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1.  A magnetic resonance imaging study of patients with Parkinson's disease with mild cognitive impairment and dementia using voxel‐based morphometry 
Background
Dementia is common in Parkinson's disease, but the underlying brain pathology is not yet fully understood.
Aim
To examine the changes in the brain of patients with Parkinson's disease with mild cognitive impairment (MCI) and dementia, using structural magnetic resonance imaging.
Methods
Using voxel‐based morphometry, the grey matter atrophy on brain images of patients with Parkinson's disease and dementia (PDD; n = 16) and Parkinson's disease without dementia (PDND; n = 20), and healthy elderly subjects (n = 20) was studied. In the PDND group, 12 subjects had normal cognitive status and 8 had MCI. Standardised rating scales for motor, cognitive and psychiatric symptoms were used.
Results
Widespread areas of cortical atrophy were found in patients with PDD compared with normal controls (in both temporal and frontal lobes and in the left parietal lobe). Grey matter reductions were found in frontal, parietal, limbic and temporal lobes in patients with PDD compared with those with PDND. In patients with PDND with MCI, areas of reduced grey matter in the left frontal and both temporal lobes were found.
Conclusion
These findings show that dementia in Parkinson's disease is associated with structural neocortical changes in the brain, and that cognitive impairment in patients with PDND may be associated with structural changes in the brain. Further studies with larger groups of patients are needed to confirm these findings.
doi:10.1136/jnnp.2006.093849
PMCID: PMC2117633  PMID: 17028119
2.  Pattern of Regional Cortical Thinning Associated with Cognitive Deterioration in Parkinson’s Disease 
PLoS ONE  2013;8(1):e54980.
Background
Dementia is a frequent and devastating complication in Parkinson’s disease (PD). There is an intensive search for biomarkers that may predict the progression from normal cognition (PD-NC) to dementia (PDD) in PD. Mild cognitive impairment in PD (PD-MCI) seems to represent a transitional state between PD-NC and PDD. Few studies have explored the structural changes that differentiate PD-NC from PD-MCI and PDD patients.
Objectives and Methods
We aimed to analyze changes in cortical thickness on 3.0T Magnetic Resonance Imaging (MRI) across stages of cognitive decline in a prospective sample of PD-NC (n = 26), PD-MCI (n = 26) and PDD (n = 20) patients, compared to a group of healthy subjects (HC) (n = 18). Cortical thickness measurements were made using the automatic software Freesurfer.
Results
In a sample of 72 PD patients, a pattern of linear and progressive cortical thinning was observed between cognitive groups in cortical areas functionally specialized in declarative memory (entorhinal cortex, anterior temporal pole), semantic knowledge (parahippocampus, fusiform gyrus), and visuoperceptive integration (banks of the superior temporal sulcus, lingual gyrus, cuneus and precuneus). Positive correlation was observed between confrontation naming and thinning in the fusiform gyrus, parahippocampal gyrus and anterior temporal pole; clock copy with thinning of the precuneus, parahippocampal and lingual gyrus; and delayed memory with thinning of the bilateral anteromedial temporal cortex.
Conclusions
The pattern of regional decreased cortical thickness that relates to cognitive deterioration is present in PD-MCI patients, involving areas that play a central role in the storage of prior experiences, integration of external perceptions, and semantic processing.
doi:10.1371/journal.pone.0054980
PMCID: PMC3554657  PMID: 23359616
3.  Grey Matter Changes in Cognitively Impaired Parkinson's Disease Patients 
PLoS ONE  2014;9(1):e85595.
Background
Cortical changes associated with cognitive decline in Parkinson's disease (PD) are not fully explored and require investigations with established diagnostic classification criteria.
Objective
We used MRI source-based morphometry to evaluate specific differences in grey matter volume patterns across 4 groups of subjects: healthy controls (HC), PD with normal cognition (PD-NC), PD with mild cognitive impairment (MCI-PD) and PD with dementia (PDD).
Methods
We examined 151 consecutive subjects: 25 HC, 75 PD-NC, 29 MCI-PD, and 22 PDD at an Italian and Czech movement disorder centre. Operational diagnostic criteria were applied to classify MCI-PD and PDD. All structural MRI images were processed together in the Czech centre. The spatial independent component analysis was used to assess group differences of local grey matter volume.
Results
We identified two independent patterns of grey matter volume deviations: a) Reductions in the hippocampus and temporal lobes; b) Decreases in fronto-parietal regions and increases in the midbrain/cerebellum. Both patterns differentiated PDD from all other groups and correlated with visuospatial deficits and letter verbal fluency, respectively. Only the second pattern additionally differentiated PD-NC from HC.
Conclusion
Grey matter changes in PDD involve areas associated with Alzheimer-like pathology while fronto-parietal abnormalities are possibly an early marker of PD cognitive decline. These findings are consistent with a non-linear cognitive progression in PD.
doi:10.1371/journal.pone.0085595
PMCID: PMC3897481  PMID: 24465612
4.  Brain amyloid and cognition in Lewy body diseases 
Background
Many patients with Parkinson disease (PD) develop dementia (PDD), a syndrome that overlaps clinically and pathologically with dementia with Lewy bodies (DLB); PDD and DLB differ chiefly in the relative timing of dementia and parkinsonism. Brain amyloid deposition is an early feature of DLB and may account in part for its early dementia. We sought to confirm this hypothesis and also to determine whether amyloid accumulation contributes to cognitive impairment and dementia in the broad range of parkinsonian diseases.
Methods
29 cognitively normal PD, 14 PD subjects with mild cognitive impairment (PD-MCI), 18 with DLB, 12 with PDD and 85 healthy control subjects (HCS) underwent standardized neurologic and neuropsychological examinations and PiB imaging with PET. Apolipoprotein (APOE) genotypes were obtained in many patients. PiB retention was expressed as the distribution volume ratio using a cerebellar tissue reference.
Results
PiB retention was significantly higher in DLB than in any of the other diagnostic groups. PiB retention did not differ across PDD, PD-MCI, PD, and HCS. Amyloid burden increased with age and with the presence of the APOEε4 allele in all patient groups. Only in the DLB group was amyloid deposition associated with impaired cognition.
Conclusions
DLB subjects have higher amyloid burden than subjects with PDD, PD-MCI, PD or HCS; amyloid deposits are linked to cognitive impairment only in DLB. Early amyloid deposits in DLB relative to PDD may account for their difference in the timing of dementia and parkinsonism.
doi:10.1002/mds.25048
PMCID: PMC3725259  PMID: 22693110
dementia; Lewy; Parkinson; amyloid; PiB
5.  Alzheimer's disease pattern of brain atrophy predicts cognitive decline in Parkinson's disease 
Brain  2011;135(1):170-180.
Research suggests overlap in brain regions undergoing neurodegeneration in Parkinson's and Alzheimer's disease. To assess the clinical significance of this, we applied a validated Alzheimer's disease-spatial pattern of brain atrophy to patients with Parkinson's disease with a range of cognitive abilities to determine its association with cognitive performance and decline. At baseline, 84 subjects received structural magnetic resonance imaging brain scans and completed the Dementia Rating Scale-2, and new robust and expanded Dementia Rating Scale-2 norms were applied to cognitively classify participants. Fifty-nine non-demented subjects were assessed annually with the Dementia Rating Scale-2 for two additional years. Magnetic resonance imaging scans were quantified using both a region of interest approach and voxel-based morphometry analysis, and a method for quantifying the presence of an Alzheimer's disease spatial pattern of brain atrophy was applied to each scan. In multivariate models, higher Alzheimer's disease pattern of atrophy score was associated with worse global cognitive performance (β = −0.31, P = 0.007), including in non-demented patients (β = −0.28, P = 0.05). In linear mixed model analyses, higher baseline Alzheimer's disease pattern of atrophy score predicted long-term global cognitive decline in non-demented patients [F(1, 110) = 9.72, P = 0.002], remarkably even in those with normal cognition at baseline [F(1, 80) = 4.71, P = 0.03]. In contrast, in cross-sectional and longitudinal analyses there was no association between region of interest brain volumes and cognitive performance in patients with Parkinson's disease with normal cognition. These findings support involvement of the hippocampus and parietal–temporal cortex with cognitive impairment and long-term decline in Parkinson's disease. In addition, an Alzheimer's disease pattern of brain atrophy may be a preclinical biomarker of cognitive decline in Parkinson's disease.
doi:10.1093/brain/awr277
PMCID: PMC3316476  PMID: 22108576
Alzheimer's disease; dementia; mild cognitive impairment; Parkinson's disease; neurodegeneration
6.  A voxel based morphometry study on mild cognitive impairment 
Background: Mild cognitive impairment (MCI) is the most widely used concept in classifying cognitive impairment in the elderly who do not fulfil the criteria for dementia. MCI is considered to confer an increased risk of progressing to dementia and most often Alzheimer's disease (AD). Various approaches such as imaging of the brain have been applied to predict the conversion of MCI to dementia. A number of volumetric magnetic resonance imaging (MRI) studies have detected atrophy of the medial temporal lobe in subjects with MCI, but for the other cerebral regions the results have been inconsistent.
Objective: To study the pattern of brain atrophy in MCI.
Methods: Thirty two controls and 51 individuals with MCI deriving from population based cohorts were studied by MRI using voxel based morphometry. The threshold of t maps was set at p<0.001.
Results: Individuals with MCI had significant unilateral atrophy in the medial temporal lobe on the right side. Less extensive atrophy was found elsewhere—for example, in the temporal lobe, left superior parietal lobule, left anterior cingulate gyrus, and bilaterally in the thalami.
Conclusions: The MRI findings in MCI resemble those seen in early AD.
doi:10.1136/jnnp.2004.035600
PMCID: PMC1739300  PMID: 15607988
7.  Hippocampal, Caudate, and Ventricular Changes in Parkinson’s Disease with and Without Dementia 
Parkinson’s disease (PD) has been associated with mild cognitive impairment (PDMCI) and with dementia (PDD). Using radial distance mapping, we studied the 3D structural and volumetric differences between the hippocampi, caudates, and lateral ventricles in 20 cognitively normal elderly (NC), 12 cognitively normal PD (PDND), 8 PDMCI, and 15 PDD subjects and examined the associations between these structures and Unified Parkinson’s Disease Rating Scale (UPDRS) Part III:motor subscale and Mini-Mental State Examination (MMSE) performance. There were no hippocampal differences between the groups. 3D caudate statistical maps demonstrated significant left medial and lateral and right medial atrophy in the PDD vs. NC, and right medial and lateral caudate atrophy in PDD vs. PDND. PDMCI showed trend-level significant left lateral caudate atrophy vs. NC. Both left and right ventricles were significantly larger in PDD relative to the NC and PDND with posterior (body/occipital horn) predominance. The magnitude of regionally significant between-group differences in radial distance ranged between 20–30% for caudate and 5–20% for ventricles. UPDRS Part III:motor subscale score correlated with ventricular enlargement. MMSE showed significant correlation with expansion of the posterior lateral ventricles and trend-level significant correlation with caudate head atrophy. Cognitive decline in PD is associated with anterior caudate atrophy and ventricular enlargement.
doi:10.1002/mds.22799
PMCID: PMC3068920  PMID: 20437538
Parkinson disease dementia (PDD); mild cognitive impairment (MCI); hippocampal atrophy; caudate atrophy; ventricular enlargement
8.  The Organization of Narrative Discourse in Lewy Body Spectrum Disorder 
Brain and language  2011;119(1):30-41.
Narrative discourse is an essential component of day-to-day communication, but little is known about narrative in Lewy Body spectrum disorder (LBSD), including Parkinson's disease (PD), Parkinson's disease with dementia (PDD), and dementia with Lewy bodies (DLB). We performed a detailed analysis of a semi-structured speech sample in 32 non-aphasic patients with LBSD, and we related their narrative impairments to gray matter (GM) atrophy using voxel-based morphometry. We found that patients with PDD and DLB have significant difficulty organizing their narrative speech. This was correlated with deficits on measures of executive functioning and speech fluency. Regression analyses associated this deficit with reduced cortical volume in inferior frontal and anterior cingulate regions. These findings are consistent with a model of narrative discourse that includes executive as well as language components and with an impairment of the organizational component of narrative discourse in patients with PDD and DLB.
doi:10.1016/j.bandl.2011.05.006
PMCID: PMC3163000  PMID: 21689852
Parkinson's disease; discourse; speech; language; Dementia with Lewy bodies
9.  Amyloid imaging of Lewy body-associated disorders 
Background
Clinicopathologic studies of Parkinson disease dementia (PDD) and dementia with Lewy bodies (DLB) commonly reveal abnormal β-amyloid deposition in addition to diffuse Lewy bodies (α-synuclein aggregates), but the relationship among these neuropathologic features and the development of dementia in these disorders remains uncertain.
Objective
To determine whether amyloid-βdeposition detected by PET imaging with Pittsburgh Compound B (PIB) distinguishes clinical subtypes of Lewy body-associated disorders.
Methods
Nine healthy controls (HC), eight PD with no cognitive impairment (PD-noCI), nine PD with mild cognitive impairment (PD-MCI), six dementia with Lewy bodies (DLB) and fifteen PD with dementia (PDD) patients underwent [11C]-PIB PET imaging, clinical examination, and cognitive testing. The binding potential (BP) of PIB for predefined regions and the mean cortical BP (MCBP) were calculated for each participant. Annual longitudinal follow-up and postmortem examinations were performed on a subset of participants.
Results
Regional PIB BPs and the proportion of individuals with abnormally elevated MCBP were not significantly different across participant groups. Elevated PIB binding was associated with worse global cognitive impairment in participants with Lewy body disorders but was not associated with any other clinical or neuropsychological features, including earlier onset or faster rate of progression of cognitive impairment.
Conclusions
These results suggest that the presence of fibrillar amyloid-βdoes not distinguish between clinical subtypes of Lewy body-associated disorders, although larger numbers are needed to more definitively rule out this association. Amyloid-βmay modify the severity of global cognitive impairment in individuals with Lewy body-associated dementia.
doi:10.1002/mds.23393
PMCID: PMC2978796  PMID: 20922808
Parkinson’s disease; Parkinson’s disease with dementia; Dementia with Lewy bodies; PET
10.  Rivastigmine for the treatment of dementia associated with Parkinson’s disease 
Parkinson’s disease (PD) afflicts millions of people worldwide and leads to cognitive impairment or dementia in the majority of patients over time. Parkinson’s disease dementia (PDD) is characterized by deficits in attention, executive and visuospatial function, and memory. The clinical diagnostic criteria and neuropathology surrounding PDD remain controversial with evidence of overlap among PDD, dementia with Lewy bodies (DLB) and Alzheimer’s disease (AD). Cortical cholinergic deficits are greater in PDD than in AD, and are well-correlated with the cognitive and neuropsychiatric dysfunction that occurs in PDD. Inhibition of acetylcholine metabolism is therefore a practical therapeutic strategy in PDD.
This review examines current evidence for rivastigmine (a cholinesterase/butyrylcholinesterase inhibitor) treatment in PDD. In addition to its efficacy, we examine the safety profile, side effects, and cost effectiveness of rivastigmine in PDD. Rivastigmine provides modest benefit in PDD and further long-term studies are needed to determine the effectiveness and safety of rivastigmine over time. Tolerability is a problem for many PDD patients treated with rivastigmine. Future studies of rivastigmine in PDD should focus on pragmatic outcomes such as time to need for nursing home placement, pharmacoeconomic outcomes and simultaneous patient/caregiver quality of life assessments.
PMCID: PMC2656320  PMID: 19300613
Parkinson’s disease; dementia; rivastigmine; cholinesterase inhibitor
11.  Imaging amyloid deposition in Lewy body diseases 
Neurology  2008;71(12):903-910.
Background:
Extrapyramidal motor symptoms precede dementia in Parkinson disease (PDD) by many years, whereas dementia occurs early in dementia with Lewy bodies (DLB). Despite this clinical distinction, the neuropsychological and neuropathologic features of these conditions overlap. In addition to widespread distribution of Lewy bodies, both diseases have variable burdens of neuritic plaques and neurofibrillary tangles characteristic of Alzheimer disease (AD).
Objectives:
To determine whether amyloid deposition, as assessed by PET imaging with the β-amyloid–binding compound Pittsburgh Compound B (PiB), can distinguish DLB from PDD, and to assess whether regional patterns of amyloid deposition correlate with specific motor or cognitive features.
Methods:
Eight DLB, 7 PDD, 11 Parkinson disease (PD), 15 AD, and 37 normal control (NC) subjects underwent PiB-PET imaging and neuropsychological assessment. Amyloid burden was quantified using the PiB distribution volume ratio.
Results:
Cortical amyloid burden was higher in the DLB group than in the PDD group, comparable to the AD group. Amyloid deposition in the PDD group was low, comparable to the PD and NC groups. Relative to global cortical retention, occipital PiB retention was lower in the AD group than in the other groups. For the DLB, PDD, and PD groups, amyloid deposition in the parietal (lateral and precuneus)/posterior cingulate region was related to visuospatial impairment. Striatal PiB retention in the DLB and PDD groups was associated with less impaired motor function.
Conclusions:
Global cortical amyloid burden is high in dementia with Lewy bodies (DLB) but low in Parkinson disease dementia. These data suggest that β-amyloid may contribute selectively to the cognitive impairment of DLB and may contribute to the timing of dementia relative to the motor signs of parkinsonism.
GLOSSARY
= Automated Anatomic Labeling;
= Alzheimer disease;
= Alzheimer’s Disease Research Center;
= American version of the National Adult Reading Test;
= analysis of covariance;
= Blessed Dementia Scale;
= cerebral amyloid angiopathy;
= Clinical Dementia Rating;
= Clinical Dementia Rating Sum of Boxes;
= dementia with Lewy bodies;
= distribution volume ratio;
= Cued Selective Reminding Test;
= Free Selective Reminding Test;
= Hoehn and Yahr;
= Massachusetts General Hospital;
= Mini-Mental State Examination;
= normal control;
= neurofibrillary tangle;
= Neuropsychiatric Inventory Questionnaire;
= not significant;
= Parkinson disease;
= Parkinson disease dementia;
= Pittsburgh Compound B;
= region of interest;
= Statistical Parametric Mapping;
= UK Parkinson’s Disease Society Brain Bank Research Center;
= United Parkinson’s Disease Rating Scale;
= Wechsler Adult Intelligence Scale–Revised.
doi:10.1212/01.wnl.0000326146.60732.d6
PMCID: PMC2637553  PMID: 18794492
12.  Relationship between cognitive impairment and white-matter alteration in Parkinson’s disease with dementia: tract-based spatial statistics and tract-specific analysis 
European Radiology  2013;23(7):1946-1955.
Objectives
We investigated the relationship between white-matter alteration and cognitive status in Parkinson’s disease (PD) with and without dementia by using diffusion tensor imaging.
Methods
Twenty PD patients, 20 PDD (Parkinson’s disease with dementia) patients and 20 age-matched healthy controls underwent diffusion tensor imaging. The mean diffusivity and fractional anisotropy (FA) map of each patient group were compared with those of the control group by using tract-based spatial statistics. Tractography images of the genu of the corpus callosum fibre tracts were generated, and mean diffusivity and FA were measured.
Results
FA values in many major tracts were significantly lower in PDD patients than in control subjects; in the prefrontal white matter and the genu of the corpus callosum they were significantly lower in PDD patients than in PD patients. There was a significant correlation between the Mini-Mental State Examination (MMSE) scores and the FA values of the prefrontal white matter and the genu of the corpus callosum in patients with PD.
Conclusions
Our study shows a relationship between cognitive impairment and alteration of the prefrontal white matter and genu of the corpus callosum. These changes may be useful in assessing the onset of dementia in PD patients.
Key Points
• Dementia is a common and important non-motor sign of Parkinson’s disease (PD).
• The neuropathological basis of dementia in PD is not clear.
• DTI shows abnormalities in the prefrontal white matter in PD with dementia.
• Prefrontal white matter alteration may be useful biomarker of dementia in PD.
doi:10.1007/s00330-013-2775-4
PMCID: PMC3674338  PMID: 23404139
Dementia; Diffusion tensor imaging; Parkinson’s disease; Tract-based spatial statistics; Tract-specific analysis
13.  Validity of the MoCA and MMSE in the detection of MCI and dementia in Parkinson disease 
Neurology  2009;73(21):1738-1745.
Background:
Due to the high prevalence of mild cognitive impairment (MCI) and dementia in Parkinson disease (PD), routine cognitive screening is important for the optimal management of patients with PD. The Montreal Cognitive Assessment (MoCA) is more sensitive than the commonly used Mini-Mental State Examination (MMSE) in detecting MCI and dementia in patients without PD, but its validity in PD has not been established.
Methods:
A representative sample of 132 patients with PD at 2 movement disorders centers was administered the MoCA, MMSE, and a neuropsychological battery with operationalized criteria for deficits. MCI and PD dementia (PDD) criteria were applied by an investigator blinded to the MoCA and MMSE results. The discriminant validity of the MoCA and MMSE as screening and diagnostic instruments was ascertained.
Results:
Approximately one third of the sample met diagnostic criteria for a cognitive disorder (12.9% PDD and 17.4% MCI). Mean (SD) MoCA and MMSE scores were 25.0 (3.8) and 28.1 (2.0). The overall discriminant validity for detection of any cognitive disorder was similar for the MoCA and the MMSE (receiver operating characteristic area under the curve [95% confidence interval]): MoCA (0.79 [0.72, 0.87]) and MMSE (0.76 [0.67, 0.85]), but as a screening instrument the MoCA (optimal cutoff point = 26/27, 64% correctly diagnosed, lack of ceiling effect) was superior to the MMSE (optimal cutoff point = 29/30, 54% correctly diagnosed, presence of ceiling effect).
Conclusions:
The Montreal Cognitive Assessment, but not the Mini-Mental State Examination, has adequate psychometric properties as a screening instrument for the detection of mild cognitive impairment or dementia in Parkinson disease. However, a positive screen using either instrument requires additional assessment due to suboptimal specificity at the recommended screening cutoff point.
GLOSSARY
= Alzheimer disease;
= area under the curve;
= deep brain stimulation;
= Diagnostic and Statistical Manual of Mental Disorders, 4th edition;
= Geriatric Depression Scale;
= Hopkins Verbal Learning Test;
= instrumental activities of daily living;
= mild cognitive impairment;
= Mini-Mental State Examination;
= Montreal Cognitive Assessment;
= negative predictive value;
= Parkinson disease;
= Parkinson disease dementia;
= positive predictive value;
= quality of life;
= receiver operating characteristic;
= Tower of London-Drexel;
= Unified Parkinson’s Disease Rating Scale.
doi:10.1212/WNL.0b013e3181c34b47
PMCID: PMC2788810  PMID: 19933974
14.  Clinical-Neuroimaging Characteristics of Dysexecutive Mild Cognitive Impairment 
Annals of neurology  2009;65(4):414-423.
Objective
Subgroups of mild cognitive impairment (MCI) have been proposed, but few studies have investigated the non-amnestic, single-domain subgroup of MCI. The goal of the study was to compare clinical and neuroimaging characteristics of two single domain MCI subgroups: amnestic MCI (aMCI) and dysexecutive MCI (dMCI).
Methods
We compared the cognitive, functional, behavioral and brain imaging characteristics of patients with aMCI (n=26), dMCI (n=32) and age- and education-matched controls (n=36) using analysis of variance and chi-squared tests. We used voxel-based morphometry (VBM) to examine group differences in brain MRI atrophy patterns.
Results
Patients with dMCI had significantly lower scores on the majority of executive function tests, increased behavioral symptoms, and left prefrontal cortex atrophy on MRI when compared to controls. In contrast, patients with aMCI had significantly lower scores on tests of memory and a pattern of atrophy including bilateral hippocampi and entorhinal cortex, right inferior parietal cortex, and posterior cingulate gyrus when compared to controls.
Interpretation
Overall, the clinical and neuroimaging findings provide support for two distinct single-domain subgroups of MCI, one involving executive function and the other involving memory. The brain imaging differences suggest that the two MCI subgroups have distinct patterns of brain atrophy.
doi:10.1002/ana.21591
PMCID: PMC2680500  PMID: 19399879
15.  Older adults with cognitive complaints show brain atrophy similar to that of amnestic MCI 
Neurology  2006;67(5):834-842.
Objective
To examine the neural basis of cognitive complaints in healthy older adults in the absence of memory impairment and to determine whether there are medial temporal lobe (MTL) gray matter (GM) changes as reported in Alzheimer disease (AD) and amnestic mild cognitive impairment (MCI).
Methods
Participants were 40 euthymic individuals with cognitive complaints (CCs) who had normal neuropsychological test performance. The authors compared their structural brain MRI scans to those of 40 patients with amnestic MCI and 40 healthy controls (HCs) using voxel-based morphometry and hippocampal volume analysis.
Results
The CC and MCI groups showed similar patterns of decreased GM relative to the HC group on whole brain analysis, with differences evident in the MTL, frontotemporal, and other neocortical regions. The degree of GM loss was associated with extent of both memory complaints and performance deficits. Manually segmented hippocampal volumes, adjusted for age and intracranial volume, were significantly reduced only in the MCI group, with the CC group showing an intermediate level.
Conclusions
Cognitive complaints in older adults may indicate underlying neurodegenerative changes even when unaccompanied by deficits on formal testing. The cognitive complaint group may represent a pre–mild cognitive impairment stage and may provide an earlier therapeutic opportunity than mild cognitive impairment. MRI analysis approaches incorporating signal intensity may have greater sensitivity in early preclinical stages than volumetric methods.
doi:10.1212/01.wnl.0000234032.77541.a2
PMCID: PMC3488276  PMID: 16966547
16.  Neuropsychiatric Symptoms in Parkinson's Disease with Mild Cognitive Impairment and Dementia 
Parkinson's Disease  2012;2012:308097.
Neuropsychiatric symptoms commonly complicate Parkinson's disease (PD), however the presence of such symptoms in mild cognitive impairment (PD-MCI) specifically has not yet been well described. The objective of this study was to examine and compare the prevalence and profile of neuropsychiatric symptoms in patients with PD-MCI (n = 48) to those with PD and no cognitive impairment (PD-NC, n = 54) and to those with dementia in PD (PDD, n = 25). PD-MCI and PDD were defined using specific consensus criteria, and neuropsychiatric symptoms were assessed with the 12-item Neuropsychiatric Inventory (NPI). Self-rated apathy, depression, and anxiety rating scales were also administered. Over 79% of all participants reported at least one neuropsychiatric symptom in the past month. The proportion in each group who had total NPI scores of ≥4 (“clinically significant”) was as follows: PD-NC, 64.8%; PD-MCI, 62%; PDD 76%. Apathy was reported in almost 50% of those with PD-MCI and PDD, and it was an important neuropsychiatric symptom differentiating PD-MCI from PD-NC. Psychosis (hallucinations and delusions) increased from 12.9% in PD-NC group; 16.7% in PD-MCI group; and 48% in PDD group. Identifying neuropsychiatric symptoms in PD-MCI may have implications for ascertaining conversion to dementia in PD.
doi:10.1155/2012/308097
PMCID: PMC3437302  PMID: 22970412
17.  Imaging amyloid deposition in Lewy body diseases 
Neurology  2008;71(12):903-910.
Background
Extrapyramidal motor symptoms precede dementia in Parkinson disease (PDD) by many years, whereas dementia occurs early in dementia with Lewy bodies (DLB). Despite this clinical distinction, the neuropsychological and neuropathologic features of these conditions overlap. In addition to widespread distribution of Lewy bodies, both diseases have variable burdens of neuritic plaques and neurofibrillary tangles characteristic of Alzheimer disease (AD).
Objectives
To determine whether amyloid deposition, as assessed by PET imaging with the β-amyloid–binding compound Pittsburgh Compound B (PiB), can distinguish DLB from PDD, and to assess whether regional patterns of amyloid deposition correlate with specific motor or cognitive features.
Methods
Eight DLB, 7 PDD, 11 Parkinson disease (PD), 15 AD, and 37 normal control (NC) subjects underwent PiB-PET imaging and neuropsychological assessment. Amyloid burden was quantified using the PiB distribution volume ratio.
Results
Cortical amyloid burden was higher in the DLB group than in the PDD group, comparable to the AD group. Amyloid deposition in the PDD group was low, comparable to the PD and NC groups. Relative to global cortical retention, occipital PiB retention was lower in the AD group than in the other groups. For the DLB, PDD, and PD groups, amyloid deposition in the parietal (lateral and precuneus)/posterior cingulate region was related to visuospatial impairment. Striatal PiB retention in the DLB and PDD groups was associated with less impaired motor function.
Conclusions
Global cortical amyloid burden is high in dementia with Lewy bodies (DLB) but low in Parkinson disease dementia. These data suggest that β-amyloid may contribute selectively to the cognitive impairment of DLB and may contribute to the timing of dementia relative to the motor signs of parkinsonism.
doi:10.1212/01.wnl.0000326146.60732.d6
PMCID: PMC2637553  PMID: 18794492
18.  Effect of levodopa on cognitive function in Parkinson's disease with and without dementia and dementia with Lewy bodies 
Background
Levodopa (L‐dopa) is the gold standard treatment for Parkinson's disease, but a lack of clear efficacy combined with a perceived liability to neuropsychiatric side effects has limited L‐dopa use in patients with parkinsonism and dementia. Therefore, the effect of L‐dopa on the cognitive profile of dementia with Lewy bodies (DLB) and Parkinson's disease with dementia (PDD) is unclear.
Aim
To ascertain the acute and long‐term effects of L‐dopa on aspects of attention and cognition in patients with DLB and PDD, and to compare these with the effects in Parkinson's disease.
Method
Baseline cognitive and motor function was assessed off L‐dopa in patients with Parkinson's disease (n = 22), PDD (n = 27) and DLB (n = 11) using standard “bedside” measures and a computerised programme detecting reaction times and accuracy. All patients then underwent an acute L‐dopa challenge with subsequent subjective and objective analysis of alertness, verbal recall, reaction times and accuracy. The same parameters were measured after 3 months on L‐dopa to assess the prolonged effect.
Results
Acute L‐dopa challenge considerably improved motor function and subjective alertness in all patients without compromising either reaction times or accuracy, but increased fluctuations were noted in both groups with dementia. Neuropsychiatric scores improved in patients with Parkinson's disease both with and without dementia on L‐dopa at 3 months. Although patients with Parkinson's disease also had better mean global cognitive function at this time, mean verbal attention and memory deteriorated, and patients with PDD had slower reaction times in some tests. No patient had a marked deterioration over this time. Patients with DLB did not experience any adverse cognitive or neuropsychiatric effects after 3 months of L‐dopa treatment.
Conclusion
The use of L‐dopa in patients with parkinsonism with dementia does not adversely affect cognitive function.
doi:10.1136/jnnp.2006.098079
PMCID: PMC2077405  PMID: 16952917
19.  Time-to-event Voxel Based Techniques to Assess Regional Atrophy Associated with MCI Risk of Progression to AD 
NeuroImage  2010;54(2):985-991.
Objective
When using imaging to predict time to progression from mild cognitive impairment (MCI) to Alzheimer's disease (AD), time-to-event statistical methods account for varying lengths of follow-up times among subjects whereas two-sample t-tests in voxel-based morphometry (VBM) do not. Our objectives were to apply a time-to-event voxel-based analytic method to identify regions on MRI where atrophy is associated with significantly increased risk of future progression to AD in subjects with MCI and to compare it to traditional voxel-level patterns obtained by applying two-sample methods. We also compared the power required to detect an association using time-to-event methods versus two-sample approaches.
Methods
Subjects with MCI at baseline were followed prospectively. The event of interest was clinical diagnosis of AD. Cox proportional hazards models adjusted for age, sex, and education were used to estimate the relative hazard of progression from MCI to AD based on rank-transformed voxel-level gray matter density (GMD) estimates.
Results
The greatest risk of progression to AD was associated with atrophy of the medial temporal lobes. Patients ranked at the 25th percentile of GMD in these regions had more than a doubling of risk of progression to AD at a given time-point compared to patients at the 75th percentile. Power calculations showed the time-to-event approach to be more efficient than the traditional two-sample approach.
Conclusions
We present a new voxel-based analytic method that incorporates time-to-event statistical methods. In the context of a progressive disease like AD, time-to-event VBM seems more appropriate and powerful than traditional two-sample methods.
doi:10.1016/j.neuroimage.2010.09.004
PMCID: PMC2997139  PMID: 20832487
Alzheimer Disease; mild cognitive impairment; magnetic resonance imaging; Cox proportional hazards model
20.  Structural MRI in Frontotemporal Dementia: Comparisons between Hippocampal Volumetry, Tensor-Based Morphometry and Voxel-Based Morphometry 
PLoS ONE  2012;7(12):e52531.
Background
MRI is an important clinical tool for diagnosing dementia-like diseases such as Frontemporal Dementia (FTD). However there is a need to develop more accurate and standardized MRI analysis methods.
Objective
To compare FTD with Alzheimer’s Disease (AD) and Mild Cognitive Impairment (MCI) with three automatic MRI analysis methods - Hippocampal Volumetry (HV), Tensor-based Morphometry (TBM) and Voxel-based Morphometry (VBM), in specific regions of interest in order to determine the highest classification accuracy.
Methods
Thirty-seven patients with FTD, 46 patients with AD, 26 control subjects, 16 patients with progressive MCI (PMCI) and 48 patients with stable MCI (SMCI) were examined with HV, TBM for shape change, and VBM for gray matter density. We calculated the Correct Classification Rate (CCR), sensitivity (SS) and specificity (SP) between the study groups.
Results
We found unequivocal results differentiating controls from FTD with HV (hippocampus left side) (CCR = 0.83; SS = 0.84; SP = 0.80), with TBM (hippocampus and amygdala (CCR = 0.80/SS = 0.71/SP = 0.94), and with VBM (all the regions studied, especially in lateral ventricle frontal horn, central part and occipital horn) (CCR = 0.87/SS = 0.81/SP = 0.96). VBM achieved the highest accuracy in differentiating AD and FTD (CCR = 0.72/SS = 0.67/SP = 0.76), particularly in lateral ventricle (frontal horn, central part and occipital horn) (CCR = 0.73), whereas TBM in superior frontal gyrus also achieved a high accuracy (CCR = 0.71/SS = 0.68/SP = 0.73). TBM resulted in low accuracy (CCR = 0.62) in the differentiation of AD from FTD using all regions of interest, with similar results for HV (CCR = 0.55).
Conclusion
Hippocampal atrophy is present not only in AD but also in FTD. Of the methods used, VBM achieved the highest accuracy in its ability to differentiate between FTD and AD.
doi:10.1371/journal.pone.0052531
PMCID: PMC3527560  PMID: 23285078
21.  Motor subtype and cognitive decline in Parkinson's disease, Parkinson's disease with dementia, and dementia with Lewy bodies 
Background
A previous cross sectional study found over‐representation of a postural instability gait difficulty (PIGD) motor subtype in Parkinson's disease patients with dementia (PDD) and dementia with Lewy bodies (DLB), compared with Parkinson's disease (PD).
Aims
(1) To examine rates of cognitive and motor decline over two years in PD (n = 40), PDD (n = 42) and DLB (n = 41) subjects, compared with age matched controls (n = 41), (2) to record whether motor phenotypes of PD, PDD, and DLB subjects changed during the study, (3) to find out if cognitive and motor decline in PD was associated with baseline motor subtype, and (4) to report the incidence of dementia in PD patients in relation to baseline motor subtype.
Results
Most of PDD and DLB participants were PIGD subtype at baseline assessment. In the non‐demented PD group, tremor dominant (TD) and PIGD subtypes were more evenly represented. Cognitive decline over two years was greater in PDD and DLB groups (mean decline in MMSE −4.5 and −3.9, respectively), compared with PD (−0.2) and controls (−0.3). There was an association between PIGD subtype and increased rate of cognitive decline within the PD group. Of 40 PD patients, 25% of the 16 PIGD subtype developed dementia over two years, compared with none of the 18 TD or six indeterminate phenotype cases (χ2 = 6.7, Fisher's exact test p<0.05).
Conclusion
A PIGD motor subtype is associated with a faster rate of cognitive decline in PD and may be considered a risk factor for incident dementia in PD.
doi:10.1136/jnnp.2005.081711
PMCID: PMC2117449  PMID: 16614017
Lewy body disease; dementia; parkinsonism; motor subtype; progression
22.  Differential Sialylation of Serpin A1 in the Early Diagnosis of Parkinson’s Disease Dementia 
PLoS ONE  2012;7(11):e48783.
The prevalence of Parkinson’s disease (PD) increases with age. Up to 50% of PD show cognitive decline in terms of a mild cognitive impairment already in early stages that predict the development of dementia, which can occur in up to 80% of PD patients over the long term, called Parkinson’s disease dementia (PDD). So far, diagnosis of PD/PDD is made according to clinical and neuropsychological examinations while laboratory data is only used for exclusion of other diseases. The aim of this study was the identification of possible biomarkers in cerebrospinal fluid (CSF) of PD, PDD and controls (CON) which predict the development of dementia in PD. For this, a proteomic approach optimized for CSF was performed using 18 clinically well characterized patients in a first step with subsequent validation using 84 patients. Here, we detected differentially sialylated isoforms of Serpin A1 as marker for differentiation of PD versus PDD in CSF. Performing 2D-immunoblots, all PDD patients could be identified correctly (sensitivity 100%). Ten out of 24 PD patients showed Serpin A1 isoforms in a similar pattern like PDD, indicating a specificity of 58% for the test-procedure. In control samples, no additional isoform was detected. On the basis of these results, we conclude that differentially sialylated products of Serpin A1 are an interesting biomarker to indicate the development of a dementia during the course of PD.
doi:10.1371/journal.pone.0048783
PMCID: PMC3493604  PMID: 23144969
23.  The Contribution of Executive Control on Verbal-Learning Impairment in Patients with Parkinson's Disease with Dementia and Alzheimer's Disease 
Deficits in learning, memory, and executive functions are common cognitive sequelae of Parkinson's disease with dementia (PDD) and Alzheimer's disease (AD); however, the pattern of deficits within these populations is distinct. Hierarchical regression was used to investigate the contribution of two measures with executive function properties (Verbal Fluency and CLOX) on list-learning performance (CVLT-II total words learned) in a sample of 25 PDD patients and 25 matched AD patients. Executive measures were predictive of list learning in the PDD group after the contribution of overall cognition and contextual verbal learning was accounted for, whereas in the AD group the addition of executive measures did not add to prediction of variance in CVLT-II learning. These findings suggest that deficits in executive functions play a vital role in learning impairments in patients with PDD; however, for AD patients, learning difficulties appear relatively independent of executive dysfunction.
doi:10.1093/arclin/acp029
PMCID: PMC2765349  PMID: 19587066
Parkinson's disease with dementia; Alzheimer's disease; Executive function; List learning; Neuropsychologic tests; Comparative studies
24.  ELEVATED TAUOPATHY AND ALPHA SYNUCLEIN PATHOLOGY IN POSTMORTEM PARKINSON’S DISEASE BRAINS WITH AND WITHOUT DEMENTIA 
Experimental neurology  2010;225(1):210-218.
Parkinson’s disease [PD], a progressive neurodegenerative disease, results in abnormal accumulation of insoluble alpha-synuclein [α-Syn] in dopaminergic neurons. Here we examined tauopathic changes and the α-Syn/p-GSK-3β/proteasome pathway in postmortem striata and inferior frontal gyri [IFG] from patients with PD and PD with dementia [PDD]. In both PD and PDD, α-Syn levels were high, especially the insoluble form of this protein; in PDD, insoluble α-Syn levels were persistently higher than PD across both brain regions. Levels of p-GSK-3β phosphorylated at Tyr 216, which hyperphosphorylates Tau to produce toxic pathological forms of p-Tau, were higher in striata of both PD and PDD compared to controls, but were unaltered in IFG. While proteasomal activity was unchanged in striatum of PD and PDD, such activity was diminished in the IFG of both PD and PDD. A decrease in 19S subunit of the proteasomes was seen in IFG of PDD, while lower levels of 20S subunits were seen in striatum and IFG of both PD and PDD patients. Parkin levels were similar in PD and PDD, suggesting lack of involvement of this protein. Most interestingly, tauopathic changes were noted only in striatum of PD and PDD, with increased hyperphosphorylation seen at Ser262 and Ser396/404; increases in Ser202 levels were seen only in PD but not in PDD striatum. We were unable to detect any tauopathy in IFG in either PD or PDD despite increased levels of α-Syn, and decreased proteasomal activity, and is probably due to lack of increase in p-GSK-3β in IFG. Unlike Alzheimer’s disease where tauopathy is more globally observed in diverse brain regions, our data demonstrates restricted expression of tauopathy in brains of PD and PDD, probably limited to dopaminergic neurons of the nigrostriatal region.
doi:10.1016/j.expneurol.2010.06.017
PMCID: PMC2922478  PMID: 20599975
synucleinopathies; tauopathies; neurodegeneration; Alzheimer’s disease; dementia; hyperphosphorylated Tau; p-GSK-3β; parkin; neurofibrillary tangles; Lewy bodies
25.  Functional response in ventral temporal cortex differentiates mild cognitive impairment from normal aging 
Human brain mapping  2010;31(8):1249-1259.
The present study sought to identify altered brain activation patterns in amnestic mild cognitive impairment (MCI) that could precede frank task impairment and neocortical atrophy. A high accuracy lexical decision (LD) task was therefore employed. Both MCI and normal senior (NS) groups completed the LD task while functional magnetic resonance imaging (fMRI) was performed. Accuracy on the LD task was high (≥ 89% correct for both groups), and both groups activated a network of occipitotemporal regions and inferior frontal cortex. However, compared to the NS group, the MCI group showed reduced fMRI activation in these regions and increased activation in bilateral portions of anterior cingluate cortex. Results from a voxel-based morphometry analysis indicate that altered activations in the MCI group were not within regions of atrophy. Receiver operating characteristic curves demonstrate that reduced fMRI response in the left and right mid-fusiform gyri accurately discriminate MCI from NS. When activation magnitude in both fusiform gyri were included in a single logistic regression model, group classification accuracy was very high (area under the curve = 0.93). These results show that a disrupted functional response in the ventral temporal lobe accurately distinguishes individuals with MCI from normal seniors, a finding which may have implications for identifying seniors at risk for cognitive decline.
doi:10.1002/hbm.20932
PMCID: PMC3004147  PMID: 20063353
Alzheimer’s disease; MCI; fMRI; structural imaging; lexical decision; fusiform gyrus

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