Brain 3D-SSP SPECT analysis in dementia with Lewy bodies, Parkinson's disease with and without dementia, and Alzheimer's disease

OBJECTIVES: Cerebral blood flow was compared among patients with dementia with Lewy bodies (DLB), Parkinson's disease with dementia (PDD), Parkinson's disease without dementia (PD), and Alzheimer's disease (AD) using three-dimensional stereotactic surface projection (3D-SSP) analysis. PURPOSE: We attempt to clarify the difference of reduction pattern on SPECT among patients having DLB, PDD, PD, AD. PATIENTS AND METHODS: Six patients with DLB, 7 patients with PDD who were matched with the DLB patients for age, unified Parkinson's disease rating scale-III (UPDRS-III) score, and degree of cognitive function disorders, 21 patients with PD who were matched with the DLB patients for age, UPDRS-III score, 12 patients with AD who were matched with the DLB patients for age and degree of cognitive function disorders, and 12 control subjects. All patients were examined by N-isopropyl-p[123I] iodoamphetamine single photon emission computed tomography (123I-IMP SPECT), and obtained images were analyzed with 3D-SSP using an image-analysis software, iSSP ver. 3.5. RESULTS: Although DLB and PDD showed similar cerebral perfusion reduction pattern at the lateral parietal association and lateral temporal association and precuneus on SPECT by the pixel-by-pixel comparison, greater perfusion reduction was observed in DLB than in PDD. Cerebral perfusion was decreased at the occipital lobe of the DLB patients compared with the AD patients. CONCLUSIONS: The regional pattern of blood flow reduction in the brain was found to be different among DLB, PD, and AD. Greater blood flow reduction was observed in DLB, although DLB and PDD showed similar reduction pattern. These regional differences were considered to suggest different and disease-specific combinations of underlying pathological and neurochemical processes.     

Parkinson's disease is associated with hippocampal atrophy.

Patients with Parkinson's disease (PD) may have hippocampal atrophy compared with controls. We compared hippocampal, and extra-hippocampal volumes between PD, PDD (patients with PD who have mild cognitive impairment or dementia), Alzheimer's disease (AD) and controls using volumetric magnetic resonance imaging (MRI). Participants (10 patients with PD, 10 with PDD, 11 with AD, and 12 control subjects) had an informant interview, neurological examination, and psychometric testing. Established, reliable methods were used to measure the hippocampus, parahippocampal gyrus, temporal, frontal, and parieto-occipital lobes. Correction for intracranial volume was carried out before comparison. There was no age difference between groups (mean age, 74 years). On the Clinical Dementia Rating scale (CDR) cognitive impairment was mild (CDR = 0.5) in the majority of PDD and AD patients. Hippocampal (P < 0.0004) volumes were smaller in the patient groups. Effect sizes compared with the control group were: PD, 0.66; PDD, 1.22; and AD, 1.81. The other volumes did not differ significantly. Among PD and PDD patients, recognition memory (r = 0.54, P = 0.015) and Mini-Mental State Examination scores (r = 0.56, P = 0.01) correlated with left, but not right hippocampal volume. In conclusion, hippocampal volume showed a pattern (Control > PD > PDD > AD) suggesting progressive hippocampal volume loss in PD. Volumetric MRI imaging might provide an early marker for dementia in PD.     

Positron emission tomography in degenerative disorders of the dopaminergic system

Summary 21 patients who had Parkinson's disease (PD), PD plus dementia of Alzheimer type (PDAT) or progressive supranuclear palsy (PSP), were studied with positron emission tomography (PET) using (¹⁸F)-2-fluoro-2-deoxy-D-glucose (FDG). In one patient with strictly unilateral PD side differences in striatal dopa uptake were studied with 6-(¹⁸F)fluoro-L-dopa (F-dopa). In patients with PD PET with FDG did not show any significant change in regional cerebral metabolic rates for glucose (rCMR(Glu)). In PDAT glucose metabolism was generally reduced, the most severe decrease was found in parietal cortex. The metabolic pattern was similar to that typically found in patients with Alzheimer's disease (AD). In the patient with strictly unilateral PD rCMR(Glu) was normal, F-dopa PET, however, revealed a distinct reduction of dopa uptake in the contralateral putamen. In PSP glucose metabolism was significantly decreased in subcortical regions (caudatum, putamen and brainstem) and in frontal cortex. Thus PET demonstrated a clear difference of metabolic pattern between PDAT and PSP.     

Rivastigmine in dementia associated with Parkinson's disease and Alzheimer's disease: similarities and differences

Parkinson's disease dementia (PDD) and Alzheimer's disease (AD) are both characterized by cognitive abnormalities, neuropsychiatric symptoms, and cholinergic deficits. We reviewed data from large, placebo-controlled clinical trials conducted with rivastigmine in patients with PDD and AD to evaluate similarities and differences in response to treatment. In placebo groups, AD patients appeared to show more rapid cognitive decline than those with PDD. Treatment effects (rivastigmine versus placebo) on cognitive performance over 6 months were quantitatively similar in both populations, but qualitatively different: in AD, cognitive abilities were stabilized by rivastigmine compared to declines in placebo groups, whereas in PDD symptomatic improvements above baseline drove treatment effects while placebo patients had limited change. On activities of daily living, stabilization (rather than improvement) was observed in both dementia types. A more aggressive course of placebo decline, and greater treatment differences (rivastigmine versus placebo), were seen in sub-populations of both PDD and AD patients with hallucinations at baseline. The safety and adverse event profiles were comparable in the two populations. In conclusion, the magnitude of effect with rivastigmine versus placebo is quantitatively comparable in patients with AD and PD, but the treatment effect tended to be one of stabilization in AD, while in PDD improvements over baseline were seen. In both populations, hallucinations may identify patients who are likely to be more treatment-responsive.     

Subjectively reported sleep quality and excessive daytime somnolence in Parkinson's disease with and without dementia, dementia with Lewy bodies and Alzheimer's disease

OBJECTIVE: We compared subjective sleep quality and excessive daytime somnolence (EDS) in controls, Parkinson's disease with (PDD) and without dementia (PD), dementia with Lewy bodies (DLB) and Alzheimer's disease (AD). We investigated whether sleep dysfunction and EDS associate with motor phenotype in PD, PDD and DLB. METHOD: Assessments included the Epworth Sleepiness Scale (ESS) and Pittsburgh Sleep Quality Index (PSQI). RESULTS: EDS was more frequent in PD, DLB and PDD patients than in AD. PDD, PD and DLB patients also had worse sleep quality when compared with AD and controls. Baseline postural instability-gait difficulty (PIGD) motor phenotype in PDD was associated with a higher ESS score and frequency of EDS, but this association was lost at two years. PSQI scores did not differ between PIGD dominant and non-dominant PD, PDD and DLB patients. CONCLUSION: EDS and poor sleep quality are greater in PD, PDD and DLB, compared with AD. The dissociation of EDS and motor phenotype suggests their pathophysiology is anatomically and/or temporally distinct.     

Everyday action impairment in Parkinson's disease dementia

This study examined everyday action impairment in participants with Parkinson's disease dementia (PDD) by comparison with participants with Parkinson's disease-no dementia (PD) or Alzheimer's disease (AD) and in reference to a neuropsychological model. Participants with PDD (n = 20), PD (n = 20), or AD (n = 20) were administered performance-based measures of everyday functioning that allowed for the quantification of overall performance and error types. Also, caregiver ratings of functional independence were obtained. On performance-based tests, the PDD group exhibited greater functional impairment than the PD group but comparable overall impairment relative to the AD group. Error patterns did not differ between PDD and PD participants but the PDD group demonstrated a higher proportion of commission errors and lower proportion of omission errors relative to the AD group. Hierarchical regression analyses showed omission errors were significantly predicted by neuropsychological measures of episodic memory, whereas commission errors were predicted by both measures of general dementia severity (MMSE) and executive control. Everyday action impairment in PDD differs quantitatively from PD but qualitatively from AD and may be characterized by a relatively high proportion of commission errors-an error type associated with executive control deficits. (JINS, 2012, 18, 1-12).     

Cognitive profiles of individual patients with Parkinson's disease and dementia: comparison with dementia with lewy bodies and Alzheimer's disease.

We describe the pattern of cognitive profiles within a community-based sample of patients with Parkinson's disease (PD) and dementia (PDD) using cluster analyses, and compare the results with data from patients with Alzheimer's disease (AD) and dementia with Lewy bodies (DLB). Fifty patients with PDD and 39 with AD from Stavanger, Norway, and 62 patients with DLB from San Diego, CA, USA were diagnosed by either standardized clinical procedures or criteria (all PDD and all AD cases) or necropsy (all DLB cases). Four subgroups were identified: two subgroups with a subcortical cognitive profile (one with mild and one with moderate dementia severity), one subgroup with global impairment and severe dementia, and one subgroup with a cortical cognitive profile and moderate dementia. Of the patients with PDD and with DLB, 56% and 55%, respectively, had a subcortical cognitive profile, compared with only 33% of the AD patients. Conversely, 30% of the patients with PDD and 26% of those with DLB had a cortical cognitive profile, compared with 67% of the patients with AD. These findings suggest that in some patients with PDD, frontosubcortical changes are the main contributing factor to dementia, whereas in other patients, cortical and hippocampal changes are more important.     

Neuropathological distinction between Parkinson's dementia and Parkinson's plus Alzheimer's disease

The distinctive clinical features of dementia in Parkinson's disease (PDD) and Parkinson's plus Alzheimer's disease (PD + AD) suggest different patterns of cerebral atrophy in these conditions. To determine the pathoanatomical substrates of dementia in PDD and PD + AD, morphometric analysis of 5 standardized coronal slices was used to identify volumetric changes in cerebral tissue. In PDD (n = 4) there were 9 to 23% reductions in cross-sectional area of cerebral cortex, a 38% loss of tissue in the globus pallidus + putamen, and an 18% reduction in area of the amygdala, whereas in PD + AD (n = 6) there was severe global atrophy of the cerebral cortex (27-29% reductions), moderate atrophy of white matter (10-19% reductions), and 40% reductions in areas of globus pallidus + putamen and the amygdala relative to neuropathologically intact controls (n = 14). Immunostaining with anti-glial fibrillary acidic protein disclosed significant gliosis of all four major subdivisions of neocortex in PD + AD and gray matter of the caudate, putamen, globus pallidus, and thalamus in both PDD and PD + AD relative to controls. The findings suggest that dementia in PDD is mainly subcortical in origin and due to neuronal degeneration in basal ganglia, the amygdala, and thalamus. In PD + AD the same pattern and degree of subcortical degeneration is evident, but there are clearly superimposed lesions involving cortical neurons and long projection fibers coursing through cerebral white matter that most likely account for the distinctive manifestations of dementia in this condition compared with PDD.     

Clinical evaluation of Parkinson's disease dementia: association with aging and visual hallucination

OBJECTIVES: In order to explore factors associated with the development of dementia in Parkinson's disease (PD) and Dementia with Lewy bodies (DLB), we systematically investigated the clinical evaluation of PD and DLB patients hospitalized in the Department of Neurology at Tottori University Hospital, Japan. RESULTS: There were 208 patients diagnosed as having PD and 39 patients diagnosed with DLB in this study. Of the patients with PD, 67 (32%) developed dementia and only five PD+ patients were considered to have cognitive impairment attributable to Alzheimer's disease (AD) or vascular dementia (VaD). Fifty-four (81%) PDD patients had visual hallucinations (VH) with or without cognitive fluctuation. The onset age of parkinsonian motor symptoms of patients with PD dementia (PDD) did not differ from that of PD patients without dementia. There was a significant inverse correlation between the onset age of motor symptoms in PD and the onset of their dementia in PDD. Seventy-five (36%) patients with PD had experienced VH and most of the PDD patients had experienced VH within 1 year before or after diagnosis of PDD. CONCLUSIONS: These results indicate that aging and VH are important factors associated with dementia in PD.     

Dementia, gliosis and expression of the small heat shock proteins hsp27 and alpha B-crystallin in Parkinson's disease.

Cognitive impairment and dementia are common in the later stages of Parkinson's disease (PD). Neuropathological examination of demented PD (PDD) patients often reveals changes that are typical of Alzheimer's disease (AD). In AD, there is a massive reactive gliosis and increased expression of the small heat shock proteins (hsp) hsp27 and alpha B-crystallin. Since these proteins are characteristic for reactive astrocytes in AD, we investigated their expression in the brains of PDD patients. The results were compared with those obtained in the brains of non-demented PD patients. We found (1) no detectable expression of hsp in PD without dementia, and low expression in PD with mild dementia; (2) reactive gliosis and increased expression of hsp in the cortex of PDD brains; (3) a strong association between hsp immunoreactivity and the severity of the AD-specific changes, especially with the number of tangles in the hippocampus; (4) a distinct immunoreaction of alpha B-crystallin in microglia in the substantia nigra and in the hippocampus in PDD. These results indicate that astrocytes react to the disease conditions in AD and in PDD in a similar way, namely by the increased expression of small heat shock proteins, and present additional evidence for the thesis that the pathology of the dementia in PD is related to that in AD.     

Positive association between an estrogen receptor gene polymorphism and Parkinson's disease with dementia

Parkinson's disease (PD) is a common cause of dementia in the elderly. Dementia in Alzheimer's disease (AD) and PD share common biologic and clinical features. The estrogen receptor (ER) gene is one of the susceptibility genes for AD. In order to test the hypothesis that the overlap between AD and PD may have a genetic basis, we determined ER gene polymorphisms in 13 PD patients with dementia (PDD) (age +/- SD; 71.9 +/- 5.5 years), 71 PD patients without dementia (PDND) (68.4 +/- 7.5 years), 86 AD patients (76.8 +/- 8.0 years) and 51 control subjects (CTL) (74.9 +/- 6.9 years). ER genotypes were classified as a P or p allele on the basis of a Pvu II-RFLP, and X and x on the basis of a Xba I-RFLP. The frequency of the P allele in the PDD group as well as the AD group was higher than that in CTL. There was no significant difference in the distribution of the P allele between CTL and PDND. There were no significant differences in the distribution of the X allele among the PDD, PDND and CTL groups, whereas a higher incidence was found in AD. We conclude that the ER gene may be a common susceptibility gene for dementia in PD as well as AD.     

Mattis Dementia Rating Scale 2: screening for MCI and dementia

Identifying patients at higher risk of developing dementia is important. The usefulness of the Mattis Dementia Rating scale-Second Edition (MDRS-2) to detect and differentiate between patients with amnestic mild cognitive impairment (A-MCI), Parkinson's disease and MCI (PD-MCI), PD with dementia (PDD), and Alzheimer's disease (AD) was investigated. In all, 22 healthy controls (HC), 22 A-MCI, 22 PD-MCI, 16 PDD, and 22 AD patients were evaluated using an extensive neuropsychological battery, including the MDRS-2. The MDRS-2 total standardized score detected all groups of patients. The dementia groups performed worse than HC on the 5 MDRS-2 subscales. Alzheimer's disease patients scored higher than PDD on MDRS-2 conceptualization and lower on memory. Healthy controls were better than PD-MCI on MDRS-2 initiation/perseveration and memory and better than A-MCI on memory. No difference was found between the MCI groups. The MDRS-2 is a suitable short scale for MCI and dementia screening but is not specific enough to differentiate between A-MCI and PD-MCI.     

Heterogeneous factors in dementia with Parkinson's disease: IMP-SPECT study

BACKGROUND: Nature of the dementing process in Parkinson's disease, and particularly its relationship with Alzheimer's disease, diffuse Lewy body disease or frontal dementia remains controversial. OBJECTIVE: We hypothesize that origins of dementia in Parkinson's disease are heterogeneous, so we compared cortical regional cerebral blood flow (rCBF) between Parkinson's disease patients with and without dementia. PATIENTS: Forty consecutive patients with Hoehn-Yahr stage III or IV Parkinson's disease were used (13 patients had dementia (PDD group), and 27 patients had no dementia (PDND group)). RESULTS: There were significant rCBF reductions in the left parietal association cortex and left frontal association cortex in PDD. Multiple logistic regression analysis demonstrated that only rCBF of the left frontal association cortex was significant. PDD patients were divided into three groups according to rCBF patterns: frontal hypoperfusion group, Alzheimer's disease-like group, and diffuse Lewy body disease-like group. CONCLUSIONS: Controversial study results involving PDD patients may be mainly due to heterogeneity in dementing processes in Parkinson's disease.     

Cerebral glucose metabolism in Parkinson's disease with and without dementia.

Although cognitive impairment is commonly associated with Parkinson's disease, the relative importance of cortical and subcortical pathologic changes to the development of dementia is controversial. Characteristic abnormalities in cortical glucose metabolism have been reported previously in Alzheimer's disease, a disease in which cortical changes predominate. We measured cerebral glucose metabolism with positron emission tomography in 20 control subjects and in 14 patients with PD with mental status ranging from normal to severely demented to determine whether changes in cortical glucose metabolism occur in early PD and whether the degree and pattern of metabolic change relate to the severity of dementia. The patients were divided into demented and nondemented groups according to the results of neuropsychological assessment. Age-adjusted covariance analyses were performed, since the age distribution varied between groups. The nondemented patients with PD showed widespread cortical glucose hypometabolism without any selective temporoparietal defects. The pattern of glucose hypometabolism seen in the demented patients with PD resembled that described in patients with Alzheimer's disease; ie, there was a global decrease in glucose metabolism, with more severe abnormalities observed in the temporoparietal regions.     

Beta-amlyoid 1-42 and tau-protein in cerebrospinal fluid of patients with Parkinson's disease dementia

Measurement of tau-protein and beta-amyloid(1-42 )(Abeta42) in cerebrospinal fluid (CSF) has gained increasing acceptance in the differential diagnosis of Alzheimer's disease. We investigated CSF tau-protein and Abeta42 concentrations in 73 patients with advanced idiopathic Parkinson's disease with dementia (PDD) and 23 patients with idiopathic Parkinson's disease without dementia (PD) and in a comparison group of 41 non-demented neurological patients (CG) using commercially available enzyme-linked-immunoabsorbant-assay (ELISA). tau-Protein levels were statistically significantly higher and Abeta42 lower in the PDD patients compared to PD patients and the CG. This observation was most marked (p < 0.05) in a subgroup of patients with PDD carrying the apolipoprotein genotype epsilon3/epsilon3. The distribution of the apolipoprotein genotypes in PDD and PD patients was similar to that of the CG. Although a significant difference in tau-protein values was observed between PDD and CG, no diagnostic cut-off value was established. These findings suggest that such protein CSF changes may help to support the clinical diagnosis of cognitive decline in PD and that there may be apolipoprotein-E-isoform-specific differences in CSF protein regulation in advanced PDD.     

Cerebrospinal fluid ferritin levels of patients with Parkinson's disease, Alzheimer's disease, and multiple system atrophy

Summary Iron is believed to play a role in the pathogenesis of both Parkinson's disease (PD) and Alzheimer's disease (AD). We measured ferritin, which is considered to be the iron storage protein, in CSF of patients with PD, AD, and multiple system atrophy (MSA) as well as control subjects. We found a significant increase in CSF ferritin in AD compared with both PD and age-matched controls. No significant differences were found between PD patients with dementia (PDD) and non-demented PD patients. For non-demented PD patients a positive correlation between CSF ferritin and age was found. Our results may indicate that iron has a role in the pathophysiology of AD.     

Executive dysfunction in non-demented Parkinson's disease patients with hallucinations

Objective –  We investigated executive function in Parkinson's disease (PD) patients, and focused on executive dysfunction in PD with hallucinations, but without dementia.
Methods –  PD patients were classified by cognitive or neuropsychotic status as PD group, PD with vivid dreaming group, PD with hallucinations group and Parkinson's disease dementia (PDD) group. Psychomotor speed tests, the Stroop test, a verbal fluency test and the Self-rating Depression Scale were performed.
Results –  The PDD group showed poorer scores in every test compared with the PD group. The PD with hallucinations group showed results similar to those of the PDD group, while the PD with vivid dreaming group was similar to the PD group.
Conclusions –  The study suggests that PD patients with hallucinations, not extensive enough to qualify as dementia, already have executive dysfunction similar to that seen in PDD patients. Executive dysfunction may be an important substrate for hallucinations even when dementia is not yet apparent.     

A comparison of cerebral glucose metabolism in Parkinson's disease, Parkinson's disease dementia and dementia with Lewy bodies

Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB) share many similar aspects, and making a clinical diagnosis of one disorder over the other relies heavily on an arbitrary criterion, so-called 1-year rule. This study was designed to search for any difference of metabolic patterns in these two disorders using F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) images.
We enrolled 16 patients with PD, 13 patients with PDD, and seven patients with DLB. FDG PET was performed, and images were reconstructed by iterative reconstruction using the computed tomography (CT) images, and were normalized to a standard template. Statistical comparison between groups were performed on a voxel-by-voxel basis using t -statistics (two-sample t -test).
Compared with the patients with PD, both PDD and DLB patients showed similar patterns of decreased metabolism in bilateral inferior and medial frontal lobes, and right parietal lobe ( P _uncorrected < 0.001). In a direct comparison, DLB patients had significant metabolic decrease ( p _uncorrected < 0.005) in the anterior cingulate compared with those with PDD. These findings support the concept that PDD and DLB have similar underlying neurobiological characteristics, and that they can be regarded as a spectrum of Lewy body disorders.     

Rivastigmine in Alzheimer's disease and Parkinson's disease dementia: an ADAS-cog factor analysis

Rivastigmine treatment is associated with significant improvements on the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog) in patients with mild-to-moderate Alzheimer's disease (AD) and Parkinson's disease dementia (PDD). Both AD and PDD are purported to have different profiles of cognitive impairment, which may respond differentially to rivastigmine treatment. This was a retrospective analysis of 3 randomized, double-blind, rivastigmine trial databases (Investigation of transDermal Exelon in ALzheimer's disease [IDEAL; AD], EXelon in PaRkinson's disEaSe dementia Study [EXPRESS; PDD], and Alzheimer's Disease with ENA 713 [ADENA; AD]). Factor analyses of the 11 baseline ADAS-cog items derived the same factors in the 2 diseases, that is, "memory" and "language". Rivastigmine-treated AD and PDD patients showed significant improvements (P < .0001 versus placebo) on both factors. For both AD and PDD, rivastigmine had a numerically greater effect on memory than language. Treatment effect sizes were numerically greater in PDD compared with AD. Rivastigmine treatment is associated with improvement in memory and language in AD and PDD. The numerically greater response in PDD is consistent with greater cholinergic deficits in this disease state.     

Performance on the dementia rating scale in Parkinson's disease with dementia and dementia with Lewy bodies: comparison with progressive supranuclear palsy and Alzheimer's disease

BACKGROUND: The relation between dementia with Lewy bodies (DLB) and Parkinson's disease with dementia (PDD) is unknown. OBJECTIVES: To compare the cognitive profiles of patients with DLB and PDD, and compare those with the performance of patients with a subcortical dementia (progressive supranuclear palsy) and a cortical dementia (Alzheimer's disease). DESIGN: Survey of cognitive features. SETTING: General community in Rogaland county, Norway, and a university dementia and movement disorder research centre in the USA. PATIENTS: 60 patients with DLB, 35 with PDD, 49 with progressive supranuclear palsy, and 29 with Alzheimer's disease, diagnosed by either standardised clinical procedures and criteria (all PDD and Alzheimer cases and 76% of cases of progressive supranuclear palsy), or necropsy (all DLB cases and 24% of cases of progressive supranuclear palsy). Level of dementia severity was matched using the total score on the dementia rating scale adjusted for age and education. MAIN OUTCOME MEASURES: Dementia rating scale subscores corrected for age. RESULTS: No significant differences between the dementia rating scale subscores in the PDD and DLB groups were found in the severely demented patients; in patients with mild to moderate dementia the conceptualisation subscore was higher in PDD than in DLB (p = 0.03). Compared with Alzheimer's disease, PDD and DLB had higher memory subscores (p < 0.001) but lower initiation and perseveration (p = 0.008 and p=0.021) and construction subscores (p = 0.009 and p = 0.001). DLB patients had a lower conceptualisation subscore (p = 0.004). Compared with progressive supranuclear palsy, PDD and DLB patients had lower memory subscores (p < 0.001). CONCLUSIONS: The cognitive profiles of patients with DLB and PDD were similar, but they differed from those of patients with Alzheimer's disease and progressive supranuclear palsy. The cognitive pattern in DLB and PDD probably reflects the superimposition of subcortical deficits upon deficits typically associated with Alzheimer's disease.