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Author(s): Pilotto, Andrea; Romagnolo, Alberto; Scalvini, Andrea; Masellis, Mario; Shimo, Yasushi; Bonanni, Laura; Camicioli, Richard; Wang, Lily L; Dwivedi, Alok K; Longardner, Katherine; Rodriguez-Porcel, Federico; DiFrancesco, Mark; Vizcarra, Joaquin A; Montanaro, Elisa; Maule, Simona; Lupini, Alessandro; Ojeda-Lopez, Carmen; Black, Sandra E; Delli Pizzi, Stefano; Gee, Myrlene; Tanaka, Ryota; Yamashiro, Kazuo; Hatano, Taku; Borroni, Barbara; Gasparotti, Roberto; Rizzetti, Maria C; Hattori, Nobutaka; Lopiano, Leonardo; Litvan, Irene; Espay, Alberto J; Padovani, Alessandro; Merola, Aristide | Abstract: ObjectiveTo evaluate whether orthostatic hypotension (OH) or supine hypertension (SH) is associated with brain atrophy and white matter hyperintensities (WMH), we analyzed clinical and radiologic data from a large multicenter consortium of patients with Parkinson disease (PD) and dementia with Lewy bodies (DLB).MethodsSupine and orthostatic blood pressure (BP) and structural MRI data were extracted from patients with PD and DLB evaluated at 8 tertiary-referral centers in the United States, Canada, Italy, and Japan. OH was defined as a systolic/diastolic BP fall ≥20/10 mm Hg within 3 minutes of standing from the supine position (severe ≥30/15 mm Hg) and SH as a BP ≥140/90 mm Hg with normal sitting BP. Diagnosis-, age-, sex-, and disease duration-adjusted differences in global and regional cerebral atrophy and WMH were appraised with validated semiquantitative rating scales.ResultsA total of 384 patients (310 with PD, 74 with DLB) met eligibility criteria, of whom 44.3% (n = 170) had OH, including 24.7% (n = 42) with severe OH and 41.7% (n = 71) with SH. OH was associated with global brain atrophy (p = 0.004) and regional atrophy involving the anterior-temporal (p = 0.001) and mediotemporal (p = 0.001) regions, greater in severe vs nonsevere OH (p = 0.001). The WMH burden was similar in those with and without OH (p = 0.49). SH was not associated with brain atrophy (p = 0.59) or WMH (p = 0.72).ConclusionsOH, but not SH, was associated with cerebral atrophy in Lewy body disorders, with prominent temporal region involvement. Neither OH nor SH was associated with WMH.

Highlights • We assessed the relationships between MRI measurements and clinical symptoms in PD. • Using longitudinal data (3 year follow-up) from 50 PD patients and 45 controls. • SN atrophy and WMHs were associated with additional motor deficits in PD patients. • WMHs and hippocampal atrophy were associated with cognitive deficit in PD patients. • Both grey and white matter damage contribute to motor and cognitive deficits in PD., Introduction Previous studies have found associations between grey matter atrophy and white matter hyperintensities (WMH) of vascular origin with cognitive and motor deficits in Parkinson’s disease (PD). Here we investigate these relationships in a sample of PD patients and age-matched healthy controls. Methods Data included 50 PD patients and 45 age-matched controls with T1-weighted and FLAIR scans at baseline, 18-months, and 36-months follow-up. Deformation-based morphometry was used to measure grey matter atrophy. SNIPE (Scoring by Nonlocal Image Patch Estimator) was used to measure Alzheimer’s disease-like textural patterns in the hippocampi. WMHs were segmented using T1-weighted and FLAIR images. The relationship between MRI features and clinical scores was assessed using mixed-effects models. The motor subscore of the Unified Parkinson's Disease Rating Scale (UPDRSIII), number of steps in a walking trial, and Dementia Rating Scale (DRS) were used respectively as measures of motor function, gait, and cognition. Results Substantia nigra atrophy was significantly associated with motor deficits, with a greater impact in PDs (p

Purpose Freezing of gait is a major source of disability associated with the progression of Parkinson's disease (PD). Our objective was to determine whether evolving changes in nigral iron content in association with declining motor function in early PD differentiates subjects who develop freezing from those who do not. Methods A cohort of previously untreated individuals with early PD (n = 19) was followed for 36 months clinically and with MRI. The cohort was divided into two groups based on the development of freezing during follow-up. A multiple gradient echo MRI sequence provided an index of basal ganglia iron content. Results There were significant baseline differences between those who developed freezing (n = 7) and those who did not (n = 12) in Unified Parkinson's Disease Rating Scale motor scores, time to complete a 14 m walk and timed up and go. There was a significant correlation between the measured change in transverse relaxation in the lateral substantia nigra pars compacta and the change in motor score from baseline to 36 months (p = 0.002). The freezing group showed a greater change in motor score and iron content than did the non-freezing group. Conclusions Individuals destined to develop freezing early in PD have more motor impairment at baseline, more rapid deterioration in motor function, and pars compacta changes suggestive of increased iron content in comparison to those who do not.

Objective To determine whether, in patients with early Parkinson's disease (PD), longitudinal changes in midbrain iron content are associated with declining motor function over a period of three years. Methods Nineteen untreated subjects with early PD and 13 age- and sex-matched controls were followed clinically for 36 months. MRI with a 3 T magnet was performed at baseline, 18 months and 36 months with a multiple gradient echo sequence designed for rapid single-scan mapping of the proton transverse relaxation rate R 2 *. R 2 * was calculated for midbrain and forebrain basal ganglia regions. Results A difference in R 2 * between patients and controls was observed at baseline ( p = 0.035) but not at 18 or 36 months in the lateral substantia nigra pars compacta (SNc). Linear regression indicated significant correlations between the change in R 2 * in the lateral SNc and the change score in UPDRS III ( p = 0.008) and the PDQ-39 -mobility sub-score ( p = 0.03) from baseline to 36 months. R 2 * tended to increase in those with more advanced disease and to decrease in those with milder disease. Conclusions High field MRI demonstrates lateral SNc abnormalities that progress over 3 years in early PD consistent with increased iron content in those with more advanced disease, corresponding to the known distribution of neuronal loss occurring in this disorder, and correlating with motor symptomatology. Larger and longer investigations with more precise mapping of iron-containing midbrain structures are needed to fully evaluate the potential of R 2 * as a biomarker of disease progression in PD.

Parkinson's disease (PD) patients are treated with levodopa (L-dopa) to help stabilize their impaired motor abilities; however, L-dopa leads to increased homocysteine (Hcy) levels, which may have a deleterious effect on brain structure and function. The purpose of this study was to examine the impact of increased Hcy concentration on global brain atrophy as determined by magnetic resonance imaging in PD patients and controls. The effect of high Hcy level on ventricular dilatation (percentage of intracranial volume [%ICV]) and total tissue volume (%ICV) was examined at baseline and longitudinally at 36 months. Age, sex, education, and L-dopa duration (in PD patients) were included as covariates. Elevated Hcy levels correlated positively with ventricular dilatation (%ICV) in the whole sample (P = 0.004) and in the PD group (P = 0.008). At baseline, adults with a high Hcy level (>14 μmol/L) had higher ventricular volume (%ICV) than adults with a low Hcy level (≤ 14 μmol/L) in the whole sample (P = 0.006) and in the PD group (P = 0.03), which persisted over 36 months in both the whole sample (P = 0.004) and the PD group (P = 0.03). PD patients with high Hcy concentrations had a greater rate of ventricular enlargement (%ICV) over time compared with those with low Hcy concentration (P = 0.02). Elevated Hcy concentration was associated with increased ventricular dilatation (%ICV) in PD patients. A larger sample with a broader age range and longer follow-up is needed to establish the consequences of high Hcy level, including interactions with genetic and environmental risk factors, in PD.

Background Parkinson's disease (PD), characterized by motor dysfunction and cognitive decline, may demonstrate specific patterns of brain atrophy. Although cross-sectional magnetic resonance imaging (MRI) studies show correlation between regional brain volume loss and cognitive impairment, there is only scarce evidence from longitudinal studies validating the link between cognition and brain anatomy in PD. Objective To test the relationship between magnitude and spatial extent of atrophy in PD patients with progressive, significant cognitive decline and dementia (PDD). Methods We followed thirty-three initially non-demented patients with prevalent PD for three years while monitoring cognitive function and brain atrophy. Longitudinally acquired T1-weighted magnetic resonance images were analyzed in the voxel-based morphometry framework of SPM. Results Groups did not differ significantly with respect to age or gender. More males developed PDD (7 males, 3 females) compared to those remaining intact (12 males, 11 females). Clusters of lower grey matter volume were found in PDD compared to PD in left uncus at baseline and an expanded region that included the left hippocampus and parahippocampal gyrus at 36 months. The cognitive status by scan interaction showed differential changes between groups in the right insula. At a more liberal statistical threshold we observed changes in the right insula and bilateral hippocampi as well as the right cuneus additional to the lower brain stem. Conclusions Region specific atrophy, consistent with the pattern of cortical Lewy body deposition seen in autopsy studies, can be detected with MRI in PD patients with significant cognitive decline. MRI may be useful for tracking cognitive decline in PD.

Age-related ventricular enlargement is accelerated in Alzheimer's disease, but its relationship to cognitive decline in Parkinson's disease is less clear, even though dementia is common in Parkinson's disease. Our goals were to determine if greater enlargement of the ventricles and gray or white matter atrophy occurred in Parkinson's disease patients developing cognitive decline. Older nondemented patients with Parkinson's 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 Parkinson's disease status were significantly associated with dementia. Ventricular change was significantly correlated with change in Mini-Mental Status Examination in the Parkinson's disease with dementia group (r = 0.87, P = .001). Gray matter atrophy was greater in Parkinson's disease with dementia, with similar change over time in both Parkinson's disease and Parkinson's disease with dementia. White matter volumes were not significantly different between Parkinson's disease and Parkinson's disease with dementia; however, the decrease over time might be greater in Parkinson's disease with dementia. Ventricular dilatation occurs early in the course of significant cognitive decline in patients with Parkinson's disease, possibly reflecting both cortical gray and white matter loss. © 2011 Movement Disorder Society

The purpose of this study was to determine if focal cortical abnormalities may occur in early Parkinson's disease (PD). We studied 26 untreated patients with early PD and 14 healthy control subjects, with cognitive screening and magnetic resonance imaging (MRI). Voxel-based morphometry was used to assess for the presence of localized cortical grey matter (GM) and/or subcortical white matter (WM) changes. Patient and control groups showed no differences in age or gender distribution. Females had a greater GM% than males (P = 0.001). Comparison of patients and controls revealed no difference in local GM volumes. In PD, however, there was decreased WM volume in the anterior right fusiform gyrus and superior temporal gyrus. There were no correlations between the California Verbal Learning Test long delay free recall, Judgment of Line Orientation, Trail Making A or B and either the GM or WM localized volumes. These results suggest that right anterior temporal lobe changes occur in untreated patients with PD. The earliest changes may occur in subcortical white matter rather than temporal cortex.

Although motor symptoms of Parkinson's disease (PD) are initially responsive to dopamine replacement therapy, nonresponsive features develop over time, suggesting that impaired dopaminergic function alone may not be wholly responsible for all the motor features of the disease. Previous studies suggest impaired function in the presupplementary motor area (pre-SMA) in PD. Our objective was to determine whether pre-SMA abnormalities are present in untreated patients with early disease. We measured N-acetyl aspartate (NAA)/creatine (Cr) and choline (Cho)/Cr ratios in pre-SMA in 26 untreated patients with early PD (disease duration 3.0 ± 2.0 yr) and 15 control subjects with single voxel magnetic resonance spectroscopy. Neither NAA/Cr nor Cho/Cr ratios differed significantly between groups. These observations suggest that, although pre-SMA function is impaired in moderately advanced PD, it is relatively spared in early disease. We suggest that pre-SMA dysfunction is in part responsible for the dopamine nonresponsive features associated with disease progression. © 2008 Movement Disorder Society

A series of organic hydrochloride salts has been investigated using solid-state 35Cl and 37Cl NMR spectroscopy at applied magnetic field strengths of 9.4 and 18.8 T. Magic-angle spinning, static Hahn-echo, and quadrupolar Carr−Purcell Meiboom−Gill (QCPMG) echo experiments have been applied to investigate the chlorine electric field gradient (EFG) and chemical shift (CS) tensors for l-tyrosine hydrochloride, l-cysteine methyl ester hydrochloride, l-cysteine ethyl ester hydrochloride, quinuclidine hydrochloride, and tris sarcosine calcium chloride. Chlorine-35 nuclear quadrupolar coupling constants for these compounds range from 2.23 to 5.25 MHz, and isotropic chemical shifts range from approximately 9 to 53 ppm relative to the chloride ion in aqueous solution. The results demonstrate the feasibility and benefits of high-field 35/37Cl NMR studies of organic chloride salts. A discussion of the data in the context of the known X-ray or neutron diffraction structures for these compounds suggests that the chlor...

Using accurate 35/37Cl spin−rotation data and the chlorine chemical shift of HCl(g) with respect to the chloride ion in aqueous solution, δ = 28 ± 3 ppm, a more reliable chlorine absolute shielding...

Parkinson's disease (PD) is a common progressive neurodegenerative movement disorder. Although motor symptoms are associated with focal loss of substantia nigra dopaminergic neurons, pathological changes in PD are widespread 1 . Dementia in patients with PD is common and patients with Parkinson's disease and dementia (PDD) have involvement of additional cortical regions compared with non- demented PD patients 2 .While PD is not known to directly affect white matter fiber tracts, changes in these tracts may reflect pathology within the neuronal cell bodies from which the axons arise and PDD patients may show different patterns of white matter involvement than PD patients. Diffusion tensor imaging (DTI) non-invasively measures the anisotropic mobility of water in the human brain 3 , which ABSTRACT: Background:InParkinson'sdisease(PD)celllossinthesubstantianigraisknowntoresultinmotorsymptoms;however widespread pathological changes occur and may be associated with non-motor symptoms such as cognitive impairment. Diffusion tensorimagingisaquantitativeimagingmethodsensitivetothemicro-structureofwhitemattertracts. Objective: Tomeasurefractional 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,1F) and controls (8 M, 7F) 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. RESUME: La tractographie du corps calleux et du cingulum dans la maladie de Parkinson. Contexte : Dans la maladie de Parkinson, il est bien

Background: Parkinson disease (PD) is a progressive neurodegenerative disorder in which the major pathologic substrate is a loss of dopaminergic neurons from the lateral substantia nigra pars compacta (SNc). Our objective was to determine whether, in patients with early PD, SNc changes evident on MRI sequences sensitive to iron content corresponded anatomically to the pathologic changes reported previously, and to correlate these changes to the duration and severity of clinical manifestations of PD. Methods: Twenty-six untreated patients with early PD and 13 age- and gender-matched control subjects had MRI with a 3 tesla magnet using a multiple gradient echo sequence designed for rapid single-scan mapping of the proton transverse relaxation rate ( R 2 * ). R 2 * was calculated for midbrain and forebrain basal ganglia regions. Clinical features were rated with the Unified Parkinson9s Disease Rating Scale. Results: A difference in measured R 2 * values between patients and controls was observed in the lateral SNc ( p ≤ 0.005). Linear regression indicated a correlation between the lateralized motor score from the clinically most affected side and R 2 * values from the opposite lateral SNc ( p = 0.01). Conclusions: High field strength MRI demonstrates lateral substantia nigra pars compacta abnormalities in early Parkinson disease (PD) consistent with increased iron content and corresponding to the known distribution of neuronal loss occurring in this disorder. This may ultimately provide an imaging marker for disease progression in PD, although longitudinal studies are required. GLOSSARY: AC = anterior commissure; CN = caudate nucleus; GP = globus pallidus; LantGP = left anterior GP; LantPu = left anterior Pu; LlatSNc = left lateral SNc; LlatSNr = left lateral SNr; LmedSNc = left medial SNc; LmedSNr = left medial SNr; LpostGP = left posterior GP; LpostPu = left posterior Pu; PC = posterior commissure; PD = Parkinson disease; Pu = putamen; RantGP = right anterior GP; RantPu = right anterior Pu; RlatSNc = right lateral SNc; RlatSNr = right lateral SNr; RmedSNc = right medial SNc; RmedSNr = right medial SNr; RN = red nucleus; ROI = region of interest; RpostGP = right posterior GP; RpostPu = right posterior Pu; SNc = substantia nigra compacta; SNr = substantia nigra reticulata; TE = echo times; UPDRS = Unified Parkinson9s Disease Rating Scale.

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 (≥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. 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.

The anterior cingulate (AC) gyrus and the presupplementary motor area (pre-SMA) show pathological changes in Parkinson's 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 Parkinson's 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.