Physical Activity and Exercise Recommendations for Stroke Survivors A Statement for Healthcare Professionals From the American Heart Association/American Stroke Association

Purpose—This scientific statement provides an overview of the evidence on physical activity and exercise recommendations for stroke survivors. Evidence suggests that stroke survivors experience physical deconditioning and lead sedentary lifestyles. Therefore, this updated scientific statement serves as an overall guide for practitioners to gain a better understanding of the benefits of physical activity and recommendations for prescribing exercise for stroke survivors across all stages of recovery.

Methods—Members of the writing group were appointed by the American Heart Association Stroke Council’s Scientific Statement Oversight Committee and the American Heart Association’s Manuscript Oversight Committee. The writers used systematic literature reviews, references to published clinical and epidemiology studies, morbidity and mortality reports, clinical and public health guidelines, authoritative statements, personal files, and expert opinion to summarize existing evidence and indicate gaps in current knowledge.

Results—Physical inactivity after stroke is highly prevalent. The assessed body of evidence clearly supports the use of exercise training (both aerobic and strength training) for stroke survivors. Exercise training improves functional capacity, the ability to perform activities of daily living, and quality of life, and it reduces the risk for subsequent cardiovascular events. Physical activity goals and exercise prescription for stroke survivors need to be customized for the individual to maximize long-term adherence.

Conclusions—The recommendation from this writing group is that physical activity and exercise prescription should be incorporated into the management of stroke survivors. The promotion of physical activity in stroke survivors should emphasize low- to moderate-intensity aerobic activity, muscle-strengthening activity, reduction of sedentary behavior, and risk management for secondary prevention of stroke.

Stroke 2014

The clinical approach to autonomic failure in neurological disorders

Central or peripheral neurological disorders can manifest with autonomic failure or autonomic hyperactivity, which may affect the sympathetic, parasympathetic and/or enteric nervous systems. Disorders causing autonomic failure can be classified according to the presence or absence of associated neurological manifestations, such as peripheral neuropathy or parkinsonism, and their temporal profile (acute or subacute, chronic progressive, static, or episodic). A systematic approach allows focused evaluation to detect treatable, potentially disabling or life-threatening conditions. Subacute isolated autonomic failure affecting sympathetic, parasympathetic and enteric nervous system function, in various combinations, occurs in autoimmune autonomic ganglionopathy, which might be the first manifestation of an underlying neoplasm. Autonomic failure can be an important feature of several types of peripheral neuropathy, including sensorimotor peripheral neuropathies, sensory ganglionopathy, and distal painful peripheral neuropathies. Progressive autonomic failure occurs in neurodegenerative synucleinopathies such as multiple system atrophy and Lewy body disorders. Autonomic failure may also occur in hereditary leukoencephalopathies or prion disorders. This Review outlines the clinical approach to patients with generalized autonomic failure, focusing predominantly on classification and diagnosis, but also touching briefly on treatment and management

Nature Reviews Neurology 2014

Preimplantation genetic diagnosis (PGD) is an option for couples at risk of having offspring with an inherited debilitating or fatal neurological disorder who wish to conceive a healthy child. PGD has been carried out for conditions with various modes of inheritance, including spinal muscular atrophy, Huntington disease, fragile X syndrome, and chromosomal or mitochondrial disorders, and for susceptibility genes for cancers with nervous system involvement. Most couples at risk of transmitting a genetic mutation would opt for PGD over prenatal testing and possible termination of a pregnancy. The aim of this Perspectives article is to assist neurologists in counselling and treating patients who wish to explore the option of PGD to enable conception of an unaffected child. PGD can be accomplished for most disorders in which the genetic basis is known, and we argue that it is time for clinicians and neurological societies to consider the evidence and to formulate guidelines for the responsible integration of PGD into modern preventative neurology.

Nature Reviews Neurology 2014

Diaschisis: past, present, future

After a century of false hopes, recent studies have placed the concept of diaschisis at the centre of the understanding of brain function. Originally, the term ‘diaschisis’ was coined by von Monakow in 1914 to describe the neurophysiological changes that occur distant to a focal brain lesion. In the following decades, this concept triggered widespread clinical interest in an attempt to describe symptoms and signs that the lesion could not fully explain. However, the first imaging studies, in the late 1970s, only partially confirmed the clinical significance of diaschisis. Focal cortical areas of diaschisis (i.e. focal diaschisis) contributed to the clinical deficits after subcortical but only rarely after cortical lesions. For this reason, the concept of diaschisis progressively disappeared from the mainstream of research in clinical neurosciences. Recent evidence has unexpectedly revitalized the notion. The development of new imaging techniques allows a better understanding of the complexity of brain organization. It is now possible to reliably investigate a new type of diaschisis defined as the changes of structural and functional connectivity between brain areas distant to the lesion (i.e. connectional diaschisis). As opposed to focal diaschisis, connectional diaschisis, focusing on determined networks, seems to relate more consistently to the clinical findings. This is particularly true after stroke in the motor and attentional networks. Furthermore, normalization of remote connectivity changes in these networks relates to a better recovery. In the future, to investigate the clinical role of diaschisis, a systematic approach has to be considered. First, emerging imaging and electrophysiological techniques should be used to precisely map and selectively model brain lesions in human and animals studies. Second, the concept of diaschisis must be applied to determine the impact of a focal lesion on new representations of the complexity of brain organization. As an example, the evaluation of remote changes in the structure of the connectome has so far mainly been tested by modelization of focal brain lesions. These changes could now be assessed in patients suffering from focal brain lesions (i.e. connectomal diaschisis). Finally, and of major significance, focal and non-focal neurophysiological changes distant to the lesion should be the target of therapeutic strategies. Neuromodulation using transcranial magnetic stimulation is one of the most promising techniques. It is when this last step will be successful that the concept of diaschisis will gain all the clinical respectability that could not be obtained in decades of research.

Brain 2014

Davunetide in patients with progressive supranuclear palsy: a randomised, double-blind, placebo-controlled phase 2/3 trial

Background

In preclinical studies, davunetide promoted microtubule stability and reduced tau phosphorylation. Because progressive supranuclear palsy (PSP) is linked to tau pathology, davunetide could be a treatment for PSP. We assessed the safety and efficacy of davunetide in patients with PSP.

Methods

In a double-blind, parallel group, phase 2/3 trial, participants were randomly assigned with permuted blocks in a 1:1 ratio to davunetide (30 mg twice daily, intranasally) or placebo for 52 weeks at 48 centres in Australia, Canada, France, Germany, the UK, and the USA. Participants met the modified Neuroprotection and Natural History in Parkinson Plus Syndrome study criteria for PSP. Primary endpoints were the change from baseline in PSP Rating Scale (PSPRS) and Schwab and England Activities of Daily Living (SEADL) scale at up to 52 weeks. All participants and study personnel were masked to treatment assignment. Analysis was by intention to treat. The trial is registered with Clinicaltrials.gov, number NCT01110720.

Findings

313 participants were randomly assigned to davunetide (n=157) or to placebo (n=156), and 241 (77%) completed the study (118 and 156 in the davunetide and placebo groups, respectively). There were no differences in the davunetide and placebo groups in the baseline PSPRS and SEADL. The davunetide and placebo groups did not differ in the change from baseline in PSPRS (median 11·8 [95% CI 10·5 to 13·0] vs 11·8 [10·5 to 13·0], respectively, p=0·41) or SEADL (−0·20 [−0·20 to −0·17] vs −0·20 [−0·22 to −0·17], respectively, p=0·92). 54 serious adverse events were reported in each of the treatment groups, including 11 deaths in the davunetide group and ten in the placebo group. The frequency of nasal adverse events was greater in the davunetide group than in the placebo group (epistaxis 18 [12%] of 156 vs 13 [8%] of 156, rhinorrhoea 15 [10%] vs eight [5%], and nasal discomfort 15 [10%] vs one [<1%]).

Interpretation

Davunetide is not an effective treatment for PSP. Clinical trials of disease-modifying treatment are feasible in patients with PSP and should be pursued with other promising tau-directed treatments

Lancet Neurology 2014

Vitamin D and Subclinical Cerebrovascular Disease The Atherosclerosis Risk in Communities Brain Magnetic Resonance Imaging Study

Importance  Vitamin D deficiency has been associated with hypertension, diabetes mellitus, and incident stroke. Little is known about the association between vitamin D and subclinical cerebrovascular disease.

Objective  To examine the relationship of 25-hydroxyvitamin D (25[OH]D) levels with cerebrovascular abnormalities as assessed on brain magnetic resonance imaging (MRI) among participants of the Atherosclerosis Risk in Communities (ARIC) Brain MRI study.

Design, Setting, and Participants  Participants were white and black adults aged 55 to 72 years with no history of clinical stroke who underwent a cerebral MRI at ARIC visit 3 (n = 1622) and a second cerebral MRI approximately 10 years later (n = 888).

Exposures  The 25(OH)D level was measured by mass spectrometry at visit 3, with levels adjusted for calendar month and categorized using race-specific quartiles.

Main Outcomes and Measures  The cross-sectional and prospective associations of 25(OH)D levels with white matter hyperintensities (WMHs) and MRI-defined infarcts were investigated using multivariable regression models.

Results  The mean age of the participants was 62 years, 59.6% were women, and 48.6% were black. Lower 25(OH)D levels were not significantly associated with WMH score of severity, prevalent high-grade WMH score (≥3), or prevalent infarcts in cross-sectional, multivariable-adjusted models (all P > .05). Similarly, no significant prospective associations were found for lower 25(OH)D levels with change in WMH volume, incident high WMH score (≥3), or incident infarcts on the follow-up MRI, which occurred approximately 10 years later.

Conclusions and Relevance  A single measure of 25(OH)D was not cross-sectionally associated with WMH grade or prevalent subclinical infarcts and was not prospectively associated with WMH progression or subclinical brain infarcts seen on serial cerebral MRIs obtained approximately 10 years apart. These findings do not support optimizing vitamin D levels for brain health.

JAMA Neurology 2014

Insights From Cerebellar Transcriptomic Analysis Into the Pathogenesis of Ataxia

Importance  The core clinical and neuropathological feature of the autosomal dominant spinocerebellar ataxias (SCAs) is cerebellar degeneration. Mutations in the known genes explain only 50% to 60% of SCA cases. To date, no effective treatments exist, and the knowledge of drug-treatable molecular pathways is limited. The examination of overlapping mechanisms and the interpretation of how ataxia genes interact will be important in the discovery of potential disease-modifying agents.

Objectives  To address the possible relationships among known SCA genes, predict their functions, identify overlapping pathways, and provide a framework for candidate gene discovery using whole-transcriptome expression data.

Design, Setting, and Participants  We have used a systems biology approach based on whole-transcriptome gene expression analysis. As part of the United Kingdom Brain Expression Consortium, we analyzed the expression profile of 788 brain samples obtained from 101 neuropathologically healthy individuals (10 distinct brain regions each). Weighted gene coexpression network analysis was used to cluster 24 SCA genes into gene coexpression modules in an unsupervised manner. The overrepresentation of SCA transcripts in modules identified in the cerebellum was assessed. Enrichment analysis was performed to infer the functions and molecular pathways of genes in biologically relevant modules.

Main Outcomes and Measures  Molecular functions and mechanisms implicating SCA genes, as well as lists of relevant coexpressed genes as potential candidates for novel SCA causative or modifier genes.

Results  Two cerebellar gene coexpression modules were statistically enriched in SCA transcripts (P = .021 for the tan module and P = 2.87 × 10−5 for the light yellow module) and contained established granule and Purkinje cell markers, respectively. One module includes genes involved in the ubiquitin-proteasome system and contains SCA genes usually associated with a complex phenotype, while the other module encloses many genes important for calcium homeostasis and signaling and contains SCA genes associated mostly with pure ataxia.

Conclusions and Relevance  Using normal gene expression in the human brain, we identified significant cell types and pathways in SCA pathogenesis. The overrepresentation of genes involved in calcium homeostasis and signaling may indicate an important target for therapy in the future. Furthermore, the gene networks provide new candidate genes for ataxias or novel genes that may be critical for cerebellar function.

JAMA Neurology 2014

Genetic risk load according to the site of intracranial aneurysms

Objective: We investigated whether risk alleles of single nucleotide polymorphisms associated with intracranial aneurysm (IA) are enriched in patients with familial IA, IA located at the middle cerebral artery (MCA), or IA rupture at a younger age.

Methods: In this case-only study, we calculated genetic risk scores (GRS) for 973 Dutch and 718 Finnish patients with IA by summing effect size–weighted risk allele counts of 7 single nucleotide polymorphisms associated with IAs previously identified through genome-wide association studies. We tested the GRS for association with presence of familial IA or IA at the MCA using logistic regression, and with age at time of IA rupture using linear regression. We also calculated odds ratios with 95% confidence intervals for the proportion of patients with each characteristic in the highest compared with the lowest GRS tertile.

Results: GRS were higher in IA at the MCA in the Dutch (p = 2.5 × 10⁻⁴), Finnish (p = 0.039), and combined cohort (p = 4.9 × 10⁻⁵). GRS were not associated with familial IA in the Dutch (p = 0.34), Finnish (p = 0.45), and combined cohort (p = 0.98), or with age at time of IA rupture in the Dutch (p = 0.28), Finnish (p = 0.86), and combined cohort (p= 0.45). In the combined cohort, odds ratios were 0.89 (0.67–1.20) for familial IA, 1.03 (0.79–1.34) for lower age, and 1.54 (1.20–1.98) for MCA aneurysms.

Conclusions: Our findings suggest that genetic risk factors have a larger role in the development of IA at the MCA than at other sites, and that genetic heterogeneity should be considered in future genetic studies.

Neurology 2014

Defining the clinical course of multiple sclerosis The 2013 revisions

Accurate clinical course descriptions (phenotypes) of multiple sclerosis (MS) are important for communication, prognostication, design and recruitment of clinical trials, and treatment decision-making. Standardized descriptions published in 1996 based on a survey of international MS experts provided purely clinical phenotypes based on data and consensus at that time, but imaging and biological correlates were lacking. Increased understanding of MS and its pathology, coupled with general concern that the original descriptors may not adequately reflect more recently identified clinical aspects of the disease, prompted a re-examination of MS disease phenotypes by the International Advisory Committee on Clinical Trials of MS. While imaging and biological markers that might provide objective criteria for separating clinical phenotypes are lacking, we propose refined descriptors that include consideration of disease activity (based on clinical relapse rate and imaging findings) and disease progression. Strategies for future research to better define phenotypes are also outlined

Neurology 2014

Effects of cannabis on cognition in patients with MS

Objective: To determine functional and structural neuroimaging correlates of cognitive dysfunction associated with cannabis use in multiple sclerosis (MS).

Methods: In a cross-sectional study, 20 subjects with MS who smoked cannabis and 19 noncannabis users with MS, matched on demographic and neurologic variables, underwent fMRI while completing a test of working memory, the N-Back. Resting-state fMRI and structural MRI data (lesion and normal-appearing brain tissue volumes, diffusion tensor imaging metrics) were also collected. Neuropsychological data pertaining to verbal (Selective Reminding Test Revised) and visual (10/36 Spatial Recall Test) memory, information processing speed (Paced Auditory Serial Addition Test [2- and 3-second versions] and Symbol Digit Modalities Test), and attention (Word List Generation) were obtained.

Results: The cannabis group performed more poorly on the more demanding of the Paced Auditory Serial Addition Test tasks (i.e., 2-second version) (p < 0.02) and the 10/36 Spatial Recall Test (p < 0.03). Cannabis users had more diffuse cerebral activation across all N-Back trials and made more errors on the 2-Back task (p < 0.006), during which they displayed increased activation relative to nonusers in parietal (p < 0.007) and anterior cingulate (p < 0.001) regions implicated in working memory. No group differences in resting-state networks or structural MRI variables were found.

Conclusions: Patients with MS who smoke cannabis are more cognitively impaired than nonusers. Cannabis further compromises cerebral compensatory mechanisms, already faulty in MS. These imaging data boost the construct validity of the neuropsychological findings and act as a cautionary note to cannabis users and prescribers.

Neurology 2014

The clinical spectrum of laryngeal dystonia includes dystonic cough: Observations of a large series

Laryngeal dystonia is a movement disorder of the muscles within the larynx, which most commonly manifests as spasmodic dysphonia (SD). Rarer reported manifestations include dystonic respiratory stridor and dyscoordinate breathing. Laryngeal dystonia has been treated successfully with botulinum neurotoxin (BTX) injections since 1984. We reviewed prospectively collected data in a consecutive series of 193 patients with laryngeal dystonia who were seen at St. Vincent's Hospital between 1991 and 2011. Patient data were analyzed in Excel, R, and Prism. Laryngeal dystonia manifested as SD (92.7%), stridor (11.9%), dystonic cough (6.2%), dyscoordinate breathing (4.1%), paroxysmal hiccups (1.6%), and paroxysmal sneezing (1.6%). There were more women (68.4%) than men (31.6%), and the average age at onset was 47 years. A positive family history of dystonia was present in 16.1% of patients. A higher incidence of extra-laryngeal dystonia (ie, torticollis and blepharospasm) and concurrent manifestations of laryngeal dystonia were present in patients with dystonic cough, dyscoordinate breathing, paroxysmal sneezing, and hiccups than in other patients (P = 0.003 and P < 0.0001, respectively). The average starting dose of BTX decreased from 2.3 to 0.5 units between 1991 and 2011. The median treatment rating was excellent across all subgroups. Patients with adductor SD, stridor, extra-laryngeal dystonia and male patients had relatively better treatment outcomes. Technical failures were rare (1.1%). Dysphonia secondary to vocal cord paresis followed 38.7% of treatments. Laryngeal dystonia manifests predominantly as SD, but other manifestations include stridor, dyscoordinate breathing, paroxysmal cough, hiccups, and sneezing. BTX injections are very effective across all subgroups. Severe adverse events are rare. 

 Movement Disorders 2014

Muscle atrophy, ubiquitin–proteasome, and autophagic pathways in dysferlinopathy

Introduction: Muscle fiber atrophy and the molecular pathways underlying this process have not been investigated in dysferlinopathy patients. Methods: In 22 muscles from dysferlinopathy patients we investigated fiber atrophy by morphometry and ubiquitin–proteasome and autophagic pathways using protein and/or transcriptional analysis of atrophy- and autophagy-related genes (MuRF1, atrogin1, LC3,p62, Bnip3). Results: Dysferlinopathy showed significant fiber atrophy and higher MuRF-1 protein and mRNA levels, which correlated with fiber size, suggesting activation of the atrophy program by proteasome induction. Conclusions: Some of the MuRF-1 upregulation and proteasome induction may be attributed to the prominent regeneration found. A potential role of impaired autophagy was suggested by p62-positive protein aggregates in atrophic fibers and significantly higher levels of LC3-II and p62 proteins and overexpression of p62 andBnip3 mRNA. Damaged muscle fibers and prominent inflammatory changes may also enhance autophagy due to the insufficient level of proteasomal degradation of mutant dysferlin. 

Muscle Nerve, 2014

Discriminative and Affective Touch: Sensing and Feeling

The multimodal properties of the human somatosensory system continue to be unravelled. There is mounting evidence that one of these submodalities—touch—has another dimension, providing not only its well-recognized discriminative input to the brain, but also an affective input. It has long been recognized that touch plays an important role in many forms of social communication and a number of theories have been proposed to explain observations and beliefs about the “power of touch.” Here, we propose that a class of low-threshold mechanosensitive C fibers that innervate the hairy skin represent the neurobiological substrate for the affective and rewarding properties of touch

Neuron 2014

Convergence of pathology in dementia with Lewy bodies and Alzheimer’s disease: a role for the novel interaction of alpha-synuclein and presenilin 1 in disease

A growing number of PSEN1 mutations have been associated with dementia with Lewy bodies and familial Alzheimer’s disease with concomitant α-synuclein pathology. The objective of this study was to determine if PSEN1 plays a direct role in the development of α-synuclein pathology in these diseases. Using mass spectrometry, immunoelectron microscopy and fluorescence lifetime image microscopy based on Forster resonance energy transfer (FLIM-FRET) we identified α-synuclein as a novel interactor of PSEN1 in wild-type mouse brain tissue. The interaction of α-synuclein with PSEN1 was detected in post-mortem brain tissue from cognitively normal cases and was significantly increased in tissue from cases with dementia with Lewy bodies and familial Alzheimer’s disease associated with known PSEN1 mutations. We confirmed an increased interaction of PSEN1 and α-synuclein in cell lines expressing well characterized familial Alzheimer’s disease PSEN1 mutations, L166P and delta exon 9, and demonstrated that PSEN1 mutations associate with increased membrane association and accumulation of α-synuclein. Our data provides evidence of a molecular interaction of PSEN1 and α-synuclein that may explain the clinical and pathophysiological overlap seen in synucleinopathies, including Parkinson’s disease, dementia with Lewy bodies, and some forms of Alzheimer’s disease.

Brain 2014

Beyond the temporal pole: limbic memory circuit in the semantic variant of primary progressive aphasia

Despite accruing evidence for relative preservation of episodic memory in the semantic variant of primary progressive aphasia (previously semantic dementia), the neural basis for this remains unclear, particularly in light of their well-established hippocampal involvement. We recently investigated the Papez network of memory structures across pathological subtypes of behavioural variant frontotemporal dementia and demonstrated severe degeneration of all relay nodes, with the anterior thalamus in particular emerging as crucial for intact episodic memory. The present study investigated the status of key components of Papez circuit (hippocampus, mammillary bodies, anterior thalamus, cingulate cortex) and anterior temporal cortex using volumetric and quantitative cell counting methods in pathologically-confirmed cases with semantic variant of primary progressive aphasia (n = 8; 61–83 years; three males), behavioural variant frontotemporal dementia with TDP pathology (n = 9; 53–82 years; six males) and healthy controls (n = 8, 50–86 years; four males). Behavioural variant frontotemporal dementia cases with TDP pathology were selected because of the association between the semantic variant of primary progressive aphasia and TDP pathology. Our findings revealed that the semantic variant of primary progressive aphasia and behavioural variant frontotemporal dementia show similar degrees of anterior thalamic atrophy. The mammillary bodies and hippocampal body and tail were preserved in the semantic variant of primary progressive aphasia but were significantly atrophic in behavioural variant frontotemporal dementia. Importantly, atrophy in the anterior thalamus and mild progressive atrophy in the body of the hippocampus emerged as the main memory circuit regions correlated with increasing dementia severity in the semantic variant of primary progressive aphasia. Quantitation of neuronal populations in the cingulate cortices confirmed the selective loss of anterior cingulate von Economo neurons in behavioural variant frontotemporal dementia. We also show that by end-stage these neurons selectively degenerate in the semantic variant of primary progressive aphasia with preservation of neurons in the posterior cingulate cortex. Overall, our findings demonstrate for the first time, severe atrophy, although not necessarily neuronal loss, across all relay nodes of Papez circuit with the exception of the mammillary bodies and hippocampal body and tail in the semantic variant of primary progressive aphasia. Despite the longer disease course in the semantic variant of primary progressive aphasia compared with behavioural variant frontotemporal dementia, we suggest here that the neural preservation of crucial memory relays (hippocampal→mammillary bodies and posterior cingulate→hippocampus) likely reflects the conservation of specific episodic memory components observed in most patients with semantic variant of primary progressive aphasia.

Brain 2014

Multiple sclerosis genetics

Genome-wide association studies have revolutionised the genetic analysis of multiple sclerosis. Through international collaborative efforts involving tens of thousands of cases and controls, more than 100 associated common variants have now been identified. These variants consistently implicate genes associated with immunological processes, overwhelmingly lie in regulatory rather than coding regions, and are frequently associated with other autoimmune diseases. The functional implications of these associated variants are mostly unknown; however, early work has shown that several variants have effects on splicing that result in meaningful changes in the balance between different isoforms in relevant tissues. Including the well established risk attributable to variants in genes encoding human leucocyte antigens, only about a quarter of reported heritability can now be accounted for, suggesting that a substantial potential for further discovery remains.

Lancet Neurology 2014

Magnetic Resonance Spectroscopy Markers of Disease Progression in Multiple Sclerosis

Importance  Predicting disease evolution is becoming essential for optimizing treatment decision making in multiple sclerosis (MS). Multiple sclerosis pathologic damage typically includes demyelination, neuro-axonal loss, and astrogliosis.

Objective  To evaluate the potential of magnetic resonance markers of central nervous system injury to predict brain-volume loss and clinical disability in multiple sclerosis.

Design, Setting, and Participants  Participants were selected from the Multiple Sclerosis Center at the University of California–San Francisco. The preliminary data set included 59 patients with MS and 43 healthy control individuals. The confirmatory data set included 220 patients from an independent, large genotype-phenotype research project.

Main Outcomes and Measures  Baseline N-acetylaspartate (NAA) level, myo-inositol (mI) in normal-appearing white and gray matter, myelin water fraction in normal-appearing white matter, markers of axonal damage, astrogliosis, and demyelination were evaluated as predictors in a preliminary data set. Potential predictors were subsequently tested for replication in a confirmatory data set. Clinical scores and percentage of brain-volume change were obtained annually over 4 years as outcomes. Predictors of outcomes were assessed using linear models, linear mixed-effects models, and logistic regression.

Results  N-acetylaspartate and mI both had statistically significant effects on brain volume, prompting the use of the mI:NAA ratio in normal-appearing white matter as a predictor. The ratio was a predictor of brain-volume change in both cohorts (annual slope in the percentage of brain-volume change/unit of increase in the ratio: −1.68; 95% CI, −3.05 to −0.30; P = .02 in the preliminary study cohort and −1.08; 95% CI, −1.95 to −0.20; P = .02 in the confirmatory study cohort). Furthermore, the mI:NAA ratio predicted clinical disability (Multiple Sclerosis Functional Composite evolution: −0.52 points annually, P < .001; Multiple Sclerosis Functional Composite sustained progression: odds ratio, 2.76/SD increase in the ratio; 95% CI, 1.32 to 6.47; P = .01) in the preliminary data set and predicted Multiple Sclerosis Functional Composite evolution (−0.23 points annually; P = .01), Expanded Disability Status Scale evolution (0.57 points annually; P = .04), and Expanded Disability Status Scale sustained progression (odds ratio, 1.46; 95% CI, 1.10 to 1.94; P = .009) in the confirmatory data set. Myelin water fraction did not show predictive value.

Conclusions and Relevance  The mI:NAA ratio in normal-appearing white matter has consistent predictive power on brain atrophy and neurological disability evolution. The combined presence of astrogliosis and axonal damage in white matter has cardinal importance in disease severity.

JAMA Neurology 2014

Prevalence, Determinants, and Effect on Quality of Life of Freezing of Gait in Parkinson Disease

Importance  Freezing of gait (FOG) is a common axial symptom of Parkinson disease (PD).

Objective  To determine the prevalence of FOG in a large group of PD patients, assess its relationship with quality of life and clinical and pharmacological factors, and explore its changes from the off to on conditions in patients with motor fluctuations.

Design, Setting, and Participants  Cross-sectional survey of 683 patients with idiopathic PD. Scores for FOG were missing in 11 patients who were not included in the analysis. Patients were recruited from referral centers and general neurology clinics in public or private institutions in France.

Exposure  Patients with FOG were identified as those with a score of 1 or greater on item 14 of the Unified Parkinson’s Disease Rating Scale (UPDRS) in the on condition. Item 14 scores for FOG in the off condition were also collected in patients with fluctuating motor symptoms.

Main Outcomes and Measures  Quality of life (measured by the 39-item Parkinson’s Disease Questionnaire and 36-Item Short Form Health Survey), anxiety and depression (Hospital Anxiety and Depression Scale), clinical features (UPDRS), and drug consumption.

Results  Of 672 PD patients, 257 reported FOG during the onstate (38.2%), which was significantly related to lower quality of life scores (P < .01). Freezing of gait was also correlated with longer PD duration (odds ratio, 1.92 [95% CI, 1.28-2.86]), higher UPDRS parts II and III scores (4.67 [3.21-6.78]), the presence of apathy (UPDRS item 4) (1.94 [1.33-2.82]), a higher levodopa equivalent daily dose (1.63 [1.09-2.43]), and more frequent exposure to antimuscarinics (3.07 [1.35-6.97]) (logistic regression). The FOG score improved from the off to on states in 148 of 174 patients with motor fluctuations (85.1%) and showed no change in 13.8%. The FOG score improved by more than 50% in 43.7% of patients. Greater improvement in the on state was observed in younger patients (r = −0.25;P < .01) with lower UPDRS II and III scores (r = −0.50; P < .01) and no antimuscarinic use (r = −0.21;P < .01).

Conclusions and Relevance  Freezing of gait in PD patients correlates with poor quality of life, disease severity, apathy, and exposure to antimuscarinics. Dopaminergic therapy improved FOG in most patients with motor fluctuations, especially younger ones with less severe disease and no antimuscarinic use. This finding suggests that quality of life is impaired in PD patients with FOG and that optimizing dopaminergic therapy and avoiding antimuscarinics should be considered.

JAMA Neurology 2014

CHMP Endorses Peginterferon-β-1a, Not Laquinimod, in MS

The European Medicines Agency (EMA) Committee for Medicinal Products for Human Use (CHMP) has endorsed peginterferon-β-1a (Plegridy, Biogen Idec) for adults with relapsing-remitting multiple sclerosis (RRMS) and rejected laquinimod (Nerventra, Teva Pharma) for the same indication, after a second look at the data.

Plegridy is a pegylated interferon administered subcutaneously. The CHMP's positive opinion on the drug is largely based on the 2-year phase 3 study known as ADVANCE, which included more than 1500 patients with MS, Biogen Idec notes in a statement.

As for laquinimod, the CHMP voted against approving the drug in January 2014, as reported previouslyby Medscape Medical News. The panel noted concerns about results from animal studies showing a higher occurrence of cancers after long-term exposure to laquinimod, noting that a similar long-term risk could not be ruled out in humans. Animal data also indicated a possible risk for teratogenic effects in offspring of women taking the drug.

Fonts: Medscape

Europe Says No to Bevacizumab (Avastin) for Glioblastoma

Looks like glioblastoma will not be added as a new indication to the product labelling for bevacizumab (Avastin) in Europe.

The European Medicines Agency Committee for Medicinal Products for Human Use (CHMP) considered the data and has recommended against approval of use of bevacizumab in newly diagnosed glioblastoma, specifically for use in combination with radiation and temozolomide.

Bevacizumab is already approved in the European Union for use in several tumor types, including colorectal, breast, lung, kidney, and ovarian cancer. The drug is also marketed for many cancer types elsewhere in the world, and is one of the top-selling products in the cancer field.

Fonts: Medscape

VARS2 and TARS2 Mutations in Patients with Mitochondrial Encephalomyopathies.

By way of whole-exome sequencing we identified: a homozygous missense mutation in VARS2, in one subject with microcephaly and epilepsy associated with isolated deficiency of the mitochondrial respiratory chain (MRC) complex I; and compound heterozygous mutations in TARS2, in two siblings presenting with axial hypotonia and severe psychomotor delay associated with multiple MRC defects. The nucleotide variants segregated within the families, were absent in SNP databases, and are predicted to be deleterious. The amount of VARS2 and TARS2 proteins and valyl-tRNA and threonyl-tRNA levels were decreased in samples of afflicted patients according to the genetic defect. Expression of the corresponding wild-type transcripts in immortalized mutant fibroblasts rescued the biochemical impairment of mitochondrial respiration and yeast modeling of the VARS2 mutation confirmed its pathogenic role. Taken together, these data demonstrate the role of the identified mutations for these mitochondriopathies. Our study reports the first mutations in the VARS2 and TARS2 genes, which encode two mitochondrial aminoacyl-tRNA synthetases, as causes of clinically distinct, early-onset mitochondrial encephalopathies. This article is protected by copyright. All rights reserved.

Human Mutation 2014