Structural brain differences in the Alzheimer's disease continuum: Insights into the heterogeneity from a large multi-site neuroimaging consortium.

INTRODUCTION: Neurodegenerative diseases require collaborative, multi-site research to comprehensively grasp their complex and diverse pathological progression, yet there is caution in aggregating global data due to data heterogeneity. The current study investigates brain structure across stages of Alzheimer's disease (AD), and how relationships vary across sources of heterogeneity. METHODS: Using 6 international datasets(n>27,000), associations of structural neuroimaging markers were investigated in relation to the AD continuum via meta-analysis. We investigated whether associations varied across elements of MRI acquisition, study design and populations. RESULTS: Modest differences in associations were found dependent on how data were acquired, however patterns were similar. Preliminary results suggest neuroimaging marker-AD relationships differ across ethnic groups. DISCUSSION: Diversity in data offers unique insights into the neural substrate of AD, however harmonised processing and transparency of data collection is needed. Global collaborations should embrace inherent heterogeneity that exists within the data and quantify its contribution to research findings at the meta-analytical stage.

Levodopa and the feedback process on set-shifting in Parkinson's disease.

OBJECTIVE: To study the interaction between levodopa and the feedback process on set-shifting in Parkinson's disease (PD). METHODS: Functional magnetic resonance imaging (fMRI) studies were performed on 13 PD subjects and 17 age-matched healthy controls while they performed a modified card-sorting task. Experimental time periods were defined based on the types of feedback provided. PD subjects underwent the fMRI experiment twice, once during "off" medication (PDoff) and again after levodopa replacement (PDon). RESULTS: Compared with normal subjects, the cognitive processing times were prolonged in PDoff but not in PDon subjects during learning through positive outcomes. The ability to set-shift through negative outcomes was not affected in PD subjects, even when "off" medication. Intergroup comparisons showed the lateral prefrontal cortex was deactivated in PDoff subjects during positive feedback learning, especially following internal feedback cues. The cortical activations were increased in the posterior brain regions in PDoff subjects following external feedback learning, especially when negative feedback cues were provided. Levodopa replacement did not completely restore the activation patterns in PD subjects to normal although activations in the corticostriatal loops were restored. CONCLUSION: PD subjects showed differential ability to set-shift, depending on the dopamine status as well as the types of feedback cues provided. PD subjects had difficulty performing set-shift tasks through positive outcomes when "off" medication, and showed improvement after levodopa replacement. The ability to set-shift through negative feedback was not affected in PD subjects even when "off" medication, possibly due to compensatory changes outside the nigrostriatal dopaminergic pathway.

Responsiveness of the EQ-5D and 8-item Parkinson's Disease Questionnaire (PDQ-8) in a 4-year follow-up study.

OBJECTIVE: The purpose of this study was to evaluate the responsiveness of the EQ-5D and the Parkinson's Disease Questionnaire (PDQ-8) to deterioration in health-related quality of life (HRQoL) in patients with Parkinson's disease (PD). METHODS: HRQoL and clinical data collected from 31 patients with PD (male: 74.2%, mean age: 61 years) who were surveyed with the EQ-5D and the PDQ-8 questionnaires in 2002 and 2006/2007 were analyzed. Responsiveness of the EQ-5D, PDQ-8, and Hoehn and Yahr (H&Y) staging were assessed according to Cohen's effect size (ES) and standardized response mean (SRM). RESULTS: The mean (standard deviation) EQ-5D index and PDQ-8 summary index (PDQ-8SI) scores were 0.76 (0.23) and 17.7 (14.2) at baseline and 0.52 (0.33) and 35.1 (17.4) at year four. Based on both ES and SRM indices, the rank order of responsiveness of the studied measures, from high to low, was PDQ-8SI (ES = 1.22), EQ-5D index score (ES = 1.06), H&Y score (ES = 0.82), and the EQ-VAS score (ES = 0.24). CONCLUSION: Both the EQ-5D and PDQ-8 are responsive to changes in health burden of the Parkinson's disease over a 4-year period.

SNCA Rep1 microsatellite length influences non-motor symptoms in early Parkinson's disease.

Long alpha-synuclein gene (SNCA) promoter (Rep1) allele-carriers are linked to higher risk for Parkinson's disease (PD) and faster motor progression. Non-motor symptoms including autonomic, neuropsychiatric, and sleep disorders are common in PD. However, the relationship between SNCA Rep1 microsatellite lengths and non-motor symptoms in early PD remains to be elucidated. 171 consecutive early PD patients were recruited from tertiary clinics and genotyped for Rep1. Multivariable regression analyses were performed to examine associations between Rep1 alleles and non-motor outcome scores. Longer Rep1 alleles significantly associated with higher total Non-Motor Symptom Scale (NMSS) scores (p=.006) and Hospital Anxiety and Depression Scale (HADS) depression subscale scores (p=.002), after adjusting for covariates and Bonferroni correction. We demonstrated that SNCA Rep1 allele length influences overall non-motor symptom burden and depression in early PD patients. Further functional studies to evaluate the role of Rep1 in non-dopaminergic systems may unravel new therapeutic targets for non-motor symptoms in PD.

'Hummingbird' Sign in a Patient with Guam Parkinsonism-Dementia Complex.

We present a case of a 71-year-old male Chamorro patient from Guam who presented with progressive supranuclear palsy (PSP)-Richardson's syndrome. Considering his strong family history of parkinsonism and a PSP phenotype, he was clinically diagnosed with Guam parkinsonism-dementia complex (PDC). Magnetic resonance imaging (MRI) of the brain revealed prominent midbrain atrophy with preserved pontine volume, forming the 'hummingbird' sign, which has not been described before in Guam PDC. Molecular analysis of the chromosome 9 open reading frame 72 gene (C9orf72) showed only 6 GGGGCC repeats. We discuss the clinico-pathological similarities and differences between PSP and Guam PDC, and highlight the topography of neuropathological changes seen in Guam PDC to explain the appearance of the 'hummingbird' sign on MRI.

Treatment Preferences at the End-of-Life in Parkinson's Disease Patients.

BACKGROUND: Few studies have been performed on palliative care in Parkinson's disease (PD). This study was undertaken to understand treatment preferences of PD patients toward end-of-life care. METHODS: A questionnaire modified from the Willingness to Accept Life-Sustaining Treatment instrument was administered to participants. Four different scenarios based on the burden of care and outcome of the treatment were presented in detail to obtain decisions for end-of-life care. The responses in each scenario were compared between PD patients and controls. Further analyses were performed to identify factors that influenced treatment preferences among PD patients. RESULTS: In total, 136 PD patients and 60 controls were recruited. Parkinson's disease patients and controls were demographically similar, except that PD patients had more previous hospital admissions (P = 0.0195). Parkinson's disease patients were more likely to opt for high-burden care with poor outcome than controls (odds ratio [OR] = 2.11, P = 0.04).In the subgroup analysis for PD patients, the factors that influenced treatment preference toward end-of-life care were belief in religion (OR: 7.43, 95% confidence interval:1.97-28.07), higher Unified Parkinson's Disease Rating Scale (UPDRS) motor score (2.51, 1.14-5.50) in scenario B; belief in religion (6.93, 2.23-21.43), married patients (6.93, 2.23-21.43) in scenario C; and Chinese patients (0.29, 0.10-0.79), better PD knowledge (0.37, 0.17-0.80), and higher UPDRS motor scores (3.05, 1.35-6.9) in scenario D. CONCLUSION: Parkinson's disease patients were more likely to agree to high-burden care with a poor outcome compared to controls. Among PD patients, race, marital status, religious status, knowledge about PD, and severity of motor impairment significantly influenced their end-of-life treatment preferences.

Montreal Cognitive Assessment for the screening and prediction of cognitive decline in early Parkinson's disease.

BACKGROUND: Early diagnosis of cognitive impairment in PD would allow appropriate monitoring and timely intervention to reduce the progression to dementia (PDD). OBJECTIVE: To study the usefulness of the Montreal Cognitive Assessment (MoCA) in the screening for mild cognitive impairment (PD-MCI) and its predictive utility in determining longitudinal cognitive decline in PD. METHODS: Prospective longitudinal study of patients with mild PD. PD-MCI and PDD was diagnosed based on the Movement Disorder taskforce (MDS) criteria. Receiver Operating Characteristic analyses and Cox regression analyses were performed. RESULTS: 95 patients; mean age 66.37 (SD 7.86); mean H&Y score of 1.99 (SD 0.45) were studied. At baseline, 34 patients fulfilled the MDS criteria for PD-MCI. MoCA, compared to the MMSE had a high discriminatory power in detecting PD-MCI [Area Under Curve (AUC) of 0.912, p < 0.001]. A MoCA score of ≤26 provided a sensitivity of 93.1% for the diagnosis of PD-MCI. In the longitudinal cohort over 2 years, baseline MOCA was useful in predicting cognitive decline (AUC of 0.707, p = 0.05). With Cox regression analyses, a 1-point lower score on baseline MoCA was associated with a 34% increased risk of cognitive decline [Hazard ratio (HR) 1.34; 95% CI: 1.03-1.74: p = 0.029]. A baseline MoCA ≤26 was highly predictive of progressive cognitive decline (HR 3.47, 95% CI: 2.38-5.07; p < 0.01). CONCLUSIONS: MoCA is a reliable tool in predicting cognitive decline in early PD. A MoCA score of ≤26 significantly increases the risk for progressive cognitive decline.