Homozygous mutations in VAMP1 cause a presynaptic congenital myasthenic syndrome

Abstract

We report 2 families with undiagnosed recessive presynaptic congenital myasthenic syndrome (CMS). Whole exome or genome sequencing identified segregating homozygous variants in VAMP1: c.51_64delAGGTGGGGGTCCCC in a Kuwaiti family and c.146G>C in an Israeli family. VAMP1 is crucial for vesicle fusion at presynaptic neuromuscular junction (NMJ). Electrodiagnostic examination showed severely low compound muscle action potentials and presynaptic impairment. We assessed the effect of the nonsense mutation on mRNA levels and evaluated the NMJ transmission in VAMP1lew/lew mice, observing neurophysiological features of presynaptic impairment, similar to the patients. Taken together, our findings highlight VAMP1 homozygous mutations as a cause of presynaptic CMS. Ann Neurol 2017

The congenital myasthenic syndromes (CMSs) are a heterogeneous group of inherited diseases of the neuromuscular junction (NMJ), with fatigable muscle weakness as the clinical hallmark.[1] Several molecular causes can be implicated in CMS pathophysiology, including mutations in genes encoding proteins associated with the muscle nicotinic acetylcholine receptor and the synaptic basal lamina, or (more rarely) involved in the NMJ presynaptic transmission.[2-6]

We describe 2 families from Kuwait and Israel where 2 of the siblings in each family presented clinical and neurophysiological features typical of a presynaptic CMS. Whole exome sequencing (WES) or whole genome sequencing (WGS) followed by Sanger sequencing unraveled either a homozygous frameshift or missense variants in VAMP1 segregating with the phenotype in the 2 families. Screening a cohort of 63 undiagnosed CMS individuals failed to show any further causative variant in VAMP1.

Annals Of Neurology 2017

Recessive dystrophic epidermolysis bullosa results in painful small fibre neuropathy

Abstract

Small fibres in the skin are vulnerable to damage in metabolic or toxic conditions such as diabetes mellitus or chemotherapy resulting in small fibre neuropathy and associated neuropathic pain. Whether injury to the most distal portion of sensory small fibres due to a primary dermatological disorder can cause neuropathic pain is still unclear. Recessive dystrophic epidermolysis bullosa (RDEB) is a rare condition in which mutations of proteins of the dermo-epidermal junction lead to cycles of blistering followed by regeneration of the skin. Damage is exclusive to the skin and mucous membranes, with no known direct compromise of the nervous system. It is increasingly recognized that most RDEB patients experience daily pain, the aetiology of which is unclear but may include inflammation (in the wounds), musculoskeletal (due to atrophy and retraction scars limiting movement) or neuropathic pain. In this study we investigated the incidence of neuropathic pain and examined the presence of nerve dysfunction in RDEB patients. Around three quarters of patients presented with pain of neuropathic characteristics, which had a length-dependent distribution. Quantitative sensory testing of the foot revealed striking impairments in thermal detection thresholds combined with an increased mechanical pain sensitivity and wind up ratio (temporal summation of noxious mechanical stimuli). Nerve conduction studies showed normal large fibre sensory and motor nerve conduction; however, skin biopsy showed a significant decrease in intraepidermal nerve fibre density. Autonomic nervous system testing revealed no abnormalities in heart rate and blood pressure variability however the sympathetic skin response of the foot was impaired and sweat gland innervation was reduced. We conclude that chronic cutaneous injury can lead to injury and dysfunction of the most distal part of small sensory fibres in a length-dependent distribution resulting in disabling neuropathic pain. These findings also support the use of neuropathic pain screening tools in these patients and treatment algorithms designed to target neuropathic pain.

Brain 2017

Serotonin and dopamine transporter PET changes in the premotor phase of LRRK2 parkinsonism: cross-sectional studies

Summary

Background

People with Parkinson's disease can show premotor neurochemical changes in the dopaminergic and non-dopaminergic systems. Using PET, we assessed whether dopaminergic and serotonin transporter changes are similar in LRRK2 mutation carriers with Parkinson's disease and individuals with sporadic Parkinson's disease, and whether LRRK2 mutation carriers without motor symptoms show PET changes.

Methods

We did two cross-sectional PET studies at the Pacific Parkinson's Research Centre in Vancouver, BC, Canada. We included LRRK2 mutation carriers with or without manifest Parkinson's disease, people with sporadic Parkinson's disease, and age-matched healthy controls, all aged 18 years or older. People with Parkinson's disease were diagnosed by a neurologist with movement disorder training, in accordance with the UK Parkinson's Disease Society Brain Bank criteria. LRRK2 carrier status was confirmed by bidirectional Sanger sequencing. In the first study, LRRK2 mutation carriers with or without manifest Parkinson's disease who were referred for investigation between July, 1999, and January, 2012, were scanned with PET tracers for the membrane dopamine transporter, and dopamine synthesis and storage (18F-6-fluoro-L-dopa; 18F-FDOPA). We compared findings with those in people with sporadic Parkinson's disease and age-matched healthy controls. In the second study, distinct groups of LRRK2 mutation carriers, individuals with sporadic Parkinson's disease, and age-matched healthy controls seen from November, 2012, to May, 2016, were studied with tracers for the serotonin transporter and vesicular monoamine transporter 2 (VMAT2). Striatal dopamine transporter binding, VMAT2 binding, 18F-FDOPA uptake, and serotonin transporter binding in multiple brain regions were compared by ANCOVA, adjusted for age.

Findings

Between January, 1997, and January, 2012, we obtained data for our first study from 40 LRRK2 mutation carriers, 63 individuals with sporadic Parkinson's disease, and 35 healthy controls. We identified significant group differences in striatal dopamine transporter binding (all age ranges in caudate and putamen, p<0·0001) and 18F-FDOPA uptake (in caudate: age ≤50 years, p=0·0002; all other age ranges, p<0·0001; in putamen: all age ranges, p<0·0001). LRRK2 mutation carriers with manifest Parkinson's disease (n=15) had reduced striatal dopamine transporter binding and 18F-FDOPA uptake, comparable with amounts seen in individuals with sporadic Parkinson's disease of similar duration. LRRK2 mutation carriers without manifest Parkinson's disease (n=25) had greater 18F-FDOPA uptake and dopamine transporter binding than did individuals with sporadic Parkinson's disease, with 18F-FDOPA uptake comparable with controls and dopamine transporter binding lower than in controls. Between November, 2012, and May, 2016, we obtained data for our second study from 16 LRRK2 mutation carriers, 13 individuals with sporadic Parkinson's disease, and nine healthy controls. Nine LRRK2 mutation carriers without manifest Parkinson's disease had significantly elevated serotonin transporter binding in the hypothalamus (compared with controls, individuals with LRRK2 Parkinson's disease, and people with sporadic Parkinson's disease, p<0·0001), striatum (compared with people with sporadic Parkinson's disease, p=0·02), and brainstem (compared with LRRK2 mutation carriers with manifest Parkinson's disease, p=0·01), after adjustment for age. Serotonin transporter binding in the cortex did not differ significantly between groups after age adjustment. Striatal VMAT2 binding was reduced in all individuals with manifest Parkinson's disease and reduced asymmetrically in one LRRK2 mutation carrier without manifest disease.

Interpretation

Dopaminergic and serotonergic changes progress in a similar fashion in LRRK2 mutation carriers with manifest Parkinson's disease and individuals with sporadic Parkinson's disease, but LRRK2 mutation carriers without manifest Parkinson's disease show increased serotonin transporter binding in the striatum, brainstem, and hypothalamus, possibly reflecting compensatory changes in serotonergic innervation preceding the motor onset of Parkinson's disease. Increased serotonergic innervation might contribute to clinical differences in LRRK2 Parkinson's disease, including the emergence of non-motor symptoms and, potentially, differences in the long-term response to levodopa.

Lancet Neurology 2017

Effect of long-term omega 3 polyunsaturated fatty acid supplementation with or without multidomain intervention on cognitive function in elderly adults with memory complaints (MAPT): a randomised, placebo-controlled trial

Summary

Background

No large trials have been done to investigate the efficacy of an intervention combining a specific compound and several lifestyle interventions compared with placebo for the prevention of cognitive decline. We tested the effect of omega 3 polyunsaturated fatty acid supplementation and a multidomain intervention (physical activity, cognitive training, and nutritional advice), alone or in combination, compared with placebo, on cognitive decline.

Methods

The Multidomain Alzheimer Preventive Trial was a 3-year, multicentre, randomised, placebo-controlled superiority trial with four parallel groups at 13 memory centres in France and Monaco. Participants were non-demented, aged 70 years or older, and community-dwelling, and had either relayed a spontaneous memory complaint to their physician, limitations in one instrumental activity of daily living, or slow gait speed. They were randomly assigned (1:1:1:1) to either the multidomain intervention (43 group sessions integrating cognitive training, physical activity, and nutrition, and three preventive consultations) plus omega 3 polyunsaturated fatty acids (ie, two capsules a day providing a total daily dose of 800 mg docosahexaenoic acid and 225 mg eicosapentaenoic acid), the multidomain intervention plus placebo, omega 3 polyunsaturated fatty acids alone, or placebo alone. A computer-generated randomisation procedure was used to stratify patients by centre. All participants and study staff were blinded to polyunsaturated fatty acid or placebo assignment, but were unblinded to the multidomain intervention component. Assessment of cognitive outcomes was done by independent neuropsychologists blinded to group assignment. The primary outcome was change from baseline to 36 months on a composite Z score combining four cognitive tests (free and total recall of the Free and Cued Selective Reminding test, ten Mini-Mental State Examination orientation items, Digit Symbol Substitution Test, and Category Naming Test) in the modified intention-to-treat population. The trial was registered with ClinicalTrials.gov (NCT00672685).

Findings

1680 participants were enrolled and randomly allocated between May 30, 2008, and Feb 24, 2011. In the modified intention-to-treat population (n=1525), there were no significant differences in 3-year cognitive decline between any of the three intervention groups and the placebo group. Between-group differences compared with placebo were 0·093 (95% CI 0·001 to 0·184; adjusted p=0·142) for the combined intervention group, 0·079 (−0·012 to 0·170; 0·179) for the multidomain intervention plus placebo group, and 0·011 (−0·081 to 0·103; 0·812) for the omega 3 polyunsaturated fatty acids group. 146 (36%) participants in the multidomain plus polyunsaturated fatty acids group, 142 (34%) in the multidomain plus placebo group, 134 (33%) in the polyunsaturated fatty acids group, and 133 (32%) in the placebo group had at least one serious emerging adverse event. Four treatment-related deaths were recorded (two in the multidomain plus placebo group and two in the placebo group). The interventions did not raise any safety concerns and there were no differences between groups in serious or other adverse events.

Interpretation

The multidomain intervention and polyunsaturated fatty acids, either alone or in combination, had no significant effects on cognitive decline over 3 years in elderly people with memory complaints. An effective multidomain intervention strategy to prevent or delay cognitive impairment and the target population remain to be determined, particularly in real-world settings.

Lancet Neurology 2017

Alzheimer Disease Signature Neurodegeneration and APOE Genotype in Mild Cognitive Impairment With Suspected Non–Alzheimer Disease Pathophysiology

Abstract

Importance  There are conflicting results claiming that Alzheimer disease signature neurodegeneration may be more, less, or similarly advanced in individuals with β-amyloid peptide (Aβ)–negative (Aβ−) suspected non–Alzheimer disease pathophysiology (SNAP) than in Aβ-positive (Aβ+) counterparts.

Objective  To examine patterns of neurodegeneration in individuals with SNAP compared with their Aβ+ counterparts.

Design, Setting, and Participants  A longitudinal cohort study was conducted among individuals with mild cognitive impairment (MCI) and cognitively normal individuals receiving care at Alzheimer’s Disease Neuroimaging Initiative sites in the United States and Canada for a mean follow-up period of 30.5 months from August 1, 2005, to June 30, 2015. Several neurodegeneration biomarkers and longitudinal cognitive function were compared between patients with distinct SNAP (Aβ− and neurodegeneration-positive [Aβ−N+]) subtypes and their Aβ+N+ counterparts.

Main Outcomes and Measures  Participants were classified according to the results of their florbetapir F-18 (Aβ) positron emission tomography and their Alzheimer disease–associated neurodegeneration status (temporoparietal glucose metabolism determined by fluorodeoxyglucose F 18 [FDG]–labeled positron emission tomography and/or hippocampal volume [HV] determined by magnetic resonance imaging: participants with subthreshold HV values were regarded as exhibiting hippocampal volume atrophy [HV+], while subthreshold mean FDG values were considered as FDG hypometabolism [FDG+]).

Results  The study comprised 265 cognitively normal individuals (135 women and 130 men; mean [SD] age, 75.5 [6.7] years) and 522 patients with MCI (225 women and 297 men; mean [SD] age, 72.6 [7.8] years). A total of 469 individuals with MCI had data on neurodegeneration biomarkers; of these patients, 107 were Aβ−N+ (22.8%; 63 FDG+, 82 HV+, and 38 FDG+HV+) and 187 were Aβ+N+ (39.9%; 135 FDG+, 147 HV+, and 95 FDG+HV+ cases). A total of 209 cognitively normal participants had data on neurodegeneration biomarkers; of these, 52 were Aβ−N+ (24.9%; 30 FDG+, 33 HV+, and 11 FDG+HV+) and 37 were Aβ+N+ (17.7%; 22 FDG+, 26 HV+, and 11 FDG+HV+). Compared with their Aβ+ counterparts, all patients with MCI SNAP subtypes displayed better preservation of temporoparietal FDG metabolism (mean [SD] FDG: Aβ–N+, 1.25 [0.11] vs Aβ+N+, 1.19 [0.11]), less severe atrophy of the lateral temporal lobe, and lower mean (SD) cerebrospinal fluid levels of tau (59.2 [32.8] vs 111.3 [56.4]). In MCI with SNAP, sustained glucose metabolism and gray matter volume were associated with disproportionately low APOE ε4 (Aβ–N+, 18.7% vs Aβ+N+, 70.6%) and disproportionately high APOE ε2 (18.7% vs 4.8%) carrier prevalence. Slower cognitive decline and lower rates of progression to Alzheimer disease (Aβ–N+, 6.5% vs Aβ+N+, 32.6%) were also seen in patients with MCI with SNAP subtypes compared with their Aβ+ counterparts. In cognitively normal individuals, neurodegeneration biomarkers did not differ between Aβ−N+ and Aβ+N+ cases.

Conclusions and Relevance  In MCI with SNAP, low APOE ε4 and high APOE ε2 carrier prevalence may account for differences in neurodegeneration patterns between Aβ−N+ and Aβ+N+ cases independent from the neuroimaging biomarker modality used to define neurodegeneration associated with Alzheimer disease.

Association of Plasma Neurofilament Light With Neurodegeneration in Patients With Alzheimer Disease

Abstract

Importance  Existing cerebrospinal fluid (CSF) or imaging (tau positron emission tomography) biomarkers for Alzheimer disease (AD) are invasive or expensive. Biomarkers based on standard blood test results would be useful in research, drug development, and clinical practice. Plasma neurofilament light (NFL) has recently been proposed as a blood-based biomarker for neurodegeneration in dementias.

Objective  To test whether plasma NFL concentrations are increased in AD and associated with cognitive decline, other AD biomarkers, and imaging evidence of neurodegeneration.

Design, Setting, and Participants  In this prospective case-control study, an ultrasensitive assay was used to measure plasma NFL concentration in 193 cognitively healthy controls, 197 patients with mild cognitive impairment (MCI), and 180 patients with AD dementia from the Alzheimer’s Disease Neuroimaging Initiative. The study dates were September 7, 2005, to February 13, 2012. The plasma NFL analysis was performed in September 2016.

Main Outcomes and Measures  Associations were tested between plasma NFL and diagnosis, Aβ pathologic features, CSF biomarkers of neuronal injury, cognition, brain structure, and metabolism.

Results  Among 193 cognitively healthy controls, 197 patients with mild cognitive impairment, and 180 patients with AD with dementia, plasma NFL correlated with CSF NFL (Spearman ρ = 0.59, P < .001). Plasma NFL was increased in patients with MCI (mean, 42.8 ng/L) and patients with AD dementia (mean, 51.0 ng/L) compared with controls (mean, 34.7 ng/L) (P < .001) and had high diagnostic accuracy for patients with AD with dementia vs controls (area under the receiver operating characteristic curve, 0.87, which is comparable to established CSF biomarkers). Plasma NFL was particularly high in patients with MCI and patients with AD dementia with Aβ pathologic features. High plasma NFL correlated with poor cognition and AD-related atrophy (at baseline and longitudinally) and with brain hypometabolism (longitudinally).

Conclusions and Relevance  Plasma NFL is associated with AD diagnosis and with cognitive, biochemical, and imaging hallmarks of the disease. This finding implies a potential usefulness for plasma NFL as a noninvasive biomarker in AD.

JAMA Neurology 2017

Association Between Childhood-Onset Epilepsy and Amyloid Burden 5 Decades Later

Abstract

Importance  The effect of childhood epilepsy on later-life cognitive and brain health is an unclear and little-explored issue.

Objective  To determine whether adults with a history of childhood-onset epilepsy exhibit increased brain amyloid accumulation, possibly predisposing to accelerated cognitive impairment or even frank cognitive disorders in later life.

Design, Setting, and Participants  Forty-one adults from a population-based cohort of individuals with childhood-onset epilepsy in southwestern Finland, together with 46 matched population-based controls, underwent amyloid ligand carbon 11–labeled Pittsburgh Compound B (PiB) positron emission tomography after long-term prospective follow-up. The PiB uptake was quantified as a region to cerebellar cortex ratio. Tracer uptake was evaluated visually and analyzed voxel by voxel over the entire brain to investigate the spatial distribution of amyloid deposition. The study was conducted from May 2011 to October 2013; data analysis was performed from January 2014 to October 2016.

Main Outcomes and Measures  Brain amyloid accumulation.

Results  The 41 individuals with epilepsy were originally enrolled in the Turku Adult Childhood Onset Epilepsy study at the mean (SD) age of 5.1 (4.5) years (range, 0-14 years). After a mean 52.5 (4.0) years of follow-up, the participants were evaluated (26 [63%] were women; the mean [SD] age was 56.0 [4.3] years). Nine individuals with childhood-onset epilepsy (22%) and 3 control participants (7%) had a visually abnormal PiB scan showing high cortical uptake in at least 1 of the evaluated brain regions (P = .04). In semiquantitative analyses, there was a significant interaction effect indicating higher prefrontal cortex uptake in apolipoprotein E (APOE) ε4 allele carriers than in noncarriers in participants (mean [SD], 1.66 [0.41] vs 1.43 [0.15]) compared with controls (1.40 [0.26) vs 1.41 [0.12]) (group × APOE interaction, F = 6.8; P = .01). In addition, there was a significant group effect showing higher tracer uptake in participants compared with controls (group effect, F = 8.0; P = .006).

Conclusions and Relevance  Adults with childhood-onset epilepsy, particularly APOE ε4 carriers, have an increased brain amyloid load at late middle age. Thus, epilepsy is linked with a biomarker that might be related to accelerated brain aging and can be considered a neurobiological predisposition to later-life cognitive disorders.

Neurology 2017

A multi-institutional study of brainstem gliomas in children with neurofibromatosis type 1

ABSTRACT

Objective: To define the clinical and radiologic features of brainstem gliomas (BSGs) in children with neurofibromatosis type 1 (NF1).

Methods: We performed a retrospective cross-sectional study of 133 children with NF1 and concurrent BSGs cared for at 4 NF1 referral centers. BSG was determined using radiographic criteria. Age at diagnosis, tumor location and appearance, clinical symptoms, treatment, and presence of a concurrent optic pathway glioma were assessed.

Results: The average age at BSG diagnosis was 7.2 years, and tumors occurred most often in the midbrain and medulla (66%). The majority of children with NF1-BSGs were asymptomatic (54%) and were not treated (88%). Only 9 of the 72 asymptomatic children received treatment because of progressive tumor enlargement. In contrast, 61 children presented with clinical signs/symptoms attributable to their BSG; these individuals were older and more often had focal lesions. Thirty-one patients underwent treatment for their tumor, and 14 received CSF diversion only. Progression-free survival was ∼3 years shorter for children receiving tumor-directed therapy relative to those who had either no treatment or CSF diversion only. Overall survival was 85% for the tumor-directed therapy group, whereas no deaths were reported in the untreated or CSF diversion groups.

Conclusions: Unlike children with sporadically occurring BSGs, most children with NF1-BSGs were asymptomatic, and few individuals died from complications of their tumor. Those requiring tumor-directed treatment tended to be older children with focal lesions, and had clinically more aggressive disease relative to those who were not treated or underwent CSF diversion only.

Neurology 2017

Intracranial atherosclerosis and dementia The Atherosclerosis Risk in Communities (ARIC) Study

ABSTRACT

Objective: To explore the association of intracranial atherosclerotic disease (ICAD) with mild cognitive impairment (MCI) and dementia.

Methods: From 2011 to 2013, 1,744 participants completed high-resolution vessel wall MRI from the population-based Atherosclerosis Risk in Communities Study by a sampling strategy that allowed weighting back to the cohort. We defined ICAD by plaque features (presence, territory, stenosis, number). Trained clinicians used an algorithm incorporating information from interviews and neuropsychological and neurologic examinations to adjudicate for MCI and dementia. We determined the relative prevalence ratio (RPR) of MCI or dementia after adjusting for risk factors at midlife using multinomial logistic regression.

Results: A total of 601 (34.5%) participants had MCI (mean age ± SD, 76.6 ± 5.2 years), 83 (4.8%) had dementia (79.1 ± 5.3 years), and 857 (49.1%) were current or former smokers. Anterior cerebral artery (ACA) plaque (adjusted RPR 3.81, 95% confidence interval [CI] 1.57–9.23), >2 territories with plaque (adjusted RPR 2.12, 95% CI 1.00–4.49), and presence of stenosis >50% (adjusted RPR 1.92, 95% CI 1.01–3.65) were associated with increased prevalence of dementia in separate models. Posterior cerebral artery plaque was associated with MCI but did not reach statistical significance for dementia (adjusted RPR MCI 1.43, 95% CI 1.04–1.98; adjusted RPR dementia 1.58, 95% CI 0.79–2.85). There were no associations with middle cerebral artery atherosclerotic lesions or cognitive impairment. Many participants had plaque in >1 territory (n = 291, 46%) and participants with ACA plaques (n = 69) had the greatest number of plaques in other territories (mean 6.0, SD 4.4).

Conclusions: This study demonstrates associations between ICAD and clinical MCI and dementia.

Neurology 2017

Reference values for developing responsive functional outcome measures across the lifespan

ABSTRACT

Objective: To generate a reference dataset of commonly performed functional outcome measures in 1,000 children and adults and investigate the influence of demographic, anthropometric, strength, and flexibility characteristics.

Methods: Twelve functional outcome measures were collected from 1,000 healthy individuals aged 3–101 years: 6-minute walk test, 30-second chair stand test, timed stairs test, long jump, vertical jump, choice stepping reaction time, balance (Star Excursion Balance Test, tandem stance eyes open and closed, single-leg stance eyes closed), and dexterity (9-hole peg test, Functional Dexterity Test). Correlation and multiple regression analyses were performed to identify factors independently associated with each measure.

Results: Age- and sex-stratified reference values for functional outcome measures were generated. Functional performance increased through childhood and adolescence, plateaued during adulthood, and declined in older adulthood. While balance did not differ between the sexes, male participants generally performed better at gross motor tasks while female participants performed better at dexterous tasks. Height was the most consistent correlate of functional performance in children, while lower limb muscle strength was a major determinant in adolescents and adults. In older adults, age, lower limb strength, and joint flexibility explained up to 63% of the variance in functional measures.

Conclusions: These normative reference values provide a framework to accurately track functional decline associated with neuromuscular disorders and assist development and validation of responsive outcome measures for therapeutic trials.

Neurology 2017

Cardiorespiratory fitness alters the influence of a polygenic risk score on biomarkers of AD

ABSTRACT

Objective: To examine whether a polygenic risk score (PRS) derived from APOE4, CLU, and ABCA7 is associated with CSF biomarkers of Alzheimer disease (AD) pathology and whether higher cardiorespiratory fitness (CRF) modifies the association between the PRS and CSF biomarkers.

Methods: Ninety-five individuals from the Wisconsin Registry for Alzheimer's Prevention were included in these cross-sectional analyses. They were genotyped for APOE4, CLU, and ABCA7, from which a PRS was calculated for each participant. The participants underwent lumbar puncture for CSF collection. β-Amyloid 42 (Aβ₄₂), Aβ₄₀, total tau (t-tau), and phosphorylated tau (p-tau) were quantified by immunoassays, and Aβ₄₂/Aβ₄₀ and tau/Aβ₄₂ ratios were computed. CRF was estimated from a validated equation incorporating sex, age, body mass index, resting heart rate, and self-reported physical activity. Covariate-adjusted regression analyses were used to test for associations between the PRS and CSF biomarkers. In addition, by including a PRS×CRF term in the models, we examined whether these associations were modified by CRF.

Results: A higher PRS was associated with lower Aβ₄₂/Aβ₄₀ (p < 0.001), higher t-tau/Aβ₄₂ (p = 0.012), and higher p-tau/Aβ₄₂ (p = 0.040). Furthermore, we observed PRS × CRF interactions for Aβ₄₂/Aβ₄₀ (p = 0.003), t-tau/Aβ₄₂ (p = 0.003), and p-tau/Aβ₄₂ (p = 0.001). Specifically, the association between the PRS and these CSF biomarkers was diminished in those with higher CRF.

Conclusions: In a late-middle-aged cohort, CRF attenuates the adverse influence of genetic vulnerability on CSF biomarkers. These findings support the notion that increased cardiorespiratory fitness may be beneficial to those at increased genetic risk for AD.

Neurology 2017

Pharmacotherapy for diabetic peripheral neuropathy pain and quality of life A systematic review

ABSTRACT

Objective: To systematically assess the effect of pharmacologic treatments of diabetic peripheral neuropathy (DPN) on pain and quality of life.

Methods: We searched PubMed and Cochrane Database of Systematic Reviews for systematic reviews from 2011 to October 12, 2015, and PubMed, Embase, and the Cochrane Central Register of Controlled Trials for primary studies from January 1, 2013, to May 24, 2016. We searched Clinicaltrials.gov on March 9, 2016. Two reviewers independently evaluated studies for eligibility, serially abstracted data, and independently evaluated risk of bias and graded strength of evidence (SOE).

Results: We updated a recently completed systematic review of 57 eligible studies with 24 additional published studies and 25 unpublished studies. For reducing neuropathy-related pain, the serotonin-norepinephrine reuptake inhibitors duloxetine and venlafaxine (moderate SOE), the anticonvulsants pregabalin and oxcarbazepine (low SOE), the drug classes tricyclic antidepressants (low SOE) and atypical opioids (low SOE), and botulinum toxin (low SOE) were more effective than placebo. We could not draw conclusions about quality of life due to incomplete reporting. All studies were short-term (less than 6 months), and all effective drugs had more than 9% dropouts from adverse effects.

Conclusions: For reducing pain, duloxetine and venlafaxine, pregabalin and oxcarbazepine, tricyclic antidepressants, atypical opioids, and botulinum toxin were more effective than placebo. However, quality of life was poorly reported, studies were short-term, drugs had substantial dropout rates, and opioids have significant risks. Future studies should evaluate longer-term outcomes, use methods and measures recommended by pain organizations, and assess patients' quality of life.

Neurology 2017

Modulating risky decision-making in Parkinson's disease by transcranial direct current stimulation.

Abstract

BACKGROUND AND PURPOSE:

Performance on gambling tasks in Parkinson's disease (PD) is of particular interest, as pathological gambling is often associated with dopamine replacement therapy in these patients. We aimed to evaluate the effects of transcranial direct current stimulation (tDCS) over the right dorsolateral prefrontal cortex (DLPFC) in modulating gambling behaviour in PD.

METHODS:

We assessed the effects of cathodal tDCS over the right DLPFC during the Iowa Gambling Task in 20 patients with PD, compared with sham stimulation. We then conducted a second experimental design, assessing the effects of anodal tDCS over the right DLPFC.

RESULTS:

We observed that cathodal tDCS over the right DLPFC increased Iowa Gambling Task scores compared with sham stimulation. In the second experimental design, we did not find significant differences between anodal and sham tDCS.

CONCLUSIONS:

Cathodal tDCS over the right DLPFC possibly reduces the pathological overdrive in frontostriatal networks in patients with PD on dopaminergic medication, thus modulating impulsive and risky decision-making.

Eur J Neurol 2017

Frontotemporal Dementia due to the Novel GRN Arg161GlyfsX36 Mutation.

Abstract

Progranulin is a multifunctional growth factor mainly expressed in neurons and microglia. Loss-of-function mutations in the Granulin (GRN) gene are causative of frontotemporal dementia with TAR DNA-binding protein-43 inclusions. We reported the case of a 51-year-old male patient affected by sporadic agrammatic variant of primary progressive aphasia, in whom we identified a novel heterozygous deletion in the exon 6 (g.10338_39delAG, p.Arg161GlyfsX36). Plasma progranulin levels were significantly reduced and in silico analysis predicted a premature termination codon. This case expands our knowledge on GRN mutations in frontotemporal dementia.

J Alzheimer DIs 2017

Restoring brain function after stroke — bridging the gap between animals and humans

Stroke is the leading cause of complex adult disability in the world. Recovery from stroke is often incomplete, which leaves many people dependent on others for their care. The improvement of long-term outcomes should, therefore, be a clinical and research priority. As a result of advances in our understanding of the biological mechanisms involved in recovery and repair after stroke, therapeutic opportunities to promote recovery through manipulation of poststroke plasticity have never been greater. This work has almost exclusively been carried out in preclinical animal models of stroke with little translation into human studies. The challenge ahead is to develop a mechanistic understanding of recovery from stroke in humans. Advances in neuroimaging techniques now enable us to reconcile behavioural accounts of recovery with molecular and cellular changes. Consequently, clinical trials can be designed in a stratified manner that takes into account when an intervention should be delivered and who is most likely to benefit. This approach is expected to lead to a substantial change in how restorative therapeutic strategies are delivered in patients after stroke.

Nature Reviews Neurology 2017

Multiple system atrophy: insights into a rare and debilitating movement disorder

Multiple system atrophy (MSA) is a devastating and fatal neurodegenerative disorder. The clinical presentation of this disease is highly variable, with parkinsonism, cerebellar ataxia and autonomic failure being the most common — and often debilitating — symptoms. These symptoms progress rapidly, and patients die from MSA-related complications after 9 years of symptom duration on average. Unfortunately, the course of the disease cannot be improved by drug or surgical treatment. In addition, symptomatic treatment options are currently limited, and therapeutic benefits are often only transient. Thus, further interventional studies of candidate disease-modifying and symptomatic therapies are essential to improve patient care. In the past 15 years, the understanding of MSA-specific requirements in trial methodology has improved, resulting in a substantial increase in high-quality interventional studies. In this Review, we discuss MSA risk factors, clinical presentation and neuropathology, and we provide a hypothesis on key pathophysiological events, a summary of recent randomized controlled trials, and an overview of ongoing international collaborations

Nature Reviews Neurology 2017

New technologies for the assessment of neuropathies

Technical advances are rapidly changing the clinical and instrumental approach to peripheral nerve diseases. Magnetic resonance neurography, diffusion tensor imaging and nerve ultrasonography are increasingly entering the diagnostic workup of peripheral neuropathies as tools that complement neurophysiology and enable investigation of proximal structures, such as plexuses and roots. Progress in the design of magnetic resonance scanners and sequences, and the development of high-frequency ultrasound probes mean that high-resolution peripheral nerve imaging is possible, enabling detailed examination of nerve size, morphology and internal fascicular structure that can integrate nerve conduction studies into clinical practice. In the growing field of small-fibre neuropathy, in which traditional nerve conduction studies are of little or no use, skin biopsy has become a reliable tool for diagnosis. Corneal confocal microscopy, nociceptive evoked potentials and microneurography are emerging techniques that are mainly used in clinical research settings, but have increasing relevance to clinical practice. We review these new and emerging techniques and their effects on diagnosis, treatment strategies and prognosis in a variety of peripheral neuropathies, including entrapments, brachial plexopathies, immune and inherited neuropathies, and small-fibre neuropathies. We discuss the most promising research findings and their potential for future application in clinical practice

Nature Reviews Neurology 2017

Neurofibrillary Tangle Stage and the Rate of Progression of Alzheimer Symptoms Modeling Using an Autopsy Cohort and Application to Clinical Trial Design

Abstract

Importance  The heterogeneity of rate of clinical progression among patients with Alzheimer disease leads to difficulty in providing clinical counseling and diminishes the power of clinical trials using disease-modifying agents.

Objective  To gain a better understanding of the factors that affect the natural history of progression in Alzheimer disease for the purpose of improving both clinical care and clinical trial design.

Design, Setting, and Participants  A longitudinal cohort study of aging from 2005 to 2014 in the National Alzheimer Coordinating Center. Clinical evaluation of the participants was conducted in 31 National Institute on Aging’s Alzheimer Disease Centers. Nine hundred eighty-four participants in the National Alzheimer Coordinating Center cohort study who died and underwent autopsy and met inclusion and exclusion criteria.

Main Outcomes and Measures  We sought to model the possibility that knowledge of neurofibrillary tangle burden in the presence of moderate or frequent plaques would add to the ability to predict clinical rate of progression during the ensuing 2 to 3 years. We examined the National Alzheimer Coordinating Center autopsy data to evaluate the effect of different neurofibrillary tangle stages on the rates of progression on several standard clinical instruments: the Clinical Dementia Rating Scale sum of boxes, a verbal memory test (logical memory), and a controlled oral word association task (vegetable naming), implementing a reverse-time longitudinal modeling approach in conjunction with latent class estimation to adjust for unmeasured sources of heterogeneity.

Results  Several correlations between clinical variables and neurocognitive performance suggest a basis for heterogeneity: Higher education level was associated with lower Clinical Dementia Rating Scale sum of boxes (β = −0.19; P < .001), and frequent vs moderate neuritic plaques were associated with higher Clinical Dementia Rating Scale sum of boxes (β = 1.64; P < .001) and lower logical memory score (β = −1.07; P = .005). The rate of change of the clinical and cognitive scores varied depending on Braak stage, when adjusting for plaques, age of death, sex, education, and APOE genotype. For example, comparing high vs low Braak stage with other variables fixed, the logical memory score decreased a substantial 0.38 additional units per year (95% CI, −0.70 to −0.06; P = .02). Using these data, we estimate that a 300-participant clinical trial with end point of a 20% improvement in slope in rate of change of Clinical Dementia Rating Scale sum of boxes has 89% power when all participants in the trial are from the high Braak stage, compared with 29% power if Braak stage had not used for eligibility.

Conclusions and Relevance  We found that knowledge of neurofibrillary tangle stage, modeled as the sort of information that could be available from tau positron-emission tomography scans and its use to determine eligibility to a trial, could dramatically improve the power of clinical trials and equivalently reduce the required sample sizes of clinical trials.

JAMA Neurology 2017