Timing and significance of pathological features in C9orf72 expansion-associated frontotemporal dementia

Summary

A GGGGCC repeat expansion in C9orf72 leads to frontotemporal dementia and/or amyotrophic lateral sclerosis. Diverse pathological features have been identified, and their disease relevance remains much debated. Here, we describe two illuminating patients with frontotemporal dementia due to the C9orf72repeat expansion. Case 1 was a 65-year-old female with behavioural variant frontotemporal dementia accompanied by focal degeneration in subgenual anterior cingulate cortex, amygdala, and medial pulvinar thalamus. At autopsy, widespread RNA foci and dipeptide repeat protein inclusions were observed, but TDP-43 pathology was nearly absent, even in degenerating brain regions. Case 2 was a 74-year-old female with atypical frontotemporal dementia–motor neuron disease who underwent temporal lobe resection for epilepsy 5 years prior to her first frontotemporal dementia symptoms. Archival surgical resection tissue contained RNA foci, dipeptide repeat protein inclusions, and loss of nuclear TDP-43 but no TDP-43 inclusions despite florid TDP-43 inclusions at autopsy 8 years after first symptoms. These findings suggest that C9orf72-specific phenomena may impact brain structure and function and emerge before first symptoms and TDP-43 aggregation.

Brain 2016

Aerobic exercise and vascular cognitive impairment A randomized controlled trial

ABSTRACT

Objective: To assess the efficacy of a progressive aerobic exercise training program on cognitive and everyday function among adults with mild subcortical ischemic vascular cognitive impairment (SIVCI).

Methods: This was a proof-of-concept single-blind randomized controlled trial comparing a 6-month, thrice-weekly, progressive aerobic exercise training program (AT) with usual care plus education on cognitive and everyday function with a follow-up assessment 6 months after the formal cessation of aerobic exercise training. Primary outcomes assessed were general cognitive function (Alzheimer's Disease Assessment Scale–Cognitive subscale [ADAS-Cog]), executive functions (Executive Interview [EXIT-25]), and activities of daily living (Alzheimer's Disease Cooperative Study–Activities of Daily Living [ADCS-ADL]).

Results: Seventy adults randomized to aerobic exercise training or usual care were included in intention-to-treat analyses (mean age 74 years, 51% female, n = 35 per group). At the end of the intervention, the aerobic exercise training group had significantly improved ADAS-Cog performance compared with the usual care plus education group (−1.71 point difference, 95% confidence interval [CI] −3.15 to −0.26, p = 0.02); however, this difference was not significant at the 6-month follow-up (−0.63 point difference, 95% CI −2.34 to 1.07, p = 0.46). There were no significant between-group differences at intervention completion and at the 6-month follow-up in EXIT-25 or ADCS-ADL performance. Examination of secondary measures showed between-group differences at intervention completion favoring the AT group in 6-minute walk distance (30.35 meter difference, 95% CI 5.82 to 54.86, p = 0.02) and in diastolic blood pressure (−6.89 mm Hg difference, 95% CI −12.52 to −1.26, p = 0.02).

Conclusions: This study provides preliminary evidence for the efficacy of 6 months of thrice-weekly progressive aerobic training in community-dwelling adults with mild SIVCI, relative to usual care plus education.

ClinicalTrials.gov identifier: NCT01027858.

Classification of evidence: This study provides Class II evidence that for adults with mild SIVCI, an aerobic exercise program for 6 months results in a small, significant improvement in ADAS-Cog performance.

Neurology  2016

Rituximab in multiple sclerosis A retrospective observational study on safety and efficacy

ABSTRACT

Objective: To investigate the safety and efficacy of rituximab in multiple sclerosis (MS).

Methods: In this retrospective uncontrolled observational multicenter study, off-label rituximab-treated patients with MS were identified through the Swedish MS register. Outcome data were collected from the MS register and medical charts. Adverse events (AEs) grades 2–5 according to the Common Terminology Criteria for Adverse Events were recorded.

Results: A total of 822 rituximab-treated patients with MS were identified: 557 relapsing-remitting MS (RRMS), 198 secondary progressive MS (SPMS), and 67 primary progressive MS (PPMS). At baseline, 26.2% had contrast-enhancing lesions (CELs). Patients were treated with 500 or 1,000 mg rituximab IV every 6–12 months, during a mean 21.8 (SD 14.3) months. During treatment, the annualized relapse rates were 0.044 (RRMS), 0.038 (SPMS), and 0.015 (PPMS), and 4.6% of patients displayed CELs. Median Expanded Disability Status Scale remained unchanged in RRMS (p = 0.42) and increased by 0.5 and 1.0 in SPMS and PPMS, respectively (p = 0.10 and 0.25). Infusion-related AEs occurred during 7.8% of infusions and most were mild. A total of 89 AEs grades ≥2 (of which 76 infections) were recorded in 72 patients. No case of progressive multifocal leukoencephalopathy was detected.

Conclusions: This is the largest cohort of patients with MS treated with rituximab reported so far. The safety, clinical, and MRI findings in this heterogeneous real-world cohort treated with different doses of rituximab were similar to those reported in previous randomized controlled trials on B-cell depletion therapy in MS.

Classification of evidence: This study provides Class IV evidence that for patients with MS, rituximab is safe and effective.

Neurology 2016

Practice advisory: The utility of EEG theta/beta power ratio in ADHD diagnosis

Objective: To evaluate the evidence for EEG theta/beta power ratio for diagnosing, or helping to diagnose, attention-deficit/hyperactivity disorder (ADHD).

Methods: We identified relevant studies and classified them using American Academy of Neurology criteria.

Results: Two Class I studies assessing the ability of EEG theta/beta power ratio and EEG frontal beta power to identify patients with ADHD correctly identified 166 of 185 participants. Both studies evaluated theta/beta power ratio and frontal beta power in suspected ADHD or in syndromes typically included in an ADHD differential diagnosis. A bivariate model combining the diagnostic studies shows that the combination of EEG frontal beta power and theta/beta power ratio has relatively high sensitivity and specificity but is insufficiently accurate.

Conclusions: It is unknown whether a combination of standard clinical examination and EEG theta/beta power ratio increases diagnostic certainty of ADHD compared with clinical examination alone.

Recommendations: Level B: Clinicians should inform patients with suspected ADHD and their families that the combination of EEG theta/beta power ratio and frontal beta power should not replace a standard clinical evaluation. There is a risk for significant harm to patients from ADHD misdiagnosis because of the unacceptably high false-positive diagnostic rate of EEG theta/beta power ratio and frontal beta power. Level R: Clinicians should inform patients with suspected ADHD and their families that the EEG theta/beta power ratio should not be used to confirm an ADHD diagnosis or to support further testing after a clinical evaluation, unless such diagnostic assessments occur in a research setting.

Neurology 2016

Objective, computerized video-based rating of blepharospasm severity

ABSTRACT

Objective: To compare clinical rating scales of blepharospasm severity with involuntary eye closures measured automatically from patient videos with contemporary facial expression software.

Methods: We evaluated video recordings of a standardized clinical examination from 50 patients with blepharospasm in the Dystonia Coalition's Natural History and Biorepository study. Eye closures were measured on a frame-by-frame basis with software known as the Computer Expression Recognition Toolbox (CERT). The proportion of eye closure time was compared with 3 commonly used clinical rating scales: the Burke-Fahn-Marsden Dystonia Rating Scale, Global Dystonia Rating Scale, and Jankovic Rating Scale.

Results: CERT was reliably able to find the face, and its eye closure measure was correlated with all of the clinical severity ratings (Spearman ρ = 0.56, 0.52, and 0.56 for the Burke-Fahn-Marsden Dystonia Rating Scale, Global Dystonia Rating Scale, and Jankovic Rating Scale, respectively, all p < 0.0001).

Conclusions: The results demonstrate that CERT has convergent validity with conventional clinical rating scales and can be used with video recordings to measure blepharospasm symptom severity automatically and objectively. Unlike EMG and kinematics, CERT requires only conventional video recordings and can therefore be more easily adopted for use in the clinic.

Neurology 2016

Refining duration and frequency thresholds of restless legs syndrome diagnosis criteria

ABSTRACT

Objective: This study assesses the prevalence of restless legs syndrome (RLS) using DSM-5 criteria and determines what is the most appropriate threshold for the frequency and duration of RLS symptoms.

Methods: The Sleep-EVAL knowledge base system queried the interviewed subjects on life, sleeping habits, and health. Questions on sleep and mental and organic disorders (DSM-5, ICD-10) were also asked. A representative sample of 19,136 noninstitutionalized individuals older than 18 years living in the United States was interviewed through a cross-sectional telephone survey. The participation rate was 83.2%.

Results: The prevalence of the 4 leg symptoms describing RLS occurring at least 1 d/wk varied between 5.7% and 12.3%. When the frequency was set to at least 3 d/wk, the prevalence dropped and varied between 1.8% and 4.5% for the 4 leg symptoms. Higher frequency of leg symptoms was associated with greater distress and impairment with a marked increase at 3 d/wk. Symptoms were mostly chronic, lasting for more than 3 months in about 97% of the cases. The prevalence of RLS according to DSM-5 was 1.6% (95% confidence interval 1.4%–1.8%) when frequency was set at 3 d/wk. Stricter criteria for frequency of restless legs symptoms resulted in a reduction of prevalence of the disorder. The prevalence was further reduced when clinical impact was taken into consideration.

Conclusions: In order to avoid inflation of case rates and to identify patients in whom treatment is truly warranted, using a more conservative threshold of 3 times or greater per week appears the most appropriate.

Neurology 2016

Emerging temporal trends in tissue plasminogen activator use Results from the BASIC project

ABSTRACT

Objective: To explore temporal trends in tissue plasminogen activator (tPA) administration for acute ischemic stroke (AIS) in a biethnic community without an academic medical center and variation in trends by age, sex, ethnicity, and stroke severity.

Methods: Cases of AIS were identified from 7 hospitals in the Brain Attack Surveillance in Corpus Christi (BASIC) project, a population-based surveillance study between January 1, 2000, and June 30, 2012. tPA, demographics, and stroke severity as assessed by the NIH Stroke Scale (NIHSS) were ascertained from medical records. Temporal trends were explored using generalized estimating equations, and adjustment made for age, sex, ethnicity, and NIHSS. Interaction terms were included to test for effect modification.

Results: There were 5,277 AIS cases identified from 4,589 unique individuals. tPA use was steady at 2% and began increasing in 2006, reaching 11% in subsequent years. Stroke severity modified temporal trends (p = 0.003) such that cases in the highest severity quartile (NIHSS > 8) had larger increases in tPA use than those in lower severity quartiles. Although ethnicity did not modify the temporal trend, Mexican Americans (MAs) were less likely to receive tPA than non-Hispanic whites (NHWs) due to emerging ethnic differences in later years.

Conclusions: Dramatic increases in tPA use were apparent in this community without an academic medical center. Primary stroke center certification likely contributed to this rise. Results suggest that increases in tPA use were greater in higher severity patients compared to lower severity patients, and a gap between MAs and NHWs in tPA administration may be emerging.

Neurology 2016