Stephanie Lessig

Efficacy and safety of rifampicin for multiple system atrophy: a randomised, double-blind, placebo-controlled trial

BACKGROUND No available treatments slow or halt progression of multiple system atrophy, which is a rare, progressive, fatal neurological disorder. In a mouse model of multiple system atrophy, rifampicin inhibited formation of α-synuclein fibrils, the neuropathological hallmark of the disease. We aimed to assess the safety and efficacy of rifampicin in patients with multiple system atrophy. METHODS In this randomised, double-blind, placebo-controlled trial we recruited participants aged 30-80 years with possible or probable multiple system atrophy from ten US medical centres. Eligible participants were randomly assigned (1:1) via computer-generated permuted block randomisation to rifampicin 300 mg twice daily or matching placebo (50 mg riboflavin capsules), stratified by subtype (parkinsonian vs cerebellar), with a block size of four. The primary outcome was rate of change (slope analysis) from baseline to 12 months in Unified Multiple System Atrophy Rating Scale (UMSARS) I score, analysed in all participants with at least one post-baseline measurement. This study is registered with ClinicalTrials.gov, number NCT01287221. FINDINGS Between April 22, 2011, and April 19, 2012, we randomly assigned 100 participants (50 to rifampicin and 50 to placebo). Four participants in the rifampicin group and five in the placebo group withdrew from study prematurely. Results of the preplanned interim analysis (n=15 in each group) of the primary endpoint showed that futility criteria had been met, and the trial was stopped (the mean rate of change [slope analysis] of UMSARS I score was 0.62 points [SD 0.85] per month in the rifampicin group vs 0.47 points [0.48] per month in the placebo group; futility p=0.032; efficacy p=0.76). At the time of study termination, 49 participants in the rifampicin group and 50 in the placebo group had follow-up data and were included in the final analysis. The primary endpoint was 0.5 points (SD 0.7) per month for rifampicin and 0.5 points (0.5) per month for placebo (difference 0.0, 95% CI -0.24 to 0.24; p=0.82). Three (6%) of 50 participants in the rifampicin group and 12 (24%) of 50 in the placebo group had one or more serious adverse events; none was thought to be related to treatment. INTERPRETATION Our results show that rifampicin does not slow or halt progression of multiple system atrophy. Despite the negative result, the trial does provide information that could be useful in the design of future studies assessing potential disease modifying therapies in patients with multiple system atrophy. FUNDING National Institutes of Health, Mayo Clinic Center for Translational Science Activities, and Mayo Funds.

Neurobehavioral mechanisms of temporal processing deficits in Parkinson's disease.

Background Parkinsons disease (PD) disrupts temporal processing, but the neuronal sources of deficits and their response to dopamine (DA) therapy are not understood. Though the striatum and DA transmission are thought to be essential for timekeeping, potential working memory (WM) and executive problems could also disrupt timing. Methodology/Findings The present study addressed these issues by testing controls and PD volunteers ‘on’ and ‘off’ DA therapy as they underwent fMRI while performing a time-perception task. To distinguish systems associated with abnormalities in temporal and non-temporal processes, we separated brain activity during encoding and decision-making phases of a trial. Whereas both phases involved timekeeping, the encoding and decision phases emphasized WM and executive processes, respectively. The methods enabled exploration of both the amplitude and temporal dynamics of neural activity. First, we found that time-perception deficits were associated with striatal, cortical, and cerebellar dysfunction. Unlike studies of timed movement, our results could not be attributed to traditional roles of the striatum and cerebellum in movement. Second, for the first time we identified temporal and non-temporal sources of impaired time perception. Striatal dysfunction was found during both phases consistent with its role in timekeeping. Activation was also abnormal in a WM network (middle-frontal and parietal cortex, lateral cerebellum) during encoding and a network that modulates executive and memory functions (parahippocampus, posterior cingulate) during decision making. Third, hypoactivation typified neuronal dysfunction in PD, but was sometimes characterized by abnormal temporal dynamics (e.g., lagged, prolonged) that were not due to longer response times. Finally, DA therapy did not alleviate timing deficits. Conclusions/Significance Our findings indicate that impaired timing in PD arises from nigrostriatal and mesocortical dysfunction in systems that mediate temporal and non-temporal control-processes. However, time perception impairments were not improved by DA treatment, likely due to inadequate restoration of neuronal activity and perhaps corticostriatal effective-connectivity.

Cognitive and Functional Decline in Huntington's Disease: Dementia Criteria Revisited

The importance of designating criteria for diagnosing dementia lies in its implications for clinical treatment, research, caregiving, and decision‐making. Dementia diagnosis in Huntingtons disease (HD) is often based on criteria developed for Alzheimers disease requiring memory loss. However, it is likely that other cognitive deficits contribute to functional impairment in HD before memory declines. The goal is to identify cognitive deficits that contribute to functional impairment to support dementia criteria that reflect HD neuropathology. Eighty‐four HD mutation‐positive subjects completed neuropsychological tests and the Unified Huntingtons Disease Rating Scale Functional Independence Scale (FIS). Functional impairment was defined as 80 or below on the FIS. Speed of processing, initiation, and attention measures accounted for 70.0% of the variance in FIS ratings (linear regression) and correctly classified 91.7% of subjects as functionally impaired or intact (logistic regression). Measures of memory, motor impairment except dysarthria, neuroleptic use, and depressed mood did not improve prediction. A definition of HD dementia that includes cognitive impairment in at least two areas of cognition but does not require a memory deficit, in the context of impaired functional abilities and a deteriorating course, more accurately reflects HD neuropathology and could lead to improved research methods and patient care.

Changes on brief cognitive instruments over time in Parkinson's disease

Two hundred and twenty‐one subjects with Parkinsons disease (PD) were examined using the Mini–Mental Status Examination (MMSE) and Montreal Cognitive Assessment (MoCA), with a subset of these (n = 98) examined on repeat testing up to 3 years. The MoCA was more sensitive in identifying cognitive deficit, specifically in the domains of visuospatial abilities, language, and memory. In longitudinal study, the MMSE changed significantly over time, particularly in patients with disease duration of >10 years. The MoCA, however, did not change significantly, even when subjects were stratified by age, MMSE score, and disease duration. This suggests that the MoCA may be more sensitive for detecting early cognitive change in PD, but that the MMSE, and not the MoCA, may be better for tracking cognitive decline.

A comparison of two brief screening measures of cognitive impairment in Huntington's disease.

The goal of this study was to explore whether the Montreal Cognitive Assessment (MoCA), a new screening instrument, would be more sensitive to mild to moderate cognitive impairment in Huntingtons disease (HD) than an established screening measure, the Mini Mental State Exam (MMSE). Our reasoning for this query is that the MoCA includes a broader range of test items and an additional assessment of executive functioning and attention compared with the MMSE. Using the receiver operating characteristic (ROC) analysis to examine performance of HD and control groups on both tests on overall scores and scores from various subdomains (i.e., visuospatial abilities) revealed that the MoCA achieved higher sensitivity without sacrificing specificity in many domains relative to the MMSE.

Validation of the Modified Fatigue Impact Scale in Parkinson's disease

INTRODUCTION Fatigue is a common symptom in Parkinsons disease (PD); however, a multidimensional scale that measures the impact of fatigue on functioning has yet to be validated in this population. The aim of this study was to examine the validity of the Modified Fatigue Impact Scale (MFIS), a self-report measure that assesses the effects of fatigue on physical, cognitive, and psychosocial functioning, in a sample of nondemented PD patients. METHODS PD patients (N = 100) completed the MFIS, the Positive and Negative Affect Schedule (PANAS-X), and several additional measures of psychosocial, cognitive, and motor functioning. A Principal Component Analysis (PCA) and item analysis using Cronbachs alpha were conducted to determine structural validity and internal consistency of the MFIS. Correlational analyses were performed between the MFIS and the PANAS-X fatigue subscale to evaluate convergent validity and between the MFIS and measures of depression, anxiety, apathy, and disease-related symptoms to determine divergent validity. RESULTS The PCA identified two viable MFIS subscales: a cognitive subscale and a combination of the original scales physical and psychosocial subscales as one factor. Item analysis revealed high internal consistency of all 21 items and the items within the two subscales. The MFIS had strong convergent validity with the PANAS-X fatigue subscale and adequate divergent validity with measures of disease stage, motor function, and cognition. CONCLUSION Overall, this study demonstrates that the MFIS is a valid multidimensional measure that can be used to evaluate the impact of fatigue on cognitive and physical/social functioning in PD patients without dementia.

Instrumental activities of daily living are impaired in Parkinson’s disease patients with mild cognitive impairment.

OBJECTIVE Although it is well known that Parkinsons disease (PD) with dementia results in functional decline, little is known about the impact of mild cognitive impairment in PD (PD-MCI) on day-to-day functioning. METHOD Forty-one individuals with PD-MCI, 56 PD patients with normal cognition (PD-NC), and 47 healthy older adults were administered two performance-based measures of instrumental activities of daily living (IADLs) that evaluated medication and financial management. Informants of the PD patients were also administered an IADL questionnaire. RESULTS There were no significant differences between PD-NC and healthy older adults on the performance-based measures of medication and financial management. However, PD-MCI patients demonstrated significantly lower scores on the performance-based measures of medication and financial management compared with healthy older adults. PD-MCI patients were also impaired compared with PD-NC patients on performance-based medication management, but no difference between these groups was observed for ability to manage finances. Performance-based financial and medication management did not correlate with scores on neuropsychological measures in PD-MCI patients. PD-MCI and PD-NC patients showed comparable scores on the informant-based IADL questionnaire. CONCLUSIONS Performance-based measures of IADLs, particularly medication management ability, are sensitive to subtle functional declines in PD-MCI. Although impairment in performance-based measures is associated with cognitive status in PD, IADLs may be a separate domain of functioning from cognitive functioning in PD-MCI as these measures did not correlate with performance on the neuropsychological measures. Overall, performance-based assessment of IADLs may add to the clinical evaluation of PD-MCI.

The utility of the Mattis Dementia Rating Scale in Parkinson's disease mild cognitive impairment

BACKGROUND The Movement Disorders Society (MDS) recently proposed guidelines for diagnosis of mild cognitive impairment in Parkinsons disease (PD-MCI) that includes two assessment levels: abbreviated (Level I) and comprehensive (Level II). The aim of this study was to determine the utility of the Mattis Dementia Rating Scale (MDRS), a recommended Level I test, for detecting Level II PD-MCI diagnosis. METHODS The study sample included 30 patients diagnosed with PD-MCI based on Level II MDS criteria and 68 PD patients with normal cognition (PD-NC). Receiver operator curve (ROC) analyses were generated to measure the sensitivity and specificity of various MDRS cutoff scores. To examine the utility of the MDRS as a screening tool, the optimal cutoff point was defined as the lowest value providing ≥80% sensitivity. For use of the MDRS as a diagnostic tool, the optimal cutoff point was defined as the highest value providing ≥80% specificity. RESULTS ROC analyses showed that the optimal MDRS cutoff score for screening purposes and diagnostic purposes were ≤140 and ≤137, respectively. However, an examination of sensitivity/specificity values for the screening cutoff scores suggested that a total score of ≤139 for screening purposes yielded a better balance between sensitivity (77%) and specificity (65%). CONCLUSIONS In a clinical setting, in which detection of PD-MCI may be important, a total MDRS score of ≤139 can be used to detect PD-MCI. In research and other settings in which diagnostic certainty is more important, a score of ≤137 may be more useful.

Reduced hypocretin (orexin) levels in dementia with Lewy bodies.

Sleep disorders are observed in Parkinsons disease, dementia with Lewy bodies, and Alzheimers disease; however, the underlying mechanisms are unclear. Reduced hypocretin (orexin) levels are reported in Parkinsons disease and sleep disorders, including narcolepsy; however, its levels in dementia with Lewy bodies and Alzheimers disease and its relationship with sleep disturbances in these disorders remain undetermined. We examined hypocretin levels in qdementia with Lewy bodies and Alzheimers disease cases and correlated these with sleep habits and clinical characteristics. Although limited hypocretin alterations were observed in Alzheimers disease, we show reduced neocortical hypocretin immunoreactivity in dementia with Lewy bodies patients correlating with hypersomnolence and α-synuclein levels. These results suggest the involvement of hypocretin in sleep disorders in dementia with Lewy bodies.

Neuropathology of dementia with Lewy bodies in advanced age: a comparison with Alzheimer disease.

Dementia with Lewy Bodies (DLB) is a common neurodegenerative disorder of the aging population characterized by α-synuclein accumulation in cortical and subcortical regions. Although neuropathology in advanced age has been investigated in dementias such as Alzheimer Disease (AD), severity of the neuropathology in the oldest old with DLB remains uncharacterized. For this purpose we compared characteristics of DLB cases divided into three age groups 70-79, 80-89 and ≥ 90 years (oldest old). Neuropathological indicators and levels of synaptophysin were assessed and correlated with clinical measurements of cognition and dementia severity. These studies showed that frequency and severity of DLB was lower in 80-89 and ≥ 90 year cases compared to 70-79 year old group but cognitive impairment did not vary with age. The extent of AD neuropathology correlated with dementia severity only in the 70-79 year group, while synaptophysin immunoreactivity more strongly associated with dementia severity in the older age group in both DLB and AD. Taken together these results suggest that the oldest old with DLB might represent a distinct group.