Formulations of hormone therapy and risk of Parkinson's disease

Hormone therapy (HT) is a class of medications widely prescribed to women in the Western world. Evidence from animal models and in vitro studies suggests that estrogen may protect against nigrostriatal system injury and increase dopamine synthesis, metabolism, and transport. Existing epidemiologic research indicates a possible reduced risk of Parkinson's disease (PD) associated with HT use. The objective of this study was to evaluate PD risk associated with specific HT formulations. Neurologist-confirmed cases and age-matched controls were identified from Group Health Cooperative (GHC) of Washington State. Final analysis included 137 female cases and 227 controls. Hormone therapy use was ascertained from the GHC pharmacy database, further classified as conjugated estrogens, esterified estrogens, and progestin. Ever use of HT formulation demonstrated a suggested elevated risk with esterified estrogen use (odds ratio [OR], 3.1; 95% confidence interval [CI], 1.0-9.8), and no risk associated with conjugated estrogen use (OR, 0.6; 95% CI, 0.6-1.3). Restricting this analysis to prescriptions that included progestin further elevated the risk associated with esterified estrogen use (OR, 6.9; 95% CI, 2.1-22.9); again, no risk was associated with conjugated estrogen use (OR, 1.7; 95% CI, 0.6-5.0). The findings from this study suggest an increase in PD risk associated with esterified estrogen use combined with progestin, and no risk associated with conjugated estrogen with progestin. These findings could have important implications for choice of HT in clinical practice.

Movement Disorders 2014

Lack of validation of variants associated with cervical dystonia risk: A GWAS replication study

A recent genome-wide association study (GWAS) has identified a putative association, not statistically confirmed, of cervical dystonia within several regions in a British population. Hence, the authors proposed dysfunction of the ion channel NALCN (for sodium leak channel, nonselective) as a plausible cause of cervical dystonia. The objective of our study was to investigate the association of five single nucleotide polymorphisms (SNPs) previously reported with high signals as putative genetic risk factors for cervical dystonia in a British GWAS, including two located in the NALCN gene region.

Methods

We performed a case-control association study in a Spanish population. The SNPs selected for genotyping were two SNPS in the NALCNgene (rs61973742 and rs1338041), one SNP in the OR4X2 gene (rs67863238), one SNP in the COL4A1 region (rs619152), and one intergenic SNP (rs1249277). Genomic DNA was collected from 252 patients with cervical dystonia, with a mean age of 55.3 ± 14.1 years (mean age at onset, 43.5 ± 15.7 years), and 342 unrelated control subjects with a mean age of 56.3 ± 14.3 years. Genotyping of SNPs was performed using TaqMan assays and SimpleProbe assays.

Results

The SNP rs619152 had to be excluded because of assay failure. No significant differences were found in allele distribution between cases and controls for all analyzed SNPs. Therefore, we found no association with cervical dystonia for the analyzed SNPs in our Spanish population.

Conclusions

We did not find any evidence supporting the association of NALCN with cervical dystonia, indicating that this gene is not implicated in the pathogenesis of this disorder in our cervical dystonia population.

Movement Disorders 2014

Emerging Therapies for Glioblastoma

Importance  Glioblastoma is the most common primary malignant brain tumor, but despite multimodal treatment with surgery, radiotherapy, and temozolomide chemotherapy, the prognosis is poor, with a median survival of 16 to 19 months and poor quality of life throughout the disease course. New treatments are needed.

Evidence Review  Articles were identified through a search of PubMed references from March 2005 through January 2014, using the terms glioblastoma, glioma, malignant glioma, and brain neoplasm, as well as by search of the authors’ files. Clinical trials were identified in the Clinicaltrials.gov registry.

Findings  Advances in the understanding of the molecular biology of glioblastoma are being rapidly translated into innovative clinical trials, capitalizing on improved genomic, epigenetic, transcriptional, and proteomic characterization of glioblastomas as well as host factors, including the brain microenvironment and immune system interactions. Therapies targeting tumor growth factor receptors and downstream pathways, angiogenesis, modulation of cancer stemlike cells, cell cycle regulation, oncolytic viruses, new radiotherapy techniques, and immunotherapy, including vaccines and modulation of immune checkpoints (eg, programmed cell death 1 and cytotoxic T-lymphocyte antigen 4), are under investigation. In addition to novel agents, techniques to circumvent the blood-brain barrier to facilitate central nervous system drug exposure are being developed.

Conclusions and Relevance  Glioblastoma is an aggressive tumor with heterogeneous molecular features and complex host interactions, many of which are amenable to therapeutic intervention. Meaningful treatment advances will depend on identifying agents that target mechanistic vulnerabilities that are relevant to specific subgroups of patients; increasing patient enrollment into clinical trials is essential to accelerate the development of patient-tailored treatments.

JAMA Neurology 2014

Effect of Statin Use During Hospitalization for Intracerebral Hemorrhage on Mortality and Discharge Disposition

Importance  Statin use during hospitalization is associated with improved survival and a better discharge disposition among patients with ischemic stroke. It is unclear whether inpatient statin use has a similar effect among patients with intracerebral hemorrhage (ICH).

Objective  To determine whether inpatient statin use in ICH is associated with improved outcomes and whether the cessation of statin use is associated with worsened outcomes.

Design, Setting, and Participants  Retrospective cohort study of 3481 patients with ICH admitted to any of 20 hospitals in a large integrated health care delivery system over a 10-year period. Detailed electronic medical and pharmacy records were analyzed to explore the association between inpatient statin use and outcomes.

Main Outcomes and Measures  The primary outcome measures were survival to 30 days after ICH and discharge to home or inpatient rehabilitation facility. We used multivariable logistic regression, controlling for demographics, comorbidities, initial severity, and code status. In addition, we used instrumental variable modeling to control for confounding by unmeasured covariates at the individual patient level.

Results  Among patients hospitalized for ICH, inpatient statin users were more likely than nonusers to be alive 30 days after ICH (odds ratio [OR], 4.25 [95% CI, 3.46-5.23]; P < .001) and were more likely than nonusers to be discharged to their home or an acute rehabilitation facility (OR, 2.57 [95% CI, 2.16-3.06]; P < .001). Patients whose statin therapy was discontinued were less likely than statin users to survive to 30 days (OR, 0.16 [95% CI, 0.12-0.21]; P < .001) and were less likely than statin users to be discharged to their home or an acute rehabilitation facility (OR, 0.26 [95% CI, 0.20-0.35]; P < .001). Instrumental variable models of local treatment environment (to control for confounding by unmeasured covariates) confirmed that a higher probability of statin therapy was associated with a higher probability of 30-day survival (with an increase in probability of 0.15 [95% CI, 0.04-0.25]; P = .01) and a better chance of being discharged to home or an acute rehabilitation facility (with an increase in probability of 0.13 [95% CI, 0.02-0.24]; P = .02).

Conclusions and Relevance  Inpatient statin use is associated with improved outcomes after ICH, and the cessation of statin use is associated with worsened outcomes after ICH. Given the association between statin cessation and substantially worsened outcomes, the risk-benefit balance of discontinuing statin therapy in the acute setting of ICH should be carefully considered.

JAMA Neurology 2014

Adult-onset autosomal dominant centronuclear myopathy due to BIN1 mutations

Centronuclear myopathies are congenital muscle disorders characterized by type I myofibre predominance and an increased number of muscle fibres with nuclear centralization. The severe neonatal X-linked form is due to mutations in MTM1, autosomal recessive centronuclear myopathy with neonatal or childhood onset results from mutations in BIN1(amphiphysin 2), and dominant cases were previously associated to mutations in DNM2 (dynamin 2). Our aim was to determine the genetic basis and physiopathology of patients with mild dominant centronuclear myopathy without mutations in DNM2. We hence established and characterized a homogeneous cohort of nine patients from five families with a progressive adult-onset centronuclear myopathy without facial weakness, including three sporadic cases and two families with dominant disease inheritance. All patients had similar histological and ultrastructural features involving type I fibre predominance and hypotrophy, as well as prominent nuclear centralization and clustering. We identified heterozygous BIN1 mutations in all patients and the molecular diagnosis was complemented by functional analyses. Two mutations in the N-terminal amphipathic helix strongly decreased the membrane-deforming properties of amphiphysin 2 and three stop-loss mutations resulted in a stable protein containing 52 supernumerary amino acids. Immunolabelling experiments revealed abnormal central accumulation of dynamin 2, caveolin-3, and the autophagic marker p62, and general membrane alterations of the triad, the sarcolemma, and the basal lamina as potential pathological mechanisms. In conclusion, we identified BIN1 as the second gene for dominant centronuclear myopathy. Our data provide the evidence that specific BIN1 mutations can cause either recessive or dominant centronuclear myopathy and that both disorders involve different pathomechanisms.

Brain 2014

Levetiracetam reduces abnormal network activations in temporal lobe epilepsy

Objective: We used functional MRI (fMRI) and a left-lateralizing verbal and a right-lateralizing visual-spatial working memory (WM) paradigm to investigate the effects of levetiracetam (LEV) on cognitive network activations in patients with drug-resistant temporal lobe epilepsy (TLE).

Methods: In a retrospective study, we compared task-related fMRI activations and deactivations in 53 patients with left and 54 patients with right TLE treated with (59) or without (48) LEV. In patients on LEV, activation patterns were correlated with the daily LEV dose.

Results: We isolated task- and syndrome-specific effects. Patients on LEV showed normalization of functional network deactivations in the right temporal lobe in right TLE during the right-lateralizing visual-spatial task and in the left temporal lobe in left TLE during the verbal task. In a post hoc analysis, a significant dose-dependent effect was demonstrated in right TLE during the visual-spatial WM task: the lower the LEV dose, the greater the abnormal right hippocampal activation. At a less stringent threshold (p < 0.05, uncorrected for multiple comparisons), a similar dose effect was observed in left TLE during the verbal task: both hippocampi were more abnormally activated in patients with lower doses, but more prominently on the left.

Conclusions: Our findings suggest that LEV is associated with restoration of normal activation patterns. Longitudinal studies are necessary to establish whether the neural patterns translate to drug response.

Classification of evidence: This study provides Class III evidence that in patients with drug-resistant TLE, levetiracetam has a dose-dependent facilitation of deactivation of mesial temporal structures.

Neurology 2014

Spinocerebellar ataxia 35 Novel mutations in TGM6 with clinical and genetic characterization

Objective: To elucidate the clinical and cellular characteristics of spinocerebellar ataxia type 35 (SCA35), which is caused by mutations in the TGM6 gene encoding transglutaminase 6 (TG6), in a Taiwanese cohort.

Methods: Mutations in TGM6 were ascertained in 109 unrelated probands of Chinese descent with molecularly unassigned SCA from 512 pedigrees, in whom mutations responsible for 15 other ataxia syndromes had been excluded. The clinical features of all patients with a TGM6 mutation were systematically analyzed. The biological consequences of the newly identified TGM6 mutations were investigated in HEK293 cells transfected with mutant complementary DNA constructs.

Results: Two missense mutations (p.R111C and p.D510H) and one 3–base pair deletion (p.E574del) in TGM6 were identified. Among them, p.R111C and p.E574del were novel. The common features of SCA35 include a slowly progressive clinical course, trunk/limb ataxia, and hand tremors. The age at onset varies from adolescence to the fifth decade. Torticollis and intellectual impairment are rare manifestations. Brain MRI reveals diffuse cerebellar atrophy without involvement of the cerebral hemispheres or brainstem. The 3 mutations identified here attenuated the protein stability and catalytic activities of TG6.

Conclusions: SCA35 is an uncommon ataxia syndrome, accounting for 0.6% (3/512) of SCAs among the Han-Chinese descent in Taiwan. This study broadens the mutational spectrum of SCA35 and stresses the importance of TG6 in cerebellar functions.

Neurology 2014

Long sleep duration in elders without dementia increases risk of dementia mortality (NEDICES)

Objective: To determine in a population-based study whether long sleep duration was associated with increased risk of dementia mortality.

Methods: In this prospective, population-based study of 3,857 people without dementia aged 65 years and older (NEDICES [Neurological Disorders in Central Spain]), participants reported their daily sleep duration. The average daily total sleep duration was grouped into 3 categories: ≤5 hours (short sleepers), 6–8 hours (reference category), and ≥9 hours (long sleepers). Community-dwelling elders were followed for a median of 12.5 years, after which the death certificates of those who died were examined.

Results: A total of 1,822 (47.2%) of 3,857 participants died, including 201 (11.0%) deaths among short sleepers, 832 (45.7%) among long sleepers, and 789 (43.3%) among those participants in the reference category. Of 1,822 deceased participants, 92 (5.1%) had a dementia condition reported on the death certificate (49 [53.3%] were long sleepers, 36 [39.1%] reported sleeping between 6 and 8 hours, and 7 [7.6%] were short sleepers). In an unadjusted Cox model, risk of dementia-specific mortality was increased in long sleepers (hazard ratio for dementia mortality in long sleepers = 1.58, p = 0.04) when compared with the reference group. In a Cox model that adjusted for numerous demographic factors and comorbidities, the hazard ratio for dementia mortality in long sleepers was 1.63 (p = 0.03).

Conclusions: Self-reported long sleep duration was associated with 58% increased risk of dementia-specific mortality in this cohort of elders without dementia. Future studies are required to confirm these findings.

Neurology 2014

Dalfampridine may activate latent trigeminal neuralgia in patients with multiple sclerosis

Objective: To determine the effect of dalfampridine (4-aminopyridine), a broad-spectrum, voltage-dependent potassium channel blocker, on patients with trigeminal nerve dysfunction due to multiple sclerosis (MS).

Methods: We reviewed histories of 71 patients in our clinic with clinically definite MS who were treated with dalfampridine for at least 2 to 3 months. Of the 71 patients, 5 had a history of either trigeminal neuralgia or altered facial sensation.

Results: Of these 5 patients, 3 with preexisting trigeminal neuralgia had a marked worsening of facial pain in close proximity to starting dalfampridine. One patient with altered facial sensation developed trigeminal pain after being on dalfampridine for 18 months. Pain in this individual rapidly subsided when dalfampridine was discontinued. Pain in the worsened 3 patients persisted, became more refractory to previously effective medications, and in one instance required trigeminal surgery for pain control.

Conclusions: Dalfampridine should be used with caution in persons with trigeminal neuralgia due to MS.

Classification of evidence: This study provides Class IV evidence that treatment with dalfampridine may precipitate or exacerbate preexisting trigeminal neuralgia.

Neurology 2014

Agreement between TOAST and CCS ischemic stroke classification. The NINDS SiGN Study

Objective: The objective of this study was to assess the level of agreement between stroke subtype classifications made using the Trial of Org 10172 Acute Stroke Treatment (TOAST) and Causative Classification of Stroke (CCS) systems.

Methods: Study subjects included 13,596 adult men and women accrued from 20 US and European genetic research centers participating in the National Institute of Neurological Disorders and Stroke (NINDS) Stroke Genetics Network (SiGN). All cases had independently classified TOAST and CCS stroke subtypes. Kappa statistics were calculated for the 5 major ischemic stroke subtypes common to both systems.

Results: The overall agreement between TOAST and CCS was moderate (agreement rate, 70%; κ = 0.59, 95% confidence interval [CI] 0.58–0.60). Agreement varied widely across study sites, ranging from 28% to 90%. Agreement on specific subtypes was highest for large-artery atherosclerosis (κ = 0.71, 95% CI 0.69–0.73) and lowest for small-artery occlusion (κ = 0.56, 95% CI 0.54–0.58).

Conclusion: Agreement between TOAST and CCS diagnoses was moderate. Caution is warranted when comparing or combining results based on the 2 systems. Replication of study results, for example, genome-wide association studies, should utilize phenotypes determined by the same classification system, ideally applied in the same manner.

Neurology 2014

GINIP, a Gαi-Interacting Protein, Functions as a Key Modulator of Peripheral GABAB Receptor-Mediated Analgesia

One feature of neuropathic pain is a reduced GABAergic inhibitory function. Nociceptors have been suggested to play a key role in this process. However, the mechanisms behind nociceptor-mediated modulation of GABA signaling remain to be elucidated. Here we describe the identification of GINIP, a Gαi-interacting protein expressed in two distinct subsets of nonpeptidergic nociceptors. GINIP null mice develop a selective and prolonged mechanical hypersensitivity in models of inflammation and neuropathy. GINIP null mice show impaired responsiveness to GABAB, but not to delta or mu opioid receptor agonist-mediated analgesia specifically in the spared nerve injury (SNI) model. Consistently, GINIP-deficient dorsal root ganglia neurons had lower baclofen-evoked inhibition of high-voltage-activated calcium channels and a defective presynaptic inhibition of lamina IIi interneurons. These results further support the role of unmyelinated C fibers in injury-induced modulation of spinal GABAergic inhibition and identify GINIP as a key modulator of peripherally evoked GABAB-receptors signaling.

Neuron 2014

Primary progressive aphasia and the evolving neurology of the language network

Primary progressive aphasia (PPA) is caused by selective neurodegeneration of the language-dominant cerebral hemisphere; a language deficit initially arises as the only consequential impairment and remains predominant throughout most of the course of the disease. Agrammatic, logopenic and semantic subtypes, each reflecting a characteristic pattern of language impairment and corresponding anatomical distribution of cortical atrophy, represent the most frequent presentations of PPA. Such associations between clinical features and the sites of atrophy have provided new insights into the neurology of fluency, grammar, word retrieval, and word comprehension, and have necessitated modification of concepts related to the functions of the anterior temporal lobe and Wernicke's area. The underlying neuropathology of PPA is, most commonly, frontotemporal lobar degeneration in the agrammatic and semantic forms, and Alzheimer disease (AD) pathology in the logopenic form; the AD pathology often displays atypical and asymmetrical anatomical features consistent with the aphasic phenotype. The PPA syndrome reflects complex interactions between disease-specific neuropathological features and patient-specific vulnerability. A better understanding of these interactions might help us to elucidate the biology of the language network and the principles of selective vulnerability in neurodegenerative diseases. We review these aspects of PPA, focusing on advances in our understanding of the clinical features and neuropathology of PPA and what they have taught us about the neural substrates of the language network.

Nature Reviews Neurology 2014

Neuropsychiatric systemic lupus erythematosus: pathogenesis and biomarkers

Systemic lupus erythematosus (SLE) is a complex clinical syndrome, elements of which remain poorly understood. Although recognized over 140 years ago when Kaposi recorded the systemic nature and manifestations of the disease, CNS involvement represents one of the least understood aspects of SLE. This knowledge gap remains despite the fact that up to 75% of adults and children with SLE will, at some point over the course of the disease and to different extents, experience the various disabling effects of neuropsychiatric SLE (NPSLE). Indeed, after decades of research, our understanding of the underlying pathophysiology of NPSLE, in particular, remains limited. Numerous factors contribute to the immune dysfunction that occurs in SLE, including genetic, environmental and hormonal influences, and the contributory or predisposing components that lead to neurological tropism of disease in some patients have not been clearly demonstrated. Features of NPSLE pathogenesis that might be directly linked to clinical manifestations have been identified; however, the complexity and variety of NPSLE symptoms and the clinical overlap with other psychiatric disorders continue to make accurate diagnosis difficult and time-consuming. Thus, efforts to define biomarkers of NPSLE are needed to improve prediction of disease outcomes and guide treatment. In this article, we review the manifestation and pathogenesis of NPSLE, focusing on the features that might aid identification of potential biomarkers.

Nature Reviews Neurology 2014

Modulation of brain plasticity in stroke: a novel model for neurorehabilitation

Noninvasive brain stimulation (NIBS) techniques can be used to monitor and modulate the excitability of intracortical neuronal circuits. Long periods of cortical stimulation can produce lasting effects on brain function, paving the way for therapeutic applications of NIBS in chronic neurological disease. The potential of NIBS in stroke rehabilitation has been of particular interest, because stroke is the main cause of permanent disability in industrial nations, and treatment outcomes often fail to meet the expectations of patients. Despite promising reports from many clinical trials on NIBS for stroke recovery, the number of studies reporting a null effect remains a concern. One possible explanation is that the interhemispheric competition model—which posits that suppressing the excitability of the hemisphere not affected by stroke will enhance recovery by reducing interhemispheric inhibition of the stroke hemisphere, and forms the rationale for many studies—is oversimplified or even incorrect. Here, we critically review the proposed mechanisms of synaptic and functional reorganization after stroke, and suggest a bimodal balance–recovery model that links interhemispheric balancing and functional recovery to the structural reserve spared by the lesion. The proposed model could enable NIBS to be tailored to the needs of individual patients.

Nature Reviews Neurology 2014

Chronic subdural haematoma: modern management and emerging therapies

Chronic subdural haematoma (CSDH) is one of the most common neurological disorders, and is especially prevalent among elderly individuals. Surgical evacuation is the mainstay of management for symptomatic patients or haematomas exerting significant mass effect. Although burr hole craniostomy is the most widely practised technique worldwide, approximately 10–20% of surgically treated patients experience postoperative recurrence necessitating reoperation. Given the increasing incidence of CSDH in a growing elderly population, a need exists for refined techniques that combine a minimally invasive approach with clinical efficacy and cost-effectiveness. In addition, nonsurgical treatment modalities, such as steroids, are attracting considerable interest, as they have the potential to reduce postoperative recurrence or even replace the need for surgery in selected patients. This Review provides an overview of the contemporary management of CSDH and presents considerations regarding future approaches that could further optimize patient care and outcomes.

Nature Reviews Neurology 2014

Deep-Brain Stimulation — Entering the Era of Human Neural-Network Modulation

Scribonius Largus, the court physician for the Roman emperor Claudius, used an electrical torpedo fish in 50 A.D. to treat headaches and gout. More than 1000 years elapsed before the idea of therapeutic brain stimulation was rekindled. In 1786, Luigi Galvani demonstrated that he could conduct electricity through the nerves in a frog's leg. Later, Alessandro Volta conducted electrical current through wires and built crude but effective battery sources. Yet none of these experimenters could have predicted the usefulness of their technology in treating human disease by applying an electrical current within the human brain...

 http://www.nejm.org/doi/full/10.1056/NEJMp1408779

NEJM 2014

Degradation of emotion processing ability in corticobasal syndrome and Alzheimer’s disease

Disturbed emotion processing and difficulty with social interactions are present to variable degrees in dementia. They are characteristic features of frontotemporal dementia, whereas these deficits tend to be mild in Alzheimer’s disease, reflecting the different patterns of neurodegeneration seen in these disorders. Corticobasal syndrome is an atypical parkinsonian disorder clinically and pathologically related to frontotemporal dementia. Corticobasal syndrome typically presents as a motor disturbance, although cognitive and behavioural changes are now recognized. Pathological changes are found in frontoparietal cortical regions and in the basal ganglia; regions that are heavily involved in emotion processing. Despite the overlap with frontotemporal dementia and the observed regions of brain atrophy, emotion processing has not been systematically explored in corticobasal syndrome. This study aimed to (i) comprehensively examine emotion processing in corticobasal syndrome in comparison to Alzheimer’s disease, to determine whether emotion processing deficits exist in this syndrome, beyond those seen in Alzheimer’s disease; and (ii) identify the neural correlates underlying emotion processing in corticobasal syndrome and Alzheimer’s disease. Sixteen patients with corticobasal syndrome, 18 patients with Alzheimer’s disease and 22 matched healthy control subjects were assessed on a comprehensive battery of face and emotion processing tasks. Behavioural analyses revealed deficits in both basic face processing and high-level emotion processing tasks in patients with corticobasal syndrome. Notably, the emotion processing disturbance persisted even after controlling for face processing deficits. In contrast, patients with Alzheimer’s disease were impaired on high-level complex and cognitively demanding emotion recognition tasks (Ekman 60, The Awareness of Social Inference Test) only. Neuroimaging analyses using FreeSurfer revealed that emotion processing deficits in corticobasal syndrome were associated with basal ganglia volume loss as well as cortical thinning of the left paracentral gyrus/precuneus region. In Alzheimer’s disease, however, emotion processing deficits were associated with atrophy in a different set of brain regions, including the right cingulate and the bilateral insulae, as well as the hippocampi, right amygdala and nucleus accumbens bilaterally. Our results demonstrate that patients with corticobasal syndrome experience widespread deficits in emotion processing, and these deficits are related to changes in brain regions known to be crucial for emotion processing. These findings have important clinical implications for the treatment and management of these patients.

Brain 204

Glutamatergic neuron-targeted loss of LGI1 epilepsy gene results in seizures

Leucin-rich, glioma inactivated 1 (LGI1) is a secreted protein linked to human seizures of both genetic and autoimmune aetiology. Mutations in the LGI1 gene are responsible for autosomal dominant temporal lobe epilepsy with auditory features, whereas LGI1 autoantibodies are involved in limbic encephalitis, an acquired epileptic disorder associated with cognitive impairment. We and others previously reported that Lgi1-deficient mice have early-onset spontaneous seizures leading to premature death at 2–3 weeks of age. Yet, where and when Lgi1 deficiency causes epilepsy remains unknown. To address these questions, we generated Lgi1 conditional knockout (cKO) mice using a set of universal Cre-driver mouse lines. Selective deletion of Lgi1 was achieved in glutamatergic pyramidal neurons during embryonic (Emx1-Lgi1cKO) or late postnatal (CaMKIIα-Lgi1cKO) developmental stages, or in gamma amino butyric acidergic (GABAergic) parvalbumin interneurons (PV-Lgi1cKO). Emx1-Lgi1cKO mice displayed early-onset and lethal seizures, whereas CaMKIIα-Lgi1cKO mice presented late-onset occasional seizures associated with variable reduced lifespan. In contrast, neither spontaneous seizures nor increased seizure susceptibility to convulsant were observed when Lgi1 was deleted in parvalbumin interneurons. Together, these data showed that LGI1 depletion restricted to pyramidal cells is sufficient to generate seizures, whereas seizure thresholds were unchanged after depletion in gamma amino butyric acidergic parvalbumin interneurons. We suggest that LGI1 secreted from excitatory neurons, but not parvalbumin inhibitory neurons, makes a major contribution to the pathogenesis of LGI1-related epilepsies. Our data further indicate that LGI1 is required from embryogenesis to adulthood to achieve proper circuit functioning.

Brain 2014

Synergistic Effect of β-Amyloid and Neurodegeneration on Cognitive Decline in Clinically Normal Individuals

Importance  Assessing the ability of Alzheimer disease neuroimaging markers to predict short-term cognitive decline among clinically normal (CN) individuals is critical for upcoming secondary prevention trials using cognitive outcomes.

Objective  To determine whether neuroimaging markers of β-amyloid (Aβ) and neurodegeneration (ND) are independently or synergistically associated with longitudinal cognitive decline in CN individuals.

Design, Setting, and Participants  Academic medical center longitudinal natural history study among 166 CN individuals (median age, 74 years; 92 women).

Main Outcomes and Measures  The Aβ status was determined with Pittsburgh Compound B–positron emission tomography, while ND was assessed using 2 a priori measures, hippocampus volume (magnetic resonance imaging) and glucose metabolism (positron emission tomography with fludeoxyglucose F 18), extracted from Alzheimer disease–vulnerable regions. Based on imaging markers, CN individuals were categorized into the following preclinical Alzheimer disease stages: stage 0 (Aβ−/ND−), stage 1 (Aβ+/ND−), stage 2 (Aβ+/ND+), and suspected non–Alzheimer disease pathology (Aβ−/ND+). Cognition was assessed with a composite of neuropsychological tests administered annually.

Results  The Aβ+ CN individuals were more likely to be classified as ND+: 59.6% of Aβ+ CN individuals were ND+, whereas 31.9% of Aβ− CN individuals were ND+ (odds ratio, 3.14; 95% CI, 1.44-7.02; P = .004). In assessing longitudinal cognitive performance, practice effects were evident in CN individuals negative for both Aβ and ND, whereas diminished practice effects were observed in CN individuals positive for either Aβ or ND. Decline over time was observed only in CN individuals positive for both Aβ and ND, and decline in this group was significantly greater than that in all other groups (P < .001 for all). A significant interaction term between Aβ and ND confirmed that this decline was greater than the additive contributions of Aβ and ND (P = .04).

Conclusions and Relevance  The co-occurrence of Aβ and ND accelerates cognitive decline in CN individuals. Therefore, both factors are important to consider in upcoming secondary prevention trials targeting CN individuals at high risk for progression to the symptomatic stages of Alzheimer disease.

JAMA Neurology 2014

Synaptotagmin 2 mutations cause an autosomal-dominant form of lambert-eaton myasthenic syndrome and nonprogressive motor neuropathy.

Synaptotagmin 2 is a synaptic vesicle protein that functions as a calcium sensor for neurotransmission but has not been previously associated with human disease. Via whole-exome sequencing, we identified heterozygous missense mutations in the C2B calcium-binding domain of the gene encoding Synaptotagmin 2 in two multigenerational families presenting with peripheral motor neuron syndromes. An essential calcium-binding aspartate residue, Asp307Ala, was disrupted by a c.920A>C change in one family that presented with an autosomal-dominant presynaptic neuromuscular junction disorder resembling Lambert-Eaton myasthenic syndrome. A c.923C>T variant affecting an adjacent residue (p.Pro308Leu) produced a presynaptic neuromuscular junction defect and a dominant hereditary motor neuropathy in a second family. Characterization of the mutation homologous to the human c.920A>C variant in Drosophila Synaptotagmin revealed a dominant disruption of synaptic vesicle exocytosis using this transgenic model. These findings indicate that Synaptotagmin 2 regulates neurotransmitter release at human peripheral motor nerve terminals. In addition, mutations in the Synaptotagmin 2 C2B domain represent an important cause of presynaptic congenital myasthenic syndromes and link them with hereditary motor axonopathies.

Am J Hum Genet 2014

Motor neuronopathy in Chediak-Higashi syndrome.

Chediak-Higashi syndrome is a rare autosomal recessive disease characterized by partial oculocutaneous albinism, recurrent pyogenic infections and the presence of giant granules in many cells such as leucocytes (hallmark of the disease). Neurological symptoms are rare. We describe two sisters who presented the same phenotype of slowly progressive motor neuronopathy (with Babinski sign in one patient); biopsy of the sural nerve showed an abnormal endoneurial accumulation of lipofuscin granules. We discuss these two observations and compare them with the few case reports of neuropathy in Chediak-Higashi syndrome.

J Neurol Sci 2014