Decline In Parkinson's Disease Research Articles

Significant cognitive decline in Parkinson's disease exacerbates the reliance on visual feedback during upper limb reaches

While upper limb reaches are often made in a feed-forward manner, visual feedback during the movement can be used to guide the reaching hand towards a target. In Parkinson's disease (PD), there is evidence that the utilisation of this visual feedback is increased. However, it is unclear if this is due solely to the characteristic slowness of movements in PD providing more opportunity for incorporating visual feedback to modify reach trajectories, or whether it is due to cognitive decline impacting (feed-forward) movement planning ability. To investigate this, we compared reaction times and movement times of reaches to a target in groups of PD patients with normal cognition (PD-NC), mild cognitive impairment (PD-MCI) or dementia (PD-D), to that of controls with normal cognition (CON-NC) or mild cognitive impairment (CON-MCI). Reaches were undertaken with full visual feedback (at a ‘natural’ and ‘fast-as-possible’ pace); with reduced visual feedback of the reaching limb to an illuminated target; and without any visual feedback to a remembered target with eyes closed.The PD-D group exhibited slower reaction times than all other groups across conditions, indicative of less efficient movement planning. When reaching to a remembered target with eyes closed, all PD groups exhibited slower movement times relative to their natural pace with full visual feedback. Crucially, this relative slowing was most pronounced for the PD-D group, compared to the PD-MCI and PD-NC groups, suggesting that substantial cognitive decline in PD exacerbates dependence on visual feedback during upper limb reaches.

Evaluation of Motor and Cognitive Performance in People with Parkinson’s Disease Using Instrumented Trail-Making Test

Introduction: Parkinson’s disease (PD) progressively impairs motor and cognitive performance. The current tools to detect decline in motor and cognitive functioning are often impractical for busy clinics and home settings. To address the gap, we designed an instrumented trail-making task (iTMT) based on a wearable sensor (worn on the shin) with interactive game-based software installed on a tablet. The iTMT test includes reaching to 5 indexed circles, a combination of numbers (1–3) and letters (A&B) randomly positioned inside target circles, in a sequential order, which virtually appears on a screen kept in front of the participants, by rotating one’s ankle joint while standing and holding a chair for safety. By measuring time to complete iTMT task (iTMT time), iTMT enables quantifying cognitive-motor performance. Purpose: This study’s objective is to examine the feasibility of iTMT to detect early cognitive-motor decline in PDs. Method: Three groups of volunteers, including 14 cognitively normal (CN) older adults, 14 PDs, and 11 mild cognitive impaireds (MCI), were recruited. Participants completed MoCA, 20 m walking test, and 3 trials of iTMT. Results: All participants enabled to complete iTMT with <3 min, indicating high feasibility. The average iTMT time for CN-Older, PD, and MCI participants were 20.9 ± 0.9 s, 32.3 ± 2.4 s, and 40.9 ± 4.5 s, respectively. After adjusting for age and education level, pairwise comparison suggested large effect sizes for iTMT between CN-older versus PD (Cohen’s d = 1.7, p = 0.024) and CN-older versus MCI (d = 1.57, p < 0.01). Significant correlations were observed when comparing iTMT time with the gait speed (r = −0.4, p = 0.011) and MoCA score (r = −0.56, p < 0.01). Conclusion: This study demonstrated the feasibility and early results supporting the potential application of iTMT to determine cognitive-motor and distinguishing individuals with MCI and PD from CN-older adults. Future studies are warranted to test the ability of iTMT to track its subtle changes over time.

Serum Neurofilament Dynamics Predicts Cognitive Progression in de novo Parkinson's Disease.

Neurofilament light (NfL) can reflect the extent of neuron/axon damage, thus providing an opportunity to examine the severity and progression of the diseases with such damage. Whether serum NfL can be used as an indicator to monitor the cognitive progress of de novo Parkinson's disease (PD) remains unclear. In this research, 144 healthy controls and 301 de novo PD patients from Parkinson's Progression Markers Initiative (PPMI) were recruited. Linear mixed effects models were used to examine the associations of baseline/longitudinal serum NfL with cognitive decline. Cox regression was used to detect cognitive progression in PD participants. We found PD patients had higher serum NfL than controls at baseline (p = 0.031), and NfL increase was faster in PD group (p < 0.001). Both baseline serum NfL and its rate of change predicted measurable cognitive decline in early PD (MoCA, β= -0.014, p < 0.001; β= -0.002, p < 0.001, respectively). Additionally, we observed that NfL levels were also able to predict progression in different diagnostic groups and Amyloid- PD and Amyloid+PD groups. After an average follow-up of 6.37±1.84 years, the baseline NfL of the third tertile of high concentrations was associated with a future high risk of PD dementia (adjusted HR 6.33, 95% CI 2.62-15.29, p < 0.001). In conclusion, our results indicated that the serum NfL concentration could function as an easily accessible biomarker to monitor the severity and progression of cognitive decline in PD.

Physical Activity May Reduce Apolipoprotein E4-Associated Cognitive Decline in Parkinson Disease

<h3>Objective</h3> To present a case-based discussion on the workup of male factor infertility and review currently available treatments. <h3>Sources of information</h3> This discussion is based on the current Canadian Urological Association and American Urological Association guidelines, with reference to landmark papers as appropriate from 2010 onward. All articles were retrieved through PubMed. <h3>Main message</h3> Approximately 15% of Canadian couples experience infertility, making it a commonly encountered condition in the primary care setting. Among couples suffering from infertility, male factors can be identified as the sole cause in 30% of cases and as a contributing issue in 20% of cases. Although many of the treatments described aim to improve a couple’s chances of naturally conceiving a child via intercourse, many patients ultimately require medical or surgical intervention to achieve pregnancy. This can be a long, protracted course for patients, with important roles for primary care providers and fertility specialists alike. <h3>Conclusion</h3> Male fertility assessment and treatment has historically been left in the hands of fertility specialists, creating a bottleneck for patients to receive fertility care. However, with increased understanding of the underlying causes of male factor infertility, the workup and initial management can occur in the primary care setting, helping to streamline care.

Morphological analysis of subcortical structures for assessment of cognitive dysfunction in Parkinson's disease using multi-atlas based segmentation.

Cognitive impairment in Parkinson's Disease (PD) is the most prevalent non-motor symptom that requires analysis of anatomical associations to cognitive decline in PD. The objective of this study is to analyse the morphological variations of the subcortical structures to assess cognitive dysfunction in PD. In this study, T1 MR images of 58 Healthy Control (HC) and 135 PD subjects categorised as 91 Cognitively normal PD (NC-PD), 25 PDwith Mild Cognitive Impairment (PD-MCI) and 19 PDwithDementia (PD-D) subjects, based on cognitive scores are utilised. The 132 anatomical regions are segmented using spatially localized multi-atlas model and volumetric analysis is carried out. The morphological alterations through textural features are captured to differentiate among the HC and PD subjects under different cognitive domains. The volumetric differences in the segmented subcortical structures of accumbens, amygdala, caudate, putamen and thalamus are able to predict cognitive impairment in PD. The volumetric distribution of the subcortical structures in PD-MCI subjects exhibit an overlap with the HC group due to lack of spatial specificity in their atrophy levels. The 3D GLCM features extracted from the significant subcortical structures could discriminate HC, NC-PD, PD-MCI and PD-D subjects with better classification accuracies. The disease related atrophy levels of the subcortical structures captured through morphological analysis provide sensitive evaluation of cognitive impairment in PD.

Arterial Blood Pressure Variability and Other Vascular Factors Contribution to the Cognitive Decline in Parkinson’s Disease

Dementia is one of the most disabling non-motor symptoms in Parkinson’s disease (PD). Unlike in Alzheimer’s disease, the vascular pathology in PD is less documented. Due to the uncertain role of commonly investigated metabolic or vascular factors, e.g., hypertension or diabetes, other factors corresponding to PD dementia have been proposed. Associated dysautonomia and dopaminergic treatment seem to have an impact on diurnal blood pressure (BP) variability, which may presumably contribute to white matter hyperintensities (WMH) development and cognitive decline. We aim to review possible vascular and metabolic factors: Renin-angiotensin-aldosterone system, vascular endothelial growth factor (VEGF), hyperhomocysteinemia (HHcy), as well as the dopaminergic treatment, in the etiopathogenesis of PD dementia. Additionally, we focus on the role of polymorphisms within the genes for catechol-O-methyltransferase (COMT), apolipoprotein E (APOE), vascular endothelial growth factor (VEGF), and for renin-angiotensin-aldosterone system components, and their contribution to cognitive decline in PD. Determining vascular risk factors and their contribution to the cognitive impairment in PD may result in screening, as well as preventive measures.

Clock-Drawing Tasks as Predictive Measurements for Disease Classification Among Patients With Parkinson’s Disease and Essential Tremor

BackgroundNonmotor cognitive symptoms are widely being recognized in both Parkinson’s Disease (PD) and Essential Tremor (ET), the two most common movement disorders. Clock-drawing (CD) test seems to be impaired early in the process of cognitive (executive) decline in PD. However, the optimal measures for detecting cognitive changes in ET patients have not been established. Examining whether the CD test is a quick test could identify frontal and visuospatial deficits in patients with Parkinson’s disease (PD) and essential tremor (ET).MethodsVisuospatial performance was assessed in 58 consecutive patients with ET and 75 with PD and 22 healthy controls (HC) who visited two neurological clinics of Athens in Greece. The CD and copy (CC) items of the PD-Cognitive Rating Scale were used as a test of visuospatial function.ResultsBoth CD and CC scores were lower for ET compared to PD patients and HC (p=<0.001 for both comparisons). A binomial logistic regression showed that both CD and CC items predict if participants had ET or PD with high sensitivity 94.7% and specificity 87.9% and an area under the curve (AUC) 0.980 (95% confidence interval, 0.962-0.997). The model explained 86.1% (Nagelkerke R2) of the variance in the disease variable (ET/PD) and correctly classified 91.7% of the cases.ConclusionPatients with ET have more visuospatial deficits compared to PD and HC. CD task may be an easy, useful tool to track cognitive changes in nondemented patients with ET in clinical practice.

Resting-state EEG alpha/theta ratio related to neuropsychological test performance in Parkinson’s Disease

ObjectiveTo determine possible associations of hemispheric-regional alpha/theta ratio (α/θ) with neuropsychological test performance in Parkinson’s Disease (PD) non-demented patients. Methods36 PD were matched to 36 Healthy Controls (HC). The α/θ in eight hemispheric regions was computed from the relative power spectral density of the resting-state quantitative electroencephalogram (qEEG). Correlations between α/θ and performance in several neuropsychological tests were conducted, significant findings were included in a moderation analysis. ResultsThe α/θ in all regions was lower in PD than in HC, with larger effect sizes in the posterior regions. Right parietal, and right and left occipital α/θ had significant positive correlations with performance in Judgement of Line Orientation Test (JLOT) in PD. Adjusted moderation analysis indicated that right, but not left, occipital α/θ influenced the JLOT performance related to PD. ConclusionsReduction of the occipital α/θ, in particular on the right side, was associated with visuospatial performance impairment in PD. SignificanceVisuospatial impairment in PD, which is highly correlated with the subsequent development of dementia, is reflected in α/θ in the right posterior regions. The right occipital α/θ may represent a useful qEEG marker for evaluating the presence of early signs of cognitive decline in PD and the subsequent risk of dementia.

Lower Plasma α-Synuclein Levels are Associated with Cognitive Impairment in Parkinson's Disease.

α-Synuclein (α-syn) has a central role in the development of Parkinson's disease (PD). Plasma α-syn has been associated with the presence of cognitive impairment in PD although data have been inconsistent. The aim of this study was to explore the correlation between plasma α-syn levels and cognitive impairment in PD. A total of 53 participants, 26 patients with PD and 27 healthy controls were included in the study. Unified Parkinson's Disease Rating Scale (UPDRS) part Ⅲ and Hohen-Yahr scale (H-Y scale) were used to detect PD severity. The cognitive function was assessed with Montreal Cognitive Assessment (MoCA) scale, Frontal Assessment Battery (FAB), Trail Making Test A (TMT-A), Verbal Function Test (VFT), Clock Drawing Test (CDT), and Rey's Auditory Verbal Learning Test (RAVLT). Enzyme-Linked Immunosorbent Assay (ELISA) method was used to measure α-syn and hemoglobin (Hb) concentration in the plasma samples collected from participants. Plasma α-syn in PD patients was significantly lower than those in the control group (p < 0.01). No associations were found between plasma α-syn and Hb or gender (p > 0.05). The decline in plasma α-syn in PD patients was negatively correlated with disease severity, including UPDRS Ⅲ scores and H-Y scale. Furthermore, lower plasma α-syn was negatively associated with the scores of MoCA, FAB, and RAVLT (immediate recall) scores in PD group. Our data suggest that lower plasma α-syn levels are associated with cognitive decline in PD. Thus, plasma α-syn may be a novel biomarker for patients at risk of cognitive decline.

Chapter 12 - Nucleus basalis of Meynert degeneration predicts cognitive impairment in Parkinson's disease

Cognitive impairment affects approximately 20%-50% of patients with Parkinson's disease (PD), with a higher prevalence as the disease advances. The nucleus basalis of Meynert (NBM) provides the majority of cholinergic innervations to the cerebral cortex. Dysfunction of the cholinergic system and degeneration of the NBM have been implicated in the pathophysiology of cognitive impairment in neurodegenerative disorders including PD. Several studies have aimed to identify risk factors associated with cognitive decline in order to construct models to predict future cognitive impairment in PD. Given the link between cholinergic dysfunction and the pathogenesis of cognitive decline in PD, a number of studies have focused on the role of the NBM underlying cognitive performance. Recently, microstructural alterations within the NBM, detected using diffusion tensor imaging, have been identified as a strong predictor for the development of cognitive impairment in patients with PD. These microstructural changes in NBM have been shown to precede structural gray matter volumetric loss and may present with an early marker to predict cognitive decline in patients with PD. Longitudinal studies are warranted to provide insights into the potential utility of cholinergic positron emission tomography imaging to predict the development of cognitive impairment in PD and other neurodegenerative disorders. Provided the urgent need for disease modifying therapies aiming to slow and ultimately halt the progression of cognitive impairment, neuromodulation of NBM, and treatments targeting the cholinergic system may hold a promising potential. In this review, we discuss the link between NBM pathology and clinical symptomatology of cognitive impairment in PD with a focus on the use of in vivo imaging techniques and potential therapeutic interventions.

Frontal functional connectivity and disease duration interactively predict cognitive decline in Parkinson's disease

ObjectiveCognitive decline does not always follow a predictable course in Parkinson’s disease (PD), with some patients remaining stable while others meet criteria for dementia from early stages. Functional connectivity has been proposed as a good correlate of cognitive decline in PD, although it has not been explored whether the association between this connectivity and cognitive ability is influenced by disease duration, which was our objective. MethodsWe included 30 patients with PD and 15 healthy controls (HC). Six cognitive domains were estimated based on neuropsychological assessment. Phase-based connectivity at frontal and posterior cortical regions was estimated from a resting EEG. ResultsThe PD group showed significant impairment for the executive, visuospatial, and language domains compared with HC. Increased connectivity at frontal regions was also found in the PD group. Frontal delta and theta connectivity negatively influenced general cognition and visuospatial performance, but this association was moderated by disease duration, with increased connectivity predicting worse performance after 8 years of disease duration. ConclusionSubtle neurophysiological changes underlie cognitive decline along PD progression, especially around a decade after motor symptoms onset. SignificanceConnectivity of EEG slow waves at frontal regions might be used as a predictor of cognitive decline in PD.

Retinal Thickness Predicts the Risk of Cognitive Decline in Parkinson Disease.

ObjectiveThis study was undertaken to analyze longitudinal changes of retinal thickness and their predictive value as biomarkers of disease progression in idiopathic Parkinson's disease (iPD).MethodsPatients with Lewy body diseases were enrolled and prospectively evaluated at 3 years, including patients with iPD (n = 42), dementia with Lewy bodies (n = 4), E46K‐SNCA mutation carriers (n = 4), and controls (n = 17). All participants underwent Spectralis retinal optical coherence tomography and Montreal Cognitive Assessment, and Unified Parkinson's Disease Rating Scale score was obtained in patients. Macular ganglion cell–inner plexiform layer complex (GCIPL) and peripapillary retinal nerve fiber layer (pRNFL) thickness reduction rates were estimated with linear mixed models. Risk ratios were calculated to evaluate the association between baseline GCIPL and pRNFL thicknesses and the risk of subsequent cognitive and motor worsening, using clinically meaningful cutoffs.ResultsGCIPL thickness in the parafoveal region (1‐ to 3‐mm ring) presented the largest reduction rate. The annualized atrophy rate was 0.63μm in iPD patients and 0.23μm in controls (p < 0.0001). iPD patients with lower parafoveal GCIPL and pRNFL thickness at baseline presented an increased risk of cognitive decline at 3 years (relative risk [RR] = 3.49, 95% confidence interval [CI] = 1.10–11.1, p = 0.03 and RR = 3.28, 95% CI = 1.03–10.45, p = 0.045, respectively). We did not identify significant associations between retinal thickness and motor deterioration.InterpretationOur results provide evidence of the potential use of optical coherence tomography–measured parafoveal GCIPL thickness to monitor neurodegeneration and to predict the risk of cognitive worsening over time in iPD. ANN NEUROL 2021;89:165–176

From the Gut to the Brain and Back: Therapeutic Approaches for the Treatment of Network Dysfunction in Parkinson's Disease.

Parkinson's disease (PD) is a complex, multisystem, progressive, degenerative disorder characterized by severe, debilitating motor dysfunction, cognitive impairments, and mood disorders. Although preclinical research has traditionally focused on the motor deficits resulting from the loss of nigrostriatal dopaminergic neurons, up to two thirds of PD patients present separate and distinct behavioral changes. Loss of basal forebrain cholinergic neurons occurs as early as the loss of dopaminergic cells and contributes to the cognitive decline in PD. In addition, attentional deficits can limit posture control and movement efficacy caused by dopaminergic cell loss. Complicating the picture further is intracellular α-synuclein accumulation beginning in the enteric nervous system and diffusing to the substantia nigra through the dorsal motor neurons of the vagus nerve. It seems that α-synuclein's role is that of mediating dopamine synthesis, storage, and release, and its function has not been completely understood. Treating a complex, multistage network disorder, such as PD, likely requires a multipronged approach. Here, we describe a few approaches that could be used alone or perhaps in combination to achieve a greater mosaic of behavioral benefit. These include (1) using encapsulated, genetically modified cells as delivery vehicles for administering neuroprotective trophic factors, such as GDNF, in a direct and sustained means to the brain; (2) immunotherapeutic interventions, such as vaccination or the use of monoclonal antibodies against aggregated, pathological α-synuclein; (3) the continuous infusion of levodopa-carbidopa through an intestinal gel pad to attenuate the loss of dopaminergic function and manage the motor and non-motor complications in PD patients; and (4) specific rehabilitation treatment programs for drug-refractory motor complications.

Comparisons of cardiovascular dysautonomia and cognitive impairment between de novo Parkinson\u2019s disease and de novo dementia with Lewy bodies

BackgroundCognitive impairment may be correlated with cardiovascular dysautonomia, including blood pressure (BP) dysregulation, in Parkinson’s disease (PD), but the association between these factors in dementia with Lewy bodies (DLB) is uncertain. This study aimed to clarify whether cardiovascular dysautonomia had an influence on cognitive function in Lewy body disease or not.MethodsNinty-nine patients with de novo PD (n = 75) and DLB (n = 24) were evaluated using the Mini-Mental State Examination (MMSE) and Frontal Assessment Battery (FAB). Cardiac 123I-metaiodobenzylguanidine (MIBG) scintigraphy, orthostatic hypotension (OH), supine hypertension (SH), postprandial hypotension (PPH), nocturnal BP fall in 24-h ambulatory blood pressure monitoring (ABPM) and constipation were estimated. Associations of these factors with cognitive and executive dysfunction were examined.ResultsIn DLB, MIBG uptake was reduced and OH, PPH and SH were severely disturbed, compared to PD. The nocturnal BP fall in ABPM was lower in DLB, and the failure of nocturnal BP fall in PD was associated with MMSE, after adjustment for other clinical features. FAB was significantly associated nocturnal BP fall, age and SH in PD, but no significant correlations among factors were found for DLB.ConclusionThe significant association between nocturnal BP dysregulation and cognitive or executive decline in PD might be due to impaired microvascular circulation or invasion of α-synuclein in the CNS. The lack of a correlation of BP insufficiency with cognitive impairment in DLB suggests initial involvement of Lewy body pathology in the neocortex, regardless of Lewy body invasion of the autonomic nervous system.

Association of PICALM with Cognitive Impairment in Parkinson's Disease.

Cognitive impairment is one of the most disabling nonmotor symptoms in Parkinson's disease (PD). Recently, a genome-wide association study in Alzheimer's disease has identified the PICALM rs3851179 polymorphism as one of the most significant susceptibility genes for Alzheimer's disease after APOE. The aim of this study was to determine the potential role of PICALM and its genetic interaction with APOE in the development of cognitive decline in PD. A discovery cohort of 712 patients with PD were genotyped for PICALM (rs3851179) and APOE (rs429358 and rs7412) polymorphisms. The association of PICALM and APOE-PICALM genetic interaction with cognitive dysfunction in PD was studied using logistic regression models, and the relationship of PICALM with cognitive decline onset was assessed with Cox regression analysis. PICALM effect was then replicated in an international, independent cohort (Parkinson's Progression Markers Initiative, N = 231). PICALM rs3851179 TT genotype was significantly associated with a decreased risk of cognitive impairment in PD (TT vs. CC + CT, P = 0.041, odds ratio = 0.309). Replication studies further demonstrated its protective effect on cognitive impairment in PD. In addition, the protective effect of the PICALM rs3851179 TT genotype was more pronounced in the APOE ε4 (-) carriers from the discovery cohort (P = 0.037, odds ratio = 0.241), although these results were not replicated in the Parkinson's Progression Markers Initiative cohort. Our results support the fact that PICALM is associated with cognitive impairment in PD. The understanding of its contribution to cognitive decline in PD could provide new targets for the development of novel therapies. © 2020 International Parkinson and Movement Disorder Society.

NREM sleep arousal-related disorders reflect cognitive impairment in Parkinson's disease

BackgroundSleep disorders and cognitive impairment are frequently reported in Parkinson's disease (PD) as non-motor disabling symptoms. While it is known that REM sleep Behaviour Disorder (RBD) in PD is associated with motor and cognitive decline, little is known about the neurobiological significance of NREM sleep arousal-related disorders.Objectives: to evaluate the cognitive and clinical correlates of arousal-related disorders in PD. MethodsClinical data and video-polysomnography were analysed from one hundred-seventy consecutive subjects with PD. Based on the neuropsychological assessment, the subjects were divided into three groups: no cognitive impairment (PD; n = 58), mild cognitive impairment (PD-MCI; n = 58) and overt dementia (PDD; n = 54). ResultsArousal-related disorders by history were reported in 32.9% of the subjects: 10.3% PD, 31.6% PD-MCI and 59.3% PDD (p = 0.001). Video-PSG captured arousal-related disorders in 1.7% PD, 21.2% MCI-PD and 35.6% PDD (p = 0.001). Arousal-related disorders and RBD were recorded in the same night in 7.7% PD, 9.8% MCI-PD and 15.6% PDD (p = 0.04). Patients with arousal-related disorders captured at V-PSG have a longer disease duration (p = 0.003), higher UPDRS score (p = 0.039), longer duration of treatment with levodopa (p = 0.017) and dopamine agonists (p = 0.018), worse H&Y staging (p = 0.001), lower MMSE score (p = 0.019) and more frequently hallucinations (p = 0.004). In multivariate analysis, cognitive impairment significantly increases the risk of arousal-related disorders (OR 3.387–95% CI 1.395–8.220, p = 0.007). ConclusionArousal-related disorders appear to be a marker of cognitive decline in PD. Recognizing arousal-related disorders should make clinicians aware of a possible cognitive decline in PD and eventually modify the therapeutic approach.

Orthostatic Hypotension Is Associated With Cognitive Decline in Parkinson Disease.

Introduction: Cognitive impairment and orthostatic hypotension (OH) are common, disabling Parkinson disease (PD) symptoms that are strongly correlated. Whether the relationship is causative or associative remains unknown. OH may occur without classic orthostatic symptoms of cerebral hypoperfusion (i.e., lightheadedness or dizziness). Whether longitudinal differences in cognition occur between symptomatic and asymptomatic OH patients has not been explored.Objectives: We characterized the prevalence of OH, orthostatic symptoms, and cognitive impairment among PD patients and compared cognition between patients with and without OH, and between patients with symptomatic and asymptomatic OH.Methods: Our cross-sectional, retrospective, observational study included 226 clinically diagnosed PD patients who underwent repeated standardized evaluations. Among these, 62 had longitudinal follow-up of > 3.5 years. We compared longitudinal Montreal Cognitive Assessment (MoCA) scores between patients remaining OH-free (n = 14) and those without baseline OH that developed OH (n = 28), matched for age, sex, education, and PD duration. We also compared MoCA scores between groups with asymptomatic OH (n = 13) and symptomatic OH (n = 13) matched for the same factors.Results: In the cross-sectional analysis, OH patients had worse cognition. In the longitudinal analysis (mean follow-up = 5.3 years), OH patients had worse cognitive decline (p = 0.027). Cognitive impairment was similar between asymptomatic and symptomatic OH patients in the cross-sectional and longitudinal analyses.Conclusions: OH is associated with cognitive impairment in PD. Further studies are needed in larger cohorts to expand our findings and to determine whether treating OH can prevent or delay cognitive dysfunction.

Early-start vs delayed-start donepezil against cognitive decline in Parkinson disease: a randomized clinical trial

ABSTRACT Background Cholinergic neurotransmission regulates neuroinflammation in Parkinson disease (PD). Research design and methods The authors conducted a delayed-start study of donepezil for cognitive decline in non-demented PD patients. The study consisted of a 96-week randomized placebo-controlled double-blind phase 1, followed by a 24-week donepezil extension phase 2. The primary outcome measure was a change in the Mini-Mental State Examination (MMSE) at week 120. Results A total of 98 patients were randomly allocated to the early-start (donepezil-to-donepezil) and delayed-start (placebo-to-donepezil) groups. Mean (SD) of the baseline MMSE was 27.6 (2.0) and 28.0 (2.1), respectively. MMSE change at week 120 was better in the early-start group than in the delayed-start group, but the difference was not significant. The MMSE declined in apolipoprotein ε4 carriers, but not in non-carriers, and the factor interaction (intervention × ε4 genotype) was highly significant (P < 0.001). Analyzed with the interaction, the difference was significant (group difference 1.95 [0.33 to 3.57], P = 0.018). The MMSE decline slope in phase 1 was significantly better in the early-start group than in the delayed-start group (P = 0.048). Conclusions Cognitive function deteriorated in ε4 carriers, but not in non-carriers, and early-start donepezil may postpone cognitive decline in the former.

The cerebral blood flow deficits in Parkinson's disease with mild cognitive impairment using arterial spin labeling MRI.

Parkinson's disease (PD) with mild cognitive impairment (PD-MCI) is currently diagnosed based on an arbitrarily predefined standard deviation of neuropsychological test scores, and more objective biomarkers for PD-MCI diagnosis are needed. The purpose of this study was to define possible brain perfusion-based biomarkers of not only mild cognitive impairment, but also risky gene carriers in PD using arterial spin labeling magnetic resonance imaging (ASL-MRI). Fifteen healthy controls (HC), 26 cognitively normal PD (PD-CN), and 27 PD-MCI subjects participated in this study. ASL-MRI data were acquired by signal targeting with alternating radio-frequency labeling with Look-Locker sequence at 3T. Single nucleotide polymorphism genotyping for rs9468 [microtubule-associated protein tau (MAPT) H1/H1 versus H1/H2 haplotype] was performed using a Stratagene Mx3005p real-time polymerase chain-reaction system (Agilent Technologies, USA). There were 15 subjects with MAPT H1/H1 and 11 subjects with MAPT H1/H2 within PD-MCI, and 33 subjects with MAPT H1/H1 and 19 subjects with MAPT H1/H2 within all PD. Voxel-wise differences of cerebral blood flow (CBF) values between HC, PD-CN and PD-MCI were assessed by one-way analysis of variance followed by pairwise post hoc comparisons. Further, the subgroup of PD patients carrying the risky MAPT H1/H1 haplotype was compared with noncarriers (MAPT H1/H2 haplotype) in terms of CBF by a two-sample t test. A pattern that could be summarized as "posterior hypoperfusion" (PH) differentiated the PD-MCI group from the HC group with an accuracy of 92.6% (sensitivity = 93%, specificity = 93%). Additionally, the PD patients with MAPT H1/H1 haplotype had decreased perfusion than the ones with H1/H2 haplotype at the posterior areas of the visual network (VN), default mode network (DMN), and dorsal attention network (DAN). The PH-type pattern in ASL-MRI could be employed as a biomarker of both current cognitive impairment and future cognitive decline in PD.

Evolution of Alzheimer's Disease Cerebrospinal Fluid Biomarkers in Early Parkinson's Disease.

ObjectiveWe analyzed the longitudinal profile of Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers in early Parkinson's disease (PD) compared with healthy controls (HCs) and tested baseline CSF biomarkers for prediction of clinical decline in PD.MethodsAmyloid‐β 1 to 42 (Aβ42), total tau (t‐tau) and phosphorylated tau (p‐tau) at the threonine 181 position were measured using the high‐precision Roche Elecsys electrochemiluminescence immunoassay in all available CSF samples from longitudinally studied patients with PD (n = 416) and HCs (n = 192) followed for up to 3 years in the Parkinson's Progression Markers Initiative (PPMI). Longitudinal CSF and clinical data were analyzed with linear‐mixed effects models.ResultsWe found patients with PD had lower CSF t‐tau (median = 157.7 pg/mL; range = 80.9–467.0); p‐tau (median = 13.4 pg/mL; range = 8.0–40.1), and Aβ42 (median = 846.2 pg/mL; range = 238.8–3,707.0) than HCs at baseline (CSF t‐tau median = 173.5 pg/mL; range = 82.0–580.8; p‐tau median = 15.4 pg/mL; range = 8.1–73.6; and Aβ42 median = 926.5 pg/mL; range = 239.1–3,297.0; p < 0.05–0.001) and a moderate‐to‐strong correlation among these biomarkers in both patients with PD and HCs (Rho = 0.50–0.97; p < 0.001). Of the patients with PD, 31.5% had pathologically low levels of CSF Aβ42 at baseline and these patients with PD had lower p‐tau levels (median = 10.8 pg/mL; range = 8.0–32.8) compared with 27.7% of HCs with pathologically low CSF Aβ42 (CSF p‐tau median = 12.8 pg/mL; range 8.2–73.6; p < 0.03). In longitudinal CSF analysis, we found patients with PD had greater decline in CSF Aβ42 (mean difference = −41.83 pg/mL; p = 0.03) and CSF p‐tau (mean difference = −0.38 pg/mL; p = 0.03) at year 3 compared with HCs. Baseline CSF Aβ42 values predicted small but measurable decline on cognitive, autonomic, and motor function in early PD.InterpretationOur data suggest baseline CSF AD biomarkers may have prognostic value in early PD and that the dynamic change of these markers, although modest over a 3‐year period, suggest biomarker profiles in PD may deviate from healthy aging. ANN NEUROL 2020;88:574–587