Voxel-based morphometry reveals extra-nigral atrophy patterns associated with dopamine refractory cognitive and motor impairment in parkinsonism
ABSTRACT To determine overall patterns of brain atrophy associated with memory, executive function (EF) and dopamine non-responsive motor measures in older parkinsonian patients.
Forty-three older PD patients (>or=65 years) and matched controls underwent a neurological examination (Unified Parkinson's Disease Rating Scale, separated into dopamine responsive and dopamine non-responsive signs) and neuropsychological testing (memory: California Verbal Learning Test (CVLT)) and a composite of index of executive function (EF): Stroop Interference, Trail Making Test Part B, and digit ordering. All underwent volumetric MRI scans analyzed using voxel-based morphometry (VBM). Group comparisons, and the correlations between MRI gray and white matter volume and motor and cognitive measures were controlled for age, sex and intracranial volume. Cerebellar volume was independently measured using a validated extraction method.
Patients and controls were matched for demographics and global cognitive measures. VBM indicated significant gray matter (GM) atrophy in the cerebellum in PD and was confirmed independently. Poor memory was associated with GM atrophy in the left (uncus, middle temporal and fusiform gyri) and right temporal lobes and left putamen. Dopamine non-responsive motor signs and EF were associated with caudate atrophy. EF was also associated with GM atrophy in the middle temporal gyri, the left precuneus and cerebellum.
Cortical and striatal atrophy were associated with dopamine non-responsive motor signs and cognitive impairment and provide a morphologic correlate for progression of PD. Cerebellar atrophy was found in older PD patients.
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ABSTRACT: Numerous voxel-based morphometry (VBM) studies on gray matter (GM) in patients with the Parkinson variant of multiple system atrophy (MSA-P) and Parkinson's disease (PD) have been separately conducted. Identifying the different neuroanatomical changes in GM between MSA-P and PD through meta-analysis may aid the differential diagnosis of MSA-P and PD. A systematic review of VBM studies on patients with MSA-P and PD compared to healthy controls (HC) from the PubMed and Embase databases between January 1995 and June 2014 was conducted. Five studies comparing MSA-P with HC and twenty-three studies comparing PD with HC were included. The anatomical distribution of the coordinates of GM volume (GMV) differences was analyzed using the anatomical likelihood estimation (ALE) method. GMV reductions were present in the bilateral putamen, claustrum, insula, midbrain and left cerebellum in MSA-P. In PD, GMV decreases were present in the frontal, parietal, occipital and limbic lobes. Subtraction meta-analysis was performed to explore the differences in GM abnormalities between MSA-P and PD during the early stage of the disease. For patients with disease duration within 5 years, compared with PD, the decrease in GMV focused on the bilateral putamen and claustrum in MSA-P. In contrast, for patients with disease duration within 3 years, no significant GMV difference was found between MSA-P and PD. Our meta-analysis indicated that the atrophy of bilateral putamen or claustrum is not a neuroanatomical marker for distinguishing MSA-P from PD during the early stage by using the VBM method. Copyright © 2014. Published by Elsevier Ireland Ltd.Neuroscience Letters 12/2014; 587. DOI:10.1016/j.neulet.2014.12.007 · 2.06 Impact Factor
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ABSTRACT: HTRA2, a serine protease in the intermembrane space, has important functions in mitochondrial stress signaling while its abnormal activity may contribute to the development of Parkinson's disease. Mice with a missense or null mutation of Htra2 fail to thrive, suffer striatal neuronal loss, and a parkinsonian phenotype that leads to death at 30-40 days of age. While informative, these mouse models cannot separate neural contributions from systemic effects due to the complex phenotypes of HTRA2 deficiency. Hence, we developed mice carrying a Htra2-floxed allele to query the consequences of tissue-specific HTRA2 deficiency. We found that mice with neural-specific deletion of Htra2 exhibited atrophy of the thymus and spleen, cessation to gain weight past postnatal (P) day 18, neurological symptoms including ataxia and complete penetrance of premature death by P40. Histologically, increased apoptosis was detected in the cerebellum, and to a lesser degree in the striatum and the entorhinal cortex, from P25. Even earlier at P20, mitochondria in the cerebella already exhibited abnormal morphology, including swelling, vesiculation, and fragmentation of the cristae. Furthermore, the onset of these structural anomalies was accompanied by defective processing of OPA1, a key molecule for mitochondrial fusion and cristae remodeling, leading to depletion of the L-isoform. Together, these findings suggest that HTRA2 is essential for maintenance of the mitochondrial integrity in neurons. Without functional HTRA2, a lifespan as short as 40 days accumulates a large quantity of dysfunctional mitochondria that contributes to the demise of mutant mice.PLoS ONE 12/2014; 9(12):e115789. DOI:10.1371/journal.pone.0115789 · 3.53 Impact Factor
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ABSTRACT: Although nigrostriatal changes are most commonly affiliated with Parkinson's disease, the role of the cerebellum in Parkinson's has become increasingly apparent. The present study used lobule-based cerebellar resting state functional connectivity to (1) compare cerebellar-whole brain and cerebellar-cerebellar connectivity in Parkinson's patients both ON and OFF L-DOPA medication and controls, and to (2) relate variations in cerebellar connectivity to behavioral performance. Results indicated that, when contrasted to the control group, Parkinson's patients OFF medication had increased levels of cerebellar-whole brain and cerebellar-cerebellar connectivity, whereas Parkinson's patients ON medication had decreased levels of cerebellar-whole brain and cerebellar-cerebellar connectivity. Moreover, analyses relating levels of cerebellar connectivity to behavioral measures demonstrated that, within each group, increased levels of connectivity were most often associated with improved cognitive and motor performance, but there were several instances where increased connectivity was related to poorer performance. Overall, the present study found medication-variant cerebellar connectivity in Parkinson's patients, further demonstrating cerebellar changes associated with Parkinson's disease and the moderating effects of medication.Frontiers in Human Neuroscience 04/2015; 9:214. DOI:10.3389/fnhum.2015.00214 · 2.90 Impact Factor