Parkinson's Disease Dementia Patients Research Articles

Lipid metabolic dysregulation is involved in Parkinson's disease dementia.

Dementia is very common in the late stage of patient with Parkinson's disease (PD). We aim to explore its underlying pathogenesis and identify candidate biomarkers using untargeted metabolomics analysis. Consecutive PD patients and healthy controls were recruited. Clinical data were assessed and patients were categorized into Parkinson's disease without dementia (PDND) and Parkinson's disease dementia (PDD). Fast plasma samples were obtained and untargeted liquid chromatography-mass spectrometry-based metabolomics analysis was performed. Based on the identified differentially-expressed metabolites from the metabolomics analysis, multivariate linear regression analyses and receiver operating characteristic (ROC) curves were further employed. According to the clinical data, the mean ages of PDND and PDD patients were significantly higher than those of healthy controls. The incidence of hypercholesterolemia was decreased in PDD patients. PDD patients also had lower levels of triglyceride, low-density lipoprotein cholesterol, and apolipoprotein B. There were 24 and 57 differentially expressed metabolites in PDD patients when compared with the healthy controls and PDND patients from the metabolomics analysis. Eleven lipid metabolites were simultaneously decreased between these two groups, and can be further subcategorized into fatty acyls, glycerolipids, glycerophospholipids, sphingolipids, and prenol lipids. The plasma levels of the eleven metabolites were positively correlated with MMSE score and can be candidate biomarkers for PDD patients with areas under the curve ranging from 0.724 to 0.806 based on the ROC curves. Plasma lipoproteins are significantly lower in PDD patients. A panel of eleven lipid metabolites were also decreased and can be candidate biomarkers for the diagnosis of PDD patients. Lipid metabolic dysregulation is involved in the pathogenesis of Parkinson's disease dementia.

Effect of cognitive reserve on cognition function in Parkinson's disease: A PRISMA-compliant meta-analysis

Background: Previous studies showed inconsistent results for the correlation between cognitive reserve (CR) and cognitive function in Parkinson's disease (PD). Additionally, conflicting results were obtained for the association between CR and risk of longitudinal cognitive decline, longitudinal progression to mild cognitive impairment (MCI) and longitudinal progression to dementia in PD patients. Thus, a meta-analysis is essential to summary these inconsistent results.

Differential Circulating Levels of Naturally Occurring Antibody to α-Synuclein in Parkinson's Disease Dementia, Alzheimer's Disease, and Vascular Dementia.

Background: Aggregation of alpha-synuclein (α-Syn) is considered to be a significant pathological hallmark and a driving force of Parkinson’s disease (PD). PD dementia (PDD) occurs in a substantial number of PD patients. Naturally occurring antibody against α-Syn (NAb-α-Syn) exists ubiquitously in human blood and is reported to be altered in PD. However, it is not clear yet whether PDD had similar changes of circulating NAb-α-Syn.Methods: In this study, we recruited 61 PDD patients, 52 patients with Alzheimer’s disease (AD), 51 patients with vascular dementia (VaD), and 50 normal controls (NCs). ELISA was used to examine NAb-α-Syn levels in serum.Results: In comparison with NCs, serum levels of NAb-α-Syn were significantly lower in patients with PDD. However, serum levels of NAb-α-Syn were comparable among AD, VaD, and NC groups. Serum levels of NAb-α-Syn were positively correlated with the cognitive function, as reflected by Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA). Serum levels of NAb-α-Syn were negatively correlated with the severity of PD [as reflected by the Unified Parkinson Disease Rating Scale (UPDRS)] and the duration of PD and PDD. Serum NAb-α-Syn can differentiate PDD patients from AD and VaD patients.Conclusion: These results suggest that circulating NAb-α-Syn might be a potential biomarker of PDD.

Nasal chemosensory tests: biomarker between dementia with Lewy bodies and Parkinson disease dementia.

Dementia with Lewy bodies (DLB) and Parkinson disease dementia (PDD) are progressive and disabling neurodegenerative disorders, which are often misdiagnosed due to theirs overlapping clinical and paraclinical features. Nevertheless, their adequate management requires an accurate differential diagnosis. The main aim of this study was to investigate the usefulness of olfactory and trigeminal nasal testing for the differential diagnosis between DLB and PDD. Odor thresholds to three odorants differentially activating the olfactory and trigeminal systems were assessed in patients with DLB, PDD and healthy controls (n = 20 per group). Odor thresholds were significantly different between the three groups of subjects. More precisely, we found that DLB patients had significantly lower detection threshold performances compared to PDD patients. Moreover, using a standard canonical discriminant analysis, we confirmed a plain differentiation between the three groups. The current study highlights that DLB patients have very poor olfactory and trigeminal detection threshold performances, which are significantly lower, compared to PDD patients. These results suggest that olfactory testing, using odorants that stimulate both the olfactory and trigeminal systems, could constitute an interesting biomarker and contribute to the differential diagnosis of PDD and DLB patients. Further researches, notably on olfacto-trigeminal interactions, are warranted in these populations to support our findings.

Resting state activity and connectivity of the nucleus basalis of Meynert and globus pallidus in Lewy body dementia and Parkinson's disease dementia

Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB) are two related diseases which can be difficult to distinguish. There is no objective biomarker which can reliably differentiate between them. The synergistic combination of electrophysiological and neuroimaging approaches is a powerful method for interrogation of functional brain networks in vivo. We recorded bilateral local field potentials (LFPs) from the nucleus basalis of Meynert (NBM) and the internal globus pallidus (GPi) with simultaneous cortical magnetoencephalography (MEG) in six PDD and five DLB patients undergoing surgery for deep brain stimulation (DBS) to look for differences in underlying resting-state network pathophysiology. In both patient groups we observed spectral peaks in the theta (2–8 Hz) band in both the NBM and the GPi. Furthermore, both the NBM and the GPi exhibited similar spatial and spectral patterns of coupling with the cortex in the two disease states. Specifically, we report two distinct coherent networks between the NBM/GPi and cortical regions: (1) a theta band (2–8 Hz) network linking the NBM/GPi to temporal cortical regions, and (2) a beta band (13–22 Hz) network coupling the NBM/GPi to sensorimotor areas. We also found differences between the two disease groups: oscillatory power in the low beta (13–22Hz) band was significantly higher in the globus pallidus in PDD patients compared to DLB, and coherence in the high beta (22–35Hz) band between the globus pallidus and lateral sensorimotor cortex was significantly higher in DLB patients compared to PDD. Overall, our findings reveal coherent networks of the NBM/GPi region that are common to both DLB and PDD. Although the neurophysiological differences between the two conditions in this study are confounded by systematic differences in DBS lead trajectories and motor symptom severity, they lend support to the hypothesis that DLB and PDD, though closely related, are distinguishable from a neurophysiological perspective.

CAN DEEP BRAIN STIMULATION BE A THERAPEUTIC OPTION FOR DEMENTIA FROM PARKINSON'S DISEASE?

Parkinson's disease is a brain ailment that results in unintentional or uncontrollable movements, such as shaking, rigidity, and problems with balance and coordination. The objective of this report to review of the clinical outcomes of deep brain stimulation in Parkinson's disease dementia patients, and discuss if deep brain stimulation could be a treatment alternative in these people. After surgery, all patients' motor symptoms improved significantly, as did some non-motor symptoms. However, in four patients, the motor gains lasted only 2 or 3 years before the patients deteriorated with the appearance of end-stage difficulties, despite the fact that there were more continuous benefits that could not have been attained with medical treatment. The surviving patient had a great response till the final follow-up, 7 years following surgery.

High discriminatory ability of peripheral and CFSF biomarkers in Lewy body diseases.

Differential diagnosis between Parkinson's disease (PD) Parkinson's disease dementia (PDD), dementia with Lewy bodies (DLB), namely spectrum of Lewy bodies disorders (LBDs), may be challenging, and their common underlying pathophysiology is debated. Our aim was to examine relationships among neurodegenerative biomarkers [alpha-synuclein (α-Syn), Alzheimer's Disease (AD)-related (beta-amyloid Aβ42, tau [total τΤ and phosphorylated τp-181]), dopaminergic imaging (DATSCAN-SPECT)] and spectrum of LBD. This is a cross-sectional prospective study in 30 PD, 18 PDD, 29 DLB patients and 30 healthy controls. We compared α-Syn in CSF, plasma and serum and CSF Aβ42, τΤ and τp-181 across these groups. Correlations between such biomarkers and motor, cognitive/neuropsychiatric tests, and striatal asymmetry indexes were examined. CSF α-Syn was higher in DLB versus PD/PDD/controls, and lower in PD and PDD patients compared to controls (all p < 0.001). Serum α-Syn levels were higher in all patient groups compared to controls. After excluding those DLB patients with CSF AD profile, plasma and serum Syn levels were higher in the LBD group as a whole compared to controls. The combination of CSF α-Syn, serum α-Syn and Aβ42 for comparison between PD and DLB [AUC = 0.96 (95% CI 0.90-1.00)] was significantly better when compared to serum α-Syn alone (p < 0.001). Correlation analyses of biomarkers with cognitive/neuropsychiatric scales revealed some associations, but no consistent, cohesive picture. Peripheral biomarkers such as serum α-Syn, and CSF α-Syn and Aβ42 may contribute as potential biomarkers to separate LBDs from controls and to differentiate DLB from the other LBDs with high sensitivity and specificity among study groups.

Abstracts of the German Congress on Parkinson\u2019s Disease and Movement Disorders (Deutscher Kongress f\xfcr Parkinson und Bewegungsst\xf6rungen), 7\u20139 March 2019, D\xfcsseldorf, Germany

Background While the efficacy of cognitive stimulation (CS) has been demonstrated in patients with dementia, no study has included patients with Parkinson's disease dementia (PDD). Objective For the first time, this randomized crossover pilot study examined the feasibility and potential effects of CS in PDD. Methods All residents of a PDD-specific long-term care unit in the Netherlands that were eligible for the study (n=12) were randomly allocated to group A (n=6) receiving CS (eight weeks, twice weekly for 60 minutes) or group B (n=6) receiving usual care (control group, CG). The CG participated in CS afterwards, resulting in an experimental group (EG), consisting of n=12. Pre- and postassessments and a six-week follow-up (FU) were conducted for cognition, neuropsychiatric symptoms, quality of life (QoL), and activities of daily living (ADL) outcomes. Results Between-group analysis with difference scores from pre- to posttest revealed a group difference for global cognition (CERAD total score) favoring the EG, with a moderate effect size and a p value just failing to reach statistical significance (p=0.067; r = 0.43). A further statistical trend was observed for neuropsychiatric symptoms, again with a moderate effect size (p=0.075; r = 0.42). Within-group analyses indicated improvement only in the EG with large effects also just failing to reach significance for global cognition (short term, p=0.060; r = 0.70) as well as for depression (long term, p=0.072; r = 0.61). ADL deteriorated significantly at FU in the EG (p=0.014; r = 0.71). Conclusions Although our data are preliminary due to the small sample size, this study shows that CS is feasible and potentially effective for cognitive and noncognitive outcomes in PDD patients. Randomized controlled trials with larger sample sizes are needed to confirm these promising results.

Predictors of dementia-free survival after bilateral subthalamic deep brain stimulation for Parkinson's disease.

Bilateral subthalamic nucleus deep brain stimulation (STN DBS) improves motor complications and quality of life (QOL) in patients with Parkinson's disease (PD). However, it does not delay or prevent the occurrence of dementia. The deleterious effects of dementia on QOL and activities of daily living (ADL) underscore the importance of identifying predictors of dementia-free survival in PD patients considered for STN DBS. The baseline clinical and neuropsychological data and the occurrence of dementia recorded during the longitudinal follow-up of a cohort of patients with PD with at least 2 years follow-up after bilateral STN DBS, were reviewed. One hundred and sixteen patients operated between 1999 to 2014 satisfied the inclusion criteria. Their mean age was 56.5 (±10) years and the mean duration of PD at surgery was 11.2 (±4.2) years. During the 542 person-years of follow-up, 30 patients developed dementia. The mean dementia-free survival after surgery was 8.7 [95% confidence interval (CI): 7.8-9.6] years. In univariate analysis, the baseline factors of older age, longer disease duration, past history of depression or psychosis, freezing of gait in OFF phase, worse ADL scores in ON phase, lower levodopa response of the Unified Parkinson's Disease Rating Scale (UPDRS) III axial sub-scores, and poor performances in the Addenbrooke's Cognitive Examination and Wisconsin Card Sorting Test (WCST) were associated with a shorter dementia-free survival. Among these, only freezing of gait and poor performance in WCST were independent predictors. Presence of freezing of gait in the drug OFF state and executive dysfunction predict the occurrence of earlier dementia in PD patients who otherwise qualify for bilateral STN DBS.

An Informant-Based Simple Questionnaire for Language Assessment in Neurodegenerative Disorders

Background/Aims: Language dysfunction is a crucial feature of brain disorders. This study investigated language dysfunction in patients with dementia with or without parkinsonism by using an informant-based simple questionnaire. Methods: Language dysfunction in normal controls (NCs), and patients with Parkinson disease (PD), Parkinson disease dementia (PDD), dementia with Lewy bodies (DLB), or Alzheimer disease (AD) were analyzed and compared. Results: A total of 1,662 individuals were studied: 285 NCs, 157 PD patients, 161 PDD patients, 248 DLB patients, and 811 AD patients. Patients with PD displayed higher frequency of language dysfunction in several language domains than NC. Patients with PDD and DLB showed higher frequency of language dysfunction in most of the language domains than those with AD. A composite score of our simple questionnaire was comparable with the score for the language domain of the Cognitive Abilities Screening Instrument (CASI) in different stages of dementia due to Lewy body diseases or not. Conclusion: Our study showed that the informant-based simple questionnaire is a practical screening tool and is comparable with the language subscale of CASI. This tool can be applied in clinical practice and in the registration platform for rapid language dysfunction screening.

No Significant Difference in Cognitive Decline and Mortality between Parkinson's Disease Dementia and Dementia with Lewy Bodies: Naturalistic Longitudinal Data from the Swedish Dementia Registry.

Whether dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) are distinct disorders or two subtypes of the same entity, is not yet fully understood. There is a dearth of knowledge on differences in longitudinal clinical outcomes between DLB and PDD. We aimed to compare longitudinal trend of cognitive decline, mortality, and their determinant factors between patients with DLB and PDD. At baseline, we recruited 1110 DLB, and 764 PDD patients registered in the Swedish dementia registry (SveDem) during 2007-2015. Cognitive status was assessed at baseline and each follow-up visit by mini-mental state examination (MMSE). At least one follow-up MMSE was available for 411 (37.0%) DLB and 229 (30.0%) PDD patients. Rate of cognitive decline and mortality risk were compared between the two groups. After an average of 2-years, the rate of cognitive decline did not differ between DLB (1.1 MMSE unit/year) and PDD (1.2 MMSE unit/year) groups (p = 0.970). There was no significant difference in the median survival time between DLB (4.0 years) and PDD (4.1 years) groups (Log rank p = 0.614). Antipsychotic drug use in DLB and larger number of medications in PDD were the most important determinants of faster annual cognitive decline. Our findings from real-world clinical practice demonstrated that the rate of cognitive decline and mortality do not differ significantly between DLB and PDD at least over 2 years, yet, various factors might determine clinical outcome in these two groups. It seems that DLB and PDD are probably similar synucleinopathies, with phenotypical variations in the order of manifestations rather than course of progression and clinical outcome.

Heart rate variability and its influencing factors in patients with dementia with Lewy bodies and patients with Parkinson disease dementia

Objective To compare the difference in heart rate variability(HRV)between patients with dementia with Lewy bodies(DLB)and those with Parkinson disease dementia(PDD)and to identify the influencing factors. Methods We retrospectively enrolled 30 patients with DLB(DLB group)and 41 patients with PDD(PDD group)at the outpatient and inpatient services of our hospital from January 2010 to December 2017 in this study, and further recruited 119 normal elderly individuals to serve as the control group.HRV was recorded with 24 h dynamic electrocardiogram and compared between the DLB group and the PDD group.Time domain measures including standard deviation of all normal to normal(NN)intervals(SDNN)and square root of the mean squared differences of successive NN intervals(rMSSD)and frequency domain measures including total power(TP), low frequency(LF), and high frequency(HF)were analyzed with a customized program.The levodopa equivalent dose(LED), mini-mental state examination(MMSE), Montreal Cognitive Assessment(MoCA), Hoehn-Yahr stage(H-Y stage)and the unified Parkinson's disease rating scale Ⅲ(UPDRS Ⅲ), and the Alzheimer's disease Cooperative Study-Activities of Daily Living scale(ADCS-ADL)were assessed in DLB and PDD patients to investigate the influencing factors. Results SDNN, TP, and LF in the DLB group and the PDD group were significantly lower than in the control group(F=14.154, 4.742, 4.897, P 0.05). The DLB group and the PDD group did not differ in HF from the control group(P>0.05). There was no significant difference in any HRV indexes between DLB and PDD patients(P>0.05). Correlation analysis showed no correlation of HRV with cognitive level(MMSE, MoCA), motor disturbance degree(UPDRS Ⅲ, H-Yahr stage), daily living ability(ADCS-ADL), or dosage of anti-PD drugs(each P>0.05). Conclusions DLB and PDD patients present similar impairments in autonomic nervous system function, which are not associated with disease severity. Key words: Dementia; Lewy bodies; Parkinson disease; Heart rate variability

Cerebrospinal fluid markers analysis in the differential diagnosis of dementia with Lewy bodies and Parkinson's disease dementia.

Dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) share a couple of clinical similarities that is often a source of diagnostic pitfalls. We evaluated the discriminatory potential of brain-derived CSF markers [tau, p-tau (181P), Aβ1-42, NSE and S100B] across the spectrum of Lewy body disorders and assessed whether particular markers are associated with cognitive status in investigated patients. The tau CSF level, amyloid β1-42 and p-tau/tau ratio were helpful in the distinction between DLB and PDD (p = 0.04, p = 0.002 and p = 0.02, respectively) as well as from PD patients (p < 0.001, p = 0.001 and p = 0.002, respectively). Furthermore, the p-tau/tau ratio enabled the differentiation of DLB with mild dementia from PDD patients (p = 0.02). The CSF tau and p-tau levels in DLB and CSF tau and p-tau/tau ratio in PDD patients reflected the severity of dementia. Rapid disease course was associated with the decrease of Aβ1-42 in DLB but not in PDD. Elevation of S100B in DLB (p < 0.0001) as well as in PDD patients (p = 0.002) in comparison to controls was estimated. Hence, with the appropriate clinical context; the CSF marker profile could be helpful in distinguishing DLB from PDD patients even in early stages of dementia.

Deep brain stimulation for dementias.

OBJECTIVE The aim of this article is to review the authors' and published experience with deep brain stimulation (DBS) therapy for the treatment of patients with Alzheimer's disease (AD) and Parkinson's disease dementia (PDD). METHODS Two targets are current topics of investigation in the treatment of AD and PDD, the fornix and the nucleus basalis of Meynert. The authors reviewed the current published clinical experience with attention to patient selection, biological rationale of therapy, anatomical targeting, and clinical results and adverse events. RESULTS A total of 7 clinical studies treating 57 AD patients and 7 PDD patients have been reported. Serious adverse events were reported in 6 (9%) patients; none resulted in death or disability. Most studies were case reports or Phase 1/2 investigations and were not designed to assess treatment efficacy. Isolated patient experiences demonstrating improved clinical response after DBS have been reported, but no significant or consistent cognitive benefits associated with DBS treatment could be identified across larger patient populations. CONCLUSIONS PDD and AD are complex clinical entities, with investigation of DBS intervention still in an early phase. Recently published studies demonstrate acceptable surgical safety. For future studies to have adequate power to detect meaningful clinical changes, further refinement is needed in patient selection, metrics of clinical response, and optimal stimulation parameters.

Disrupted network topology in patients with Lewy bodies dementia compared to Alzheimer's disease, Parkinson disease dementia and Health Control.

The clinical manifestation of Lewy body dementia (DLB) is distinct from Alzheimer's disease (AD), but overlap with Parkinson's disease dementia (PDD). However, little is known about different topology properties of abnormal brain networks associated with these neurodegenerative diseases. In order to study the difference of brain networks in various dementia subtypes, we used $^{\mathbf {18}}\text{F}$-Fluorodeoxyglucose positron emission tomography ($^{\mathbf {18}}\text{F}$-FDG PET) images and graph theory methods to investigate altered whole-brain intrinsic glucose metabolic functional networks in three Chinese dementia groups compared to healthy control (HC) group, including 22 AD patients, 18 PDD patients, 22 DLB patients and 22 HC subjects from Huashan Hospital, Shanghai, China. The experimental results disclosed that in the three dementia groups, compared to HC group, the small-world characteristics were lost. Additionally, compared with HC group, the clustering coefficients of three dementia groups were higher; the characteristic path lengths were longer. In terms of local efficiency and global efficiency, it was at the lowest level in DLB group. We also found differences about distributions of hub regions amongst the four groups. This finding could further help physicians to understand pathological mechanisms of different dementia.

Deep Brain Stimulation: A Potential Treatment for Dementia in Alzheimer's Disease (AD) and Parkinson's Disease Dementia (PDD).

Damage to memory circuits may lead to dementia symptoms in Alzheimer's disease (AD) and Parkinson's disease dementia (PDD). Recently, deep brain stimulation (DBS) has been shown to be a novel means of memory neuromodulation when critical nodes in the memory circuit are targeted, such as the nucleus basalis of Meynert (NBM) and fornix. Potential memory improvements have been observed after DBS in patients with AD and PDD. DBS for the treatment of AD and PDD may be feasible and safe, but it is still preliminary. In this review, we explore the potential role of DBS for the treatment of dementia symptoms in AD and PDD. Firstly, we discuss memory circuits linked to AD and PDD. Secondly, we summarize clinical trials and case reports on NBM or fornix stimulation in AD or PDD patients and discuss the outcomes and limitations of these studies. Finally, we discuss the challenges and future of DBS for the treatment of AD and PDD. We include the latest research results from Gratwicke et al. (2017) and compare them with the results of previous relevant studies, and this would be a worthy update of the literature on DBS for dementia. In addition, we hypothesize that the differences between AD and PDD may ultimately lead to different results following DBS treatment.

The impact of Apolipoprotein E alleles on cognitive performance in patients with Parkinson's disease

Apolipoprotein E (ApoE) is a vital component of several lipoproteins and plays a major role in lipid metabolism. APOE gene comprises of three alleles determined by two single nucleotide polymorphisms (rs429358 and rs7412) resulting in the protein isoforms, among which ApoE4 is a confirmed risk factor for Alzheimer's Disease. However, the impact of APOE genotypes on Parkinson's Disease Dementia (PDD) is still inconclusive. The PDD diagnostic criteria are very inconsistent, and could be complemented with genetic factors. Our study covers a total of 237 patients diagnosed with Parkinson's Disease (PD) according to UK PD Brain Bank criteria, who were classified as subjects with (PDD, n equals 73) and without (nPDD, n equals 164) dementia, using neuropsychological assessment tests. TaqMan real-time PCR assays were used to determine APOE allele. No statistically significant differences in APOE alleles frequencies between nPDD and PDD patients have been observed. The study results revealed that the APOE polymorphism is not associated with cognitive status in PD patients.

Parkinson's Disease Dementia and Dementia with Lewy Bodies Have Similar Neuropsychological Profiles.

Parkinson’s disease dementia (PDD) and dementia with Lewy bodies (DLB) are common causes of dementia worldwide. Although considered separate entities based on the relative temporal onset of motor symptoms vs. diagnosis of dementia, it is unknown if these diseases truly have distinct cognitive profiles. We hypothesized that patients divided into PDD and DLB categories strictly by temporal criteria would have different neuropsychological profiles. We investigated this question via neuropsychological testing of PDD and DLB patients at the University of Iowa. We performed retrospective chart analysis and review of neuropsychological testing of clinically diagnosed patients with PDD or DLB, who had presented to University of Iowa’s dementia and movement disorder clinics. Forty-seven patients diagnosed by the treating neurologist as PDD or DLB were included. Neuropsychological performance was compared between groups, and as a function of the relative timing of the motor diagnosis vs. diagnosis of dementia. We found that both PDD and DLB patients showed severe deficits in executive function, visual–spatial processing, and verbal learning. However, we found no significant differences in neuropsychological performance between groups, and neuropsychological performance could not reliably account for the relative timing of motor diagnosis vs. diagnosis of dementia. Our data support the idea that DLB and PDD are on a neuropsychological spectrum.

The Role of Insulin/IGF-1/PI3K/Akt/GSK3β Signaling in Parkinson's Disease Dementia.

Dementia, a condition that frequently afflicts patients in advanced stages of Parkinson's disease (PD), results in decreased quality of life and survival time. Nevertheless, the pathological mechanisms underlying Parkinson's disease dementia (PDD) are not completely understood. The symptoms characteristic of PDD may be the result of functional and structural deficiencies. The present study implicates the accumulation of Lewy bodies in the cortex and limbic system as a potent trigger in the development of PDD. In addition, significant Alzheimer-type pathologies, including amyloid-β (Aβ) plaques and NFTs, are observed in almost half of PDD patients. Interestingly, links between PDD pathogenesis and the mechanisms underlying the development of insulin resistance have begun to emerge. Furthermore, previous studies have demonstrated that insulin treatment reduces amyloid plaques in Alzheimer's disease (AD), and normalizes the production and functionality of dopamine and ameliorates motor impairments in 6-OHDA-induced rat PD models. GSK3β, a downstream substrate of PI3K/Akt signaling following induction by insulin and IGF-1, exerts an influence on AD and PD physiopathology. The genetic overexpression of GSK3β in cortex and hippocampus results in signs of neurodegeneration and spatial learning deficits in in vivo models (Lucas et al., 2001), whereas its inhibition results in improvements in cognitive impairment in these rodents, including AD and PD. Accordingly, insulin- or IGF-1-activated PI3K/Akt/GSK3β signaling may be involved in PDD pathogenesis, at least in the pathology of PD-type + AD-type.

Monoaminergic Markers Across the Cognitive Spectrum of Lewy Body Disease.

Lewy body disorders, including Parkinson's disease (PD), Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB), are characterized by profound central and peripheral monoaminergic dysfunction. To investigate whether these alterations depend on dementia status, we measured cerebrospinal fluid (CSF) and serum monoamine and metabolite levels across subgroups of the cognitive spectrum, and evaluated their marker potential afterwards. In total, 153 subjects were included, of which 43 healthy controls (HC), 28 PD patients with normal cognition (PD-NC), 26 patients with PD and mild cognitive impairment (PD-MCI), 18 PDD patients, and 38 DLB patients. The levels of monoamines and metabolites in paired CSF and serum samples were analyzed applying reversed-phase high-performance liquid chromatography with electrochemical detection. Firstly, when comparing subgroups, CSF 3-methoxy-4-hydroxyphenylglycol (MHPG) levels were found lowest in HC and PD-NC groups and significantly higher in PDD/DLB patients. In addition, CSF 5-hydroxyindoleacetic acid (5-HIAA) levels differed significantly between HC and PD-MCI/PDD, and DLB patients (P≤0.001), but not between HC and PD-NC patients. Secondly, when performing logistic regression, it was shown that particularly CSF/serum MHPG levels and the serum MHPG to noradrenaline (NA) ratio effectively differentiated between HC and (non-)pooled PD subgroups (AUC = 0.914-0.956), and PDD and DLB patients (AUC = 0.822), respectively. Furthermore, CSF 5-HIAA was the most discriminative parameter to differentiate between PD-NC and PD-MCI (AUC = 0.808), and, PD-NC and PDD subgroups (AUC = 0.916). Our data revealed that especially alterations of the noradrenergic neurotransmitter system could distinguish between Lewy body disorder subtypes, pinpointing CSF/serum MHPG and NA as potential stage markers across the cognitive spectrum.