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Figure.
Gray matter comparison between patients with Parkinson disease with dementia (PDD) and healthy control subjects. Voxels reaching significance at the uncorrected P<.001 level are rendered on a normal T1-weighted image. Clusters of density differences are observed bilaterally in the hippocampus, thalamus, putamen, and anterior cingulate regions.

Gray matter comparison between patients with Parkinson disease with dementia (PDD) and healthy control subjects. Voxels reaching significance at the uncorrected P<.001 level are rendered on a normal T1-weighted image. Clusters of density differences are observed bilaterally in the hippocampus, thalamus, putamen, and anterior cingulate regions.

Table 1. 
Demographic and Clinical Variables*
Demographic and Clinical Variables*
Table 2. 
Brain Areas Showing Significant Differences Between Groups*
Brain Areas Showing Significant Differences Between Groups*
1.
de Rijk  MCBreteler  MMGraveland  GA  et al.  Prevalence of Parkinson’s disease in the elderly: The Rotterdam Study. Neurology 1995;452143- 2146
PubMedArticle
2.
Aarsland  DTandberg  ELarsen  JPCummings  JL Frequency of dementia in Parkinson disease. Arch Neurol 1996;53538- 542
PubMedArticle
3.
Aarsland  DAndersen  KLarsen  JPLolk  ANielsen  HKragh-Sørensen  P Risk of dementia in Parkinson’s disease: a community-based, prospective study. Neurology 2001;56730- 736
PubMedArticle
4.
Rinne  JORummukainen  JPaljärvi  LRinne  UK Dementia in Parkinson’s disease is related to neuronal loss in the medial substantia nigra. Ann Neurol 1989;2647- 50
PubMedArticle
5.
de la Monte  SMWells  SEHedley-Whyte  ETGrowdon  JH Neuropathological distinction between Parkinson’s dementia and Parkinson’s plus Alzheimer’s disease. Ann Neurol 1989;26309- 320
PubMedArticle
6.
Perry  EKCurtis  MDick  DJ  et al.  Cholinergic correlates of cognitive impairment in Parkinson’s disease: comparisons with Alzheimer’s disease. J Neurol Neurosurg Psychiatry 1985;48413- 421
PubMedArticle
7.
Zweig  RMCardillo  JECohen  MGiere  SHedreen  JC The locus ceruleus and dementia in Parkinson’s disease. Neurology 1993;43986- 991
PubMedArticle
8.
Hurtig  HITrojanowski  JQGalvin  J  et al.  Alpha-synuclein cortical Lewy bodies correlate with dementia in Parkinson’s disease. Neurology 2000;541916- 1921
PubMedArticle
9.
Apaydin  HAhlskog  JEParisi  JEBoeve  BFDickson  DW Parkinson disease neuropathology: later-developing dementia and loss of the levodopa response. Arch Neurol 2002;59102- 112
PubMedArticle
10.
Mattila  PMRöyttä  MTorikka  HDickson  DWRinne  JO Cortical Lewy bodies and Alzheimer-type changes in patients with Parkinson’s disease. Acta Neuropathol (Berl) 1998;95576- 582
PubMedArticle
11.
Jellinger  KASeppi  KWenning  GKPoewe  W Impact of coexistent Alzheimer pathology on the natural history of Parkinson’s disease. J Neural Transm 2002;109329- 339
PubMedArticle
12.
Hanyu  HAsano  TSakurai  HTanaka  YTakasaki  MAbe  K MR Analysis of the substantia innominata in normal aging, Alzheimer disease, and other types of dementia. AJNR Am J Neuroradiol 2002;2327- 32
PubMed
13.
Laakso  MPPartanen  KRiekkinen  P  et al.  Hippocampal volumes in Alzheimer’s disease, Parkinson’s disease with and without dementia, and in vascular dementia: an MRI study. Neurology 1996;46678- 681
PubMedArticle
14.
Hu  MTWhite  SJChaudhuri  KRMorris  RGBydder  GMBrooks  DJ Correlating rates of cerebral atrophy in Parkinson’s disease with measures of cognitive decline. J Neural Transm 2001;108571- 580
PubMedArticle
15.
Ashburner  JFriston  KJ Voxel-based morphometry: the methods. Neuroimage 2000;11805- 821
PubMedArticle
16.
Good  CDJohnsrude  ISAshburner  JHenson  RNAFriston  KJFrackowiak  RS A voxel-based morphometric study of ageing in 465 normal adult human brains. Neuroimage 2001;1421- 36
PubMedArticle
17.
Good  CDScahill  RIFox  NC  et al.  Automatic differentiation of anatomical patterns in the human brain: validation with studies of degenerative dementias. Neuroimage 2002;1729- 46
PubMedArticle
18.
Frisoni  GBTesta  CZorzan  A  et al.  Detection of grey matter loss in mild Alzheimer’s disease with voxel based morphometry. J Neurol Neurosurg Psychiatry 2002;73657- 664
PubMedArticle
19.
Matsuda  HKitayama  NOhnishi  T  et al.  Longitudinal evaluation of both morphologic and functional changes in the same individuals with Alzheimer’s disease. J Nucl Med 2002;43304- 311
PubMed
20.
Busatto  GFGarrido  GEAlmeida  OP  et al.  A voxel-based morphometry study of temporal lobe grey matter reductions in Alzheimer’s disease. Neurobiol Aging 2003;24221- 231
PubMedArticle
21.
Burton  EJKaras  GPaling  SM  et al.  Patterns of cerebral atrophy in dementia with Lewy bodies using voxel-based morphometry. Neuroimage 2002;17618- 630
PubMedArticle
22.
Chételat  GDesgranges  Bde la Sayette  VViader  FEustache  FBaron  JC Mapping grey matter loss with voxel-based morphometry in mild cognitive impairment. Neuroreport 2002;131939- 1943
PubMedArticle
23.
Kassubek  JJuengling  FDHellwig  BSpreer  JLücking  CH Thalamic grey matter changes in unilateral Parkinsonian resting tremor: a voxel-based morphometric analysis of 3-dimensional magnetic resonance imaging. Neurosci Lett 2002;32329- 32
PubMedArticle
24.
Summerfield  CGómez-Ansón  BTolosa  E  et al.  Dementia in Parkinson’s disease: a proton magnetic resonance spectroscopy study. Arch Neurol 2002;591415- 1420
PubMedArticle
25.
Daniel  SELees  AJ Parkinson’s Disease Society Brain Bank, London: overview and research. J Neural Transm Suppl 1993;39165- 172
PubMed
26.
American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition.  Washington, DC: American Psychiatric Association; 1994
27.
Morris  JC Clinical dementia rating: a reliable and valid diagnostic and staging measure for dementia of the Alzheimer type. Int Psychogeriatr 1997;9(suppl 1)173- 176
PubMedArticle
28.
Folstein  MFFolstein  SEMcHugh  PR “Mini-mental state”: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12189- 198
PubMedArticle
29.
Fahn  SElton  RLMembers of UPDRS Committee Recent Developments in Parkinson’s Disease Unified Parkinson’s Disease Rating Scale and Appendices I and II. In: Fahn  S,Marsden  CD, Goldstein  M, Calne  DM, eds. New York, NY: Macmillan Publishing Co Inc; 1987:153-163
30.
Friston  KJHolmes  APWorsley  KJPoline  JPFrith  CDFrackowiak  RS Statistical parametric maps in functional imaging: a general linear approach. Hum Brain Mapp 1994;2189- 210Article
31.
Maldjian  JALaurienti  PJKraft  RABurdettea  JH An automated method for neuroanatomic and cytoarchitectonic atlas-based interrogation of fMRI data sets. Neuroimage 2003;191233- 1239
PubMedArticle
32.
Braak  HBraak  E Pathoanatomy of Parkinson’s disease. J Neurol 2000;247(suppl 2)II3- II10
PubMedArticle
33.
Mattila  PMRinne  JOHelenius  HRoytta  M Neuritic degeneration in the hippocampus and amygdala in Parkinson’s disease in relation to Alzheimer pathology. Acta Neuropathol (Berl) 1999;98157- 164
PubMedArticle
34.
de Vos  RACansen  ENStam  FCRavid  RSwaab  D Lewy body disease: clinico-pathological correlations in 18 consecutive cases of Parkinson’s disease with and without dementia. Clin Neurol Neurosurg 1995;9713- 22
PubMedArticle
35.
Rüb  UDel Tredici  KSchultz  C  et al.  Parkinson’s disease: the thalamic components of the limbic loop are severely impaired by α-synuclein immunopositive inclusion body pathology. Neurobiol Aging 2002;23245- 254
PubMedArticle
36.
Hishikawa  NHashizume  YYoshida  MSobue  G Clinical and neuropathological correlates of Lewy body disease. Acta Neuropathol (Berl) 2003;105341- 350
PubMed
37.
Salmon  DPGalasko  DHansen  LA  et al.  Neuropsychological deficits associated with diffuse Lewy body disease. Brain Cogn 1996;31148- 165
PubMedArticle
38.
Harding  AJBroe  GAHalliday  GM Visual hallucinations in Lewy body disease relate to Lewy bodies in the temporal lobe. Brain 2002;125391- 403
PubMedArticle
39.
Bookstein  FL “Voxel-based morphometry” should not be used with imperfectly registered images. Neuroimage 2001;141454- 1462
PubMedArticle
Original Contribution
February 2005

Structural Brain Changes in Parkinson Disease With DementiaA Voxel-Based Morphometry Study

Author Affiliations

Author Affiliations: Department de Psiquiatria i Psicobiologia, Universitat de Barcelona (Mr Summerfield, Drs Junqué and Salgado-Pineda, and Ms Ramírez-Ruíz), Institut d’Investigacions Biomèdiques August Pi i Sunyer (Drs Junqué, Tolosa, Gómez-Ansón, Martí, and Mercader); Parkinson’s Disease and Movement Disorders Unit, Neurology Service, Institut Clínic de Malalties del Sistema Nerviós, Hospital Clínic de Barcelona (Drs Tolosa, Martí, and Pastor); and the Centre de Diagnòstic per la Imatge, Hospital Clínic de Barcelona (Drs Gómez-Ansón and Mercader), Barcelona, Spain.

Arch Neurol. 2005;62(2):281-285. doi:10.1001/archneur.62.2.281
Abstract

Background  Parkinson disease with dementia (PDD) results from neuropathological changes in cortical and subcortical brain regions. Voxel-based morphometric analysis of magnetic resonance images can contribute to in vivo identification of the cerebral regions predominantly involved in PDD.

Objective  To identify structural cerebral regions most closely related to the presence of PDD.

Design  Magnetic resonance images were obtained from 16 patients who had PDD, 13 patients with PD without dementia, and 13 age-matched healthy control subjects. Gray matter volumes were compared using optimized voxel-based morphometric analyses.

Results  Compared with healthy controls, patients with PDD showed gray matter volume decreases in several of the following regions: bilateral putamen, accumbens nuclei, left side of the thalamus, bilateral hippocampus, parahippocampal region, and anterior cingulate gyrus. Patients with PD also showed gray matter reductions compared with healthy controls in the right side of the hippocampus, left anterior cingulate gyrus, and left superior temporal gyrus.

Conclusions  The hippocampus, thalamus, and anterior cingulate are the regions most affected in PDD. Our results agree with recent neuropathological findings suggesting the involvement of the limbic and cortical areas in PD.

Parkinson disease (PD) is among the most frequent chronic neurodegenerative diseases.1 The estimated prevalence of PD with dementia (PDD) is approximately 30%2 and the risk of dementia in patients with PD is almost 6 times higher than in the general elderly population.3

The neuropathological basis responsible for the presence of PDD remains controversial. Degeneration in the subcortical structures, notably the medial part of the substantia nigra4 ; the basal ganglia, amygdala, and thalamus5 ; nucleus basalis of Meynert6 ; and locus coeruleus7 have variously been implicated in PDD. However, recent studies also emphasize the importance of cortical changes. An association has been observed between dementia and the presence of cortical Lewy bodies.8,9 The presence of Alzheimer-type neuropathology in PD is another likely contributor to dementia.10,11

Magnetic resonance imaging (MRI) allows in vivo identification of global and regional atrophy. Studies have shown PDD to be associated with volumetric changes in the substantia inominata,12 the hippocampus,13 and total cerebral volume.14 Voxel-based morphometry (VBM) allows the determination of brain density and/or volume changes without a priori region of interest selection.15,16 This technique has been used in degenerative disorders such as Alzheimer disease,1720 dementia with Lewy bodies (DLB),21 and mild cognitive impairment.22 In PD, it has been used to determine the structures involved in the generation of parkinsonian resting tremor.23

The aim of this study was to use VBM to examine more closely the structural brain changes responsible for PDD. We, therefore, compared brain changes in patients with PDD, in patients with PD without dementia, and in healthy age-matched control subjects.

METHODS
SUBJECTS

Forty-two subjects between the ages of 54 and 84 years participated in this study as well as having been in a previously published study.24 Three groups of patients (16 patients with PDD, 13 patients with PD, and 13 controls) were recruited from the Parkinson Disease and Movement Disorders Unit, Hospital Clinic, Barcelona, Spain, during a 9-month period (Table 1). The study was approved by the local ethics committee. Written informed consent was obtained from the patient or the patient’s caregiver.

DIAGNOSTIC CRITERIA AND SELECTION

Idiopathic PD was diagnosed using the criteria of the Parkinson’s Disease Society Brain Bank, London, England.25 All patients had a good or an excellent initial response to levodopa treatment. Dementia was assessed using 3 standardized instruments: the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV),26 the Clinical Dementia Rating scale,27 and the Mini-Mental State Examination.28 Subjects needed a Clinical Dementia Rating scale score of 1, a Mini-Mental State Examination score of less than 23, and both DSM-IV items to fulfill dementia criteria. The Clinical Dementia Rating scale and DSM-IV were administered by a trained clinician (J.M. or Francesc Valldeoriola, MD), and the Mini-Mental State Examination by an experienced neuropsychologist (C.S.). Where required for the Clinical Dementia Rating scale, collateral information was drawn from the patient’s spouse or caregiver. The control group was matched for sex and age (SD, ±5 years) to the patient with PDD. Three patients were excluded owing to MRI movement artifacts. Patients were clinically assessed using the Unified Parkinson’s Disease Rating Scale.29

MAGNETIC RESONANCE IMAGING

Magnetic resonance imaging was obtained in all subjects using a 1.5-T scanner (GE Medical Systems Co, Milwaukee, Wis) and the head coil. A strict imaging protocol was used, including a 3-dimensional inversion recovery preparation spoiled gradient recalled echo sequence of the entire brain in the axial plane, and the following parameters: repetition time, 17 milliseconds; echo time, 5 milliseconds; inversion time, 300 milliseconds; section thickness, 1.5 mm; field of view, 24× 256 cm; and number of excitations, 1.

VOXEL-BASED MORPHOMETRY

The MRIs were analyzed using SPM99 (WDCN, London or http://www.fil.ion.ucl.ac.uk/spm).30 All the automated image processing was done by a single masked investigator (C.S.). One subject with PD was excluded from VBM analysis because visual inspection of the MRI revealed marked hypointensities consistent with basal ganglia calcifications.

All MRI processing was carried out in accord with the optimized VBM protocol.16 Briefly, the processing steps outlined by this protocol are (1) the creation of a customized anatomical T1-weighted template and prior probability images separately for each group, by normalizing the brain images to the default SPM T1-weighted template, segmenting, averaging, and smoothing the averaged brains in each group; (2) normalization of the structural brain images in each group using these customized templates, segmenting and cleaning the original T1-weighted images, normalizing the brain images to the customized templates, segmentation and cleaning of normalized brain images, and modulation of gray matter images by the determinant of the Jacobian matrix derived from the spatial normalization step. This procedure has been previously described in detail.16

Differences in gray matter were examined using analysis of variance with post hoc comparisons (controls>patients with PD; controls>patients with PDD; patients with PD>patients with PDD). Statistical thresholds were corrected for the 3 post hoc comparisons used here, using the SPM99 compare-populations 1 scan per subject. Exclusive masking was used to determine which voxel differences were specific to one disease process. Results were thresholded for the group being studied at P<.001 (uncorrected for multiple comparisons). Only those clusters exceeding a size of 10 voxels were included in the analysis.

Owing to the characteristics of our acquisition protocol and head size differences among subjects, the most superior and/or inferior regions were absent in some subjects or not clearly visible after reorientation. Therefore, we restricted the volumetric analysis to a region of interest comprising the temporal lobes, caudate, lentiform nuclei, cingulate gyrus, anterior cingulate, thalami, insula, extranuclear region, amygdala, hippocampi, and parahippocampus gyri. This was achieved by means of the Wake Forest University–PickAtlas software31 (available at: http://www.fmri.wfubmc.edu).

RESULTS
PATIENTS WITH PDD vs CONTROLS

When patients with PDD were compared with normal age-matched controls, several cortical and subcortical areas showed gray matter differences. Table 2 summarizes the brain areas in which we observed voxels that differed significantly between patients with PD and controls, the size of the cluster of statistically significant voxels, the Talairach coordinates of the peak voxel, and the z scores. In the basal ganglia we observed bilateral gray matter loss in the putamen, nucleus accumbens, and the left side of the thalamus (Figure, center row). In the limbic region, both sides of the hippocampus were reduced in size (Figure, top row), as was the left parahippocampal region. In the cortical region the anterior cingulate gyrus was also bilaterally decreased (Figure, bottom row).

PATIENTS WITH PD vs CONTROLS

Patients with PD showed a gray matter reduction in the following 3 regions compared with the controls: the right side of the hippocampus, the left anterior cingulate, and the left superior temporal gyri (Table 2).

PATIENTS WITH PDD vs PATIENTS WITH PD

The comparison of patients with PDD and patients with PD showed statistically significant differences in the left superior temporal gyrus and right side of the hippocampus.

COMMENT

This study aimed to identify structural brain changes in PDD using VBM. Our results showed that volumes of the following several structures were reduced in patients with PDD relative to age-matched controls: hippocampus, putamen, accumbens and thalamic nuclei, parahippocampal regions, and anterior cingulate gyrus.

Hippocampal atrophy has been consistently described as a feature in dementia. In our study, VBM results showed a bilateral hippocampal reduction in patients with PDD, which was more pronounced in the right hemisphere. Previous studies have observed hippocampal degeneration in PD.13,32 Hippocampal reductions may be due to both Lewy body and Alzheimer-type changes.10,33,34

We also found a relationship between reduction of the left side of the thalamus and dementia. The thalamus has also recently been identified as a major target for neuropathological inclusions such as Lewy bodies in patients with PD,35 and an earlier study of neuropathology and dementia in PD also identified volumetric loss in the thalamus as a predictor of dementia.5 Because in our study, the patients with PDD had greater motor impairment than patients with PD, it is possible that tissue loss observed in the thalamus and putamen may reflect motor as well as cognitive impairment in PDD.

Analysis of cortical regions with VBM showed a marked volume decrease in the anterior cingulate in patients with PDD compared with controls. The anterior cingulate has been shown to be particularly vulnerable to Lewy body inclusions in PDD8,36 and DLB.36 Volumetric reduction of the anterior cingulate may be involved in the attentional deficits described in PDD.37

We also found extensive volumetric reduction in the parahippocampal gyrus. In DLB, cases with well-formed visual hallucinations exhibited high densities of Lewy bodies in the amygdala and parahippocampus.38 Several subjects with dementia in our sample had a history of visual hallucinations.

Patients with PD but without dementia also differed from controls in the hippocampus and anterior cingulate, although reductions were less marked than for patients with PDD. Further, the comparison between patients with PDD and patients with PD revealed differences in the right side of the hippocampus and the left superior temporal regions. Together these results suggest that there may be a gradient of neuropathology affecting cingulate and medial temporal lobe structures in parkinsonism. Consistent with this idea, postmortem studies have demonstrated that all patients with PD have some degree of cortical Lewy body pathology.32

Our study has the limitations implicit to VBM procedures. One should be cautious when using automated image processing packages for investigations in degenerative diseases because the software was not specifically designed to measure atrophy.39 We attempted to solve this problem by creating a local template comprising both patients with PDD, patients with PD, and controls. Also, our sample was exclusive to patients from a clinical population and may not be representative of patients with PD and patients with PDD in the wider community. We also used criteria for enrollment in the PDD group that excluded patients with questionable or early-onset dementia and that focused on memory impairment rather than visuospatial or attentional deficits. Our results may, thus, pertain more to patients in the more-advanced stages of dementia, and further studies with patients exhibiting a spectrum of dementia severity may be required to establish whether MRI is a useful technique for differential diagnosis of PDD.

CONCLUSIONS

Voxel-based morphometric methods were used to examine structural brain changes in PDD; gray matter loss at both cortical and subcortical sites was observed. Results revealed volumetric reductions in thalamic, hippocampal, and anterior cingulate regions, corroborating previous neuropathological findings in PDD.

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Article Information

Correspondence: Carme Junqué, PhD, Departament de Psiquiatria i Psicobiologia, Universitat de Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer, Casanova 143, 08036 Barcelona, Spain (cjunque@ub.edu).

Accepted for Publication: May 10, 2004.

Author Contributions:Study concept and design: Summerfield, Junqué, Tolosa, Martí, and Mercader. Acquisition of data: Summerfield, Gómez-Ansón, Pastor, and Mercader. Analysis and interpretation of data: Summerfield, Junqué, Tolosa, Salgado-Pineda, and Ramírez-Ruíz. Drafting of the manuscript: Summerfield, Junqué, Tolosa, Gómez-Ansón, Pastor, and Ramírez-Ruíz. Critical revision of the manuscript for important intellectual content: Summerfield, Junqué, Tolosa, Martí, and Mercader. Statistical analysis: Summerfield, Salgado-Pineda, and Ramírez-Ruíz. Obtained funding: Junqué and Tolosa. Administrative, technical, and material support: Junqué, Tolosa, Salgado-Pineda, Gómez-Ansón, Pastor, and Mercader. Study supervision: Junqué, Tolosa, and Martí.

Acknowledgment: We thank Francesc Valldeoriola, MD, for facilitating patients’ data.

References
1.
de Rijk  MCBreteler  MMGraveland  GA  et al.  Prevalence of Parkinson’s disease in the elderly: The Rotterdam Study. Neurology 1995;452143- 2146
PubMedArticle
2.
Aarsland  DTandberg  ELarsen  JPCummings  JL Frequency of dementia in Parkinson disease. Arch Neurol 1996;53538- 542
PubMedArticle
3.
Aarsland  DAndersen  KLarsen  JPLolk  ANielsen  HKragh-Sørensen  P Risk of dementia in Parkinson’s disease: a community-based, prospective study. Neurology 2001;56730- 736
PubMedArticle
4.
Rinne  JORummukainen  JPaljärvi  LRinne  UK Dementia in Parkinson’s disease is related to neuronal loss in the medial substantia nigra. Ann Neurol 1989;2647- 50
PubMedArticle
5.
de la Monte  SMWells  SEHedley-Whyte  ETGrowdon  JH Neuropathological distinction between Parkinson’s dementia and Parkinson’s plus Alzheimer’s disease. Ann Neurol 1989;26309- 320
PubMedArticle
6.
Perry  EKCurtis  MDick  DJ  et al.  Cholinergic correlates of cognitive impairment in Parkinson’s disease: comparisons with Alzheimer’s disease. J Neurol Neurosurg Psychiatry 1985;48413- 421
PubMedArticle
7.
Zweig  RMCardillo  JECohen  MGiere  SHedreen  JC The locus ceruleus and dementia in Parkinson’s disease. Neurology 1993;43986- 991
PubMedArticle
8.
Hurtig  HITrojanowski  JQGalvin  J  et al.  Alpha-synuclein cortical Lewy bodies correlate with dementia in Parkinson’s disease. Neurology 2000;541916- 1921
PubMedArticle
9.
Apaydin  HAhlskog  JEParisi  JEBoeve  BFDickson  DW Parkinson disease neuropathology: later-developing dementia and loss of the levodopa response. Arch Neurol 2002;59102- 112
PubMedArticle
10.
Mattila  PMRöyttä  MTorikka  HDickson  DWRinne  JO Cortical Lewy bodies and Alzheimer-type changes in patients with Parkinson’s disease. Acta Neuropathol (Berl) 1998;95576- 582
PubMedArticle
11.
Jellinger  KASeppi  KWenning  GKPoewe  W Impact of coexistent Alzheimer pathology on the natural history of Parkinson’s disease. J Neural Transm 2002;109329- 339
PubMedArticle
12.
Hanyu  HAsano  TSakurai  HTanaka  YTakasaki  MAbe  K MR Analysis of the substantia innominata in normal aging, Alzheimer disease, and other types of dementia. AJNR Am J Neuroradiol 2002;2327- 32
PubMed
13.
Laakso  MPPartanen  KRiekkinen  P  et al.  Hippocampal volumes in Alzheimer’s disease, Parkinson’s disease with and without dementia, and in vascular dementia: an MRI study. Neurology 1996;46678- 681
PubMedArticle
14.
Hu  MTWhite  SJChaudhuri  KRMorris  RGBydder  GMBrooks  DJ Correlating rates of cerebral atrophy in Parkinson’s disease with measures of cognitive decline. J Neural Transm 2001;108571- 580
PubMedArticle
15.
Ashburner  JFriston  KJ Voxel-based morphometry: the methods. Neuroimage 2000;11805- 821
PubMedArticle
16.
Good  CDJohnsrude  ISAshburner  JHenson  RNAFriston  KJFrackowiak  RS A voxel-based morphometric study of ageing in 465 normal adult human brains. Neuroimage 2001;1421- 36
PubMedArticle
17.
Good  CDScahill  RIFox  NC  et al.  Automatic differentiation of anatomical patterns in the human brain: validation with studies of degenerative dementias. Neuroimage 2002;1729- 46
PubMedArticle
18.
Frisoni  GBTesta  CZorzan  A  et al.  Detection of grey matter loss in mild Alzheimer’s disease with voxel based morphometry. J Neurol Neurosurg Psychiatry 2002;73657- 664
PubMedArticle
19.
Matsuda  HKitayama  NOhnishi  T  et al.  Longitudinal evaluation of both morphologic and functional changes in the same individuals with Alzheimer’s disease. J Nucl Med 2002;43304- 311
PubMed
20.
Busatto  GFGarrido  GEAlmeida  OP  et al.  A voxel-based morphometry study of temporal lobe grey matter reductions in Alzheimer’s disease. Neurobiol Aging 2003;24221- 231
PubMedArticle
21.
Burton  EJKaras  GPaling  SM  et al.  Patterns of cerebral atrophy in dementia with Lewy bodies using voxel-based morphometry. Neuroimage 2002;17618- 630
PubMedArticle
22.
Chételat  GDesgranges  Bde la Sayette  VViader  FEustache  FBaron  JC Mapping grey matter loss with voxel-based morphometry in mild cognitive impairment. Neuroreport 2002;131939- 1943
PubMedArticle
23.
Kassubek  JJuengling  FDHellwig  BSpreer  JLücking  CH Thalamic grey matter changes in unilateral Parkinsonian resting tremor: a voxel-based morphometric analysis of 3-dimensional magnetic resonance imaging. Neurosci Lett 2002;32329- 32
PubMedArticle
24.
Summerfield  CGómez-Ansón  BTolosa  E  et al.  Dementia in Parkinson’s disease: a proton magnetic resonance spectroscopy study. Arch Neurol 2002;591415- 1420
PubMedArticle
25.
Daniel  SELees  AJ Parkinson’s Disease Society Brain Bank, London: overview and research. J Neural Transm Suppl 1993;39165- 172
PubMed
26.
American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition.  Washington, DC: American Psychiatric Association; 1994
27.
Morris  JC Clinical dementia rating: a reliable and valid diagnostic and staging measure for dementia of the Alzheimer type. Int Psychogeriatr 1997;9(suppl 1)173- 176
PubMedArticle
28.
Folstein  MFFolstein  SEMcHugh  PR “Mini-mental state”: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12189- 198
PubMedArticle
29.
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