Telehealth Cognitive Behavior Therapy to Reduce Anxiety in People Living with Cognitive Impairment: A Randomized Feasibility Pilot Study.

OBJECTIVES: To evaluate the feasibility of telehealth-based cognitive behavior therapy for people living with cognitive impairment experiencing anxiety (Tele-CBT), and to assess whether this leads to improvements in anxiety, depression, and quality of life post-intervention. METHODS: This was a single-blind randomized feasibility pilot trial of the Tele-CBT versus usual care. People living with mild cognitive impairment or dementia experiencing anxiety were recruited and randomized to receive Tele-CBT (n = 5) or continue usual care (n = 5). Feasibility data comprised recruitment uptake and retention, adherence, and ease of use. Outcomes of anxiety (primary outcome - Rating Anxiety in Dementia; RAID), depression, stress, and quality of life were measured pre- and post-intervention. RESULTS: Intervention feasibility was demonstrated through minimal attrition, acceptability, and ease of use via videoconferencing. Both groups showed a decrease of anxiety symptoms (RAID) from baseline to post-assessment. CONCLUSIONS: The Tele-CBT program was acceptable to use via videoconferencing. Reduced anxiety symptoms were observed in both groups at post-. An RCT with a larger sample is required to determine the efficacy and implementation of the intervention. CLINICAL IMPLICATIONS: This study indicates the feasibility of videoconference CBT to address anxiety experienced by people living with cognitive impairment with minimal assistance from support persons.

Hippocampal resting-state connectivity is associated with posterior-cortical cognitive impairment in Parkinson's disease.

AIM: Frontal and posterior-cortical cognitive subtypes in Parkinson's disease (PD) present with executive/attention and memory/visuospatial deficits, respectively. As the posterior-cortical subtype is predicted to progress rapidly toward dementia, the present study aimed to explore biological markers of this group using resting-state functional magnetic resonance imaging (rs-fMRI). METHODS: K-means cluster analysis delineated subtypes (cognitively intact, frontal, posterior-cortical, and globally impaired) among 85 people with PD. A subset of PD participants (N = 42) and 20 healthy controls (HCs) underwent rs-fMRI. Connectivity of bilateral hippocampi with regions of interest was compared between posterior-cortical, cognitively intact, and HC participants using seed-based analysis, controlling for age. Exploratory correlations were performed between areas of interest from the group analysis and a series of cognitive tests. RESULTS: The posterior-cortical subtype (N = 19) showed weaker connectivity between the left hippocampus and right anterior temporal fusiform cortex compared to the cognitively intact (N = 11) group, p-false discovery rate (FDR) = .01, and weaker connectivity between bilateral hippocampi and most fusiform regions compared to HCs (N = 20). No differences were found between HCs and cognitively intact PD. Exploratory analyses revealed strongest associations between connectivity of the right anterior temporal fusiform cortex and left hippocampus with category fluency (p-FDR = .01). CONCLUSION: Results suggest that weakened connectivity between the hippocampus and fusiform region is a unique characteristic of posterior-cortical cognitive deficits in PD. Further exploration of hippocampal and fusiform functional integrity as a marker of cognitive decline in PD is warranted.

Levetiracetam for the treatment of mild cognitive impairment in Parkinson's disease: a double-blind controlled proof-of-concept trial protocol.

BACKGROUND: Mild memory impairment, termed amnestic mild cognitive impairment (aMCI), is associated with rapid progression towards dementia in Parkinson's disease (PD). Studies have shown hyperactivation of hippocampal DG/CA3 subfields during an episodic memory task as a biomarker of aMCI related to Alzheimer's disease. This project investigates the feasibility of a trial to establish the efficacy of a repurposed antiepileptic drug, levetiracetam, in low doses as a putative treatment to target DG/CA3 hyperactivation and improve episodic memory deficits in aMCI in PD. Based on previous work, it is hypothesized that levetiracetam will normalize DG/CA3 overactivation in PD-aMCI participants and improve memory performance. METHODS: Twenty-eight PD-aMCI participants, 28 PD participants without memory impairment (PD-nMI), and 28 healthy controls will be recruited. PD-aMCI participants will undertake a 12-week randomized, placebo-controlled, double-blind cross-over trial with a 14-day treatment of 125 mg levetiracetam or placebo twice daily, separated by a 4-week washout period. After each treatment period, participants will complete an episodic memory task designed to tax hippocampal subregion-specific function during high-resolution functional magnetic resonance imaging (fMRI). PD-nMI and healthy controls will undergo the fMRI protocol only, to compare baseline DG/CA3 subfield activity. RESULTS: Episodic memory task performance and functional activation in the DG/CA3 subfield during the fMRI task will be primary outcome measures. Global cognition, PD severity, and adverse events will be measured as secondary outcomes. Recruitment, eligibility, and study completion rates will be explored as feasibility outcomes. CONCLUSIONS: This study, the first of its kind, will establish hippocampal subregion functional impairment and proof of concept of levetiracetam as an early therapeutic option to reduce dementia risk in PD. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04643327 . Registered on 25 November 2020.

Longitudinal follow up of data-driven cognitive subtypes in Parkinson's disease.

AIM: The dual syndrome hypothesis proposes that there are two cognitive subtypes in Parkinson's disease (PD): a frontal subtype with executive/attention impairment and gradual cognitive decline, and a posterior-cortical subtype with memory/visuospatial deficits and rapid cognitive decline. We aimed to compare the rate of global cognitive decline between subtypes derived using data-driven methods and explore their longitudinal performance within specific cognitive domains to better understand the prognosis of each subtype. METHOD: Frontal, posterior-cortical, globally impaired, and cognitively intact PD subtypes were identified at baseline using k-means clustering (N = 85), and 29 participants (34%) returned for follow-up assessments on average 4.87 years from baseline. Linear mixed effects models compared progression of subtypes on global cognition; psychological symptoms; parkinsonism; and the memory, attention, executive, language, and visuospatial cognitive domains. RESULTS: The frontal subtype was lost to attrition. While rate of change in parkinsonism, anxiety, and apathy differed between subtypes, there was no difference in the rate of global cognitive decline. However, the posterior-cortical subtype declined most rapidly in verbal memory, card sorting, trail making, and judgement of line orientation (JLO), while the cognitively intact group declined most rapidly on verbal memory and semantic fluency. The globally impaired subtype declined most rapidly in JLO, although this should be interpreted with caution due to high attrition. CONCLUSION: Despite limited sample size, the present study supports the differential progression of the posterior-cortical subtype compared to cognitively intact and globally impaired PD. These results encourage further, large-scale longitudinal investigations of cognitive subtypes in PD.

Global assessment, cognitive profile, and characteristics of mild cognitive impairment in Parkinson's disease.

BACKGROUND: Cognitive deficits are evident throughout the course of Parkinson's disease (PD), with 24% of patients experiencing subtle cognitive disturbances at the time of diagnosis, and with up to 80% of patients developing PD dementia (PDD) at advanced stages of the disease PD patients with mild cognitive impairment (MCI), an at-risk phenotype of PDD, present with heterogeneous clinical characteristics that complicate the management of PD. OBJECTIVES: This study aims to examine the characteristics of PD-MCI by using the Movement Disorder Society (MDS) diagnostic criteria and evaluate the validity of global cognitive scales in identifying PD-MCI. METHODS: Seventy-nine (79) PD patients completed neuropsychological assessments and a comprehensive cognitive battery. PD-MCI was classified according to the level 2 MDS task force criteria. Mini-Mental State Examination (sMMSE), Montreal Cognitive Assessment (MoCA) and Parkinson's Disease Cognitive Rating Scale (PDCRS) were examined against a level 2 dichotomised PD-MCI diagnosis. Characteristics of PD-MCI were evaluated using logistic regression analysis. RESULTS: Twenty-seven patients met criteria for PD-MCI (34%). The MoCA and PDCRS demonstrated high validity to screen for PD-MCI. Impairments in multiple cognitive domains were observed in 77.8% of PD-MCI patients. There were significantly more males in the PD-MCI group compared to PD patients without MCI (p < 0.01). CONCLUSIONS: PD patients with MCI exhibited impairments in the attention/working memory, executive function and memory domains. Heterogeneous cognitive characteristics in PD warrant further investigation into specific cognitive subtypes to advance understanding and effective evaluation of PD-MCI.

Systematic review of data-driven cognitive subtypes in Parkinson disease.

BACKGROUND AND PURPOSE: Recent application of the mild cognitive impairment concept to Parkinson disease (PD) has proven valuable in identifying patients at risk of dementia. However, it has sparked controversy regarding the existence of cognitive subtypes. The present review evaluates the current literature pertaining to data-driven subtypes of cognition in PD. METHODS: Following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, systematic literature searches for peer-reviewed articles on the topic of cognitive subtyping in PD were performed. RESULTS: Twenty-two relevant articles were identified in the systematic search. Subtype structures showed either a spectrum of severity or specific domains of impairment. Domain-specific subtypes included amnestic/nonamnestic, memory/executive, and frontal/posterior dichotomies, as well as more complex structures with less definitive groupings. Preliminary longitudinal evidence showed some differences in cognitive progression among subtypes. Neuroimaging evidence provided insight into distinct patterns of brain alterations among subtypes. CONCLUSIONS: Recurring phenotypes in the literature suggest strong clinical relevance of certain cognitive subtypes in PD. Although the current literature is limited, it raises critical questions about the utility of data-driven methods in cognitive research. The results encourage further integration of neuroimaging research to define the latent neural mechanisms behind divergent subtypes. Although there is no consensus, there appears to be growing consistency and inherent value in identifying cognitive subtypes in PD.

Semantic fluency deficits and associated brain activity in Parkinson's disease with mild cognitive impairment.

People living with Parkinson's disease (PD) with poor verbal fluency have an increased risk of developing dementia. This study examines the neural mechanisms underpinning semantic fluency deficits in patients with PD with mild cognitive impairment (PD-MCI) compared to those without MCI (PD-NC) and control participants without PD (non-PD). Thirty-seven (37) participants with PD completed a cognitive assessment battery to identify MCI (13 PD-MCI). Twenty sex- and age-matched non-PD patients also participated. Participants were scanned (3T Siemens PRISMA) while performing semantic fluency, semantic switching, and automatic speech tasks. The number of responses and fMRI data for semantic generation and semantic switching were analyzed. Participants also completed a series of verbal fluency tests outside the scanner, including letter fluency. Participants with PD-MCI performed significantly worse than PD-NC and non-PD participants during semantic fluency and semantic switching tasks. PD-MCI patients showed greater activity in the right angular gyrus than PD-NC and non-PD patients during semantic switching. Increased right angular activity correlated with worse verbal fluency performance outside the scanner. Our study showed that the PD-MCI group performed worse on semantic fluency than either the PD-NC or non-PD groups. Increased right angular gyrus activity in participants with PD-MCI during semantic switching suggests early compensatory mechanisms, predicting the risk of future dementia in PD.

The Attention Network Test in Parkinson and Lewy Body Disease: A Systematic Review.

BACKGROUND: The Attention Network Test (ANT) is a well-established measure of efficiency for the alerting, orienting, and executive attentional networks. However, its novel application in Parkinson disease (PD) and Lewy body dementia (LBD) research more broadly has yet to be evaluated systematically. OBJECTIVE: To compare and consolidate the outcomes of studies reporting use of the ANT in PD and LBD groups and to identify the methodological considerations for the conduct of such studies. METHOD: We performed a systematic literature search for articles exploring attention in PD and LBD groups using the ANT. We excluded articles on the basis of irrelevant scope, non-English, and groups other than PD and LBD. Once the full text articles were identified, we extracted the data and assessed the studies' quality. RESULTS: The final sample included 16 articles ranging from low to moderate quality. Behavioral findings suggested a general slowing of responses yet preserved accuracy from the PD group compared with controls. Overall, the evidence was inconclusive regarding the state of the alerting network in the PD and LBD groups, mostly supportive of an intact orienting network, and strongly suggestive of an impaired executive network. Differences in sample stratification, patient symptomatology, and dopaminergic medication levels were identified as influential factors in the attentional results across studies. CONCLUSION: Although sparse, the existing evidence indicates that the ANT is a viable option for measuring attention in PD; it can also be harnessed to explore the impact of symptoms and medications on attentional networks in PD and LBD groups.

Anxiety disorders are associated with verbal memory impairment in patients with Parkinson's disease without dementia.

INTRODUCTION: Preliminary evidence has demonstrated a link between anxiety and memory impairment in Parkinson's disease (PD). This study further investigated this association using the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria for anxiety disorders and a standardized cognitive test battery. METHODS: A convenience sample of 89 PD patients without dementia was recruited from neurology outpatient clinics. A cross-sectional design was applied. Participants completed two semi-structured interviews. The first interview diagnosed DSM-5 anxiety disorders, unspecified anxiety disorder, and no anxiety. The second interview applied a neurocognitive test battery comprising two tests for each domain. Logistic regression models compared cognitive characteristics associated with anxiety disorders to no anxiety. RESULTS: Clinically significant anxiety was associated with immediate verbal memory impairment compared to the no anxiety group (OR, 95% CI 0.52, 0.30-0.89; p = 0.018), controlling for sex and age. The anxiety disorders group demonstrated immediate (OR, 95% CI 0.46, 0.26-0.83; p = 0.010) and delayed (OR, 95% CI 0.63, 0.40-0.99; p = 0.047) verbal memory impairments compared to those without anxiety, controlling for sex and age. This association remained for immediate (OR, 95% CI 0.43, 0.22-0.84; p = 0.013), but not delayed verbal memory impairment (OR, 95% CI 0.65, 0.39-1.06; p = 0.081) when additionally controlling for disease severity, education and levodopa dose. CONCLUSION: These findings present first evidence that anxiety disorders are associated with verbal memory impairment in PD and have implications for the management and treatment of anxiety in PD.

Hippocampal correlates of episodic memory in Parkinson's disease: A systematic review of magnetic resonance imaging studies.

The present review asks whether magnetic resonance imaging (MRI) studies are able to define neural correlates of episodic memory within the hippocampus in Parkinson's disease (PD). Systematic searches were performed in PubMed, Web of Science, Medline, CINAHL, and EMBASE using search terms related to structural and functional MRI (fMRI), the hippocampus, episodic memory, and PD. Risk of bias was assessed for each study using the Newtown-Ottawa Scale. Thirty-nine studies met inclusion criteria; eight fMRI, seven diffusion MRI (dMRI), and 24 structural MRI (14 exploring whole hippocampus and 10 exploring hippocampal subfields). Critical analysis of the literature revealed mixed evidence from functional and dMRI, but stronger evidence from sMRI of the hippocampus as a biomarker for episodic memory impairment in PD. Hippocampal subfield studies most often implicated CA1, CA3/4, and subiculum volume in episodic memory and cognitive decline in PD. Despite differences in imaging methodology, study design, and sample characteristics, MRI studies have helped elucidate an important neural correlate of episodic memory impairment in PD with both clinical and theoretical implications. Natural progression of this work encourages future research on hippocampal subfield function as a potential biomarker of, or therapeutic target for, episodic memory dysfunction in PD.

Neural correlates of attentional deficits in Parkinson's disease patients with mild cognitive impairment.

INTRODUCTION: Deficits in attentional processing observed in Parkinson's disease (PD) patients with mild cognitive impairment (MCI) increase risk of PD dementia. However, the neural basis of these attentional deficits are presently unknown. The present study aimed to explore the neural correlates of attention dysfunction in PD-MCI using the Attention Network Test (ANT) and functional Magnetic Resonance Imaging (fMRI). METHOD: Fifteen (15) PD-MCI patients, 26 PD patients without MCI (PD-NC) and 22 healthy controls (HC) were scanned (3T Siemens PRISMA) whilst performing the ANT. Reaction time, accuracy and fMRI BOLD activation were compared between groups for the three attentional task components of 1) alerting, 2) orienting, and 3) executive control. RESULTS: PD-MCI patients showed an overall slower reaction time compared to PD-NC and HC, and showed less interference of reaction time in the orienting effect than HC. fMRI data demonstrated greater activation in the bilateral cerebellum crus 1 during the alerting attention condition in both PD-MCI and PD-NC compared to HC. However, activation was supressed in the left postcentral gyrus in PD-MCI compared to PD-NC and HC. DISCUSSION: Alterations in the alerting attention functional network despite intact task performance in PD-MCI suggests that functional brain changes may precede cognitive changes in the attention domain. Furthermore, increased activation in the cerebellum may reflect an attentional compensatory mechanism unique to the PD pathology. Taken together, the findings suggest that PD has a complex effect on attentional ability that can, at least in part, be elucidated using functional neuroimaging.

Identifying subtypes of mild cognitive impairment in Parkinson's disease using cluster analysis.

INTRODUCTION: The concept of Mild Cognitive Impairment (MCI) in Parkinson's disease (PD) has shown the potential for identifying at-risk dementia patients. Identifying subtypes of MCI is likely to assist therapeutic discoveries and better clinical management of patients with PD (PWP). Recent cluster-based approaches have demonstrated dominance in memory and executive impairment in PD. The present study will further explore the role of memory and executive impairment and associated clinical features in non-demented PWP. METHOD: A K-means cluster analysis was performed on ten "frontal" and "posterior" cognitive variables derived from a dataset of 85 non-demented PWP. The resulting cluster structure was chosen based on quantitative, qualitative, theoretical, and clinical validity. Cluster profiles were then created through statistical analysis of cognitive and clinical/demographic variables. A descriptive analysis of each cluster's performance on a comprehensive PD-MCI diagnostic battery was also explored. RESULTS: The resulting cluster structure revealed four distinct cognitive phenotypes: (1) frontal-dominant impairment; (2) posterior-cortical-dominant impairment; (3) global impairment, and (4) cognitively intact. Demographic profiling revealed significant differences in the age, gender split, global cognitive ability, and motor symptoms between these clusters. However, there were no significant differences between the clusters on measures of depression, apathy, and anxiety. CONCLUSION: These results validate the existence of distinct cognitive phenotypes within PD-MCI and encourage future research into their clinical trajectory and neuroimaging correlates.