Abstract
Journal of Alzheimer Disease 2017
sabato 30 settembre 2017
NEWS FROM BRESCIA- Voluptuary Habits and Risk of Frontotemporal Dementia: A Case Control Retrospective Study
NEWS FROM THE WORLD-Alcohol improves cerebellar learning deficit in myoclonus–dystonia: A clinical and electrophysiological investigation
Abstract
Objective
To characterize neurophysiological subcortical abnormalities in myoclonus–dystonia and their modulation by alcohol administration.
Methods
Cerebellar associative learning and basal ganglia–brainstem interaction were investigated in 17 myoclonus–dystonia patients with epsilon-sarcoglycan (SGCE) gene mutation and 21 age- and sex-matched healthy controls by means of classical eyeblink conditioning and blink reflex recovery cycle before and after alcohol intake resulting in a breath alcohol concentration of 0.08% (0.8g/l). The alcohol responsiveness of clinical symptoms was evaluated by 3 blinded raters with a standardized video protocol and clinical rating scales including the Unified Myoclonus Rating Scale and the Burke–Fahn–Marsden Dystonia Rating Scale.
Results
Patients showed a significantly reduced number of conditioned eyeblink responses before alcohol administration compared to controls. Whereas the conditioning response rate decreased under alcohol intake in controls, it increased in patients (analysis of variance: alcohol state × group, p = 0.004). Blink reflex recovery cycle before and after alcohol intake did not differ between groups. Myoclonus improved significantly after alcohol intake (p = 0.016). The severity of action myoclonus at baseline correlated negatively with the conditioning response in classical eyeblink conditioning in patients.
Interpretation
The combination of findings of reduced baseline acquisition of conditioned eyeblink responses and normal blink reflex recovery cycle in patients who improved significantly with alcohol intake suggests a crucial role of cerebellar networks in the generation of symptoms in these patients.
Ann Neurol 2017
NEWS FROM THE WORLD-Genome engineering: a new approach to gene therapy for neuromuscular disorders
Abstract
For many neuromuscular disorders, including Duchenne muscular dystrophy, spinal muscular atrophy and myotonic dystrophy, the genetic causes are well known. Gene therapy holds promise for the treatment of these monogenic neuromuscular diseases, and many such therapies have made substantial strides toward clinical translation. Recently, genome engineering tools, including targeted gene editing and gene regulation, have become available to correct the underlying genetic mutations that cause these diseases. In particular, meganucleases, zinc finger nucleases, TALENs, and the CRISPR–Cas9 system have been harnessed to make targeted and specific modifications to the genome. However, for most gene therapy applications, including genome engineering, gene delivery remains the primary hurdle to clinical translation. In preclinical models, genome engineering tools have been delivered via gene-modified cells or by non-viral or viral vectors to correct a diverse array of genetic diseases. In light of the positive results of these studies, genome engineering therapies are being enthusiastically explored for several genetic neuromuscular disorders. This Review summarizes the genome engineering strategies that are currently under preclinical evaluation for the treatment of degenerative neuromuscular disorders, with a focus on the molecular tools that show the greatest potential for clinical translation of these therapies.
Nature Reviews Neurology 2017
NEWS FROM THE WORLD- A systemic view of Alzheimer disease — insights from amyloid-β metabolism beyond the brain
Abstract
Alzheimer disease (AD) is the most common type of dementia, and is currently incurable; existing treatments for AD produce only a modest amelioration of symptoms. Research into this disease has conventionally focused on the CNS. However, several peripheral and systemic abnormalities are now understood to be linked to AD, and our understanding of how these alterations contribute to AD is becoming more clearly defined. This Review focuses on amyloid-β (Aβ), a major hallmark of AD. We review emerging findings of associations between systemic abnormalities and Aβ metabolism, and describe how these associations might interact with or reflect on the central pathways of Aβ production and clearance. On the basis of these findings, we propose that these abnormal systemic changes might not only develop secondary to brain dysfunction but might also affect AD progression, suggesting that the interactions between the brain and the periphery have a crucial role in the development and progression of AD. Such a systemic view of the molecular pathogenesis of AD could provide a novel perspective for understanding this disease and present new opportunities for its early diagnosis and treatment.
Nature Reviews Neurology 2017
NEWS FROM THE WORLD -Correlation of Peripheral Immunity With Rapid Amyotrophic Lateral Sclerosis Progression
Abstract
Importance Amyotrophic lateral sclerosis (ALS) has an immune component, but previous human studies have not examined immune changes over time.
Objectives To assess peripheral inflammatory markers in participants with ALS and healthy control individuals and to track immune changes in ALS and determine whether these changes correlate with disease progression.
Design, Setting, and Participants In this longitudinal cohort study, leukocytes were isolated from peripheral blood samples from 35 controls and 119 participants with ALS at the ALS Clinic of the University of Michigan, Ann Arbor, from June 18, 2014, through May 26, 2016. Follow-up visits occurred every 6 to 12 months. Fifty-one participants with ALS provided samples at multiple points. Immune cell populations were measured and compared between control and ALS groups. Surface marker expression of CD11b+ myeloid cells was also assessed. Changes over time were correlated with disease progression using multivariate regression.
Main Outcomes and Measures The number of immune cells per milliliter of blood and the fold expression of cell surface markers. Multivariate regression models were used to correlate changes in immune metrics with changes on the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R).
Results Thirty-five controls (17 women [48.6%] and 18 men [51.4%]; mean [SD] age, 63.5 [9.9] years) and 119 participants with ALS (50 women [42.0%] and 69 men [68.0%]; mean [SD] age, 61.4 [11.5] years) were enrolled. Compared with controls, participants with ALS had increased mean (SEM) counts ( × 106/mL) of total leukocytes (4.57 [0.29; 95% CI, 3.94-5.11] vs 5.53 [0.16; 95% CI, 5.21-5.84]), neutrophils (2.87 [0.23; 95% CI, 2.40-3.35] vs 3.80 [0.12; 95% CI, 3.56-4.04]), CD16+ monocytes (0.03 [0.003; 95% CI, 0.02-0.04] vs 0.04 [0.002; 95% CI, 0.03-0.04]), CD16− monocytes (0.25 [0.02; 95% CI, 0.21-0.30] vs 0.29 [0.01; 95% CI, 0.27-0.31]), and natural killer cells (0.13 [0.02; 95% CI, 0.10-0.17] vs 0.18 [0.01; 95% CI, 0.16-0.21]). We also observed an acute, transient increase in a population of CD11b+ myeloid cells expressing HLA-DR, CD11c, and CX3CR1. Finally, early changes in immune cell numbers had a significant correlation with disease progression measured by change in ALSFRS-R score, particularly neutrophils (−4.37 [95% CI, −6.60 to −2.14] per 11.47 × 104/mL [SD, 58.04 × 104/mL] per year) and CD4 T cells (−30.47 [95% CI, −46.02 to −14.94] per −3.72 × 104/mL [SD, 26.21 × 104/mL] per year).
Conclusions and Relevance Changes in the immune system occur during ALS and may contribute to the pathologic features of ALS.
JAMA Neurology 2017
NEWS FROM THE WORLD- Association Between Poor Cognitive Functioning and Risk of Incident Parkinsonism The Rotterdam Study
Abstract
Importance Cognitive dysfunction is a common feature among patients with parkinsonism, including Parkinson disease (PD). However, there is a scarcity of data on cognitive functioning before parkinsonism diagnosis, a stage at which patients may still respond to putative disease-modifying interventions.
Objective To assess whether poor cognitive functioning is associated with an increased risk of parkinsonism.
Design, Setting, and Participants Between January 8, 2002, and December 14, 2008, baseline cognitive function was assessed in 7386 participants of the Rotterdam Study who were free of parkinsonism and dementia. Four tests were administered (Stroop color word test, letter-digit substitution, verbal fluency, and word learning) and a global cognition score was derived from principal component analysis. Subsequently, participants were followed up until January 1, 2015, for the onset of parkinsonism through serial in-person examinations and complete access to medical records. Parkinsonism was defined as the (1) presence of hypokinesia or bradykinesia plus at least 1 other cardinal sign and/or (2) clinical diagnosis by a neurologist or geriatrician. Patients with dementia diagnosis before parkinsonism diagnosis were considered to have probable PD.
Main Outcomes and Measures Hazard ratios (HRs) for incident parkinsonism per SD decrease in global cognition, adjusted for age, sex, and study subcohort.
Results A total of 7386 patients were included in the analysis; of these, 4236 (57.4%) were women and mean (SD) age was 65.3 (10.2) years. During follow-up (median, 8.3 years; range, 0-15 years), 79 (1.1%) individuals received a diagnosis of incident parkinsonism; of these, 57 (72.2%) received a diagnosis of probable PD. Among patients with incident parkinsonism, 24 (30.4%) also developed dementia (10 before and 14 after parkinsonism onset). Poor global cognition at baseline was associated with a higher hazard of incident parkinsonism (hazard ratio [HR], 1.79; 95% CI, 1.37-2.33). The association remained robust beyond the first 8 years (HR, 1.59; 95% CI, 1.01-2.59) and after removing individuals with dementia onset before parkinsonism (HR, 1.72; 95% CI, 1.28-2.27). Poor global cognition at baseline was also associated with incident probable PD (HR, 1.52; 95% CI, 1.11-2.08). Letter-digit substitution (HR, 1.59; 95% CI, 1.22-2.04), verbal fluency (HR, 1.61; 95% CI, 1.23-2.08), and inverted interference task Stroop color word test (HR, 1.56; 95% CI, 1.25-1.96) scores were each associated with incident parkinsonism, whereas the association with word learning delayed-task scores was weaker (HR, 1.18; 95% CI, 0.92-1.52).
Conclusions and Relevance Poor cognitive functioning is associated with an increased risk of incident parkinsonism, including probable PD. Cognition indicates the probability of parkinsonism over long intervals and extends beyond patients with onset of parkinsonism after dementia. The findings suggest that cognitive dysfunction can be considered a sign of prodromal PD.
JAMA Neurology 2017
NEWS FROM THE WORLD- Clinical Imaging Factors Associated With Infarct Progression in Patients With Ischemic Stroke During Transfer for Mechanical Thrombectomy
Abstract
Importance When transferred from a referring hospital (RH) to a thrombectomy-capable stroke center (TCSC), patients with initially favorable imaging profiles (Alberta Stroke Program Early CT Score [ASPECTS] ≥6) often demonstrate infarct progression significant enough to make them ineligible for mechanical thrombectomy at arrival. In rapidly evolving stroke care networks, the question of the need for vascular imaging at the RHs remains unsolved, resulting in an important amount of futile transfers for thrombectomy.
Objective To examine the clinical imaging factors associated with unfavorable imaging profile evolution for thrombectomy in patients with ischemic stroke initially transferred to non-TCSCs.
Design, Setting, and Participants Data from patients transferred from 1 of 30 RHs in our regional stroke network and presenting at our TCSC from January 1, 2010, to January 1, 2016, were retrospectively analyzed. Consecutive patients with acute ischemic stroke initially admitted to a non–thrombectomy-capable RH and transferred to our center for which a RH computed tomography (CT) and a CT angiography (CTA) at arrival were available for review.
Main Outcomes and Measures ASPECTS were evaluated. The adequacy of leptomeningeal collateral blood flow was rated as no or poor, decreased, adequate, or augmented per the adapted Maas scale. The main outcome was an ASPECTS decay, defined as an initial ASPECTS of 6 or higher worsening between RH and TCSC CTs to a score of less than 6 (making the patient less likely to derive clinical benefit from thrombectomy at arrival).
Results A total of 316 patients were included in the analysis (mean [SD] age, 70.3 [14.2] years; 137 [43.4%] female). In multivariable models, higher National Institutes of Health Stroke Score, lower baseline ASPECTSs, and no or poor collateral blood vessel status were associated with ASPECTS decay, with collateral blood vessel status demonstrating the highest adjusted odds ratio of 5.14 (95% CI, 2.20-12.70; P < .001). Similar results were found after stratification by vessel occlusion level.
Conclusions and Relevance In patients with ischemic stroke transferred for thrombectomy, poor collateral blood flow and stroke clinical severity are the main determinants of ASPECTS decay. Our findings suggest that in certain subgroups vascular imaging, including collateral assessment, can play a crucial role in determining the benefits of transfer for thrombectomy.
JAMA Neurology 2017
NEWS FROM THE WORLD- Migraine and risk of stroke: a national population-based twin study
Abstract
Numerous studies have indicated an increased risk for stroke in patients with migraine, especially migraine with aura; however, many studies used self-reported migraine and only a few controlled for familial factors. We aimed to investigate migraine as a risk factor for stroke in a Swedish population-based twin cohort, and whether familial factors contribute to an increased risk. The study population included twins without prior cerebrovascular disease who answered a headache questionnaire during 1998 and 2002 for twins born 1935–58 and during 2005–06 for twins born between 1959 and 1985. Migraine with and without aura and probable migraine was defined by an algorithm mapping on to clinical diagnostic criteria according to the International Classification of Headache Disorders. Stroke diagnoses were obtained from the national patient and cause of death registers. Twins were followed longitudinally, by linkage of national registers, from date of interview until date of first stroke, death, or end of study on 31 Dec 2014. In total, 8635 twins had any migraineous headache, whereof 3553 had migraine with aura and 5082 had non-aura migraineous headache (including migraine without aura and probable migraine), and 44 769 twins had no migraine. During a mean follow-up time of 11.9 years we observed 1297 incident cases of stroke. The Cox proportional hazards model with attained age as underlying time scale was used to estimate hazard ratios with 95% confidence intervals for stroke including ischaemic and haemorrhagic subtypes related to migraine with aura, non-aura migraineous headache, and any migraineous headache. Analyses were adjusted for gender and cardiovascular risk factors. Where appropriate; within-pair analyses were performed to control for confounding by familial factors. The age- and gender-adjusted hazard ratio for stroke related to migraine with aura was 1.27 (95% confidence interval 1.00–1.62), P= 0.05, and 1.07 (95% confidence interval 0.91–1.26), P = 0.39 related to any migraineous headache. Multivariable adjusted analyses showed similar results. When stratified by gender and attained age of ≤50 or >50 years, the estimated hazard ratio for stroke was higher in twins younger than 50 years and in females; however, non-significant. In the within-pair analysis, the hazard ratio for stroke related to migraine with aura was attenuated [hazard ratio 1.09 (95% confidence interval 0.81–1.46), P = 0.59]. In conclusion, we observed no increased stroke risk related to migraine overall but there was a modestly increased risk for stroke related to migraine with aura, and within-pair analyses suggested that familial factors might contribute to this association.
Brain 2017
NEWS FROM THE WORLD- Risk of natalizumab-associated progressive multifocal leukoencephalopathy in patients with multiple sclerosis: a retrospective analysis of data from four clinical studies
Summary
Background
Previous estimates of risk of progressive multifocal leukoencephalopathy (PML) in patients with multiple sclerosis receiving natalizumab were stratified by three risk factors: anti-John Cunningham virus (JCV) antibodies in serum, previous immunosuppressant use, and treatment duration, which were estimated using population-based assumptions. We aimed to calculate PML risk estimates from patient-level risk-factor data and to stratify risk by concentrations of anti-JCV antibody in serum (anti-JCV antibody index).
Methods
Data on natalizumab-treated patients were pooled from four large, observational, open-label studies: STRATIFY-2, STRATA, TOP, and TYGRIS. Data were analysed with and without imputation for missing values of anti-JCV antibody status and previous immunosuppressant use. For anti-JCV antibody-positive patients in this pooled cohort, cumulative PML risk with or without previous immunosuppressant use was estimated using Kaplan-Meier analysis. Annual PML risks (per 12 natalizumab infusions) for patients without PML in the preceding year were estimated using conditional probability based on the life table method. For anti-JCV antibody-positive patients without previous immunosuppressant use, risk estimates were further stratified using a probability distribution for anti-JCV antibody index values, separately for patients with or without PML. Anti-JCV antibody index cutoffs were selected via sensitivity and specificity assessments for identifying PML cases in an index cohort.
Findings
156 (<1%) of 37 249 patients in the pooled cohort had PML. We imputed missing values on anti-JCV antibody status (3912 patients) and on previous immunosuppresant use (544 patients) using a multiple imputation method. For anti-JCV antibody-negative patients (n=13 996), estimated PML risk was less than 0·07 per 1000 patients (95% CI 0·00–0·40). In anti-JCV antibody-positive patients (n=21 696), estimated cumulative PML probability over 6 years (72 infusions of natalizumab) was 2·7% (95% CI 1·8–4·0) in patients with previous immunosuppressant use and 1·7% (1·4–2·1) in those without. In patients without previous immunosuppressant use (n=18 616), estimated annual PML risks per 1000 patients, conditional on having no PML before that year, ranged from 0·01 (0·00–0·03) in year 1 (1–12 infusions) to 0·6 (0·0–1·5) in year 6 (61–72 infusions) for people with an index of 0·9 or less; from 0·1 (0·0–0·2) in year 1 to 3·0 (0·2–5·8) in year 6 for those with an index of more than 0·9 up to and including 1·5; and from 0·2 (0·0–0·5) in year 1 to 10·0 (5·6–14·4) in year 6 for those with an index of more than 1·5.
Interpretation
Our risk estimates calculated from patient-level clinical data allow individualised annual prediction of risk of PML in patients receiving natalizumab for multiple sclerosis, supporting yearly benefit–risk re-evaluation in clinical practice. Further, our estimates are generally consistent with previously calculated estimates. Incorporating anti-JCV antibody index allows further risk stratification for anti-JCV antibody-positive patients who have not previously taken immunosuppressants.
Lancet Neurology 2017
NEWS FROM THE WORLD-Brain network connectivity differs in early-onset neurodegenerative dementia
ABSTRACT
Objective: To investigate functional brain network architecture in early-onset Alzheimer disease (EOAD) and behavioral variant frontotemporal dementia (bvFTD).
Methods: Thirty-eight patients with bvFTD, 37 patients with EOAD, and 32 age-matched healthy controls underwent 3D T1-weighted and resting-state fMRI. Graph analysis and connectomics assessed global and local functional topologic network properties, regional functional connectivity, and intrahemispheric and interhemispheric between-lobe connectivity.
Results: Despite similarly extensive cognitive impairment relative to controls, patients with EOAD showed severe global functional network alterations (lower mean nodal strength, local efficiency, clustering coefficient, and longer path length), while patients with bvFTD showed relatively preserved global functional brain architecture. Patients with bvFTD demonstrated reduced nodal strength in the frontoinsular lobe and a relatively focal altered functional connectivity of frontoinsular and temporal regions. Functional connectivity breakdown in the posterior brain nodes, particularly in the parietal lobe, differentiated patients with EOAD from those with bvFTD. While EOAD was associated with widespread loss of both intrahemispheric and interhemispheric functional correlations, bvFTD showed a preferential disruption of the intrahemispheric connectivity.
Conclusions: Disease-specific patterns of functional network topology and connectivity alterations were observed in patients with EOAD and bvFTD. Graph analysis and connectomics may aid clinical diagnosis and help elucidate pathophysiologic differences between neurodegenerative dementias.
Neurology 2017
NEWS FROM THE WORLD- COL4A2 is associated with lacunar ischemic stroke and deep ICH Meta-analyses among 21,500 cases and 40,600 controls
ABSTRACT
Objective: To determine whether common variants in familial cerebral small vessel disease (SVD) genes confer risk of sporadic cerebral SVD.
Methods: We meta-analyzed genotype data from individuals of European ancestry to determine associations of common single nucleotide polymorphisms (SNPs) in 6 familial cerebral SVD genes (COL4A1, COL4A2, NOTCH3, HTRA1, TREX1, and CECR1) with intracerebral hemorrhage (ICH) (deep, lobar, all; 1,878 cases, 2,830 controls) and ischemic stroke (IS) (lacunar, cardioembolic, large vessel disease, all; 19,569 cases, 37,853 controls). We applied data quality filters and set statistical significance thresholds accounting for linkage disequilibrium and multiple testing.
Results: A locus in COL4A2 was associated (significance threshold p < 3.5 × 10−4) with both lacunar IS (lead SNP rs9515201: odds ratio [OR] 1.17, 95% confidence interval [CI] 1.11–1.24, p = 6.62 × 10−8) and deep ICH (lead SNP rs4771674: OR 1.28, 95% CI 1.13–1.44, p = 5.76 × 10−5). A SNP in HTRA1 was associated (significance threshold p< 5.5 × 10−4) with lacunar IS (rs79043147: OR 1.23, 95% CI 1.10–1.37, p = 1.90 × 10−4) and less robustly with deep ICH. There was no clear evidence for association of common variants in either COL4A2 or HTRA1 with non-SVD strokes or in any of the other genes with any stroke phenotype.
Conclusions: These results provide evidence of shared genetic determinants and suggest common pathophysiologic mechanisms of distinct ischemic and hemorrhagic cerebral SVD stroke phenotypes, offering new insights into the causal mechanisms of cerebral SVD.
Neurology 2017
NEWS FROM THE WORLD- Caffeine as symptomatic treatment for Parkinson disease (Café-PD) A randomized trial
ABSTRACT
Objective: To assess effects of caffeine on Parkinson disease (PD).
Methods: In this multicenter parallel-group controlled trial, patients with PD with 1–8 years disease duration, Hoehn & Yahr stages I–III, on stable symptomatic therapy were randomized to caffeine 200 mg BID vs matching placebo capsules for 6–18 months. The primary research question was whether objective motor scores would differ at 6 months (Movement Disorder Society–sponsored Unified Parkinson's Disease Rating Scale [MDS-UPDRS]–III, Class I evidence). Secondary outcomes included safety and tolerability, motor symptoms (MDS-UPDRS-II), motor fluctuations, sleep, nonmotor symptoms (MDS-UPDRS-I), cognition (Montreal Cognitive Assessment), and quality of life.
Results: Sixty patients received caffeine and 61 placebo. Caffeine was well-tolerated with similar prevalence of side effects as placebo. There was no improvement in motor parkinsonism (the primary outcome) with caffeine treatment compared to placebo (difference between groups −0.48 [95% confidence interval −3.21 to 2.25] points on MDS-UPDRS-III). Similarly, on secondary outcomes, there was no change in motor signs or motor symptoms (MDS-UPDRS-II) at any time point, and no difference on quality of life. There was a slight improvement in somnolence over the first 6 months, which attenuated over time. There was a slight increase in dyskinesia with caffeine (MDS-UPDRS-4.1+4.2 = 0.25 points higher), and caffeine was associated with worse cognitive testing scores (average Montreal Cognitive Assessment = 0.66 [0.01, 1.32] worse than placebo).
Conclusion: Caffeine did not provide clinically important improvement of motor manifestations of PD (Class I evidence). Epidemiologic links between caffeine and lower PD risk do not appear to be explained by symptomatic effects.
Neurology 2017
NEWS FROM THE WORLD- UFM1 founder mutation in the Roma population causes recessive variant of H-ABC
ABSTRACT
Objective: To identify the gene defect in patients with hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) who are negative for TUBB4A mutations.
Methods: We performed homozygosity mapping and whole exome sequencing (WES) to detect the disease-causing variant. We used a Taqman assay for population screening. We developed a luciferase reporter construct to investigate the effect of the promoter mutation on expression.
Results: Sixteen patients from 14 families from different countries fulfilling the MRI criteria for H-ABC exhibited a similar, severe clinical phenotype, including lack of development and a severe epileptic encephalopathy. The majority of patients had a known Roma ethnic background. Single nucleotide polymorphism array analysis in 5 patients identified one large overlapping homozygous region on chromosome 13. WES in 2 patients revealed a homozygous deletion in the promoter region of UFM1. Sanger sequencing confirmed homozygosity for this variant in all 16 patients. All patients shared a common haplotype, indicative of a founder effect. Screening of 1,000 controls from different European Roma panels demonstrated an overall carrier rate of the mutation of 3%–25%. Transfection assays showed that the deletion significantly reduced expression in specific CNS cell lines.
Conclusions: UFM1 encodes ubiquitin-fold modifier 1 (UFM1), a member of the ubiquitin-like family involved in posttranslational modification of proteins. Its exact biological role is unclear. This study associates a UFM1 gene defect with a disease and sheds new light on possible UFM1 functional networks.
Neurology 2017
NEWS FROM THE WORLD: A phase 3 randomized placebo-controlled trial of tadalafil for Duchenne muscular dystrophy
ABSTRACT
Objective: To conduct a randomized trial to test the primary hypothesis that once-daily tadalafil, administered orally for 48 weeks, lessens the decline in ambulatory ability in boys with Duchenne muscular dystrophy (DMD).
Methods: Three hundred thirty-one participants with DMD 7 to 14 years of age taking glucocorticoids were randomized to tadalafil 0.3 mg·kg−1·d−1, tadalafil 0.6 mg·kg−1·d−1, or placebo. The primary efficacy measure was 6-minute walk distance (6MWD) after 48 weeks. Secondary efficacy measures included North Star Ambulatory Assessment and timed function tests. Performance of Upper Limb (PUL) was a prespecified exploratory outcome.
Results: Tadalafil had no effect on the primary outcome: 48-week declines in 6MWD were 51.0 ± 9.3 m with placebo, 64.7 ± 9.8 m with low-dose tadalafil (p = 0.307 vs placebo), and 59.1 ± 9.4 m with high-dose tadalafil (p = 0.538 vs placebo). Tadalafil also had no effect on secondary outcomes. In boys >10 years of age, total PUL score and shoulder subscore declined less with low-dose tadalafil than placebo. Adverse events were consistent with the known safety profile of tadalafil and the DMD disease state.
Conclusions: Tadalafil did not lessen the decline in ambulatory ability in boys with DMD. Further studies should be considered to confirm the hypothesis-generating upper limb data and to determine whether ambulatory decline can be slowed by initiation of tadalafil before 7 years of age.
Clinicaltrials.gov identifier: NCT01865084.
Classification of evidence: This study provides Class I evidence that tadalafil does not slow ambulatory decline in 7- to 14-year-old boys with Duchenne muscular dystrophy
Neurology 2017
sabato 23 settembre 2017
NEWS FROM THE WORLD -Cortical pathology in multiple sclerosis detected by the T1/T2-weighted ratio from routine magnetic resonance imaging
Abstract
Objective
In multiple sclerosis, neuropathological studies have shown widespread changes in the cerebral cortex. In vivo imaging is critical, because the histopathological substrate of most measurements is unknown.
Methods
Using a novel magnetic resonance imaging analysis technique, based on the ratio of T1- and T2-weighted signal intensities, we studied the cerebral cortex of a large cohort of patients in early stages of multiple sclerosis. A total of 168 patients with clinically isolated syndrome or relapsing–remitting multiple sclerosis (Expanded Disability Status Scale: median = 1, range = 0–3.5) and 80 age- and sex-matched healthy controls were investigated. We also searched for the histopathological substrate of the T1/T2-weighted ratio by combining postmortem imaging and histopathology in 9 multiple sclerosis brain donors.
Results
Patients showed lower T1/T2-weighted ratio values in parietal and occipital areas. The 4 most significant clusters appeared in the medial occipital and posterior cingulate cortex (each left and right). The decrease of the T1/T2-weighted ratio in the posterior cingulate was related to performance in attention. Analysis of the T1/T2-weighted ratio values of postmortem imaging yielded a strong correlation with dendrite density but none of the other parameters including myelin.
Interpretation
The T1/T2-weighted ratio decreases in early stages of multiple sclerosis in a widespread manner, with a preponderance of posterior areas and with a contribution to attentional performance; it seems to reflect dendrite pathology. As the method is broadly available and applicable to available clinical scans, we believe that it is a promising candidate for studying and monitoring cortical pathology or therapeutic effects in multiple sclerosis.
Annals of Neurology 2017
NEWS FROM THE WORLD -Mutations in DNM1L, as in OPA1, result indominant optic atrophy despite opposite effectson mitochondrial fusion and fission
Abstract
Dominant optic atrophy is a blinding disease due to the degeneration of the retinal ganglion cells, the axons of which form the optic nerves. In most cases, the disease is caused by mutations in OPA1, a gene encoding a mitochondrial large GTPase involved in cristae structure and mitochondrial network fusion. Using exome sequencing, we identified dominant mutations in DNM1L on chromosome 12p11.21 in three large families with isolated optic atrophy, including the two families that defined the OPA5 locus on chromosome 19q12.1-13.1, the existence of which is denied by the present study. Analyses of patient fibroblasts revealed physiological abundance and homo-polymerization of DNM1L, forming aggregates in the cytoplasm and on highly tubulated mitochondrial network, whereas neither structural difference of the peroxisome network, nor alteration of the respiratory machinery was noticed. Fluorescence microscopy of wild-type mouse retina disclosed a strong DNM1L expression in the ganglion cell layer and axons, and comparison between 3-month-old wild-type and Dnm1l+/− mice revealed increased mitochondrial length in retinal ganglion cell soma and axon, but no degeneration. Thus, our results disclose that in addition to OPA1, OPA3, MFN2, AFG3L2 and SPG7, dominant mutations in DNM1L jeopardize the integrity of the optic nerve, suggesting that alterations of the opposing forces governing mitochondrial fusion and fission, similarly affect retinal ganglion cell survival.
Brain 2017
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