Evaluation of mild cognitive impairment subtypes in Parkinson's disease

Mild cognitive impairment in Parkinson's disease (PD-MCI) is common and increases the risk for dementia. Establishing distinct PD-MCI cognitive subtypes could be valuable for eventually predicting those most likely to convert to dementia. However, the study of PD-MCI subtypes has not yielded consistent results among cohorts. To determine whether there are distinct cognitive subtypes among participants diagnosed with PD-MCI in the Pacific Northwest Udall Center Clinical Consortium, we cognitively subtyped 95 patients with PD-MCI, using the Movement Disorders Society Task Force diagnostic guidelines. Psychometric test scores were then subjected to principle components factor analysis to determine whether similar cognitive subgroups could be identified using statistical methodology. Multiple-domain PD-MCI was diagnosed in 95% of the sample, and a range of cognitive impairments were noted. Factor analysis yielded seven factors and demonstrated overlap of phonemic verbal fluency on two factors, as well as the loading of verbal fluency on the same factor as a visuospatial measure; however, these factors did not partition the sample into distinct cognitive subtypes. Separation of cognitive subtypes based on the current PD-MCI criteria, or via statistical methods, may not provide sufficient information to describe distinct PD groups. Future efforts to validate the PD-MCI criteria and identify combinations of genetic or other risk factors for cognitive impairment are warranted. 

Movement Disorders 2014

Measuring Disease Progression in Early Parkinson Disease The National Institutes of Health Exploratory Trials in Parkinson Disease (NET-PD) Experience

Importance  Optimizing assessments of rate of progression in Parkinson disease (PD) is important in designing clinical trials, especially of potential disease-modifying agents.

Objective  To examine the value of measures of impairment, disability, and quality of life in assessing progression in early PD.

Design, Setting, and Participants  Inception cohort analysis of data from 413 patients with early, untreated PD who were enrolled in 2 multicenter, randomized, double-blind clinical trials.

Interventions  Participants were randomly assigned to 1 of 5 treatments (67 received creatine, 66 received minocycline, 71 received coenzyme Q10, 71 received GPI-1485, and 138 received placebo). We assessed the association between the rates of change in measures of impairment, disability, and quality of life and time to initiation of symptomatic treatment.

Main Outcomes and Measures  Time between baseline assessment and need for the initiation of symptomatic pharmaceutical treatment for PD was the primary indicator of disease progression.

Results  After adjusting for baseline confounding variables with regard to the Unified Parkinson’s Disease Rating Scale (UPDRS) Part II score, the UPDRS Part III score, the modified Rankin Scale score, level of education, and treatment group, we assessed the rate of change for the following measurements: the UPDRS Part II score; the UPDRS Part III score; the Schwab and England Independence Scale score (which measures activities of daily living); the Total Functional Capacity scale; the 39-item Parkinson’s Disease Questionnaire, summary index, and activities of daily living subscale; and version 2 of the 12-item Short Form Health Survey Physical Summary and Mental Summary. Variables reaching the statistical threshold in univariate analysis were entered into a multivariable Cox proportional hazards model using time to symptomatic treatment as the dependent variable. More rapid change (ie, worsening) in the UPDRS Part II score (hazard ratio, 1.15 [95% CI, 1.08-1.22] for 1 scale unit change per 6 months), the UPDRS Part III score (hazard ratio, 1.09 [95% CI, 1.06-1.13] for 1 scale unit change per 6 months), and the Schwab and England Independence Scale score (hazard ratio, 1.29 [95% CI, 1.12-1.48] for 5 percentage point change per 6 months) was associated with earlier need for symptomatic therapy.

Conclusions and Relevance  In early PD, the UPDRS Part II score and Part III score and the Schwab and England Independence Scale score can be used to measure disease progression, whereas the 39-item Parkinson’s Disease Questionnaire and summary index, Total Functional Capacity scale, and the 12-item Short Form Health Survey Physical Summary and Mental Summary are not sensitive to change.

JAMA Neurology 2014

Phase 3 Trials of Solanezumab and Bapineuzumab for Alzheimer's Disease

Salloway et al. (Jan. 23 issue)1 report on two trials of bapineuzumab in mild-to-moderate Alzheimer's disease, and in the same issue, Doody et al.2 report on two trials of solanezumab for this condition. The negative results of these phase 3 trials may be interpreted in two ways: either treatment was too late in the course of the disease or amyloid-beta (Aβ) alone is the wrong target for an effective treatment of Alzheimer's disease. The first interpretation may be clarified when the results of ongoing treatment trials involving persons with preclinical Alzheimer's disease are available. These trials include the Dominantly Inherited Alzheimer Network Trial (DIAN-TU; ClinicalTrials.gov number, NCT01760005), Alzheimer's Prevention Initiative (API; NCT01998841), and the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease study (A4 Study; NCT02008357). The second interpretation has not yet been tested. Several tau-related vaccines are in advanced preclinical stages and will soon enter clinical trials. Since the pathologic process of Alzheimer's disease is characterized by the accumulation of both amyloid plaques and neurofibrillary tangles,3 it is reasonable to assume that a treatment strategy focusing on both targets may be more beneficial than a strategy focusing only on one.

NEJM 2014

Efficacy of occupational therapy for patients with Parkinson's disease: a randomised controlled trial

Background

There is insufficient evidence to support use of occupational therapy interventions for patients with Parkinson's disease. We aimed to assess the efficacy of occupational therapy in improving daily activities of patients with Parkinson's disease.

Methods

We did a multicentre, assessor-masked, randomised controlled clinical trial in ten hospitals in nine Dutch regional networks of specialised health-care professionals (ParkinsonNet), with assessment at 3 months and 6 months. Patients with Parkinson's disease with self-reported difficulties in daily activities were included, along with their primary caregivers. Patients were randomly assigned (2:1) to the intervention or control group by a computer-generated minimisation algorithm. The intervention consisted of 10 weeks of home-based occupational therapy according to national practice guidelines; control individuals received usual care with no occupational therapy. The primary outcome was self-perceived performance in daily activities at 3 months, assessed with the Canadian Occupational Performance Measure (score 1—10). Data were analysed using linear mixed models for repeated measures (intention-to-treat principle). Assessors monitored safety by asking patients about any unusual health events during the preceding 3 months. This trial is registered with ClinicalTrials.gov, NCT01336127.

Findings

Between April 14, 2011, and Nov 2, 2012, 191 patients were randomly assigned to the intervention group (n=124) or the control group (n=67). 117 (94%) of 124 patients in the intervention group and 63 (94%) of 67 in the control group had a participating caregiver. At baseline, the median score on the Canadian Occupational Performance Measure was 4·3 (IQR 3·5—5·0) in the intervention group and 4·4 (3·8—5·0) in the control group. At 3 months, these scores were 5·8 (5·0—6·4) and 4·6 (4·6—6·6), respectively. The adjusted mean difference in score from baseline between groups at 3 months was in favour of the intervention group (1·2; 95% CI 0·8—1·6; p<0·0001). There were no adverse events associated with the study.

Interpretation

Home-based, individualised occupational therapy led to an improvement in self-perceived performance in daily activities in patients with Parkinson's disease. Further work should identify which factors related to the patient, environmental context, or therapist might predict which patients are most likely to benefit from occupational therapy.

Lancet Neurology 2014

Mutations in the SPG7 gene cause chronic progressive external ophthalmoplegia through disordered mitochondrial DNA maintenance

Despite being a canonical presenting feature of mitochondrial disease, the genetic basis of progressive external ophthalmoplegia remains unknown in a large proportion of patients. Here we show that mutations in SPG7 are a novel cause of progressive external ophthalmoplegia associated with multiple mitochondrial DNA deletions. After excluding known causes, whole exome sequencing, targeted Sanger sequencing and multiplex ligation-dependent probe amplification analysis were used to study 68 adult patients with progressive external ophthalmoplegia either with or without multiple mitochondrial DNA deletions in skeletal muscle. Nine patients (eight probands) were found to carry compound heterozygousSPG7 mutations, including three novel mutations: two missense mutations c.2221G>A; p.(Glu741Lys), c.2224G>A; p.(Asp742Asn), a truncating mutation c.861dupT; p.Asn288*, and seven previously reported mutations. We identified a further six patients with single heterozygous mutations in SPG7, including two further novel mutations: c.184-3C>T (predicted to remove a splice site before exon 2) and c.1067C>T; p.(Thr356Met). The clinical phenotype typically developed in mid-adult life with either progressive external ophthalmoplegia/ptosis and spastic ataxia, or a progressive ataxic disorder. Dysphagia and proximal myopathy were common, but urinary symptoms were rare, despite the spasticity. Functional studies included transcript analysis, proteomics, mitochondrial network analysis, single fibre mitochondrial DNA analysis and deep re-sequencing of mitochondrial DNA. SPG7 mutations caused increased mitochondrial biogenesis in patient muscle, and mitochondrial fusion in patient fibroblasts associated with the clonal expansion of mitochondrial DNA mutations. In conclusion, the SPG7 gene should be screened in patients in whom a disorder of mitochondrial DNA maintenance is suspected when spastic ataxia is prominent. The complex neurological phenotype is likely a result of the clonal expansion of secondary mitochondrial DNA mutations modulating the phenotype, driven by compensatory mitochondrial biogenesis.

Brain 2014

Narcolepsy is a common phenotype in HSAN IE and ADCA-DN

We report on the extensive phenotypic characterization of five Italian patients from four unrelated families carrying dominant heterozygousDNMT1 mutations linked to two distinct autosomal dominant diseases: hereditary sensory and autonomic neuropathy with dementia and hearing loss type IE (HSAN IE) and autosomal dominant cerebellar ataxia, deafness and narcolepsy (ADCA-DN). Patients underwent genetic analysis of DNMT1gene, neurophysiological tests investigating sleep, auditory functions and peripheral nervous system, ophthalmological studies including optical coherence tomography, lymphoscintigraphy, brain magnetic resonance and nuclear imaging, cerebrospinal fluid hypocretin-1, total tau, phosphorylated tau, amyloid-β_1–42 and 14-3-3 proteins measurement, skin, muscular and sural nerve biopsies. Exome and direct sequencing studies disclosed two different point mutations affecting exon 21 ofDNMT1 gene in patients with ADCA-DN, a novel heterozygous point mutation in exon 20 in two affected HSAN IE siblings, and a trinucleotide deletion in exon 20 in the latter patient with HSAN IE. Phenotypic characterization pinpoints that ADCA-DN and HSAN IE represent two discrete clinical entities belonging to the same disease spectrum, with variable degree of overlap. Remarkably, narcolepsy with or without cataplexy with low/intermediate or normal cerebrospinal fluid hypocretin-1 is present in both diseases. The human leukocyte antigen DQB1*06:02 was absent in all patients. Other common symptoms and features observed in our cases, involving the central and peripheral nervous system, include deafness, optic neuropathy-previously not reported in HSAN IE-large and small fibres polyneuropathy and lower limbs oedema. Overall, the two syndromes share more characteristics than previously recognized and narcolepsy is common to both. HSAN IE and ADCA-DN are two extreme phenotypic manifestations of a DNMT1 methylopathy.

Brain 2014

Faster cognitive decline in elders without dementia and decreased risk of cancer mortality

Objective: To assess whether faster cognitive decline in elders without dementia is associated with decreased risk of cancer mortality.

Methods: In this population-based, prospective study of 2,627 people without dementia aged 65 years and older (Neurological Disorders in Central Spain), a 37-item version of the Mini-Mental State Examination (37-MMSE) was administered at 2 visits (baseline and follow-up, approximately 3 years later). We divided change in 37-MMSE into tertiles (lower tertile ≥2 point improvement in score, higher tertile ≥2 point decline in score). Community-dwelling elders were followed for a median of 12.9 years, after which the death certificates of those who died were examined.

Results: A total of 1,003 (38.2%) died, including 339 (33.8%) deaths among participants who were in the higher tertile of 37-MMSE change and 664 (66.2%) deaths among those in the remaining tertiles. Cancer was reported significantly less often in those in the higher tertile of MMSE change (20.6%) than in those in the remaining tertiles (28.6%): in an unadjusted Cox model, hazard ratio for cancer mortality in participants within the higher tertile = 0.75 (p = 0.04) compared with the participants within the remaining tertiles. In a Cox model that adjusted for a variety of demographic factors and comorbidities, hazard ratio for cancer mortality in participants within the higher tertile = 0.70 (p = 0.01).

Conclusion: In this population-based, prospective study of community-dwelling elders without dementia, faster cognitive decline was associated with a decreased risk of cancer mortality. Further studies are required to elucidate this inverse association in elders without dementia.

Neurology 2014