PDD Patients Research Articles

Decreased resting-state functional connectivity and brain network abnormalities in the prefrontal cortex of elderly patients with Parkinson's disease accompanied by depressive symptoms.

This study aimed to explore the brain network characteristics in elderly patients with Parkinson's disease (PD) with depressive symptoms. Thirty elderly PD patients with depressive symptoms (PD-D) and 26 matched PD patients without depressive symptoms (PD-NOD) were recruited based on HAMD-24 with a cut-off of 7. The resting-state functional connectivity (RSFC) was conducted by 53-channel functional near-infrared spectroscopy (fNIRS). There were no statistically significant differences in MMSE scores, disease duration, Hoehn-Yahr stage, daily levodopa equivalent dose, and MDS-UPDRS III between the two groups. However, compared to the PD-NOD group, the PD-D group showed significantly higher MDS-UPDRS II, HAMA-14, and HAMD-24. The interhemispheric FC strength and the FC strength between the left dorsolateral prefrontal cortex (DLPFC-L) and the left frontal polar area (FPA-L) was significantly lower in the PD-D group (FDR p < 0.05). As for graph theoretic metrics, the PD-D group had significantly lower degree centrality (aDc) and node efficiency (aNe) in the DLPFC-L and the FPA-L (FDR, p < 0.05), as well as decreased global efficiency (aEg). Pearson correlation analysis indicated moderate negative correlations between HAMD-24 scores and the interhemispheric FC strength, FC between DLPFC-L and FPA-L, aEg, aDc in FPA-L, aNe in DLPFC-L and FPA-L. In conclusion, PD-D patients show decreased integration and efficiency in their brain networks. Furthermore, RSFC between DLPFC-L and FPA-L regions is negatively correlated with depressive symptoms. These findings propose that targeting DLPFC-L and FPA-L regions via non-invasive brain stimulation may be a potential intervention for alleviating depressive symptoms in elderly PD patients.

Lower oddball event-related EEG delta and theta responses in patients with dementia due to Parkinson's and Lewy body than Alzheimer's disease

Oddball task-related EEG delta and theta responses are associated with frontal executive functions, which are significantly impaired in patients with dementia due to Parkinson's disease (PDD) and Lewy bodies (DLB). The present study investigated the oddball task-related EEG delta and theta responses in patients with PDD, DLB, and Alzheimer's disease dementia (ADD). During visual and auditory oddball paradigms, EEG activity was recorded in 20 ADD, 17 DLB, 20 PDD, and 20 healthy (HC) older adults. Event-related EEG power spectrum and phase-locking analysis were performed at the delta (1–4 Hz) and theta (4–7 Hz) frequency bands for target and nontarget stimuli. Compared to the HC persons, dementia groups showed lower frontal and central delta and theta power and phase-locking associated with task performance and neuropsychological test scores. Notably, this effect was more significant in the PDD and DLB than in the ADD. In conclusion, oddball task-related frontal and central EEG delta and theta responses may reflect frontal supramodal executive dysfunctions in PDD and DLB patients.

Abnormalities of reactivity of posterior resting‐state electroencephalographic alpha rhythms during eyes opening in patients with dementia due to Alzheimer’s disease and Parkinson’s disease

AbstractBackgroundPatients with dementia due to Alzheimer’s disease (ADD) and Parkinson’s disease (PDD) suffer from vigilance dysregulation. We hypothesized that such dysregulation may be reflected by altered reactivity of posterior resting‐state electroencephalographic (rsEEG) alpha rhythms during the vigilance transition from eyes‐closed to ‐open condition.MethodA Eurasian database provided clinical, demographic, and rsEEG datasets in 73 PDD patients, 35 ADD patients, and 25 matched cognitively unimpaired (Healthy) persons. The eLORETA freeware was used to estimate cortical rsEEG sources at delta, theta, alpha, beta, and gamma frequency bands during eyes‐closed and‐open conditions.ResultResults showed substantial (&gt; ‐10%) reduction (reactivity) in the posterior alpha source activities from the eyes‐closed to the eyes‐open condition in 88% of the Healthy seniors, 57% of the ADD patients, and only 35% of the PDD patients (Figure 1). In these alpha‐reactive participants, there were lower reductions in the posterior alpha activities in the ADD and PDD groups than in the Healthy group. That reduction in the parietal region was lower in the PDD than in the ADD group (Figure 2).ConclusionThese results suggest that ADD and PDD is characterized by poor reactivity of mechanisms desynchronizing posterior rsEEG alpha rhythms in response to visual inputs. This finding could be an interesting biomarker of impaired vigilance regulation in the quiet wakefulness in ADD and PDD patients. Such biomarkers may provide endpoints targets for pharmacological intervention and brain electromagnetic stimulations to improve the ADD and PDD patients’ general ability to regulate vigilance and visual primary consciousness in the activities of daily living.

Alzheimer’s disease and Parkinson’s disease dementia: Practical tips for physicians

Dementia is a progressive disorder that weakens the intellectual abilities and causes the cognitive, behavioral, and functional decline in occupational and social areas. This research is targeted to extract a profile for the dementia diagnostic and clinical characteristics by evaluating the near-term effects of Alzheimer&amp;rsquo;s disease (AD) and Parkinson&amp;rsquo;s disease dementia (PD-D). A total of 240 individuals, including 60 AD patients, 60 PD-D patients, and 120 healthy controls, were included in the study. Data of individuals treated in a local dementia outpatient clinic between 2013 and 2023 were obtained from the clinic database. AD and PD-D diagnoses were made based on the revised National Institute on Aging and Alzheimer&amp;rsquo;s Association (NIA-AA) criteria and movement disorder society (MDS) clinical diagnostic criteria, respectively. Functional, clinical, and neuropsychological evaluations of the patients were made by the same neurologist. Dementia staging and daily living activities were determined and categorized. In the patient group, functionality and instrumental activities of daily living (ADLs) scores were significantly worse than those of the control group, but there was no difference between the AD and PD-D groups. Calculation, verbal fluency, word list, early learning, and clock drawing test scores were lower in the AD group than in the PD-D group. Apathy, disinhibition, elution, irritability, abnormal motor movements, sleep, and appetite scores were significantly higher in the patient group than in the control group. While depression parameters were not significantly different between all the groups, hallucinations and anxiety parameters were significantly higher in the PD-D group than in the AD group. As an important predictor of independent living and the burden of disease, functional impairment is an important issue in patients with AD compared to those with PD-D. This study also highlights the neuropsychiatric perception disorder in terms of functional loss in AD and significant anxiety disorder for PD-D accompanied by early functional losses.

Serum glial cell line-derived neurotrophic factor (GDNF) a potential biomarker of executive function in Parkinson's disease.

Evidence shows that the impairment of executive function (EF) is mainly attributed to the degeneration of frontal-striatal dopamine pathway. Glial cell line-derived neurotrophic factor (GDNF), as the strongest protective neurotrophic factor for dopaminergic neurons (DANs), may play a role in EF to some extent. This study mainly explored the correlation between serum GDNF concentration and EF performance in Parkinson's disease (PD). This study recruited 45 healthy volunteers (health control, HC) and 105 PD patients, including 44 with mild cognitive impairment (PD-MCI), 20 with dementia (PD-D), and 20 with normal cognitive function (PD-N). Neuropsychological tests were performed to evaluate EF (working memory, inhibitory control, and cognitive flexibility), attention, language, memory, and visuospatial function. All subjects were tested for serum GDNF and homovanillic acid (HVA) levels by ELISA and LC-ESI-MS/MS, respectively. PD-MCI patients showed impairments in the trail making test (TMT) A (TMT-A), TMT-B, clock drawing test (CDT) and semantic fluency test (SFT), whereas PD-D patients performed worse in most EF tests. With the deterioration of cognitive function, the concentration of serum GDNF and HVA in PD patients decreased. In the PD group, the serum GDNF and HVA levels were negatively correlated with TMT-A (r GDNF = -0.304, P < 0.01; r HVA = -0.334, P < 0.01) and TMT-B (r GDNF = -0.329, P < 0.01; r HVA = -0.323, P < 0.01) scores. Serum GDNF levels were positively correlated with auditory verbal learning test (AVLT-H) (r = 0.252, P < 0.05) and SFT (r = 0.275, P < 0.05) scores. Serum HVA levels showed a positively correlation with digit span test (DST) (r = 0.277, P < 0.01) scores. Stepwise linear regression analysis suggested that serum GDNF and HVA concentrations and UPDRS-III were the influence factors of TMT-A and TMT-B performances in PD patients. The decrease of serum GDNF concentration in PD patients was associated with impaired inhibitory control, cognitive flexibility, and attention performances. The changes of GDNF and HVA might synergistically participate in the occurrence and development of executive dysfunction in PD patients.

Clinical outcomes and treatment patterns of older adults with dementia-related psychosis by dementia type in the United States

BackgroundLittle is known about the incidence of clinical events and treatment patterns among older adults with dementia-related psychosis. Given that dementia-related psychosis comprises various dementia types, this study describes the incidence of clinical events and treatment patterns by dementia type after patients with dementia are diagnosed with psychosis.MethodsAdults aged ≥ 65 years with dementia and newly diagnosed with psychosis were identified in US Medicare claims during 2013–2018. Baseline characteristics were evaluated at the time of the psychosis diagnosis. After the initial psychosis diagnosis, incidence rates (IRs) of clinical events (e.g., falls/fractures, infections, healthcare utilization), mortality, and patterns of antipsychotic treatment were described for each dementia type (Alzheimer’s disease [AD], Parkinson’s disease dementia [PDD], dementia with Lewy bodies [DLB], frontotemporal dementia [FTD], vascular dementia [VD], and unspecified dementia). Daily mean cumulative counts were estimated to describe the incidence of recurrent events over time. Mortality was described using Kaplan–Meier survival curves.ResultsWe identified 484,520 patients with dementia-related psychosis: mean age, 84 years (standard deviation, 7.8); female, 66%. At the time of psychosis diagnosis, the most prevalent type of dementia was unspecified dementia (56%), followed by AD (31%), VD (12%), PDD (10%), DLB (3%), and FTD (< 1%), and most patients had scores indicating severe illness on the Charlson Comorbidity Index (71%) and frailty index (62%). Across all dementia types, IRs (per 100 person-years) were high for emergency department visits, oral anti-infective use, and urinary tract infections after the initial psychosis diagnosis. Patients with DLB had the highest incidence of most clinical outcomes. After 1 year of follow-up, the cumulative probability of death was about 30% for all dementia types, and after 5 years, was about 80% among patients with DLB, VD, AD, or PDD and about 60%-65% among patients with FTD or unspecified dementia.ConclusionsPatients with dementia-related psychosis had a high burden of comorbidities, frailty, emergency department visits, infections, and death. Specifically, after DRP diagnosis, patients with DLB and VD had the highest burden of clinical events of interest.

A task-specific cognitive domain decline is correlated with plasma and neuroimaging markers in patients with Parkinson's disease.

Cognitive impairment is a disabling non-motor symptom of Parkinson's disease (PD). It remains uncertain whether declines in specific cognitive domains relate to imaging or plasma biomarkers across the disease continuum. We investigated whether neuroimaging and plasma biomarkers correlate with individual task-specific cognitive domain declines evidenced by computerized neuropsychological tests in PD patients. A total of 107 participants, including 87 PD patients (30 with normal cognition [PD-NC], 30 with mild cognitive impairment [PD-MCI], 27 with dementia [PDD]), and 20 healthy controls, were recruited. All received the Cambridge Neuropsychological Test Automatic Battery (CANTAB) test, brain MRI, and assays of plasma biomarkers, including α-synuclein, tau, Aβ42, and Aβ40. PD patients had generally poorer cognitive performance than controls. Patients with PD-MCI and PDD had worse performance in visual, verbal, and working memory and executive function than those with PD-NC. After adjusting for covariates, PDD patients had global cortical thinning, especially in the temporal and parietal lobes, and higher plasma α-synuclein levels and tau:Aβ42 ratios than PD-NC group. Plasma α-synuclein level was associated with frontal lobe-mediated tasks, while the tau:Aβ42 ratio was associated with posterior cortical-mediated tasks. Facial emotion recognition tasks and visual pattern recognition associated with frontotemporal cortical thinning. The accuracy of predicting PDD using age alone (area under the curve [AUC] 0.756) increased by incorporating plasma biomarkers (AUC = 0.851, p = 0.025). Cognitive decline in PD patients has a task-specific correlation with neuroimaging and plasma biomarkers, which may implicate the underlying neuropathological process of PDD.

Patterns of dementia treatment in older adults with Parkinson\u2019s disease using nationwide medical claims data

BackgroundDementia is a common feature in Parkinson’s disease (PD); however, data on dementia treatment patterns in patients with PD are scarce. This study aimed to evaluate the incidence of dementia in individuals with PD and to describe the dementia treatment patterns in the Korean elderly population.MethodsWe conducted a retrospective population-based cohort study using data obtained from the Korean National Health Insurance Service-Senior Cohort (NHIS-SC) database. The dataset comprised more than 500,000 health insurance beneficiaries from January 1, 2002 to December 31, 2015. We estimated the incidence of patients newly diagnosed with dementia during this observational period, compared patient demographics, and analyzed the exposure to anticholinergic drugs among PD patients with (PD + D) and without (PD-D) dementia. Furthermore, the duration to dementia diagnosis and patterns of dementia treatment were evaluated.ResultsA cohort of 28,537 patients aged 60 years or older who were diagnosed with PD by the NHIS was established. Within this cohort, 8620 patients were eligible study participants according to strict inclusion/exclusion criteria. Of these individuals, 3879 (45.0%) patients were newly diagnosed with dementia; the incidence of dementia in PD was 15.2 per 1000 person-years. The proportion of women was higher in the PD + D (64.6%) than the PD-D group (58.2%) (P < 0.001); furthermore, the use of anticholinergic medication was greater in PD + D (37.6%) than in PD-D (24.0%) patients. The incidence curves for dementia over time were the steepest during the first year and decreased every year thereafter. Approximately 60% of PD patients were diagnosed with dementia during the first 3 years. Regarding the use of anti-dementia drugs, 2539 (65.5%) of 3879 PD + D were prescribed medication. During the observation period, 1799 (70.9%) patients were prescribed only one type of anti-dementia drug. In this monotherapy group, the most commonly prescribed medication was donepezil (1313[73.0%]), followed by rivastigmine (capsule and patch; 246[13.7%]), memantine (187[10.4%]), and galantamine (53[2.9%]).ConclusionsIn Korea, dementia was observed to occur relatively soon after the diagnosis of PD. Anti-dementia medication was prescribed to approximately 66% of PD + D patients, with the majority receiving donepezil as monotherapy.

Abnormal event‐related EEG theta responses in patients with dementia with Lewy bodies and Parkinson's disease dementia

AbstractBackgroundParkinson's disease with dementia (PDD) and dementia with Lewy bodies (DLB) are characterized by intracellular Lewy bodies in the brain neurons and clinical symptoms including cognitive impairment and flucations, motor symptoms, and hallucinations with some differences, namely non‐motor symptoms appear earlier in DLB over PDD patients (McKeith et al., 2017). An unmet need in the actual diagnostic criteria is the availability of biomarkers probing working brain cognitive systems. A promising biomarker may be derived from the frequency analysis of electroencephalographic oscillatory responses (EROs) during cognitive demands, as a decrease of frontal‐central EROs at theta (4‐7 Hz) frequencies was reapatedly demonstrated in Alzheimer’s disease patients with mild cognitive impairment and dementia over cognitively unimpaired (CU) persons (Yener et al., 2007; Guntekin et al., 2008). In this line, the present study tested the hypothesis of abnormal event‐related EROs at theta frequencies in PDD and DLB patients.MethodElectroencephalographic activity was recorded during a visual oddball paradigm (i.e., 30% of target stimuli requiring mental counting intermingled with 70% of stimuli to be ignored) in 15 PDD, 12 DLB, and 15 CU persons. EROs at theta power and phase‐locking were computed for the oddball target stimuli and compared among the groups (ANOVA, p &lt; 0.05).ResultAs compared to the CU group, both PDD and DLB groups showed a strong topographically widespread reduction in ERO theta power (p &lt; 0.005) (Figure 1). They also showed a strong reduction in ERO theta phase‐locking, especially in frontal‐central locations (p &lt; 0.0001)( Figure 2).ConclusionThe present study showed that ERO theta power and phase‐locking during a standard visual oddball paradigm probing visual focused attention and short‐term memory may be suitable biomarkers to investigate working cognitive brain systems in both PDD and LBD patients.

Updated treatment of dementia with bosutinib: An open‐label study of a tyrosine kinase inhibitor

AbstractBackgroundA 2020 publication from Mahdavi and colleagues reported on clinical status changes observed among a sample of 31 older adults with neurodegenerative conditions who completed 12 months of bosutinib therapy. This abstract provides updated results for an additional 21 patients who have completed the 12‐month regimen since the time of the initial publication. This study pursues and updates data on an effective therapeutic intervention for dementia using TKI’s such as bosutinib.Method52 patients with probable Alzheimer’s dementia (AD) or Parkinson’s spectrum disorder with dementia (PDD) completed 12 months of bosutinib therapy. The Clinical Dementia Rating scale (CDR) as estimated by the Quick Dementia Rating System (QDRS) was the primary cognitive status outcome measure.ResultsFor the updated sample size of 52 individuals who have completed the protocol, bosutinib was associated with improved CDR scores for 40% of participants (36% AD, and 46% PDD); bosutinib was also associated with clinically stable CDR scores for 38% of patients (36% AD, and 46% PDD). After completion of the protocol intervention, 29% of the AD population yielded decreased CDR scores while only 8% of PDD patients had decreased CDR scores.ConclusionThese results update findings from the previously reported study (Mahdavi et al., 2020) and continue to warrant further investigation of bosutinib as a potential therapeutic agent for dementia. The data continue to suggest an overall positive or stable outcome among participants after a year of bosutinib, with a clinical improvement rate of approximately 40% and a 38% rate of clinical stabilization. This observation remains consistent regardless of severity of cognitive impairment at baseline. We expect to report on an update for an additional 30 participants in the next year.

Mortality rates are higher in lewy body and parkinson's disease dementia compared to Alzheimer's dementia in patients referred into a secondary care mental health service. Why?

AimsWe compared survival in four cohorts of dementia patients– Lewy body (LBD), Parkinson's (PDD), Vascular (VD) and Alzheimer's dementia (AD) - in patients referred into Cambridge and Peterborough NHS Foundation Trust (CPFT) mental health services.Additionally, we investigated reasons for variation in survival in the four cohorts.MethodUsing electronic records we identified retrospective cohorts of patients referred into services from 2013 onwards. Cases of LBD and PDD were identified using text searches, and comparison cohorts with AD or VD identified using ICD10 diagnosis codes ((F00.*) or (F01.*) respectively).We collected referral (date of referral and service referred into), demographic (date of birth and gender) and diagnosis data on the patients in the four cohorts. Dates of death were available, through central NHS reporting to Trusts.We used date of first referral as start of the follow-up and end of follow-up, death or 31/12/19. We used Kaplan-Meier and Cox survival analysis to compare survival in the four cohorts.The cohorts were crossed with Hospital Episode Statistics (HES) data to extract hospital admission diagnoses. We extracted diagnoses of pneumonia due to aspiration and recurrent falls from hospital admissions data using ICD codes (J69.0 and R29.6 respectively). We calculated prevalence of these diagnoses in the dementia groups, in males and females separately.ResultIn Cox analysis (controlling for age at referral, gender and service referred into), the hazard ratio (HR) for death was highest for the PDD group (HR 2.0 (95% CI 1.7–2.4)), followed by LBD (HR 1.4 (95% CI 1.3–1.6)), then VD (HR 1.2 (95% CI 1.0–1.3)), with the AD group as reference. In the same analysis repeated separately for males and females, the highest HR was found in males with PDD (HR 2.3 (95% CI 1.8–2.8)).Referrals to liaison psychiatry were associated with reduced survival compared to other mental health services (HR 1.7 (95% CI 1.5–2.0)).The AD cohort showed the lowest rates of pneumonia due to aspiration and recurrent falls in males and in females. The highest rate of pneumonia due to aspiration was found in the male PDD group (27%).ConclusionIn patients with dementia referred into mental health services, those with AD survive longer compared to other dementia groups, with PDD patients at highest risk of death. Physical frailty including risk of aspiration, is likely to account for some of this difference in survival.

Networks Are Associated With Depression in Patients With Parkinson's Disease: A Resting-State Imaging Study.

BackgroundDisturbance of networks was recently proposed to be associated with the occurrence of depression in Parkinson’s disease (PD). However, the neurobiological mechanism of depression underlying PD remains unclear.ObjectiveThis study was conducted to investigate whether intra-network and inter-network brain connectivity is differently changed in PD patients with and without depression (PDD and PDND patients, respectively).MethodsForty-one PDD patients, 64 PDND patients, and 55 healthy controls (HCs) underwent resting-state functional magnetic resonance imaging (fMRI). The default mode network (DMN), executive control network (ECN), salience network (SN), precuneus network (PCUN), and sensorimotor network (SMN) were extracted using independent component analysis (ICA), and then the functional connectivity (FC) values within and between these networks were measured.ResultsPDD patients exhibited abnormal FC values within the DMN, ECN, SN, PCUN, and SMN. In addition, PDD patients demonstrated decreased connectivity between anterior SN (aSN) and bilateral ECN, between posterior SN (pSN) and dorsal DMN (dDMN), and between PCUN and dDMN/SMN/bilateral ECN. Connectivity within the left hippocampus of dDMN and the right medial superior frontal gyrus of aSN was a significant predictor of depression level in PD patients.ConclusionsAberrant intra- and inter-network FC is involved in several important hubs in the large-scale networks, which can be a biomarker for distinguishing PDD from PDND.

Cortical connectivity of the nucleus basalis of Meynert in Parkinson's disease and Lewy body dementias.

Parkinson’s disease dementia (PDD) and dementia with Lewy bodies (DLB) are related conditions that are associated with cholinergic system dysfunction. Dysfunction of the nucleus basalis of Meynert (NBM), a basal forebrain structure that provides the dominant source of cortical cholinergic innervation, has been implicated in the pathogenesis of both PDD and DLB. Here we leverage the temporal resolution of magnetoencephalography with the spatial resolution of MRI tractography to explore the intersection of functional and structural connectivity of the NBM in a unique cohort of PDD and DLB patients undergoing deep brain stimulation of this structure. We observe that NBM-cortical structural and functional connectivity correlate within spatially and spectrally segregated networks including: (i) a beta band network to supplementary motor area, where activity in this region was found to drive activity in the NBM; (ii) a delta/theta band network to medial temporal lobe structures encompassing the parahippocampal gyrus; and (iii) a delta/theta band network to visual areas including lingual gyrus. These findings reveal functional networks of the NBM that are likely to subserve important roles in motor control, memory and visual function, respectively. Furthermore, they motivate future studies aimed at disentangling network contribution to disease phenotype.

The ANeED study: Ambroxol in new and early dementia with Lewy bodies

AbstractBackgroundThe mechanisms by which GBA and APOE mutations result in PD or DLB are not fully understood, however there is evidence that it may be connected to reduced levels of GCase enzyme activity. CNS penetration has been confirmed for Ambroxol, and has been shown to increase glucocerebrosidase activity and protein levels in animal and human studies. One small open study with Ambroxol 420mg TID in PD for 186 days found excellent target engagement and improved motor symptoms, and a RCT with 50 PDD patients is ongoing in London, Canada.MethodWe will execute a national multicenter phase III RCT clinical intervention study with Ambroxol in prodromal and mild DLB in Memory Clinics in Norway. We will include persons living with prodromal (DLB‐MCI) or mild DLB with MMSE &gt;=15 to Ambroxol or placebo. We will stratify participants based on genotypes for APOE and GBA and the CSF biomarkers A‐beta, total and phosphorylated tau protein. We will build a national trial platform for drug trials in neurodegenerative disorders in Norway and aim to include more centers in Europe for next phase studies via the European DLB Consortium (E‐DLB). We will execute a PPI program to raise awareness and reduce stigma for people living with DLB and their families.ResultThe ANeED‐study has received funding from the national Norwegian health authorities. Formal approvals for ethics, data protection and Medicine Agency are ongoing. We are planning a national start‐up meeting in Norway in September 2020, and we are currently building a national platform in Norway to be able to run clinical intervention studies in neurodegenerative disorders. We are building a PPI program to recruit patients and caregivers to clinical studies.ConclusionPhase III studies with Ambroxol in PD, PDD and DLB are currently being planned. APOE, GBA and GCase are central to the disease process in both PD, PDD and in DLB. Patients, carers and health providers now need to be offered participation in clinical studies also when diagnosed with one of the α‐synucleinopathies. Preliminary data find Ambroxol to be potentially disease modifying in these disorders.

α-Synuclein modulates tau spreading in mouse brains.

α-Synuclein (α-syn) and tau aggregates are the neuropathological hallmarks of Parkinson's disease (PD) and Alzheimer's disease (AD), respectively, although both pathologies co-occur in patients with these diseases, suggesting possible crosstalk between them. To elucidate the interactions of pathological α-syn and tau, we sought to model these interactions. We show that increased accumulation of tau aggregates occur following simultaneous introduction of α-syn mousepreformed fibrils (mpffs) and AD lysate-derived tau seeds (AD-tau) both in vitro and in vivo. Interestingly, the absence of endogenous mouse α-syn in mice reduces the accumulation and spreading of tau, while the absence of tau did not affect the seeding or spreading capacity of α-syn. These in vivo results are consistent with our in vitro data wherein the presence of tau has no synergistic effects on α-syn. Our results point to the important role of α-syn as a modulator of tau pathology burden and spreading in the brains of AD, PDD, and DLB patients.

Combined subthalamic and nucleus basalis of Meynert deep brain stimulation for Parkinson\u2019s disease with dementia (DEMPARK-DBS): protocol of a randomized, sham-controlled trial

IntroductionDementia in Parkinson’s disease (PDD) is a common non-motor symptom of advanced disease, associated with pronounced neocortical cholinergic deficits due to neurodegeneration of the nucleus basalis of Meynert (NBM) and its cholinergic terminals. In advanced PD, patients often require advanced therapies such as infusion therapy or deep brain stimulation (DBS) to improve motor control. However, patients with associated dementia are commonly excluded from DBS because of potential deterioration of cognitive functions. Yet marked reductions in dopaminergic medication and the subsequent risk of side effects (e.g., cognitive decline, psychosis, delirium) suggest that critical re-consideration of DBS of the subthalamic nucleus (STN-DBS) for advanced stages of PD and PDD is worthwhile. In this Phase 1b study, we will provide STN-DBS to a cohort of PDD patients with severe motor fluctuations and combine two additional electrodes for augmentative neurostimulation of the NBM.MethodsWe aim to include 12 patients with mild-to-moderately severe PDD who fulfill indication criteria regarding motor symptoms for STN-DBS. Eligible patients will undergo implantation of a neurostimulation system with bilateral electrodes in both the STN and NBM. After 12 weeks of STN-DBS (visit 1/V1), participants will be randomized to receive either effective neurostimulation of the NBM (group 1) or sham stimulation of the NBM (group 2). NBM-DBS will be activated in all participants after 24 weeks of blinded treatment (visit 2/V2). The primary outcome will be the safety of combined bilateral STN- and NBM-DBS, determined by spontaneously-reported adverse events. Other outcome measures will comprise changes on scales evaluating cognition, activities of daily living functioning and clinical global impression, as well as motor functions, mood, behavior, caregiver burden and health economic aspects, and several domain-specific cognitive tests. Changes in scores (V1 – V2) for both treatment arms will undergo analysis of covariances, with baseline scores as covariates.PerspectiveThe feasibility and safety of combined STN-NBM-DBS in patients with PDD will be assessed to determine whether additional NBM-DBS improves or slows the progression of cognitive decline. Positive results would provide a basic concept for future studies evaluating the efficacy of NBM-DBS in larger PDD cohorts. Indirectly, proof-of-safety of STN-DBS in PDD might influence patient selection for this standard treatment option in advanced PD.Trial registrationClinicalTrials.gov identifier (NCT number): NCT02589925.

Impairments in face discrimination and emotion recognition are related to aging and cognitive dysfunctions in Parkinson\u2019s disease with dementia

Patients with Parkinson’s disease (PD) suffer from motor and non-motor symptoms; 40% would develop dementia (PD-D). Impaired face and emotion processing in PD has been reported; however, the deficits of face processing in PD-D remain unclear. We investigated three essential aspects of face processing capacity in PD-D, and the associations between cognitive, neuropsychiatric assessments and task performances. Twenty-four PD-D patients (mean age: 74.0 ± 5.55) and eighteen age-matched healthy controls (HC) (mean age: 71.0 ± 6.20) received three computerized tasks, morphing-face discrimination, dynamic facial emotion recognition, and expression imitation. Compared to HC, PD-D patients had lower sensitivity (d’) and greater neural internal noises in discriminating faces; responded slower and had difficulties with negative emotions; imitated some expressions but with lower strength. Correlation analyses revealed that patients with advancing age, slow mentation, and poor cognition (but not motor symptoms) showed stronger deterioration in face perception. Importantly, these correlations were absent in the age-matched HC. The present study is among the first few examined face processing in patients with PD-D, and found consistent deficits correlated with advancing age and slow mentation. We propose that face discrimination task could be included as a potential test for the early detection of dementia in PD.

P1479Deterioration in right ventricular strain precedes occurrence of pulmonary hypertension in patients with preclinical diastolic disfunction

Abstract Preclinical diastolic disfunction (PDD) often progresses to heart failure and distinct clinical predictors for this transformation are yet to be defined. Since deterioration of longitudinal strain (LS) can occur before the changes of more conventional parameters, we assumed that right ventricular free wall longitudinal strain (RVLS) might start deteriorating before the pulmonary hypertension can be established. Methods We followed up 243 patients (143 female) 67±9 years with PDD for 3 years. All patients had an impaired relaxation or pseudo normal transmitral patterns and E/e' 8–13 at rest, normal NT-proBNP values, and systolic pulmonary artery pressure (sPAP) ≤30 mm Hg. PDD was diagnosed by stress echocardiography (SE) if E/e' ≥13, transmittal E wave deceleration time reduction &gt;50ms, systolic pulmonary artery pressure (sPAP) &lt;30 mmHg, and patients remained asymptomatic during SE. RVLS as average of RV free wall 3 segments values, left atrial peak reservoir LS (LALS) as average of two LA basal segments in four chamber view and left ventricular peak systolic global LS (LVGLS) were measured by speckle tracking (ST). ST and SE was performed with 6 months intervals. 35 healthy subject served as controls. Results Patients with PDD had higher RVLS, LVGLS, and lower LALS compared with controls (RVLS –23.2±4.2% vs –27.3±5.1%, p&lt;0.001; LVGLS –17.8±5.2% vs –21.9±2.8%, p&lt;0.001; LALS 39.7±3.7% vs 44.1±4.9%, p&lt;0.002). 76 (31.3%) patients developed sPAP increase &gt;30 mmHg at rest or SE during follow up of which 34 (44.7%) had dyspnea. Patients with increased sPAP had higher RVLS and lower LALS values at baseline compared with the rest of PDD patients without significant differences in other parameters (RVLS –17.9±2.8% vs –24.8±3.6%, p&lt;0.002; LALS 37.7±2.3% vs 41.5±3.6%, p&lt;0.003; LVGLS –17.4±4.8% vs –18.2±5.1%, p&gt;0.05). Both LALS and RVLS correlated with LA end diastolic volume index (LALS r=0.51, p&lt;0.01; RVLS r=0.54, p&lt;0.01). Additionally RVLS was an independent predictor of sPAP rise (OR=2.7; 95% CI=2.43–6.92; p&lt;0.01). Conclusion RVLS is an independent predictor of sPAP increase in patients with PDD.

Can behavioral symptoms differentiate cortical from subcortical dementia - A comparative study of behavioral profile of Parkinson’s disease dementia and behavioral variant of frontotemporal dementia

Patients of behavioural variant of frontotemporal dementia (bvFTD) exhibit prominent behavioural abnormalities along with executive dysfunction. Whereas executive dysfunction is also common in subcortical dementias because of disturbance in fronto-subcortical connection, behavioural symptoms are less frequent. To determine the frequencies of behavioural symptomatology of patients with subcortical (Parkinson's disease with dementia or PDD) and frontal cortical dementia (behavioural variant of Frontotemporal dementia or bvFTD) and to find out the discriminating value of behavioural characteristics in differentiating these two group of patients. Patients were consecutively recruited from Cognitive and Movement Disorder Clinics following standard diagnostic criteria. A total 20 bvFTD and 20 PDD patients were recruited. Behavioural symptoms were noted from reliable caregiver following the questionnaire prepared by Bathgate et al. (2000). Whereas eating and vegetative behaviour were more frequent in bvFTD (85% vs 45%, p = 0.018), the neuropsychiatric behaviours were more common in PDD group 80.0% vs 50.0%, p = 0.095). Although didn’t achieve statistical significance, other symptoms found to be discriminating in two condition were (i) sensory behaviour (p = 0.056), (ii) cognitive mediated behaviour (p = 0.794), (iii) affect-social behaviour (p = 0.162), and (iv) compulsion-ritual behaviour (p = 0.33). The behaviour related to environmental dependency were not found prominent in either groups (p = 0.155), although utilization behavior and echopraxia were more common in bvFTD. Behavioural abnormalities were more common in bvFTD group with prominent abnormality in eating & vegetative behaviour, sensory behaviour, cognitive mediated behaviour, affect-social behaviour, compulsion-ritual behaviour and the PDD group showed marked neuropsychiatry behavioural abnormalities.

Clinical Correlates of Cerebral Amyloid Deposition in Parkinson's Disease Dementia: Evidence from a PET Study.

Dementia in Parkinson's disease (PDD) is common presumably due to combined neuropathological substrates. Amyloid-β (Aβ) plaques are well described in PDD but their contribution in synucleinopathies is still controversial. To investigate regional [18F]Florbetapir binding and its relative contribution to cognitive dysfunction in a cohort of PDD patients and to test whether PDD patients with comorbid amyloidopathy have different clinical and neuropsychological characteristics. 21 PDD patients, 20 with Alzheimer's disease (AD), and 9 control subjects underwent amyloid positron emission tomography (PET) imaging, neurological, and neuropsychological assessment. Radioligand binding was compared across the groups. PDD scans were interpreted qualitatively and semiquantitatively and categorized as positive or negative. Annual longitudinal Mini-Mental State Examination (MMSE) of PDD subjects was retrospectively collected in order to relate Aβ burden to the course of cognitive impairment. [18F]Florbetapir PET imaging was positive in 11 PDD patients (52.38%) using the semi-quantitative method. There were no group differences between PDD subjects with increased cortical [18F]Florbetapir (+) and those without (-), according to demographic and clinical parameters. PDD+ performed worse on Digit Span Foward and on Rey Auditory Verbal Learning Test delayed recall than the PDD- with a significant negative correlation between global cortical retention and specific memory tests. Aβ load did not correlate with MMSE ratings although PDD+ demonstrated a faster clinical progression of dementia. Significant Aβ deposition is common in PDD patients contributing to memory impairment and driving a faster rate of cognitive decline.