PMPCA mutations cause abnormal mitochondrial protein processing in patients with non-progressive cerebellar ataxia

Non-progressive cerebellar ataxias are a rare group of disorders that comprise approximately 10% of static infantile encephalopathies. We report the identification of mutations in PMPCA in 17 patients from four families affected with cerebellar ataxia, including the large Lebanese family previously described with autosomal recessive cerebellar ataxia and short stature of Norman type and localized to chromosome 9q34 (OMIM #213200). All patients present with non-progressive cerebellar ataxia, and the majority have intellectual disability of variable severity. PMPCA encodes α-MPP, the alpha subunit of mitochondrial processing peptidase, the primary enzyme responsible for the maturation of the vast majority of nuclear-encoded mitochondrial proteins, which is necessary for life at the cellular level. Analysis of lymphoblastoid cells and fibroblasts from patients homozygous for the PMPCA p.Ala377Thr mutation and carriers demonstrate that the mutation impacts both the level of the alpha subunit encoded by PMPCA and the function of mitochondrial processing peptidase. In particular, this mutation impacts the maturation process of frataxin, the protein which is depleted in Friedreich ataxia. This study represents the first time that defects in PMPCA and mitochondrial processing peptidase have been described in association with a disease phenotype in humans.

Neurology 2015

Contactin 1 IgG4 associates to chronic inflammatory demyelinating polyneuropathy with sensory ataxia

A Spanish group recently reported that four patients with chronic inflammatory demyelinating polyneuropathy carrying IgG4 autoantibodies against contactin 1 showed aggressive symptom onset and poor response to intravenous immunoglobulin. We aimed to describe the clinical and serological features of Japanese chronic inflammatory demyelinating polyneuropathy patients displaying the anti-contactin 1 antibodies. Thirteen of 533 (2.4%) patients with chronic inflammatory demyelinating polyneuropathy had anti-contactin 1 IgG4 whereas neither patients from disease or normal control subjects did (P = 0.02). Three of 13 (23%) patients showed subacute symptom onset, but all of the patients presented with sensory ataxia. Six of 10 (60%) anti-contactin 1 antibody-positive patients had poor response to intravenous immunoglobulin, whereas 8 of 11 (73%) antibody-positive patients had good response to corticosteroids. Anti-contactin 1 IgG4 antibodies are a possible biomarker to guide treatment option.

Neurology 2015

Adult-onset painful axonal polyneuropathy caused by a dominant NAGLU mutation

Late-onset painful sensory neuropathies are usually acquired conditions associated with common diseases. Adult presentations of known hereditary forms are often accompanied by other organ involvement. We recruited a large French-Canadian family with a dominantly inherited late-onset painful sensory neuropathy. The main clinical feature is recurrent leg pain that progresses to constant painful paraesthesias in the feet and later the hands. As it evolves, some patients develop a mild sensory ataxia. We selected four affected individuals for whole exome sequencing. Analysis of rare variants shared by all cases led to a list of four candidate variants. Segregation analysis in all 45 recruited individuals has shown that only the p.Ile403Thr variant in the α-N-acetyl-glucosaminidase (NAGLU) gene segregates with the disease. Recessive NAGLU mutations cause the severe childhood lysosomal disease mucopolysacharidosis IIIB. Family members carrying the mutation showed a significant decrease of the enzymatic function (average 45%). The late-onset and variable severity of the symptoms may have precluded the description of such symptoms in parents of mucopolysaccharidosis IIIB cases. The identification of a dominant phenotype associated with a NAGLU mutation supports that some carriers of lysosomal enzyme mutations may develop later in life much milder phenotypes.

Neurology 2015

Structural and functional MRI abnormalities of cerebellar cortex and nuclei in SCA3, SCA6 and Friedreich’s ataxia

Spinocerebellar ataxia type 3, spinocerebellar ataxia type 6 and Friedreich’s ataxia are common hereditary ataxias. Different patterns of atrophy of the cerebellar cortex are well known. Data on cerebellar nuclei are sparse. Whereas cerebellar nuclei have long been thought to be preserved in spinocerebellar ataxia type 6, histology shows marked atrophy of the nuclei in Friedreich’s ataxia and spinocerebellar ataxia type 3. In the present study susceptibility weighted imaging was used to assess atrophy of the cerebellar nuclei in patients with spinocerebellar ataxia type 6 (n = 12, age range 41–76 years, five female), Friedreich’s ataxia (n = 12, age range 21–55 years, seven female), spinocerebellar ataxia type 3 (n = 10, age range 34–67 years, three female), and age- and gender-matched controls (total n = 23, age range 22–75 years, 10 female). T1-weighted magnetic resonance images were used to calculate the volume of the cerebellum. In addition, ultra-high field functional magnetic resonance imaging was performed with optimized normalization methods to assess function of the cerebellar cortex and nuclei during simple hand movements. As expected, the volume of the cerebellum was markedly reduced in spinocerebellar ataxia type 6, preserved in Friedreich’s ataxia, and mildy reduced in spinocerebellar ataxia type 3. The volume of the cerebellar nuclei was reduced in the three patient groups compared to matched controls (P-values < 0.05; two-sample t-tests). Atrophy of the cerebellar nuclei was most pronounced in spinocerebellar ataxia type 6. On a functional level, hand-movement-related cerebellar activation was altered in all three disorders. Within the cerebellar cortex, functional magnetic resonance imaging signal was significantly reduced in spinocerebellar ataxia type 6 and Friedreich’s ataxia compared to matched controls (P-values < 0.001, bootstrap-corrected cluster-size threshold; two-sample t-tests). The difference missed significance in spinocerebellar ataxia type 3. Within the cerebellar nuclei, reductions were significant when comparing spinocerebellar ataxia type 6 and Friedreich’s ataxia to matched controls (P < 0.01, bootstrap-corrected cluster-size threshold; two-sample t-tests). Susceptibility weighted imaging allowed depiction of atrophy of the cerebellar nuclei in patients with Friedreich’s ataxia and spinocerebellar ataxia type 3. In spinocerebellar ataxia type 6, pathology was not restricted to the cerebellar cortex but also involved the cerebellar nuclei. Functional magnetic resonance imaging data, on the other hand, revealed that pathology in Friedreich’s ataxia and spinocerebellar ataxia type 3 is not restricted to the cerebellar nuclei. There was functional involvement of the cerebellar cortex despite no or little structural changes.

Neurology 2015

Microbleeds, Mortality, and Stroke in Alzheimer Disease The MISTRAL Study

Importance  Microbleeds are more prevalent in patients with Alzheimer disease (AD) compared with the general elderly population. In addition, microbleeds have been found to predict mortality in AD.

Objective  To investigate whether microbleeds in AD increase the risk for mortality, stroke (including intracerebral hemorrhage), and cardiovascular events.

Design, Setting and Participants  The MISTRAL (do MIcrobleeds predict STRoke in ALzheimer’s disease) Study is a longitudinal cohort study within the memory clinic–based Amsterdam Dementia Cohort. We selected all patients with AD with a baseline visit between January 2, 2002, and December 16, 2009, and microbleeds (n = 111) and matched those (1:2) for age, sex, and magnetic resonance imaging scanner to 222 patients with AD without microbleeds. After a minimal follow-up of 3 years, information on all-cause mortality, stroke-related mortality, and cardiovascular mortality was obtained between November 1, 2012, and May 1, 2014. In addition, we obtained information on the occurrence of incident stroke or transient ischemic attack, cardiovascular events, and nursing home admittance.

Main Outcomes and Measures  Stroke-related mortality, incident stroke, and intracerebral hemorrhage.

Results  Patients had a mean (SD) age of 71.2 (7.8) years and 127 (42%) were female. Compared with having no microbleeds, microbleeds in lobar locations were associated with an increased risk for stroke-related mortality (hazard ratio [HR], 33.9; 95% CI, 2.5-461.7), whereas nonlobar microbleeds were associated with an increased risk for cardiovascular mortality (HR, 12.0; 95% CI, 3.2-44.7). In addition, lobar microbleeds were associated with an increased risk for incident stroke (HR, 3.8; 95% CI, 1.5-10.1) and nonlobar microbleeds with an increased risk for cardiovascular events (HR, 6.2; 95% CI, 1.5-25.0). Even higher risks for incident stroke and cardiovascular events were found in patients using antithrombotic medication. All 5 patients with an intracerebral hemorrhage had lobar microbleeds at baseline; 4 of them used antithrombotics.

Conclusions and Relevance  In patients with AD, the presence of nonlobar microbleeds was associated with an increased risk for cardiovascular events and cardiovascular mortality. Patients with lobar microbleeds had an increased risk for stroke and stroke-related mortality, indicating that these patients should be treated with the utmost care.

Neurology 2015

An 8-Year Follow-up on the Effect of Subthalamic Nucleus Deep Brain Stimulation on Pain in Parkinson Disease

Importance  Pain is a common and distressing feature in Parkinson disease (PD). The major indication of subthalamic nucleus deep brain stimulation (STN DBS) is motor complications in advanced PD; however, pain reduction after STN DBS has been noted.

Objective  To evaluate the long-term effect of STN DBS on pain in PD.

Design, Setting, and Participants  Twenty-four patients who underwent STN DBS at the Movement Disorder Center at Seoul National University Hospital from June 1, 2005, through March 31, 2006, were studied. The assessments of pain were performed preoperatively and 8 years after surgery. Because 13 of the total 24 patients had additional 2-year postoperative data, the serial change between the preoperative and the 2- and 8-year follow-ups after surgery was also evaluated.

Main Outcomes and Measures  Motor symptoms were assessed using the Unified Parkinson’s Disease Rating Scale and the Hoehn and Yahr staging scale. The severity of pain was scored according to an ordinal scale ranging from 0 (absent) to 10 (maximal pain) in 7 parts of the body (head, neck, trunk, and the upper and lower extremities on each side of the body). For each body part, the quality of pain was grouped into 1 of 4 categories: dystonic, musculoskeletal, radiculoneuritic, and central.

Results  Sixteen of the 24 patients (67%) experienced pain at baseline when not taking medication (off-state). All off-state pain at baseline improved or disappeared at 8 years after surgery. The number of body parts with pain was 21 at baseline and decreased to 11 at 8 years after the surgery. The mean (SD) and median scores of the off-state pain were 6.2 (2.5) and 7.0 at baseline and improved to 3.5 (2.2) and 2.5 at 8 years after the surgery, respectively. However, new pain developed in 18 of 24 patients (75%) during the 8-year follow-up period. The number of body parts with newly developed pain was 47, and the mean (SD) and median scores for new pain were 4.4 (3.0) and 3.0, respectively. The types of new pain at 8 years were musculoskeletal in 11 patients, central in 4 patients, radiculoneuritic in 3 patients, and dystonic in 1 patient.

Conclusions and Relevance  Pain associated with PD is improved by STN DBS, and the beneficial effect persists after a long-term follow-up of 8 years. In addition, new pain, especially the musculoskeletal type, developed in most patients, becoming a long-term distressing problem.

JAMA Neurology 2015

Association between brain imaging signs, early and late outcomes, and response to intravenous alteplase after acute ischaemic stroke in the third International Stroke Trial (IST-3): secondary analysis of a randomised controlled trial

Background

Brain scans are essential to exclude haemorrhage in patients with suspected acute ischaemic stroke before treatment with alteplase. However, patients with early ischaemic signs could be at increased risk of haemorrhage after alteplase treatment, and little information is available about whether pre-existing structural signs, which are common in older patients, affect response to alteplase. We aimed to investigate the association between imaging signs on brain CT and outcomes after alteplase.

Methods

IST-3 was a multicentre, randomised controlled trial of intravenous alteplase (0·9 mg/kg) versus control within 6 h of acute ischaemic stroke. The primary outcome was independence at 6 months (defined as an Oxford Handicap Scale [OHS] score of 0–2). 3035 patients were enrolled to IST-3 and underwent prerandomisation brain CT. Experts who were unaware of the random allocation assessed scans for early signs of ischaemia (tissue hypoattenuation, infarct extent, swelling, and hyperattenuated artery) and pre-existing signs (old infarct, leukoaraiosis, and atrophy). In this prespecified analysis, we assessed interactions between these imaging signs, symptomatic intracranial haemorrhage (a secondary outcome in IST-3) and independence at 6 months, and alteplase, adjusting for age, National Institutes of Health Stroke Scale (NIHSS) score, and time to randomisation. This trial is registered at ISRCTN.com, number ISRCTN25765518.

Findings

3017 patients were assessed in this analysis, of whom 1507 were allocated alteplase and 1510 were assigned control. A reduction in independence was predicted by tissue hypoattenuation (odds ratio 0·66, 95% CI 0·55–0·81), large lesion (0·51, 0·38–0·68), swelling (0·59, 0·46–0·75), hyperattenuated artery (0·59, 0·47–0·75), atrophy (0·74, 0·59–0·94), and leukoaraiosis (0·72, 0·59–0·87). Symptomatic intracranial haemorrhage was predicted by old infarct (odds ratio 1·72, 95% CI 1·18–2·51), tissue hypoattenuation (1·54, 1·04–2·27), and hyperattenuated artery (1·54, 1·03–2·29). Some combinations of signs increased the absolute risk of symptomatic intracranial haemorrhage (eg, both old infarct and hyperattenuated artery, excess with alteplase 13·8%, 95% CI 6·9–20·7; both signs absent, excess 3·2%, 1·4–5·1). However, no imaging findings—individually or combined—modified the effect of alteplase on independence or symptomatic intracranial haemorrhage.

Interpretation

Some early ischaemic and pre-existing signs were associated with reduced independence at 6 months and increased symptomatic intracranial haemorrhage. Although no interaction was noted between brain imaging signs and effects of alteplase on these outcomes, some combinations of signs increased some absolute risks. Pre-existing signs should be considered, in addition to early ischaemic signs, during the assessment of patients with acute ischaemic stroke.

Neurology 2015

Brain-derived neurotrophic factor Regulation, effects, and potential clinical relevance

Brain-derived neurotrophic factor (BDNF) is the most ubiquitous and intensively studied member of the family of neurotrophins in the CNS. The transcriptional regulation of BDNF is complex and involves both epigenetic control and transcription factors. BDNF is produced “on demand” in response to neuronal activity from a precursor pro-BDNF that is transported and processed via the secretory pathway. The effects of mature BDNF are mediated by the tropomyosin-related kinase B (TrkB, tyrosine kinase B) receptor, which triggers phosphorylation cascades that promote protein synthesis, axonal growth, dendritic maturation, use-dependent synaptic plasticity, and neuroprotection. In contrast, pro-BDNF binds to the common neurotrophin receptor p75^NTR and promotes apoptosis. BDNF can also be released from microglia and may bidirectionally affect inhibitory neurotransmission in the CNS. Disturbances in epigenetic control, transport, or signaling by BDNF may contribute to a variety of neurologic and psychiatric disorders, including Alzheimer disease (AD), Huntington disease (HD), spinocerebellar ataxia type 6 (SCA6), neuropathic pain, Rett syndrome, and depression, schizophrenia, and drug addiction. There are several recent reviews on these subjects

Neurology 2015

Causes of withdrawal of duodenal levodopa infusion in advanced Parkinson disease

Objective: We performed a real-life observation of patients with Parkinson disease (PD) who received duodenal levodopa infusion (DLI) to determine which adverse events caused treatment discontinuation and when such events occurred.

Methods: All consecutive patients with PD treated at the Carlo Besta Neurological Institute were included. The patients were evaluated at baseline and after DLI at regular intervals. Their motor condition was assessed and adverse events were recorded.

Results: Thirty-five patients with PD (15 men and 20 women) were included. They received DLI implants between October 2007 and September 2013. Four patients died of causes unrelated to the procedure. At the end of the study, 21 patients (60%) were still on treatment. DLI provided efficacious motor control in all patients. Discontinuation was most frequently caused by device- or infusion-related adverse events. Ten patients of the remaining 31 discontinued DLI. There were 2 main causes of withdrawal: stoma infection (4 patients), and worsening of dyskinesias not manageable with infusion reduction (3 patients). In most patients, discontinuations occurred during the first year after implant. Risk of discontinuation was related to age at implant, but no other demographic or clinical variables.

Conclusions: We identified 2 main causes leading to DLI withdrawal during the first year postimplant and suggest adopting measures to prevent such occurrences. Elderly patients are at higher risk of treatment discontinuation.

Neurology 2015

Neuronal Na+/K+ ATPase is an autoantibody target in paraneoplastic neurologic syndrome

Objectives: To identify an autoreactivity in a 66-year-old woman who presented with combined brainstem and cerebellar syndrome including vertical gaze palsy, severe progressive ataxia, and spastic tetraparesis, an acute deterioration of vision, dysarthria, and dysphagia with concurrent diagnosis of a colon adenocarcinoma.

Methods: Patient's serum and CSF underwent comprehensive autoantibody screening by indirect immunofluorescence assay and immunoblot. For autoantigen purification, a histo-immunoprecipitation technique was developed followed by mass spectrometrical analysis. Recombinant candidate antigens were expressed in HEK293 and used to verify the identification.

Results: Indirect immunofluorescence assay screening revealed strong immunoglobulin G reactivity with neural tissues in serum and CSF, but not with a panel of 28 recombinantly expressed established neural autoantigens. The hitherto unknown target antigen was identified as the neuronal Na⁺/K⁺ ATPase. Epitope mapping and competitive inhibition experiments showed that the autoantibodies were directed against the membrane-spanning alpha 3 subunit (ATP1A3) of the enzyme but did not bind to extracellular epitopes. Immunohistochemical analysis revealed overexpression of this subunit in the patient's tumor.

Conclusions: We describe a case of an anti-ATP1A3–associated neurologic disorder. Mutations in the gene encoding this neuronal surface protein have already been recognized as the cause of infantile alternating hemiplegia, rapid-onset dystonia parkinsonism, and CAPOS syndrome. Although the autoantibodies are unlikely to be pathogenic, they are likely to be rare biomarkers for the apparently paraneoplastic neurologic syndrome or for the tumor itself.

Neurology 2015

Congenital autophagic vacuolar myopathy is allelic to X-linked myopathy with excessive autophagy

X-linked myopathy with excessive autophagy (XMEA) is characterized by weakness and wasting primarily of the proximal muscles of the lower extremities. Onset is usually after age 5 and progression is extremely slow with ambulation maintained well into the 50s. The heart, CNS, peripheral nervous system, and other organs are clinically spared. Pathology reveals large autophagic vacuoles enclosing incompletely degraded cytoplasmic components, which translocate to the myofiber surface and extrude their contents, forming a field of cell debris between multiplied layers of basal lamina. XMEA is caused by mutations of the VMA21 gene, which reduce, but do not eliminate, expression of the chief assembly chaperone (VMA21) of the main proton pump (V-ATPase [vacuolar-type H⁺–adenosine triphosphatase]) of all mammalian cells.

Neurology 2015

Pharmacological treatment of migraine during pregnancy and breastfeeding

Migraine affects up to 25% of women of reproductive age. In the majority of these women, migraine improves progressively during pregnancy, but symptoms generally recur shortly after delivery. As suboptimally treated migraine in pregnancy could have negative consequences for both mother and fetus, the primary aim of clinicians should be to provide optimal treatment according to stage of pregnancy, while minimising possible risks related to drug therapy. Nonpharmacological approaches are always first-line treatment, and should also be used to complement any required drug treatment. Paracetamol is the preferred drug for acute treatment throughout pregnancy. If paracetamol is not sufficiently effective, sporadic use of sumatriptan can be considered. NSAIDs such as ibuprofen can also be used under certain circumstances, though their intake in the first and third trimesters is associated with specific risks and contraindications. Preventive treatment should only be considered in the most severe cases. In women contemplating pregnancy, counselling is essential to promote a safe and healthy pregnancy and postpartum period for the mother and child, and should involve a dialogue addressing maternal concerns and expectations about drug treatment. This Review summarizes current evidence of the safety of the most common antimigraine medications during pregnancy and breastfeeding, and provides treatment recommendations for use in clinical practice.

Nature Reviews Neurology 2015

Expert consensus document: Mind the gaps—advancing research into short-term and long-term neuropsychological outcomes of youth sports-related concussions

Sports-related concussions and repetitive subconcussive exposure are increasingly recognized as potential dangers to paediatric populations, but much remains unknown about the short-term and long-term consequences of these events, including potential cognitive impairment and risk of later-life dementia. This Expert Consensus Document is the result of a 1-day meeting convened by Safe Kids Worldwide, the Alzheimer's Drug Discovery Foundation, and the Andrews Institute for Orthopaedics and Sports Medicine. The goal is to highlight knowledge gaps and areas of critically needed research in the areas of concussion science, dementia, genetics, diagnostic and prognostic biomarkers, neuroimaging, sports injury surveillance, and information sharing. For each of these areas, we propose clear and achievable paths to improve the understanding, treatment and prevention of youth sports-related concussions.

Nature Reviews Neurology 2015

CHD2 variants are a risk factor for photosensitivity in epilepsy

Photosensitivity is a heritable abnormal cortical response to flickering light, manifesting as particular electroencephalographic changes, with or without seizures. Photosensitivity is prominent in a very rare epileptic encephalopathy due to de novo CHD2 mutations, but is also seen in epileptic encephalopathies due to other gene mutations. We determined whether CHD2 variation underlies photosensitivity in common epilepsies, specific photosensitive epilepsies and individuals with photosensitivity without seizures. We studied 580 individuals with epilepsy and either photosensitive seizures or abnormal photoparoxysmal response on electroencephalography, or both, and 55 individuals with photoparoxysmal response but no seizures. We compared CHD2 sequence data to publicly available data from 34 427 individuals, not enriched for epilepsy. We investigated the role of unique variants seen only once in the entire data set. We sought CHD2 variants in 238 exomes from familial genetic generalized epilepsies, and in other public exome data sets. We identified 11 unique variants in the 580 individuals with photosensitive epilepsies and 128 unique variants in the 34 427 controls: unique CHD2variation is over-represented in cases overall (P = 2·17 × 10−5). Among epilepsy syndromes, there was over-representation of unique CHD2 variants (3/36 cases) in the archetypal photosensitive epilepsy syndrome, eyelid myoclonia with absences (P = 3·50 × 10−4). CHD2 variation was not over-represented in photoparoxysmal response without seizures. Zebrafish larvae with chd2 knockdown were tested for photosensitivity. Chd2 knockdown markedly enhanced mild innate zebrafish larval photosensitivity.CHD2 mutation is the first identified cause of the archetypal generalized photosensitive epilepsy syndrome, eyelid myoclonia with absences. Unique CHD2 variants are also associated with photosensitivity in common epilepsies. CHD2 does not encode an ion channel, opening new avenues for research into human cortical excitability.

Brain 2015

Autism: reduced connectivity between cortical areas involved in face expression, theory of mind, and the sense of self

Whole-brain voxel-based unbiased resting state functional connectivity was analysed in 418 subjects with autism and 509 matched typically developing individuals. We identified a key system in the middle temporal gyrus/superior temporal sulcus region that has reduced cortical functional connectivity (and increased with the medial thalamus), which is implicated in face expression processing involved in social behaviour. This system has reduced functional connectivity with the ventromedial prefrontal cortex, which is implicated in emotion and social communication. The middle temporal gyrus system is also implicated in theory of mind processing. We also identified in autism a second key system in the precuneus/superior parietal lobule region with reduced functional connectivity, which is implicated in spatial functions including of oneself, and of the spatial environment. It is proposed that these two types of functionality, face expression-related, and of one’s self and the environment, are important components of the computations involved in theory of mind, whether of oneself or of others, and that reduced connectivity within and between these regions may make a major contribution to the symptoms of autism.

Brain 2015

Diagnosis, prognosis, and clinical management of mild traumatic brain injury

Concussion and mild traumatic brain injury (TBI) are interchangeable terms to describe a common disorder with substantial effects on public health. Advances in brain imaging, non-imaging biomarkers, and neuropathology during the past 15 years have required researchers, clinicians, and policy makers to revise their views about mild TBI as a fully reversible insult that can be repeated without consequences. These advances have led to guidelines on management of mild TBI in civilians, military personnel, and athletes, but their widespread dissemination to clinical management in emergency departments and community-based health care is still needed. The absence of unity on the definition of mild TBI, the scarcity of prospective data concerning the long-term effects of repeated mild TBI and subconcussive impacts, and the need to further develop evidence-based interventions to mitigate the long-term sequelae are areas for future research that will improve outcomes, reduce morbidity and costs, and alleviate delayed consequences that have only recently come to light. 

Lancet Neurology 2015

Age, Sex, and APOE ε4 Effects on Memory, Brain Structure, and β-Amyloid Across the Adult Life Span

Importance  Typical cognitive aging may be defined as age-associated changes in cognitive performance in individuals who remain free of dementia. Ideally, the full adult age spectrum should be included to assess brain imaging findings associated with typical aging.

Objective  To compare age, sex, and APOE ε4 effects on memory, brain structure (adjusted hippocampal volume [HVa]), and amyloid positron emission tomography (PET) in cognitively normal individuals aged 30 to 95 years old.

Design, Setting, and Participants  Cross-sectional observational study (March 2006 to October 2014) at an academic medical center. We studied 1246 cognitively normal individuals, including 1209 participants aged 50 to 95 years old enrolled in a population-based study of cognitive aging and 37 self-selected volunteers aged 30 to 49 years old.

Main Outcomes and Measures  Memory, HVa, and amyloid PET.

Results  Overall, memory worsened from age 30 years through the 90s. The HVa worsened gradually from age 30 years to the mid-60s and more steeply beyond that age. The median amyloid PET was low until age 70 years and increased thereafter. Memory was worse in men than in women overall (P < .001) and more specifically beyond age 40 years. The HVa was lower in men than in women overall (P < .001) and more specifically beyond age 60 years. There was no sex difference in amyloid PET at any age. Within each sex, memory performance and HVa were not different by APOE ε4 status at any age. From age 70 years onward,APOE ε4 carriers had significantly greater median amyloid PET than noncarriers. However, the ages at which 10% of the population were amyloid PET positive were 57 years for APOE ε4 carriers and 64 years for noncarriers.

Conclusions and Relevance  Male sex is associated with worse memory and HVa among cognitively normal individuals, while APOE ε4 is not. In contrast, APOE ε4 is associated with greater amyloid PET (from age 70 years onward), while sex is not. Worsening memory and HVa occur at earlier ages than abnormal amyloid PET. Therefore, neuropathological processes other than β-amyloidosis must underlie declines in brain structure and memory function in middle age. Our findings are consistent with a model of late-onset Alzheimer disease in which β-amyloidosis arises in later life on a background of preexisting structural and cognitive decline that is associated with aging and not with β-amyloid deposits.

JAMA Neurology 2015

Predicting Reduction of Cerebrospinal Fluid β-Amyloid 42 in Cognitively Healthy Controls

Importance  Alzheimer disease has a long preclinical stage characterized by β-amyloid (Aβ) accumulation without symptoms. Several trials focus on this stage and use biomarkers to include Aβ-positive participants, but an even earlier prevention of Aβ accumulation may be an effective treatment strategy.

Objective  To determine whether people who appear to be Aβ negative but are at high risk for Aβ positivity within the near future can be identified.

Design, Setting, and Participants  Longitudinal biomarker cohort study involving 35 cognitively healthy individuals who underwent cerebrospinal fluid (CSF) sampling for up to 3 years during the study (October 24, 2005, to September 1, 2014). All participants had normal CSF Aβ42 levels at baseline.

Main Outcomes and Measures  Predictors of future Aβ positivity (levels of CSF Aβ42 declining below a previously validated cutoff level of 192 ng/L) tested by random forest models. Tested predictors included levels of protein in the CSF, hippocampal volume, genetics, demographics, and cognitive scores.

Results  The CSF Aβ42 levels declined in 11 participants, and the CSF became Aβ positive. The baseline CSF Aβ42 level was a strong predictor of future positivity (accuracy, 79% [95% CI, 70%-87%]). Ten of 11 decliners had baseline CSF Aβ42 levels in the lower tertile of the reference range (<225 ng/L), and 22 of 24 nondecliners had baseline CSF Aβ42 levels in the upper 2 tertiles (≥225 ng/L). A high CSF P-tau level was associated with decline (accuracy, 68%; 95% CI, 55%-81%).

Conclusions and Relevance  Baseline CSF Aβ42 levels in the lower part of the reference range are strongly associated with future Aβ positivity. This finding can be used in trials on very early prevention of Alzheimer disease to identify people at high risk for Aβ accumulation as defined by low CSF Aβ42 levels.

JAMA Neurology 2015

Cost-effectiveness estimate of prehospital thrombolysis Results of the PHANTOM-S Study

Objective: To analyze the cost-effectiveness of shorter delays to treatment and increased thrombolysis rate as shown in the PHANTOM-S (Prehospital Acute Neurological Treatment and Optimization of Medical Care in Stroke) Study.

Methods: In addition to intermediate outcomes (time to thrombolysis) and treatment rates, we registered all resource consequences of the intervention. The analyzed treatment effects of the intervention were restricted to distribution of IV thrombolysis (IVT) administrations according to time intervals. Intermediate outcomes were extrapolated to final outcomes according to numbers needed to treat derived from pooled IVT trials and translated to gains in quality-adjusted life-years (QALYs).

Results: The net annual cost of the Stroke Emergency Mobile (STEMO) prehospital stroke concept was €963,954. The higher frequency of IVT administrations per year (310 vs 225) and higher proportions of patients treated in the early time interval (within 90 minutes: 48.1% vs 37.4%; 91–180 minutes: 37.4% vs 50%; 181–270 minutes: 14.5% vs 12.8%) resulted in an annual expected health gain of avoidance of 18 cases of disability equaling 29.7 QALYs. This produced an incremental cost-effectiveness ratio of €32,456 per QALY.

Conclusions: Depending on willingness-to-pay thresholds in societal perspectives, the STEMO prehospital stroke concept has the potential of providing a reasonable innovation even in health-economic dimensions.

Neurology 2015

Ion channels in nociceptors Recent developments

Nociceptors are specialized high-threshold sensory afferents from dorsal root ganglion (DRG) or other primary sensory (e.g., trigeminal) neurons that innervate the skin, muscle, joints, and viscera and respond to noxious or potentially damaging stimuli. Nociceptors express a unique repertoire of voltage-gated sodium (Na⁺) channels (Na_v), potassium (K⁺) and calcium (Ca²⁺) channels, as well as cation channels of the transient receptor potential (TRP), acid-sensing ion channel (ASIC), and purinergic P2X families. These channels are responsible for the basic properties of nociceptors, including the lack of spontaneous activity and high threshold of activation. Products of inflammation or axonal injury trigger changes in the expression and function of these channels, resulting in increased excitability (reduced threshold of activation) of nociceptors. This process, known as peripheral nociceptor sensitization, manifests with spontaneous nociceptor activity (resulting in spontaneous pain), increased responsiveness and size of receptor fields for noxious stimulation (primary and secondary hyperalgesia), and nociceptor responses to innocuous mechanical or thermal stimuli (allodynia). These features characterize neuropathic and inflammatory pain. The wide variety of chemical signals that elicit nociceptor sensitization act via several types of receptors expressed in nociceptors, including G-protein-coupled receptors and tyrosine kinase receptors, which affect the expression or sensitivity of cation channels, particularly Na_v1.7, Na_v1.8, Na_v1.9, TRP vanilloid 1 (TRPV1), and TRP ankyrin 1 (TRPA1) channels. Gain-of-function mutations affecting these channels are linked to familial syndromes characterized by episodic pain sporadic painful small fiber neuropathies (SFN); loss-of function mutations are associated with congenital insensitivity to pain. There are extensive and excellent reviews on all these subjects.


Neurology 2015