Parkinson's Disease Dementia Cases Research Articles

Metallomic analysis of brain tissues distinguishes between cases of dementia with Lewy bodies, Alzheimer's disease, and Parkinson's disease dementia.

Dementia with Lewy bodies (DLB) can be difficult to distinguish from Alzheimer's disease (AD) and Parkinson's disease dementia (PDD) at different stages of its progression due to some overlaps in the clinical and neuropathological presentation of these conditions compared with DLB. Metallomic changes have already been observed in the AD and PDD brain-including widespread decreases in Cu levels and more localised alterations in Na, K, Mn, Fe, Zn, and Se. This study aimed to determine whether these metallomic changes appear in the DLB brain, and how the metallomic profile of the DLB brain appears in comparison to the AD and PDD brain. Brain tissues from ten regions of 20 DLB cases and 19 controls were obtained. The concentrations of Na, Mg, K, Ca, Zn, Fe, Mn, Cu, and Se were determined using inductively coupled plasma-mass spectrometry (ICP-MS). Case-control differences were evaluated using Mann-Whitney U tests. Results were compared with those previously obtained from AD and PDD brain tissue, and principal component analysis (PCA) plots were created to determine whether cerebral metallomic profiles could distinguish DLB from AD or PDD metallomic profiles. Na was increased and Cu decreased in four and five DLB brain regions, respectively. More localised alterations in Mn, Ca, Fe, and Se were also identified. Despite similarities in Cu changes between all three diseases, PCA plots showed that DLB cases could be readily distinguished from AD cases using data from the middle temporal gyrus, primary visual cortex, and cingulate gyrus, whereas DLB and PDD cases could be clearly separated using data from the primary visual cortex alone. Despite shared alterations in Cu levels, the post-mortem DLB brain shows very few other similarities with the metallomic profile of the AD or PDD brain. These findings suggest that while Cu deficiencies appear common to all three conditions, metal alterations otherwise differ between DLB and PDD/AD. These findings can contribute to our understanding of the underlying pathogenesis of these three diseases; if these changes can be observed in the living human brain, they may also contribute to the differential diagnosis of DLB from AD and/or PDD.

Sensitivity of Clock Drawing Test Alone to Screen for Cognitive Impairment in Patients with Parkinson's Disease.

Cognitive impairment is a prevalent non-motor symptom of Parkinson's disease (PD), significantly impacting patient quality of life. The Clock Drawing Test (CDT) evaluates cognitive abilities, including planning, organization, and executive functions such as attention, memory, and visuospatial skills. This study aimed to determine the sensitivity of the CDT in diagnosing cognitive impairment in PD. We reviewed the records of 44 PD patients (16 female, 28 male) diagnosed with dementia (30 patients) or mild cognitive impairment (14 patients) between 2018 and 2022. These patients were compared to 106 visitors to the neurological outpatient clinic, serving as a control group. A separate researcher assessed the patients' CDT scores, maintaining confidentiality of all other patient data except age and education level. Among the 44 PD patients, two with mild cognitive impairment were rated as normal, while all PD dementia cases were identified solely through the CDT. In the healthy control group, 72 out of 106 individuals reported no cognitive complaints, whereas 34 individuals (32.1%) reported cognitive complaints as assessed by a blind investigator. The CDT demonstrated a positive predictive value of 55.3% and a negative predictive value of 97.3%. Sensitivity was calculated at 95.5%, and specificity was 67.9%. The findings suggest that the CDT is sensitive in detecting cognitive impairment in PD patients with cognitive deficits. While the CDT serves as an effective rapid screening tool, high scores indicate the absence of cognitive impairment, but low scores alone are insufficient for a definitive diagnosis of dementia. Comprehensive neurological evaluation and detailed cognitive assessment remain essential for confirming dementia diagnoses.

The association of APOE ‐ε4 with clinicopathological, cognitive, neuropsychiatric, and neuroimaging features in α‐synucleinopathies

The ε4-allele of apolipoprotein E (APOE-ε4) presents an elevated risk not only for Alzheimer's disease (AD), but also for Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB). Indeed, the independent influence of APOE-ε4 on the promotion and exacerbation of α-synuclein pathology has recently been suggested. However, the precise phenotypic associations of APOE-ε4 in α-synucleinopathies are variable. The primary objective of this first, comprehensive systematic review was to identify biomarkers, phenotypes, or other clinicopathological characteristics that reliably associate with APOE-ε4 in α-synucleinopathies [Parkinson's disease (PD), DLB, PDD, and multiple system atrophy (MSA)], which may in turn uncover important pathophysiological mechanisms.Electronic databases were systematically searched from January 1st , 1995 through December 31st , 2020, as per the PRISMA guidelines. Studies evaluating the association of APOE-ε4 with clinicopathological, cognitive, neuropsychiatric, and neuroimaging phenotypes in clinically and/or pathologically diagnosed cases of PD, PDD, DLB, and MSA cases were reviewed.A total of 136 studies were eligible for inclusion (Figure). APOE-ε4 was found to be consistently associated with: 1) lower cerebrospinal fluid levels of amyloid-β 1-42 in PDD and DLB, 2) cognitive deficits in the memory domain in PD, PDD, and DLB, 3) mediotemporal cortical atrophy primarily in DLB, 3) cerebral amyloid angiopathy, shorter survival, and accelerated decline in global cognition in DLB, as well as 4) the co-occurrence of AD-type neuropathological features. Furthermore, APOE-ε4 was associated, albeit inconsistently, with: 1) the presence and severity of diffuse neocortical Lewy body pathology and, 2) elevated tracer retention on amyloid positron emission tomography in PD, PDD, and DLB, 3) greater odds of dementia in PD, and 4) other genetic and pathophysiological factors to enhance the cumulative risk for DLB. APOE-ε4 was not associated with disease risk or α-synuclein pathology in MSA. Studies also highlighted the relationship of APOE-ε4 with neuropsychiatric, epigenetic (DNA methylation), sleep, immunohistochemical, and biochemical factors in α-synucleinopathies, which will be presented.In addition to its role in AD, APOE-ε4 influences the disease presentation and progression particularly in PDD and DLB. Guided by reliable biomarkers, further research to unravel the underlying mechanisms will assist in developing early prevention strategies targeting the APOE protein.

Differential blood DNA methylation across Lewy body dementias.

IntroductionDementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) are characterized by cognitive alterations, visual hallucinations, and motor impairment. Diagnosis is based on type and timing of clinical manifestations; however, determination of clinical subtypes is challenging. The utility of blood DNA methylation as a biomarker for Lewy body disorders (LBD) is mostly unexplored.MethodsWe performed a cross‐sectional analysis of blood methylation in 42 DLB and 50 PDD cases applying linear models to compare groups and logistic least absolute shrinkage and selection operator regression to explore the discriminant power of methylation signals.ResultsDLB blood shows differential methylation compared to PDD. Some methylation changes associate with core features of LBD. Sets of probes show high predictive value to discriminate between variants.DiscussionOur study is the first to explore LBD blood methylation. Despite overlapping clinical presentation, we detected differential epigenetic signatures that, if confirmed in independent cohorts, could be developed into useful biomarkers.

Alzheimer's disease pathology explains association between dementia with Lewy bodies and APOE-ε4/TOMM40 long poly-T repeat allele variants

IntroductionThe role of TOMM40-APOE 19q13.3 region variants is well documented in Alzheimer's disease (AD) but remains contentious in dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD). MethodsWe dissected genetic profiles within the TOMM40-APOE region in 451 individuals from four European brain banks, including DLB and PDD cases with/without neuropathological evidence of AD-related pathology and healthy controls. ResultsTOMM40-L/APOE-ε4 alleles were associated with DLB (ORTOMM40-L = 3.61; P value = 3.23 × 10−9; ORAPOE-ε4 = 3.75; P value = 4.90 × 10−10) and earlier age at onset of DLB (HRTOMM40-L = 1.33, P value = .031; HRAPOE-ε4 = 1.46, P value = .004), but not with PDD. The TOMM40-L/APOE-ε4 effect was most pronounced in DLB individuals with concomitant AD pathology (ORTOMM40-L = 4.40, P value = 1.15 × 10−6; ORAPOE-ε4 = 5.65, P value = 2.97 × 10−8) but was not significant in DLB without AD. Meta-analyses combining all APOE-ε4 data in DLB confirmed our findings (ORDLB = 2.93, P value = 3.78 × 10−99; ORDLB+AD = 5.36, P value = 1.56 × 10−47). DiscussionAPOE-ε4/TOMM40-L alleles increase susceptibility and risk of earlier DLB onset, an effect explained by concomitant AD-related pathology. These findings have important implications in future drug discovery and development efforts in DLB.

Association Between Pathology and Electroencephalographic Activity in Parkinson's Disease.

The key mechanisms that connect Parkinson's disease pathology with dementia are unclear. We tested the hypothesis that the quantitative spectral electroencephalographic measure, delta bandpower, correlates with Lewy type synucleinopathy on pathological examination in Parkinson's disease. As a corollary hypothesis, we analyzed whether there would be delta bandpower electroencephalographic differences between Parkinson's disease dementia cases with and without pathological criteria for Alzheimer's disease. We used pathological examination results from 44 Parkinson's disease subjects from our brain bank with various degrees of cognitive decline, who had undergone electroencephalography. Pathological grading for Lewy type synucleinopathy, plaques, tangles, and indications of vascular pathology in subcortical and cortical areas were correlated with the most associated electroencephalographic biomarker with Parkinson's disease dementia in our laboratory, delta bandpower. Group differences for all spectral electroencephalographic measures were also analyzed between cases with and without pathological criteria for Alzheimer's disease. Findings revealed significant correlations between delta bandpower with Lewy type synucleinopathy, whereas indications of Alzheimer's disease or vascular pathology had nonsignificant correlation. The strongest association was with delta bandpower and Lewy type synucleinopathy in the anterior cingulate region. Mean delta bandpower was higher in the group for Parkinson's disease dementia with Alzheimer's disease pathology criteria than without. Lewy type synucleinopathy severity appears to be more associated with increased delta bandpower than with Alzheimer's disease pathology or indications of vascular pathology over all cases. However, the presence of Alzheimer's pathology may associate with more cortex physiological disruption in a subset of cases.

QUANTIFICATION OF PATHOLOGICAL LESIONS DETECTS CLINICOPATHOLOGICAL PHENOTYPES OF MIXED AD/LBD

Dementing disorders are defined neuropathologically by their most prevalent pathology. However, some brains of demented subjects show high burdens of neuropathological hallmark lesions of more than one disease. Cases that neuropathologically fulfil criteria for both Alzheimer's disease (AD) and Lewy body disease (LBD - Dementia with Lewy bodies (DLB) or Parkinson's disease dementia (PDD)) are classified as mixed AD/LBD. Using semi-quantitative scoring, no differences were detected in mixed AD/LBD between cases that presented clinically with AD or LBD. We investigated whether a quantitative approach could reveal differences in the amounts of AD and LBD pathology in mixed AD/LBD cases. 19 mixed AD/LBD cases, which presented clinically as AD (n=8), DLB (n=8) or PDD (n=3), 5 pure AD and 5 pure DLB cases (mean age 75.26 +/- 9.1 years) were stained for antibodies against tau, β amyloid and α-synuclein and percentage burden of each pathology was quantified in neocortical, limbic and brainstem regions. Differences in the burden of pathology between clinically AD and LBD in various regions were detected quantitatively, as a significant increase in the amount of tau pathology was observed in the hippocampus (p<0.05), striatum (p<0.05), neocortex (p<0.05) and locus coeruleus (p<0.01) in clinically AD compared to LBD patients, respectively. When compared against the PDD phenotype, clinically AD cases have greater burden of tau pathology in the majority of areas analysed. Of note, we found an increase of α-synuclein in the substantia nigra of clinically AD and DLB cases compared to clinically PDD cases. When comparing neuropathologically mixed AD/LBD with pure AD and DLB cases we observed an increase in all 3 protein aggregates in the substantia nigra in the mixed AD/LBD group. Moreover, we found a significant correlation between hyperphosphorylated tau and α synuclein (p<0.01 and R 2 =0.616) in mixed AD/LBD group. Our findings suggest that cases neuropathologically diagnosed as mixed AD/LBD can be separated into different clinico-pathological phenotypes when quantitative neuropathological methods are applied. However, the question whether clinical diagnosis reflects the primary underlying pathology, which may be confounded by concomitant pathologies, warrants further investigation.

P4‐018: Biochemical correlates of clinical symptoms in dementia with Lewy bodies and Parkinson's disease dementia

Dementia with Lewy bodies (DLB) and Parkinson's Disease Dementia (PDD) are common causes of dementia. The biochemical basis of cognitive and psychiatric symptoms of these conditions remains poorly understood. Synaptic dysfunction is hypothesised to be a major correlate of cognitive dysfunction and to contribute to specific psychiatric symptoms, therefore alterations in key synaptic proteins have been investigated. A cohort of 98 PDD and DLB brains, significantly larger than most previous studies, with 28 control brains and a depth of supporting clinical data was available for study. Semi-quantitative Western blotting was used to investigate the levels of key synaptic proteins: zinc transporter (ZnT3, implicated in mouse models to be involved in age-dependent memory loss), PSD95 (an important regulator of post-synaptic neurotransmitter receptors), beta-III-tubulin (a cytoskeletal neuronal marker) and specific markers of vesicle release and recycling such as synaptophysin (SPP, presynaptic vesicle protein), syntaxin1 (transmembrane SNARE protein), Munc18 (vesicle docking regulator) and dynamin1 (vesicle endocytosis regulator) in two cortical regions. Measurements made in the prefrontal cortex (BA9) of PDD and control cases indicate decreases in the levels of the following synaptic proteins in PDD cases; ZnT3 (-57%), PSD-95 (-54%), synaptophysin (-34%), Munc18 (-34%), Dynamin1 (-41%), and beta-III-tubulin (-18%). PSD95 and ZnT3 were decreased in DLB compared to control (both -47%). All changes were statistically significant (ANOVA P<0.05, DLB n = 22-50, PDD n = 25-32, control n = 10-24). No significant changes were found in BA24, except for Munc18 expression decreased in PDD group compared to DLB group (-23%). Furthermore, a negative correlation was found between SPP levels in BA9 and depression and agitation/aggression (NPI) scores; Munc18 levels in BA9 and BA24 positively correlate with hallucinations scores. Our data suggest a greater synaptic dysfunction in processes of vesicle docking, neurotransmitter release and reuptake in BA9 of PDD cases. The similarities in prefrontal ZnT3 and PSD95 levels could be related to a common underlying cause or that zinc released synaptically has an influence the post-synaptic density. It would appear that some of the behavioural symptoms associated with DLB/PDD may be linked to synaptic dysfunction in the prefrontal cortex and may suggest novel treatment strategies.

Short latency afferent inhibition in Parkinson's disease patients with dementia

Cortical cholinergic deficiency occurs in Parkinson's disease (PD) and is more severe in PD dementia (PDD). Short-latency afferent inhibition (SAI) can be used as an in vivo test for the evaluation of the cholinergic circuit in the cerebral motor cortex. SAI and neuropsychological profile were studied in nondemented PD, PDD, Alzheimer's disease (AD) patients, and age-matched controls. SAI was significantly impaired in AD cases (94.7 ± 6.2 versus 55.5 ± 4.0; P < 0.0001). In PD patients, it was not different from controls (61.4 ± 5.8 versus 55.5 ± 4.0; P = 0.412). PDD cases demonstrated a significant impairment in SAI (91.4 ± 5.2 versus 55.5 ± 4.0; P < 0.0001). A high correlation was found between SAI and Mini-Mental State Examination (r = -0.68; P < 0.0001). These findings add further evidence that differential cholinergic deficiency occurs in PD and PDD. SAI can be a neurophysiological correlate of PDD.

Clinical validation of movement disorder society–recommended diagnostic criteria for Parkinson's disease with dementia

The objective of this work was to evaluate the Movement Disorders Society (MDS) Task Force-proposed screening checklist for detecting Parkinson's disease dementia (PD-D) in relation to full neuropsychological testing. An MDS Task Force has proposed diagnostic procedures for PD-D, which have not been fully validated against more extensive neuropsychological testing. PD subjects were recruited from 2 specialty centers. A neuropsychologist evaluated them for dementia as part of routine clinical care. Independent clinical neurologists administered the MDS PD-D screening checklist. Diagnosis of PD-D by the 2 methods was compared. Ninety-one PD subjects had a mean age of 66.3 (SD = 9.7) years and a mean PD duration of 8.8 (SD = 6.1) years. Seven subjects (7.7%) met all 8 screening checklist criteria from the MDS PD-D screening tool and were classified as probable PD-D. Fifteen (16.5%) subjects were classified as PD-D by full neuropsychological assessment. The screening checklist showed 100% specificity, but only 46.7% sensitivity, for diagnosing PD-D compared to the full neuropsychological assessment. PD-D cases missed by the PD-D screening tool were largely due to 2 checklist items that were not endorsed (absence of depression and Mini-Mental State Examination [MMSE] scores <26). There was moderate agreement between these 2 methods for determination of PD-D (kappa = 0.59, P < .001). The MDS-PD-D screening checklist is highly accurate for detecting PD-D if all items are endorsed. However, for cases that do not meet these criteria, full neuropsychological testing is needed to differentiate PD-D from milder cognitive impairment. Revision of the checklist by altering or eliminating the 2 problematic checklist items may improve sensitivity.

Distribution of cerebral amyloid deposition and its relevance to clinical phenotype in Lewy body dementia

Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB) are clinically distinguished based only on the duration of parkinsonism prior to dementia. It is known that there is considerable pathological overlap between these two conditions, but the pathological difference between them remains unknown. We evaluated Alzheimer-type pathology in 30 brains of patients with Lewy body dementia using standardized methods based on those of the Brain-Net Europe (BNE) Consortium. Only 2 of 13 PDD cases (15%) showed Aβ-immunoreactive pathology in the midbrain (amyloid phase IV). In contrast, 12 of 17 DLB cases (71%) exhibited midbrain involvement. Four of the DLB cases (24%) but none of the PDD cases exhibited Aβ-immunoreactive pathology in the cerebellum (amyloid phase V). The ratio of cases with subtentorial involvement of amyloid deposition was significantly higher in DLB than in PDD. The median of amyloid phases was significantly greater in DLB than in PDD, but there was no difference in neurofibrillary tangle (NFT) Braak stages or in Lewy body scores. When patients were classified according to whether dementia or parkinsonism had occurred first, the rate of dementia having occurred first was significantly greater in amyloid phase IV and V than in phase 0–I, with phase III in the middle, though there was no significant difference in median NFT Braak stage or mean Lewy body score associated with amyloid phase. These results suggest that amyloid deposition may contribute to the timing of the onset of dementia relative to that of parkinsonism in Lewy body dementia.