Adherence to Non-Pharmacological Interventions in Parkinson's Disease: A Rapid Evidence Assessment of the Literature.

Background: Low adherence to non-pharmacological interventions can impact treatment effectiveness. Yet, there is limited information on adherence barriers and facilitators to non-pharmacological interventions in Parkinson's disease (PD). Objective: 1) To examine the quality of adherence reporting and 2) to identify key determinants of adherence to PD non-pharmacological interventions. Methods: A rapid evidence assessment was conducted, following PRISMA guidelines, that included controlled studies of exercise, physiotherapy, occupational therapy, speech-language therapy with explicit reporting of 'adherence' OR 'compliance', published in the last 15 years. Data extracted included: adherence rates, adherence outcomes, and factors associated with adherence. A collaborative thematic analysis was conducted to identify determinants of adherence. Results: The search yielded 2,445 articles of which 114 met criteria for full screening with 45 studies meeting all inclusion criteria. High quality adherence data that aligned with the intervention goals were reported by 22.22%(N = 10) of studies, with the majority reporting attendance/attrition rates only 51.11%(N = 23). Four major themes (34 subthemes) emerged: disease and health, personal, program design, and system and environmental. Conclusions: There has been limited progress in the quality of adherence reporting in PD non-pharmacological interventions over the last decade. Acknowledging this limitation, key determinants of adherence included: alignment with personal beliefs, attitudes, and expectations; the demands of the intervention and worsening disease symptoms and personal/time obligations; and accessibility and safety concerns. Program design elements found to facilitate adherence included: opportunities for social engagement and in-person offerings linked to higher levels of interventionist support, performative feedback, and social reinforcement.

Comparative Roles of the Caudate and Putamen in the Serial Order of Behavior: Effects of Striatal Glutamate Receptor Blockade on Variable versus Fixed Spatial Self-Ordered Sequencing in Marmosets.

Self-ordered sequencing is an important executive function involving planning and executing a series of steps to achieve goal-directed outcomes. The lateral frontal cortex is implicated in this behavior, but downstream striatal outputs remain relatively unexplored. We trained marmosets on a three-stimulus self-ordered spatial sequencing task using a touch-sensitive screen to explore the role of the caudate nucleus and putamen in random and fixed response arrays. By transiently blocking glutamatergic inputs to these regions, using intrastriatal CNQX microinfusions, we demonstrate that the caudate and putamen are both required for, but contribute differently to, flexible and fixed sequencing. CNQX into either the caudate or putamen impaired variable array accuracy, and infusions into both simultaneously elicited greater impairment. We demonstrated that continuous perseverative errors in variable array were caused by putamen infusions, likely due to interference with the putamen's established role in monitoring motor feedback. Caudate infusions, however, did not affect continuous errors, but did cause an upward trend in recurrent perseveration, possibly reflecting interference with the caudate's established role in spatial working memory and goal-directed planning. In contrast to variable array performance, while both caudate and putamen infusions impaired fixed array responding, the combined effects were not additive, suggesting possible competing roles. Infusions into either region individually, but not simultaneously, led to continuous perseveration. Recurrent perseveration in fixed arrays was caused by putamen, but not caudate, infusions. These results are consistent overall with a role of caudate in planning and flexible responding and the putamen in more rigid habitual or automatic responding.

Improving preclinical to clinical translation of cognitive function for aging-related disorders: the utility of comprehensive touchscreen testing batteries in common marmosets.

Concerns about poor animal to human translation have come increasingly to the fore, in particular with regards to cognitive improvements in rodent models, which have failed to translate to meaningful clinical benefit in humans. This problem has been widely acknowledged, most recently in the field of Alzheimer's disease, although this issue pervades the spectrum of central nervous system (CNS) disorders, including neurodevelopmental, neuropsychiatric, and neurodegenerative diseases. Consequently, recent efforts have focused on improving preclinical to clinical translation by incorporating more clinically analogous outcome measures of cognition, such as touchscreen-based assays, which can be employed across species, and have great potential to minimize the translational gap. For aging-related research, it also is important to incorporate model systems that facilitate the study of the long prodromal phase in which cognitive decline begins to emerge and which is a major limitation of short-lived species, such as laboratory rodents. We posit that to improve translation of cognitive function and dysfunction, nonhuman primate models, which have conserved anatomical and functional organization of the primate brain, are necessary to move the field of translational research forward and to bridge the translational gaps. The present studies describe the establishment of a comprehensive battery of touchscreen-based tasks that capture a spectrum of domains sensitive to detecting aging-related cognitive decline, which will provide the greatest benefit through longitudinal evaluation throughout the prolonged lifespan of the marmoset.

Association of plasma biomarkers with cognition, cognitive decline, and daily function across and within neurodegenerative diseases: Results from the Ontario Neurodegenerative Disease Research Initiative.

INTRODUCTION: We investigated whether novel plasma biomarkers are associated with cognition, cognitive decline, and functional independence in activities of daily living across and within neurodegenerative diseases. METHODS: Glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), phosphorylated tau (p-tau)181 and amyloid beta (Aß)42/40 were measured using ultra-sensitive Simoa immunoassays in 44 healthy controls and 480 participants diagnosed with Alzheimer's disease/mild cognitive impairment (AD/MCI), Parkinson's disease (PD), frontotemporal dementia (FTD) spectrum disorders, or cerebrovascular disease (CVD). RESULTS: GFAP, NfL, and/or p-tau181 were elevated among all diseases compared to controls, and were broadly associated with worse baseline cognitive performance, greater cognitive decline, and/or lower functional independence. While GFAP, NfL, and p-tau181 were highly predictive across diseases, p-tau181 was more specific to the AD/MCI cohort. Sparse associations were found in the FTD and CVD cohorts and for Aß42/40 . DISCUSSION: GFAP, NfL, and p-tau181 are valuable predictors of cognition and function across common neurodegenerative diseases, and may be useful in specialized clinics and clinical trials.

Premotor cortex is hypoactive during sustained vowel production in individuals with Parkinson's disease and hypophonia.

Introduction: Hypophonia is a common feature of Parkinson's disease (PD); however, the contribution of motor cortical activity to reduced phonatory scaling in PD is still not clear. Methods: In this study, we employed a sustained vowel production task during functional magnetic resonance imaging to compare brain activity between individuals with PD and hypophonia and an older healthy control (OHC) group. Results: When comparing vowel production versus rest, the PD group showed fewer regions with significant BOLD activity compared to OHCs. Within the motor cortices, both OHC and PD groups showed bilateral activation of the laryngeal/phonatory area (LPA) of the primary motor cortex as well as activation of the supplementary motor area. The OHC group also recruited additional activity in the bilateral trunk motor area and right dorsal premotor cortex (PMd). A voxel-wise comparison of PD and HC groups showed that activity in right PMd was significantly lower in the PD group compared to OHC (p < 0.001, uncorrected). Right PMd activity was positively correlated with maximum phonation time in the PD group and negatively correlated with perceptual severity ratings of loudness and pitch. Discussion: Our findings suggest that hypoactivation of PMd may be associated with abnormal phonatory control in PD.

User-centered design of feedback regarding health-related behaviors derived from wearables: An approach targeting older adults and persons living with neurodegenerative disease.

Objective: There has been tremendous growth in wearable technologies for health monitoring but limited efforts to optimize methods for sharing wearables-derived information with older adults and clinical cohorts. This study aimed to co-develop, design and evaluate a personalized approach for information-sharing regarding daily health-related behaviors captured with wearables. Methods: A participatory research approach was adopted with: (a) iterative stakeholder, and evidence-led development of feedback reporting; and (b) evaluation in a sample of older adults (n = 15) and persons living with neurodegenerative disease (NDD) (n = 25). Stakeholders included persons with lived experience, healthcare providers, health charity representatives and individuals involved in aging/NDD research. Feedback report information was custom-derived from two limb-mounted inertial measurement units and a mobile electrocardiography device worn by participants for 7-10 days. Mixed methods were used to evaluate reporting 2 weeks following delivery. Data were summarized using descriptive statistics for the group and stratified by cohort and cognitive status. Results: Participants (n = 40) were 60% female (median 72 (60-87) years). A total of 82.5% found the report easy to read or understand, 80% reported the right amount of information was shared, 90% found the information helpful, 92% shared the information with a family member or friend and 57.5% made a behavior change. Differences emerged in sub-group comparisons. A range of participant profiles existed in terms of interest, uptake and utility. Conclusions: The reporting approach was generally well-received with perceived value that translated into enhanced self-awareness and self-management of daily health-related behaviors. Future work should examine potential for scale, and the capacity for wearables-derived feedback to influence longer-term behavior change.

Chemogenetics identifies separate area 25 brain circuits involved in anhedonia and anxiety in marmosets.

Poor outcomes are common in individuals with anxiety and depression, and the brain circuits underlying symptoms and treatment responses remain elusive. To elucidate these neural circuits, experimental studies must specifically manipulate them, which is only possible in animals. Here, we used a chemogenetics strategy involving engineered designer receptors exclusively activated by designer drugs (DREADDs) to activate a region of the marmoset brain that is dysfunctional in human patients with major depressive disorder, called the subcallosal anterior cingulate cortex area 25 (scACC-25). Using this DREADDs system, we identified separate scACC-25 neural circuits that underlie specific components of anhedonia and anxiety in marmosets. Activation of the neural pathway connecting the scACC-25 to the nucleus accumbens (NAc) caused blunting of anticipatory arousal (a form of anhedonia) in marmosets in response to a reward-associated conditioned stimulus in an appetitive Pavlovian discrimination test. Separately, activation of the circuit between the scACC-25 and the amygdala increased a measure of anxiety (the threat response score) when marmosets were presented with an uncertain threat (human intruder test). Using the anhedonia data, we then showed that the fast-acting antidepressant ketamine when infused into the NAc of marmosets prevented anhedonia after scACC-25 activation for more than 1 week. These neurobiological findings provide targets that could contribute to the development of new treatment strategies.

Cognitive correlates of antisaccade behaviour across multiple neurodegenerative diseases.

Oculomotor tasks generate a potential wealth of behavioural biomarkers for neurodegenerative diseases. Overlap between oculomotor and disease-impaired circuitry reveals the location and severity of disease processes via saccade parameters measured from eye movement tasks such as prosaccade and antisaccade. Existing studies typically examine few saccade parameters in single diseases, using multiple separate neuropsychological test scores to relate oculomotor behaviour to cognition; however, this approach produces inconsistent, ungeneralizable results and fails to consider the cognitive heterogeneity of these diseases. Comprehensive cognitive assessment and direct inter-disease comparison are crucial to accurately reveal potential saccade biomarkers. We remediate these issues by characterizing 12 behavioural parameters, selected to robustly describe saccade behaviour, derived from an interleaved prosaccade and antisaccade task in a large cross-sectional data set comprising five disease cohorts (Alzheimer's disease/mild cognitive impairment, amyotrophic lateral sclerosis, frontotemporal dementia, Parkinson's disease, and cerebrovascular disease; n = 391, age 40-87) and healthy controls (n = 149, age 42-87). These participants additionally completed an extensive neuropsychological test battery. We further subdivided each cohort by diagnostic subgroup (for Alzheimer's disease/mild cognitive impairment and frontotemporal dementia) or degree of cognitive impairment based on neuropsychological testing (all other cohorts). We sought to understand links between oculomotor parameters, their relationships to robust cognitive measures, and their alterations in disease. We performed a factor analysis evaluating interrelationships among the 12 oculomotor parameters and examined correlations of the four resultant factors to five neuropsychology-based cognitive domain scores. We then compared behaviour between the abovementioned disease subgroups and controls at the individual parameter level. We theorized that each underlying factor measured the integrity of a distinct task-relevant brain process. Notably, Factor 3 (voluntary saccade generation) and Factor 1 (task disengagements) significantly correlated with attention/working memory and executive function scores. Factor 3 also correlated with memory and visuospatial function scores. Factor 2 (pre-emptive global inhibition) correlated only with attention/working memory scores, and Factor 4 (saccade metrics) correlated with no cognitive domain scores. Impairment on several mostly antisaccade-related individual parameters scaled with cognitive impairment across disease cohorts, while few subgroups differed from controls on prosaccade parameters. The interleaved prosaccade and antisaccade task detects cognitive impairment, and subsets of parameters likely index disparate underlying processes related to different cognitive domains. This suggests that the task represents a sensitive paradigm that can simultaneously evaluate a variety of clinically relevant cognitive constructs in neurodegenerative and cerebrovascular diseases and could be developed into a screening tool applicable to multiple diagnoses.

Suitability of Goal Attainment Scaling in Older Adult Populations with Neurodegenerative Disease Experiencing Cognitive Impairment: A Systematic Review and Meta-Analysis.

INTRODUCTION: Identifying responsive outcome measures for assessing functional change related to cognition, communication, and quality of life for individuals with neurodegenerative disease is important for intervention design and clinical care. Goal Attainment Scaling (GAS) has been used as an outcome measure to formally develop and systematically measure incremental progress toward functional, patient-centered goals in clinical settings. Evidence suggests that GAS is reliable and feasible for use in older adult populations and in adult populations with cognitive impairment, but no review has assessed the suitability of GAS in older adults with neurodegenerative disease experiencing dementia or cognitive impairment, based on responsiveness. This study conducted a systematic review to evaluate the suitability of GAS as an outcome measure for older adult populations with neurodegenerative disease experiencing dementia or cognitive impairment, based on responsiveness. METHODS: The review was registered with PROSPERO and performed by searching ten electronic scientific databases (PubMed, Medline OVID, CINAHL, Cochrane, Embase, Web of Science, PsycINFO, Scopus, OTSeeker, REHABDATA) and four registries (Clinicaltrials.gov, Grey Literature Report, Mednar, OpenGrey). A summary measure of responsiveness (post-intervention minus pre-intervention mean GAS T-score) was compared across eligible studies using a random-effects meta-analysis. Risk of bias in included studies was assessed using the NIH Quality Assessment Tool for Before-After (Pre-Post) Studies with No Control Group. RESULTS: 882 eligible articles were identified and screened by two independent reviewers. Ten studies met inclusion criteria for the final analysis. Of the ten included reports, 3 focus on all-cause dementia, 3 on multiple sclerosis, 1 on Parkinson's disease, 1 on mild cognitive impairment, 1 on Alzheimer's disease, and 1 on primary progressive aphasia. Responsiveness analyses showed pre- and post-intervention GAS goals were significantly different from zero (Z = 7.48, p < 0.001), with post-intervention GAS scores being higher than pre-intervention GAS scores. Three included studies showed a high risk of bias, 3 showed a moderate risk of bias, and 4 showed a low risk of bias. Overall risk of bias of included studies was rated as moderate. CONCLUSION: GAS showed an improvement in goal attainment across different dementia patient populations and intervention types. The overall moderate risk of bias suggests that while bias is present across included studies (e.g., small sample size, unblinded assessors), the observed effect likely represents the true effect. This suggests that GAS is responsive to functional change and may be suitable for use in older adult populations with neurodegenerative disease experiencing dementia or cognitive impairment.

Predictive language comprehension in Parkinson's disease.

Verb and action knowledge deficits are reported in persons with Parkinson's disease (PD), even in the absence of dementia or mild cognitive impairment. However, the impact of these deficits on combinatorial semantic processing is less well understood. Following on previous verb and action knowledge findings, we tested the hypothesis that PD impairs the ability to integrate event-based thematic fit information during online sentence processing. Specifically, we anticipated persons with PD with age-typical cognitive abilities would perform more poorly than healthy controls during a visual world paradigm task requiring participants to predict a target object constrained by the thematic fit of the agent-verb combination. Twenty-four PD and 24 healthy age-matched participants completed comprehensive neuropsychological assessments. We recorded participants' eye movements as they heard predictive sentences (The fisherman rocks the boat) alongside target, agent-related, verb-related, and unrelated images. We tested effects of group (PD/control) on gaze using growth curve models. There were no significant differences between PD and control participants, suggesting that PD participants successfully and rapidly use combinatory thematic fit information to predict upcoming language. Baseline sentences with no predictive information (e.g., Look at the drum) confirmed that groups showed equivalent sentence processing and eye movement patterns. Additionally, we conducted an exploratory analysis contrasting PD and controls' performance on low-motion-content versus high-motion-content verbs. This analysis revealed fewer predictive fixations in high-motion sentences only for healthy older adults. PD participants may adapt to their disease by relying on spared, non-action-simulation-based language processing mechanisms, although this conclusion is speculative, as the analyses of high- vs. low-motion items was highly limited by the study design. These findings provide novel evidence that individuals with PD match healthy adults in their ability to use verb meaning to predict upcoming nouns despite previous findings of verb semantic impairment in PD across a variety of tasks.

White matter hyperintensity burden predicts cognitive but not motor decline in Parkinson's disease: results from the Ontario Neurodegenerative Diseases Research Initiative.

BACKGROUND AND PURPOSE: The pathophysiology of Parkinson's disease (PD) negatively affects brain network connectivity, and in the presence of brain white matter hyperintensities (WMHs) cognitive and motor impairments seem to be aggravated. However, the role of WMHs in predicting accelerating symptom worsening remains controversial. The objective was to investigate whether location and segmental brain WMH burden at baseline predict cognitive and motor declines in PD after 2 years. METHODS: Ninety-eight older adults followed longitudinally from Ontario Neurodegenerative Diseases Research Initiative with PD of 3-8 years in duration were included. Percentages of WMH volumes at baseline were calculated by location (deep and periventricular) and by brain region (frontal, temporal, parietal, occipital lobes and basal ganglia + thalamus). Cognitive and motor changes were assessed from baseline to 2-year follow-up. Specifically, global cognition, attention, executive function, memory, visuospatial abilities and language were assessed as were motor symptoms evaluated using the Movement Disorder Society Unified Parkinson's Disease Rating Scale Part III, spatial-temporal gait variables, Freezing of Gait Questionnaire and Activities Specific Balance Confidence Scale. RESULTS: Regression analysis adjusted for potential confounders showed that total and periventricular WMHs at baseline predicted decline in global cognition (p < 0.05). Also, total WMH burden predicted the decline of executive function (p < 0.05). Occipital WMH volumes also predicted decline in global cognition, visuomotor attention and visuospatial memory declines (p < 0.05). WMH volumes at baseline did not predict motor decline. CONCLUSION: White matter hyperintensity burden at baseline predicted cognitive but not motor decline in early to mid-stage PD. The motor decline observed after 2 years in these older adults with PD is probably related to the primary neurodegenerative process than comorbid white matter pathology.

The Aversive Lens: Stress effects on the prefrontal-cingulate cortical pathways that regulate emotion.

ARNSTEN, A.F.T., M.K.P. Joyce and A.C. Roberts. The Aversive Lens: Stress effects on the prefrontal-cingulate cortical pathways that regulate emotion. NEUROSCI BIOBEHAV REV XXX-XXX, 2022. The symptoms of major-depressive-disorder include psychic pain and anhedonia, i.e. seeing the world through an "aversive lens". The neurobiology underlying this shift in worldview is emerging. Here these data are reviewed, focusing on how activation of subgenual cingulate (BA25) induces an "aversive lens", and how higher prefrontal cortical (PFC) areas (BA46/10/32) provide top-down regulation of BA25 but are weakened by excessive dopamine and norepinephrine release during stress exposure, and dendritic spine loss with chronic stress exposure. These changes may generate an attractor state, which maintains the brain under the control of BA25, requiring medication or neuromodulatory treatments to return connectivity to a more flexible state. In line with this hypothesis, effective anti-depressant treatments reduce the activity of BA25 and restore top-down regulation by higher circuits, e.g. as seen with SSRI medications, ketamine, deep brain stimulation of BA25, or rTMS to strengthen dorsolateral PFC. This research has special relevance in an era of chronic stress caused by the COVID19 pandemic, political unrest and threat of climate change.

Characteristics of the Ontario Neurodegenerative Disease Research Initiative cohort.

INTRODUCTION: Understanding synergies between neurodegenerative and cerebrovascular pathologies that modify dementia presentation represents an important knowledge gap. METHODS: This multi-site, longitudinal, observational cohort study recruited participants across prevalent neurodegenerative diseases and cerebrovascular disease and assessed participants comprehensively across modalities. We describe univariate and multivariate baseline features of the cohort and summarize recruitment, data collection, and curation processes. RESULTS: We enrolled 520 participants across five neurodegenerative and cerebrovascular diseases. Median age was 69 years, median Montreal Cognitive Assessment score was 25, median independence in activities of daily living was 100% for basic and 93% for instrumental activities. Spousal study partners predominated; participants were often male, White, and more educated. Milder disease stages predominated, yet cohorts reflect clinical presentation. DISCUSSION: Data will be shared with the global scientific community. Within-disease and disease-agnostic approaches are expected to identify markers of severity, progression, and therapy targets. Sampling characteristics also provide guidance for future study design.

The ventromedial prefrontal cortex and emotion regulation: lost in translation?

Neuroimaging studies implicate the ventromedial prefrontal cortex (vmPFC) in a wide range of emotional and cognitive functions, and changes in activity within vmPFC have been linked to the aetiology and successful treatment of depression. However, this is a large, structurally heterogeneous region and the extent to which this structural heterogeneity reflects functional heterogeneity remains unclear. Causal studies in animals should help address this question but attempts to map findings from vmPFC studies in rodents onto human imaging studies highlight cross-species discrepancies between structural homology and functional analogy. Bridging this gap, recent studies in marmosets - a species of new world monkey in which the overall organization of vmPFC is more like humans than that of rodents - have revealed that over-activation of the caudal subcallosal region of vmPFC, area 25, but not neighbouring area 32, heightens reactivity to negatively valenced stimuli whilst blunting responsivity to positively valenced stimuli. These co-occurring states resemble those seen in depressed patients, which are associated with increased activity in caudal subcallosal regions. In contrast, only reward blunting but not heightening of threat reactivity is seen following over-activation of the structurally homologous region in rodents. To further advance understanding of the role of vmPFC in the aetiology and treatment of depression, future work should focus on the behaviourally specific networks by which vmPFC regions have their effects, together with characterization of cross-species similarities and differences in function.

Understanding them to understand ourselves: The importance of NHP research for translational neuroscience.

Studying higher brain function presents fundamental scientific challenges but has great potential for impactful translation to the clinic, supporting the needs of many patients suffering from conditions that relate to neuronal dysfunction. For many key questions relevant to human neurological conditions and clinical interventions, non-human primates (NHPs) remain the only suitable model organism and the only effective way to study the relationship between brain structure and function with the knowledge and tools currently available. Here we present three exemplary studies of current research yielding important findings that are directly translational to human clinical patients but which would be impossible without NHP studies. Our first example shows how studies of the NHP prefrontal cortex are leading to clinically relevant advances and potential new treatments for human neuropsychiatric disorders such as depression and anxiety. Our second example looks at the relevance of NHP research to our understanding of visual pathways and the visual cortex, leading to visual prostheses that offer treatments for otherwise blind patients. Finally, we consider recent advances in treatments leading to improved recovery of movement and motor control in stroke patients, resulting from our improved understanding of brain stem parallel pathways involved in movement in NHPs. The case for using NHPs in neuroscience research, and the direct benefits to human patients, is strong but has rarely been set out directly. This paper reviews three very different areas of neuroscience research, expressly highlighting the unique insights offered to each by NHP studies and their direct applicability to human clinical conditions.

Region-specific microRNA alterations in marmosets carrying SLC6A4 polymorphisms are associated with anxiety-like behavior.

BACKGROUND: Psychiatric diseases such as depression and anxiety are multifactorial conditions, highly prevalent in western societies. Human studies have identified a number of high-risk genetic variants for these diseases. Among them, polymorphisms in the promoter region of the serotonin transporter gene (SLC6A4) have attracted much attention. However, due to the paucity of experimental models, molecular alterations induced by these genetic variants and how they correlate to behavioral deficits have not been examined. In this regard, marmosets have emerged as a powerful model in translational neuroscience to investigate molecular underpinnings of complex behaviors. METHODS: Here, we took advantage of naturally occurring genetic polymorphisms in marmoset SLC6A4 gene that have been linked to anxiety-like behaviors. Using FACS-sorting, we profiled microRNA contents in different brain regions of genotyped and behaviorally-phenotyped marmosets. FINDINGS: We revealed that marmosets bearing different SLC6A4 variants exhibit distinct microRNAs signatures in a region of the prefrontal cortex whose activity has been consistently altered in patients with depression/anxiety. We also identified Deleted in Colorectal Cancer (DCC), a gene previously linked to these diseases, as a downstream target of the differently expressed microRNAs. Significantly, we showed that levels of both microRNAs and DCC in this region were highly correlated to anxiety-like behaviors. INTERPRETATION: Our findings establish links between genetic variants, molecular modifications in specific cortical regions and complex behavioral responses, providing new insights into gene-behavior relationships underlying human psychopathology. FUNDING: This work was supported by France National Agency, NRJ Foundation, Celphedia and Fondation de France as well as the Wellcome Trust.

Communication Bridge™-2 (CB2): an NIH Stage 2 randomized control trial of a speech-language intervention for communication impairments in individuals with mild to moderate primary progressive aphasia.

BACKGROUND: Primary progressive aphasia (PPA) is a clinical dementia syndrome. Impairments in language (speaking, reading, writing, and understanding) are the primary and persistent symptoms. These impairments progress insidiously and devastate communication confidence, participation, and quality of life for persons living with PPA. Currently, there are no effective disease modifying treatments for PPA. Speech-language interventions hold promise for mitigating communication challenges and language symptoms. However, evidence regarding their efficacy in PPA is of low quality and there are currently no rigorous randomized trials. METHOD: Communication Bridge™-2 (CB2) is a Stage 2, superiority, single-blind, randomized, parallel group, active-control, behavioral clinical trial delivered virtually within a telehealth service delivery model to individuals with PPA. Ninety carefully characterized participants with clinically confirmed PPA will be randomized to one of two speech-language intervention arms: (1) Communication Bridge™ a dyadic intervention based in communication participation therapy models that incorporates salient training stimuli or (2) the control intervention a non-dyadic intervention based in impairment therapy models addressing word retrieval and language production that incorporates fixed stimuli. The superiority of Communication Bridge™ over the Control arm will be evaluated using primary outcomes of communication confidence and participation. Other outcomes include accuracy for trained words and scripts. Participants complete two therapy blocks over a 12-month period. Outcomes will be measured at baseline, at each therapy block, and at 12 months post enrollment. DISCUSSION: The CB2 trial will supply Level 2 evidence regarding the efficacy of the Communication Bridge™ intervention delivered in a telehealth service delivery model for individuals with mild to moderate PPA. An important by-product of the CB2 trial is that these data can be used to evaluate the efficacy of speech-language interventions delivered in both trial arms for persons with PPA. The impact of these data should not be overlooked as they will yield important insights examining why interventions work and for whom, which will advance effectiveness trials for speech-language interventions in PPA. TRIAL REGISTRATION: ClinicalTrials.gov NCT03371706 . Registered prospectively on December 13, 2017.

Caregiving concerns and clinical characteristics across neurodegenerative and cerebrovascular disorders in the Ontario neurodegenerative disease research initiative.

OBJECTIVES: Caregiving burdens are a substantial concern in the clinical care of persons with neurodegenerative disorders. In the Ontario Neurodegenerative Disease Research Initiative, we used the Zarit's Burden Interview (ZBI) to examine: (1) the types of burdens captured by the ZBI in a cross-disorder sample of neurodegenerative conditions (2) whether there are categorical or disorder-specific effects on caregiving burdens, and (3) which demographic, clinical, and cognitive measures are related to burden(s) in neurodegenerative disorders? METHODS/DESIGN: N = 504 participants and their study partners (e.g., family, friends) across: Alzheimer's disease/mild cognitive impairment (AD/MCI; n = 120), Parkinson's disease (PD; n = 136), amyotrophic lateral sclerosis (ALS; n = 38), frontotemporal dementia (FTD; n = 53), and cerebrovascular disease (CVD; n = 157). Study partners provided information about themselves, and information about the clinical participants (e.g., activities of daily living (ADL)). We used Correspondence Analysis to identify types of caregiving concerns in the ZBI. We then identified relationships between those concerns and demographic and clinical measures, and a cognitive battery. RESULTS: We found three components in the ZBI. The first was "overall burden" and was (1) strongly related to increased neuropsychiatric symptoms (NPI severity r = 0.586, NPI distress r = 0.587) and decreased independence in ADL (instrumental ADLs r = -0.566, basic ADLs r = -0.43), (2) moderately related to cognition (MoCA r = -0.268), and (3) showed little-to-no differences between disorders. The second and third components together showed four types of caregiving concerns: current care of the person with the neurodegenerative disease, future care of the person with the neurodegenerative disease, personal concerns of study partners, and social concerns of study partners. CONCLUSIONS: Our results suggest that the experience of caregiving in neurodegenerative and cerebrovascular diseases is individualized and is not defined by diagnostic categories. Our findings highlight the importance of targeting ADL and neuropsychiatric symptoms with caregiver-personalized solutions.

The Reliability of Telepractice Administration of the Western Aphasia Battery-Revised in Persons With Primary Progressive Aphasia.

PURPOSE: The use of telepractice in the field of communication disorders offers an opportunity to provide care for those with primary progressive aphasia (PPA). The Western Aphasia Battery-Revised (WAB-R) is used for differential diagnosis, to assess severity of aphasia, and to identify a language profile of strengths and challenges. Telehealth administration of the WAB-R is supported for those with chronic aphasia due to stroke but has not yet been systematically explored in neurodegenerative dementia syndromes. To fill this gap, in-person and telehealth performance on the WAB-R from participants with mild to moderate PPA was compared. METHOD: Nineteen participants with mild to moderate PPA were administered the WAB-R in person and over videoconferencing. Videoconferencing administration included modifications to the testing protocol to ensure smooth completion of the assessment. Subtest and Aphasia Quotient (WAB-AQ) summary scores were compared using concordance coefficients to measure the relationship between the administration modes. RESULTS: In-person and telehealth scores showed strong concordance for the WAB-AQ, Auditory Verbal Comprehension subtest, and Naming & Word Finding subtest. The Spontaneous Speech test summary score had slightly lower concordance, indicating the need for caution when comparing these scores across administration modes. CONCLUSION: These findings support extending the use of telehealth administration of the WAB-R via videoconferencing to those with mild to moderate PPA given appropriate modifications to testing protocol.

Higher-order brain regions show shifts in structural covariance in adolescent marmosets.

Substantial progress has been made studying morphological changes in brain regions during adolescence, but less is known of network-level changes in their relationship. Here, we compare covariance networks constructed from the correlation of morphometric volumes across 135 brain regions of marmoset monkeys in early adolescence and adulthood. Substantial shifts are identified in the topology of structural covariance networks in the prefrontal cortex (PFC) and temporal lobe. PFC regions become more structurally differentiated and segregated within their own local network, hypothesized to reflect increased specialization after maturation. In contrast, temporal regions show increased inter-hemispheric covariances that may underlie the establishment of distributed networks. Regionally selective coupling of structural and maturational covariance is revealed, with relatively weak coupling in transmodal association areas. The latter may be a consequence of continued maturation within adulthood, but also environmental factors, for example, family size, affecting brain morphology. Advancing our understanding of how morphological relationships within higher-order brain areas mature in adolescence deepens our knowledge of the developing brain's organizing principles.