Thomas Bouchard

Age and dementia-associated atrophy predominates in the hippocampal head and amygdala in Parkinson's disease.

The hippocampus (HC) and amygdala (AG) decrease in volume with age and in Parkinsons disease (PD) with (PDD) and without dementia. We compared 44 PD to 44 age, sex and education-matched subjects without PD (non-PD) and 13 PDD subjects. T1-weighted MR images were used to manually segment the head, body and tail of the HC and the AG. HC volumes, corrected to intracranial volume, were smaller in PDD than non-PD (p=0.04), reflected predominantly by head atrophy. Right AG volumes were smaller in PD compared to non-PD (p=0.03). HC volumes in older (>70), but not younger, non-demented PD differed from non-PD (HC, p=0.02; head, p=0.03). Age correlated negatively with overall HC (r=-0.43, p=0.004) and head (r=-0.48, p=0.001) in PD, but not in non-PD. In PD, left HC head volumes correlated with recall, but not recognition scores on the CVLT-II (r=0.35, p=0.02) and BVMT-R (r=0.35, p=0.02); AG volumes correlated with CVLT-II recall (r=0.35, p=0.02). No correlations were found in non-PD (p>0.4). In conclusion, functionally meaningful age-associated hippocampal and amygdala atrophy occurs in PD.

Three-dimensional volumetric analysis and reconstruction of amygdala and hippocampal head, body and tail

Volumetric changes in the amygdala and hippocampus are relevant to many disorders, but their close proximity makes it difficult to separate these structures by magnetic resonance imaging, leading many volumetric protocols to exclude problematic slices from analysis, or to analyze the amygdalo-hippocampal complex conjointly. The hippocampus tail is also often excluded, because of the difficulty in separating it from the thalamus. We have developed a reliable protocol for volumetric analysis and 3-D reconstruction of the amygdala and hippocampus (as a whole and in its anatomical parts). Twenty volunteers from clinical and healthy populations were recruited. T1-weighted images were acquired at 1.5 Tesla with native spatial resolution of 1.5 mm x 1.0 mm x 1.0 mm. Volumetric analyses were performed blind to diagnosis, using the interactive software package DISPLAY. Inter-rater (intrarater) intraclass correlations for the method were: 0.95 (0.88) for hippocampus tail, 0.83 (0.93) for hippocampus body, 0.95 (0.92) for hippocampus head, 0.96 (0.86) for total hippocampus and 0.86 (0.94) for amygdala. Volumes (mean+/-S.D.) corrected for intracranial volume for this mixed group were for the hippocampal tail: 0.325+/-0.087 cm(3); hippocampal body: 0.662+/-0.120 cm(3); hippocampal head: 1.23+/-0.174 cm(3); total hippocampus: 2.218+/-0.217 cm(3), and amygdala: 0.808+/-0.185 cm(3). In conclusion, the study demonstrates that the amygdala and hippocampal parts can be quantified reliably.

Voxel-based morphometry reveals extra-nigral atrophy patterns associated with dopamine refractory cognitive and motor impairment in parkinsonism

OBJECTIVES To determine overall patterns of brain atrophy associated with memory, executive function (EF) and dopamine non-responsive motor measures in older parkinsonian patients. DESIGN Forty-three older PD patients (>or=65 years) and matched controls underwent a neurological examination (Unified Parkinsons 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. RESULTS 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. CONCLUSIONS 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.

Aging hippocampus and amygdala

Earlier studies suggest that the anterior hippocampus may show resilience to age-associated volume loss. This study compared high-resolution magnetic resonance images obtained from younger (n=28; age range: 22–50 years) and older (n=39; age range: 65–84 years) healthy right-handed individuals to determine whether age-related volume changes varied between the hippocampal head, body and tail. Volumetric reductions were progressively more severe from hippocampal head to tail. Amygdala volume differences were intermediate in size. Although limited by the cross-sectional design, these data suggest that hippocampal subregions show a gradient of volume reduction in healthy aging that contrasts with the preferential reduction of anterior hippocampal volumes in Alzheimers and Parkinsons diseases.

Intact limbic-prefrontal connections and reduced amygdala volumes in Parkinson's disease with mild depressive symptoms.

BACKGROUND Depression is very common in Parkinsons disease (PD). The neuropathological basis for this remains unclear; however, dysfunction in prefrontal and limbic regions may play a role. METHODS We examined non-demented PD patients with and without depression and healthy controls (n = 6 per group) for differences in limbic structures and connections between these structures and the prefrontal cortex. Depressed individuals were selected from a representative sample of 33 PD patients using scores from the 15 question geriatric depression scale (GDS). Magnetic resonance diffusion tensor imaging (DTI) tractography was used to examine the structural integrity of the uncinate fasciculus (UF), a white matter tract that projects from the hippocampus, amygdala and temporal pole to the orbitofrontal cortex, and the corpus callosum. Integrity of the UF and corpus callosum was established through measures of mean diffusivity (MD), fractional anisotropy (FA) and tract length. A volumetric analysis of the hippocampal head, body and tail, as well as the amygdala was performed to determine whether volume differences in these structures in PD relate to depression. RESULTS The depressed PD group showed smaller amygdala volumes compared to healthy controls, but the groups did not differ on any other measure. CONCLUSIONS The present study found intact limbic connectivity but suggests that amygdala atrophy may be present in Parkinsons disease with depression. Further work is needed to replicate these findings.

Magnetic resonance spectroscopic evidence for presupplementary motor area neuronal dysfunction in Parkinson's disease

The anterior cingulate (AC) gyrus and the presupplementary motor area (pre‐SMA) show pathological changes in Parkinsons disease (PD). We examined if PD patients show magnetic resonance spectroscopy (MRS) changes in NAA/Cr in the AC, pre‐SMA, or posterior cingulate (PC). Forty‐four (27 male, 17 female) healthy nondemented PD patients and 38 controls (18 male, 20 female) 65 years of age and older were examined using the Unified Parkinsons Disease Rating Scale (UPDRS), Mini‐Mental State Examination, Frontal Assessment Battery, and Geriatric Depression Scale. MRS was performed at 1.5 T. Voxels (8 cc; PRESS; TE = 80; TR = 1,600 ms) were placed mid‐sagittally. Gray matter and white matter volumes were measured within voxels using SPM2. Spectra were analyzed using LC model to yield NAA/Cr and Cho/Cr. Demographic and cognitive measures did not differ between groups. Motor UPDRS was 17.7 ± 8.8 for PD. Pre‐SMA NAA/Cr was lower in PD (PD: 1.39 ± 0.17; control: 1.47 ± 0.16; P = 0.045) and correlated negatively with age (r = 0.39; P = 0.01), but not with UPDRS, disease duration, or dopamine equivalents. AC and PC NAA/Cr and Cho/Cr in any region did not differ (P > 0.05). In conclusion, pre‐SMA NAA/Cr was selectively decreased in PD, consistent with neuronal dysfunction. This should be further examined as a biomarker of disease in PD.

Ventricular dilatation and brain atrophy in patients with Parkinson's disease with incipient dementia

Age‐related ventricular enlargement is accelerated in Alzheimers disease, but its relationship to cognitive decline in Parkinsons disease is less clear, even though dementia is common in Parkinsons disease. Our goals were to determine if greater enlargement of the ventricles and gray or white matter atrophy occurred in Parkinsons disease patients developing cognitive decline. Older nondemented patients with Parkinsons disease (33) and age‐ and sex‐matched controls (39) were recruited and prospectively assessed for the development of significant cognitive decline over 36 months. Magnetic resonance imaging was obtained every 18 months, and ventricular volume and total brain gray and white matter volumes were measured using reliable segmentation of T1‐weighted volumetric scans. Subjects with incidental intracranial abnormalities, an atypical course, and stroke as well as dropouts were excluded from a cohort of 52 patients and 50 controls. Among 33 patients and 39 controls, 10 patients and 3 controls developed significant cognitive impairment or dementia. Ventricular change and Parkinsons disease status were significantly associated with dementia. Ventricular change was significantly correlated with change in Mini‐Mental Status Examination in the Parkinsons disease with dementia group (r = 0.87, P = .001). Gray matter atrophy was greater in Parkinsons disease with dementia, with similar change over time in both Parkinsons disease and Parkinsons disease with dementia. White matter volumes were not significantly different between Parkinsons disease and Parkinsons disease with dementia; however, the decrease over time might be greater in Parkinsons disease with dementia. Ventricular dilatation occurs early in the course of significant cognitive decline in patients with Parkinsons disease, possibly reflecting both cortical gray and white matter loss.

Corpus Callosum and Cingulum Tractography in Parkinson's Disease

BACKGROUND In Parkinsons disease (PD) cell loss in the substantia nigra is known to result in motor symptoms; however widespread pathological changes occur and may be associated with non-motor symptoms such as cognitive impairment. Diffusion tensor imaging is a quantitative imaging method sensitive to the micro-structure of white matter tracts. OBJECTIVE To measure fractional anisotropy (FA) and mean diffusivity (MD) values in the corpus callosum and cingulum pathways, defined by diffusion tensor tractography, in patients with PD, PD with dementia (PDD) and controls and to determine if these measures correlate with Mini-Mental Status Examination (MMSE) scores in parkinsonian patients. METHODS Patients with PD (17 Males [M], 12 Females [F]), mild PDD (5 M, 1 F) and controls (8 M, 7 F) underwent cognitive testing and MRI scans. The corpus callosum was divided into four regions and the cingulum into two regions bilaterally to define tracts using the program DTIstudio (Johns Hopkins University) using the fiber assignment by continuous tracking algorithm. Volumetric MRI scans were used to measure white and gray matter volumes. RESULTS Groups did not differ in age or education. There were no overall FA or MD differences between groups in either the corpus callosum or cingulum pathways. In PD subjects the MMSE score correlated with MD within the corpus callosum. These findings were independent of age, sex and total white matter volume. CONCLUSIONS The data suggest that the corpus callosum or its cortical connections are associated with cognitive impairment in PD patients.

Homocysteine is not associated with global motor or cognitive measures in nondemented older Parkinson's disease patients.

Levodopa (L‐dopa) treatment of Parkinsons disease (PD) is associated with elevated homocysteine (Hcy). To examine the relationship between Hcy, methylenetetrahydrofolate reductase polymorphisms (MTHFR: 677C/T; 1298A/C), and B‐vitamins in older PD patients and whether Hcy or MTHFR polymorphisms were associated with clinical measures. MTHFR polymorphisms, B‐vitamin intake, and blood concentrations of Hcy, vitamin B12 and folate, and creatinine were determined and compared between groups (PD and controls). The relationship of Hcy to clinical measures was examined in PD. Among 51 patients [30M/21F, mean age (SD): 71.5 (4.7)] and 50 controls [29M/21F, 71.5 (4.8)], Hcy was higher in PD [13.6 (3.8); controls: 10.5 (2.5), P < 0.0005]. Hcy was associated with B‐vitamin intake [F = 21.7, P < 0.0005], folate level (R = 0.31, P = 0.035), and the interaction of intake with MTHFR 677T (F = 5.2, P = 0.007), but not MTHFR 1298C genotype. Hcy did not correlate with global measures of cognition, mood, or parkinsonism in PD or with dyskinesias, fluctuations, or freezing. Higher vitamin B12 levels were associated with lower dyskinesia risk. Hcy was influenced by PD, MTHFR 677 genotype, and vitamin use, but not by the MTHFR 1298 genotype. There was no clear association with motor or cognitive measures, but dyskinesias were less likely with higher B12.

Axial signs and magnetic resonance imaging correlates in Parkinson's disease

BACKGROUND Age-related brain changes may contribute to axial features in Parkinsons disease (PD). OBJECTIVES To determine if ventricular volume and white matter high signal changes (WMC) are related to motor signs in PD and controls independent of age. METHODS Patients were rated with the Unified Parkinsons Disease Rating Scale (subscore A: tremor, rigidity, bradykinesia, and facial expression; subscore B: speech and axial impairment). Steps and time taken to walk 9.144 meters were measured. Total ventricular volume (TVV) and intracranial volume (ICV) were measured on T1-weighted MRI using manual tracing software. WMC were rated on axial T2-weighted, dual-echo or FLAIR MR images using a visual scale. RESULTS TVV (cm3) (PD: 36.48 +/- 15.93; controls: 32.16 +/- 14.20, p = 0.21) and WMC did not differ between groups (PD: 3.7 +/- 4.2; controls: 3.2 +/- 3.1, p = 0.55). Age correlated positively with ICV-corrected TVV and WMC in PD (cTVV: r = 0.48, p = 0.003; WMC: r = 0.42, p = 0.01) and controls (cTVV: r = 0.31, p = 0.04; WMC: r = 0.44, p = 0.003). Subscore B (r = 0.42, p = 0.01) but not subscore A (r = 0.25, p = 0.14) correlated with cTVV in PD. Steps and walking time correlated with cTVV and WMC in PD; cadence correlated with cTVV and steps with WMC in controls. Age-adjustment eliminated correlations. CONCLUSION Subscore B, but not subscore A correlated positively with ventricular volume in PD, though this association was accounted for by age. Age-related brain change super-imposed on PD may contribute to axial features.