Transplantation of spinal cord–derived neural stem cells for ALS Analysis of phase 1 and 2 trials

Objective: To test the safety of spinal cord transplantation of human stem cells in patients with amyotrophic lateral sclerosis (ALS) with escalating doses and expansion of the trial to multiple clinical centers.

Methods: This open-label trial included 15 participants at 3 academic centers divided into 5 treatment groups receiving increasing doses of stem cells by increasing numbers of cells/injection and increasing numbers of injections. All participants received bilateral injections into the cervical spinal cord (C3-C5). The final group received injections into both the lumbar (L2-L4) and cervical cord through 2 separate surgical procedures. Participants were assessed for adverse events and progression of disease, as measured by the ALS Functional Rating Scale–Revised, forced vital capacity, and quantitative measures of strength. Statistical analysis focused on the slopes of decline of these phase 2 trial participants alone or in combination with the phase 1 participants (previously reported), comparing these groups to 3 separate historical control groups.

Results: Adverse events were mostly related to transient pain associated with surgery and to side effects of immunosuppressant medications. There was one incident of acute postoperative deterioration in neurologic function and another incident of a central pain syndrome. We could not discern differences in surgical outcomes between surgeons. Comparisons of the slopes of decline with the 3 separate historical control groups showed no differences in mean rates of progression.

Conclusions: Intraspinal transplantation of human spinal cord–derived neural stem cells can be safely accomplished at high doses, including successive lumbar and cervical procedures. The procedure can be expanded safely to multiple surgical centers.

Classification of evidence: This study provides Class IV evidence that for patients with ALS, spinal cord transplantation of human stem cells can be safely accomplished and does not accelerate the progression of the disease. This study lacks the precision to exclude important benefit or safety issues.

Neurology 2016

International consensus guidance for management of myasthenia gravis

Objective: To develop formal consensus-based guidance for the management of myasthenia gravis (MG).

Methods: In October 2013, the Myasthenia Gravis Foundation of America appointed a Task Force to develop treatment guidance for MG, and a panel of 15 international experts was convened. The RAND/UCLA appropriateness methodology was used to develop consensus guidance statements. Definitions were developed for goals of treatment, minimal manifestations, remission, ocular MG, impending crisis, crisis, and refractory MG. An in-person panel meeting then determined 7 treatment topics to be addressed. Initial guidance statements were developed from literature summaries. Three rounds of anonymous e-mail votes were used to attain consensus on guidance statements modified on the basis of panel input.

Results: Guidance statements were developed for symptomatic and immunosuppressive treatments, IV immunoglobulin and plasma exchange, management of impending and manifest myasthenic crisis, thymectomy, juvenile MG, MG associated with antibodies to muscle-specific tyrosine kinase, and MG in pregnancy.

Conclusion: This is an international formal consensus of MG experts intended to be a guide for clinicians caring for patients with MG worldwide.

Neurology 2016

Detecting depression in Parkinson disease A systematic review and meta-analysis

Background: Failure to detect depression in patients with Parkinson disease (PD) can lead to worsened outcomes for patients and caregivers. Accurate identification of depression would enable practitioners to provide comprehensive care for their patients with PD.

Methods: Our objective was to examine the diagnostic accuracy of tools for detecting depression in adult outpatients with PD. We searched MEDLINE, PsycINFO, and EMBASE (inception to December 1, 2015), gray literature, and bibliographies of included studies. The pooled prevalence of depression across studies and diagnostic accuracy estimates were calculated using random-effects models. Diagnostic accuracy estimates were calculated across the best-reported cutoffs from each study and across specific cutoffs, when feasible.

Results: Out of 8,184 citations, 21 studies were included, evaluating 24 tools, with 4 amenable to meta-analysis. The pooled prevalence of major depression was 22.9% (95% confidence interval [CI] 18.1–27.7). The 15-item Geriatric Depression Scale (GDS-15) had a pooled sensitivity of 0.81 (95% CI 0.64–0.91) and specificity of 0.91 (95% CI 0.87–0.94). The most sensitive cutoff for the GDS-15 was 5 at 0.91 (95% CI 0.83–1.00). The Beck Depression Inventory I/Ia had a pooled sensitivity of 0.79 (95% CI 0.61–0.90) and specificity of 0.85 (95% CI 0.79–0.90). The Montgomery-Åsberg Depression Rating Scale yielded a pooled sensitivity of 0.77 (95% CI 0.69–0.83) and specificity of 0.92 (95% CI 0.79–0.97). The Unified Parkinson's Disease Rating Scale had a pooled sensitivity of 0.72 (95% CI 0.64–0.79) and specificity of 0.80 (95% CI 0.70–0.87). All estimates had heterogeneity.

Conclusions: There are several valid tools for detecting depression in patients with PD. Practitioners should choose one that fits their clinical practice.

Neurology 2016

The clinical spectrum of Caspr2 antibody–associated disease

Objective: To report a large cohort of patients with antibodies against contactin-associated protein-like 2 (Caspr2) and provide the clinical spectrum of this disorder.

Methods: Serum and CSF samples were assessed at 2 neuroimmunology centers in Barcelona and Rotterdam. Patients were included if Caspr2 antibodies were confirmed with 2 independent techniques, including brain immunohistochemistry and cell-based assay. Clinical information was obtained by the authors or provided by treating physicians after patients' informed consent.

Results: Median age at symptom onset was 66 years. Of 38 patients, 34 were male. Median time to nadir of disease was 4 months (in 30% >1 year). The most frequent syndromes included limbic encephalitis (42%) and Morvan syndrome (29%). Seventy-seven percent of the patients had ≥3 of the following symptoms: encephalopathy (cognitive deficits/seizures), cerebellar dysfunction, peripheral nervous system hyperexcitability, dysautonomia, insomnia, neuropathic pain, or weight loss. A tumor, mostly thymoma, occurred in 19% of the patients. Immunoglobulin G4 subclass antibodies were present in all patients; 63% also had immunoglobulin G1 antibodies. Treatment response occurred in 93% of the patients and 25% had clinical relapses.

Conclusions: Caspr2 antibodies associate with a treatable disorder that predominantly affects elderly men. The resulting syndrome may vary among patients but it usually includes a set of well-established symptoms. Recognition of this spectrum of symptoms and consideration of the protracted clinical course are important for early diagnosis of this disorder. Prompt immunotherapy and tumor therapy (if needed) often result in improvement.

Neurology 2016

Social disinhibition is a heritable subphenotype of tics in Tourette syndrome

Objective: To identify heritable symptom-based subtypes of Tourette syndrome (TS).

Methods: Forty-nine motor and phonic tics were examined in 3,494 individuals (1,191 TS probands and 2,303 first-degree relatives). Item-level exploratory factor and latent class analyses (LCA) were used to identify tic-based subtypes. Heritabilities of the subtypes were estimated, and associations with clinical characteristics were examined.

Results: A 6-factor exploratory factor analysis model provided the best fit, which paralleled the somatotopic representation of the basal ganglia, distinguished simple from complex tics, and separated out socially disinhibited and compulsive tics. The 5-class LCA model best distinguished among the following groups: unaffected, simple tics, intermediate tics without social disinhibition, intermediate with social disinhibition, and high rates of all tic types. Across models, a phenotype characterized by high rates of social disinhibition emerged. This phenotype was associated with increased odds of comorbid psychiatric disorders, in particular, obsessive-compulsive disorder and attention-deficit/hyperactivity disorder, earlier age at TS onset, and increased tic severity. The heritability estimate for this phenotype based on the LCA was 0.53 (SE 0.08, p 1.7 × 10⁻¹⁸).

Conclusions: Expanding on previous modeling approaches, a series of TS-related phenotypes, including one characterized by high rates of social disinhibition, were identified. These phenotypes were highly heritable and may reflect underlying biological networks more accurately than traditional diagnoses, thus potentially aiding future genetic, imaging, and treatment studies.

Neurology 2016

The ARIC-PET amyloid imaging study Brain amyloid differences by age, race, sex, and APOE

Objective: To evaluate differences in amyloid deposition in a community-based cohort without dementia by age, sex, race, education, and APOE ε4 allele status.

Methods: Recruited from the longitudinal Atherosclerosis Risk in Communities study, 329 participants without dementia, ages 67–88 years, were imaged using florbetapir PET at 3 US community sites (Washington County, Maryland; Forsyth County, North Carolina; and Jackson, Mississippi). Standardized uptake value ratios (SUVRs) were calculated; global cortical SUVR >1.2 was evaluated as the primary outcome. Age, race, sex, education level, and number of APOE ε4 alleles were evaluated in multivariable models including vascular risk factors, brain white matter hyperintensity and total intracranial volume, and cognitive status.

Results: A total of 141 of the participants (43%) were black. In multivariable models, odds of elevated SUVR was increased in participants with increasing age (odds ratio [OR] 1.63, 95% confidence interval [CI] 1.01–2.65 per 10 years of age) and black race (OR 2.08, 95% CI 1.23–3.51) but did not differ by educational level. Each ε4 allele was associated with increased odds of elevated SUVR (OR 2.65, 95% CI 1.61–4.39).

Conclusions: In this community-based cohort without dementia, florbetapir uptake is associated with older age andAPOE genotype. Black race was associated with higher SUVR, after adjusting for demographics, vascular risk factors, cognitive status, white matter hyperintensity volume, and APOE genotype, with effect sizes nearing those seen for APOE ε4. Replication of these findings is needed in other cohorts, and reasons for and consequences of these observed differences by race warrant further study.

Neurology 2016

A/T/N: An unbiased descriptive classification scheme for Alzheimer disease biomarkers

Biomarkers have become an essential component of Alzheimer disease (AD) research and because of the pervasiveness of AD pathology in the elderly, the same biomarkers are used in cognitive aging research. A number of current issues suggest that an unbiased descriptive classification scheme for these biomarkers would be useful. We propose the “A/T/N” system in which 7 major AD biomarkers are divided into 3 binary categories based on the nature of the pathophysiology that each measures. “A” refers to the value of a β-amyloid biomarker (amyloid PET or CSF Aβ₄₂); “T,” the value of a tau biomarker (CSF phospho tau, or tau PET); and “N,” biomarkers of neurodegeneration or neuronal injury ([¹⁸F]-fluorodeoxyglucose–PET, structural MRI, or CSF total tau). Each biomarker category is rated as positive or negative. An individual score might appear as A+/T+/N−, or A+/T−/N−, etc. The A/T/N system includes the new modality tau PET. It is agnostic to the temporal ordering of mechanisms underlying AD pathogenesis. It includes all individuals in any population regardless of the mix of biomarker findings and therefore is suited to population studies of cognitive aging. It does not specify disease labels and thus is not a diagnostic classification system. It is a descriptive system for categorizing multidomain biomarker findings at the individual person level in a format that is easy to understand and use. Given the present lack of consensus among AD specialists on terminology across the clinically normal to dementia spectrum, a biomarker classification scheme will have broadest acceptance if it is independent from any one clinically defined diagnostic scheme.

Neurology 2016