vivo visualization of tau deposits in corticobasal syndrome by 18F-THK5351 PET

ABSTRACT

Objective: To determine whether ¹⁸F-THK5351 PET can be used to visualize tau deposits in brain lesions in live patients with corticobasal syndrome (CBS).

Methods: We evaluated the in vitro binding of ³H-THK5351 in postmortem brain tissues from a patient with corticobasal degeneration (CBD). In clinical PET studies, ¹⁸F-THK5351 retention in 5 patients with CBS was compared to that in 8 age-matched normal controls and 8 patients with Alzheimer disease (AD).

Results: ³H-THK5351 was able to bind to tau deposits in the postmortem brain with CBD. In clinical PET studies, the 5 patients with CBS showed significantly higher ¹⁸F-THK5351 retention in the frontal, parietal, and globus pallidus than the 8 age-matched normal controls and patients with AD. Higher ¹⁸F-THK5351 retention was observed contralaterally to the side associated with greater cortical dysfunction and parkinsonism.

Conclusions: ¹⁸F-THK5351 PET demonstrated high tracer signal in sites susceptible to tau deposition in patients with CBS. ¹⁸F-THK5351 should be considered as a promising candidate radiotracer for the in vivo imaging of tau deposits in CBS.

Neurology 2016

Cerebrovascular reactivity and white matter integrity

ABSTRACT

Objective: To compare the diffusion and perfusion MRI metrics of normal-appearing white matter (NAWM) with and without impaired cerebrovascular reactivity (CVR).

Methods: Seventy-five participants with moderate to severe leukoaraiosis underwent blood oxygen level–dependent CVR mapping using a 3T MRI system with precise carbon dioxide stimulus manipulation. Several MRI metrics were statistically compared between areas of NAWM with positive and negative CVR using one-way analysis of variance with Bonferroni correction for multiple comparisons.

Results: Areas of NAWM with negative CVR showed a significant reduction in fractional anisotropy by a mean (SD) of 3.7% (2.4), cerebral blood flow by 22.1% (8.2), regional cerebral blood volume by 22.2% (7.0), and a significant increase in mean diffusivity by 3.9% (3.1) and time to maximum by 10.9% (13.2) (p < 0.01), compared to areas with positive CVR.

Conclusions: Impaired CVR is associated with subtle changes in the tissue integrity of NAWM, as evaluated using several quantitative diffusion and perfusion MRI metrics. These findings suggest that impaired CVR may contribute to the progression of white matter disease.

Neurology 2016

FGF21 is a biomarker for mitochondrial translation and mtDNA maintenance disorders

ABSTRACT

Objective: To validate new mitochondrial myopathy serum biomarkers for diagnostic use.

Methods: We analyzed serum FGF21 (S-FGF21) and GDF15 from patients with (1) mitochondrial diseases and (2) nonmitochondrial disorders partially overlapping with mitochondrial disorder phenotypes. We (3) did a meta-analysis of S-FGF21 in mitochondrial disease and (4) analyzed S-Fgf21 and skeletal muscle Fgf21 expression in 6 mouse models with different muscle-manifesting mitochondrial dysfunctions.

Results: We report that S-FGF21 consistently increases in primary mitochondrial myopathy, especially in patients with mitochondrial translation defects or mitochondrial DNA (mtDNA) deletions (675 and 347 pg/mL, respectively; controls: 66 pg/mL, p < 0.0001 for both). This is corroborated in mice (mtDNA deletions 1,163 vs 379 pg/mL, p < 0.0001). However, patients and mice with structural respiratory chain subunit or assembly factor defects showed low induction (human 335 pg/mL, p < 0.05; mice 335 pg/mL, not significant). Overall specificities of FGF21 and GDF15 to find patients with mitochondrial myopathy were 89.3% vs 86.4%, and sensitivities 67.3% and 76.0%, respectively. However, GDF15 was increased also in a wide range of nonmitochondrial conditions.

Conclusions: S-FGF21 is a specific biomarker for muscle-manifesting defects of mitochondrial translation, including mitochondrial transfer-RNA mutations and primary and secondary mtDNA deletions, the most common causes of mitochondrial disease. However, normal S-FGF21 does not exclude structural respiratory chain complex or assembly factor defects, important to acknowledge in diagnostics.

Classification of evidence: This study provides Class III evidence that elevated S-FGF21 accurately distinguishes patients with mitochondrial myopathies from patients with other conditions, and FGF21 and GDF15 mitochondrial myopathy from other myopathies

Neurology 2016

Neurological manifestations of autosomal dominant familial Alzheimer's disease: a comparison of the published literature with the Dominantly Inherited Alzheimer Network observational study (DIAN-OBS)

Background

Autosomal dominant familial Alzheimer's disease (ADAD) is a rare disorder with non-amnestic neurological symptoms in some clinical presentations. We aimed to compile and compare data from symptomatic participants in the Dominantly Inherited Alzheimer Network observational study (DIAN-OBS) with those reported in the literature to estimate the prevalences of non-amnestic neurological symptoms in participants with ADAD.

Methods

We prospectively collected data from the DIAN-OBS database, which recruited participants from study centres in the USA, Europe, and Australia, between Feb 29, 2008, and July 1, 2014. We also did a systematic review of publications to extract individual-level clinical data for symptomatic participants with ADAD. We used data for age of onset (from first report of cognitive decline), disease course from onset to death, and the presence of 13 neurological findings that have been reported in association with ADAD. Using multivariable linear regression, we investigated the prevalences of various non-amnestic neurological symptoms and the contributions of age of onset and specific mutation type on symptoms.

Findings

The DIAN-OBS dataset included 107 individuals with detailed clinical data (forming the DIAN-OBS cohort). Our systematic review yielded 188 publications reporting on 1228 symptomatic individuals, with detailed neurological examination descriptions available for 753 individuals (forming the published data cohort). The most prevalent non-amnestic cognitive manifestations in participants in the DIAN-OBS cohort were those typical of mild to moderate Alzheimer's disease, including visual agnosia (55·1%, 95% CI 45·7–64·6), aphasia (57·9%, 48·6–67·3), and behavioural changes (61·7%, 51·5–70·0). Non-amnestic cognitive manifestations were less prevalent in the published data cohort (eg, visual agnosia [5·6%, 3·9–7·2], aphasia [23·0%, 20·0–26·0], and behavioural changes [31·7%, 28·4–35·1]). Prevalence of non-cognitive neurological manifestations in the DIAN-OBS cohort was low, including myoclonus and spasticity (9·3%, 95% CI 3·8–15·0), and seizures (2·8%, 0·5–5·9) and moderate for parkinsonism (11·2%, 5·3–17·1). By constrast, prevalence was higher in the published data cohort for myoclonus and spasticity (19·4%, 16·6–22·2 and 15·0%, 12·5–17·6, respectively), parkinsonism (12·5%, 10·1–15·0), and seizures (20·3%, 17·4–23·2). In an analysis of the published data cohort, ischaemic stroke was more prevalent at older ages of onset of symptoms of ADAD (odds ratio 1·09 per 1 year increase in age of onset, 95% CI 1·04–1·14, p=0·0003); and motor symptoms were more common at younger age of onset (myoclonus 0·93, 0·90–0·97, p=0·0007; seizures 0·95, 0·92–0·98, p=0·0018; corticobulbar deficits 0·91, 0·86–0·96, p=0·0012; and cerebellar ataxia 0·82, 0·74–0·91, p=0·0002). In the DIAN-OBS cohort, non-cognitive symptoms were more common at more severe stages of disease.

Interpretation

The non-cognitive clinical manifestations of Alzheimer's disease seem to affect a small proportion of participants with mild to moderate ADAD, and are probably influenced by disease severity, environmental, and genetic factors. When evaluating patients with potential ADAD, clinicians should note that cognitive symptoms typical of sporadic Alzheimer's disease are the most consistent finding, with some patients manifesting non-cognitive neurological symptoms. Future work is needed to determine the environmental and genetic factors that cause these neurological symptoms.

Lancet Neurology 2016

Clinical phenotype and genetic associations in autosomal dominant familial Alzheimer's disease: a case series

Background

The causes of phenotypic heterogeneity in familial Alzheimer's disease with autosomal dominant inheritance are not well understood. We aimed to characterise clinical phenotypes and genetic associations with APP and PSEN1 mutations in symptomatic autosomal dominant familial Alzheimer's disease (ADAD).

Methods

We retrospectively analysed genotypic and phenotypic data (age at symptom onset, initial cognitive or behavioural symptoms, and presence of myoclonus, seizures, pyramidal signs, extrapyramidal signs, and cerebellar signs) from all individuals with ADAD due to APP or PSEN1 mutations seen at the Dementia Research Centre in London, UK. We examined the frequency of presenting symptoms and additional neurological features, investigated associations with age at symptom onset, APOEgenotype, and mutation position, and explored phenotypic differences between APP and PSEN1mutation carriers. The proportion of individuals presenting with various symptoms was analysed with descriptive statistics, stratified by mutation type.

Findings

Between July 1, 1987, and Oct 31, 2015, age at onset was recorded for 213 patients (168 with PSEN1mutations and 45 with APP mutations), with detailed history and neurological examination findings available for 121 (85 with PSEN1 mutations and 36 with APP mutations). We identified 38 differentPSEN1 mutations (four novel) and six APP mutations (one novel). Age at onset differed by mutation, with a younger onset for individuals with PSEN1 mutations than for those with APP mutations (mean age 43·6 years [SD 7·2] vs 50·4 years [SD 5·2], respectively, p<0·0001); within the PSEN1 group, 72% of age at onset variance was explained by the specific mutation. A cluster of five mutations with particularly early onset (mean age at onset <40 years) involving PSEN1's first hydrophilic loop suggests critical functional importance of this region. 71 (84%) individuals with PSEN1 mutations and 35 (97%) with APP mutations presented with amnestic symptoms, making atypical cognitive presentations significantly more common in PSEN1 mutation carriers (n=14; p=0·037). Myoclonus and seizures were the most common additional neurological features; individuals with myoclonus (40 [47%] with PSEN1 mutations and 12 [33%] with APP mutations) were significantly more likely to develop seizures (p=0·001 for PSEN1; p=0·036 for APP), which affected around a quarter of the patients in each group (20 [24%] and nine [25%], respectively). A number of patients with PSEN1mutations had pyramidal (21 [25%]), extrapyramidal (12 [14%]), or cerebellar (three [4%]) signs.

Interpretation

ADAD phenotypes are heterogeneous, with both age at onset and clinical features being influenced by mutation position as well as causative gene. This highlights the importance of considering genetic testing in young patients with dementia and additional neurological features in order to appropriately diagnose and treat their symptoms, and of examining different mutation types separately in future research.

Lancet Neurology 2016

Genome-wide association study in essential tremor identifies three new loci

Summary

We conducted a genome-wide association study of essential tremor, a common movement disorder characterized mainly by a postural and kinetic tremor of the upper extremities. Twin and family history studies show a high heritability for essential tremor. The molecular genetic determinants of essential tremor are unknown. We included 2807 patients and 6441 controls of European descent in our two-stage genome-wide association study. The 59 most significantly disease-associated markers of the discovery stage were genotyped in the replication stage. After Bonferroni correction two markers, one (rs10937625) located in the serine/threonine kinase STK32B and one (rs17590046) in the transcriptional coactivator PPARGC1A were associated with essential tremor. Three markers (rs12764057, rs10822974, rs7903491) in the cell-adhesion molecule CTNNA3 were significant in the combined analysis of both stages. The expression of STK32B was increased in the cerebellar cortex of patients and expression quantitative trait loci database mining showed association between the protective minor allele of rs10937625 and reduced expression in cerebellar cortex. We found no expression differences related to disease status or marker genotype for the other two genes. Replication of two lead single nucleotide polymorphisms of previous small genome-wide association studies (rs3794087 in SLC1A2, rs9652490 in LINGO1) did not confirm the association with essential tremor.

Brain 2016