Differentiating Prodromal Dementia with Lewy Bodies from Prodromal Alzheimer's Disease: A Pragmatic Review for Clinicians.

This pragmatic review synthesises the current understanding of prodromal dementia with Lewy bodies (pDLB) and prodromal Alzheimer's disease (pAD), including clinical presentations, neuropsychological profiles, neuropsychiatric symptoms, biomarkers, and indications for disease management. The core clinical features of dementia with Lewy bodies (DLB)-parkinsonism, complex visual hallucinations, cognitive fluctuations, and REM sleep behaviour disorder are common prodromal symptoms. Supportive clinical features of pDLB include severe neuroleptic sensitivity, as well as autonomic and neuropsychiatric symptoms. The neuropsychological profile in mild cognitive impairment attributable to Lewy body pathology (MCI-LB) tends to include impairment in visuospatial skills and executive functioning, distinguishing it from MCI due to AD, which typically presents with impairment in memory. pDLB may present with cognitive impairment, psychiatric symptoms, and/or recurrent episodes of delirium, indicating that it is not necessarily synonymous with MCI-LB. Imaging, fluid and other biomarkers may play a crucial role in differentiating pDLB from pAD. The current MCI-LB criteria recognise low dopamine transporter uptake using positron emission tomography or single photon emission computed tomography (SPECT), loss of REM atonia on polysomnography, and sympathetic cardiac denervation using meta-iodobenzylguanidine SPECT as indicative biomarkers with slowing of dominant frequency on EEG among others as supportive biomarkers. This review also highlights the emergence of fluid and skin-based biomarkers. There is little research evidence for the treatment of pDLB, but pharmacological and non-pharmacological treatments for DLB may be discussed with patients. Non-pharmacological interventions such as diet, exercise, and cognitive stimulation may provide benefit, while evaluation and management of contributing factors like medications and sleep disturbances are vital. There is a need to expand research across diverse patient populations to address existing disparities in clinical trial participation. In conclusion, an early and accurate diagnosis of pDLB or pAD presents an opportunity for tailored interventions, improved healthcare outcomes, and enhanced quality of life for patients and care partners.

The role of genetics in the treatment of dystonia with deep brain stimulation: Systematic review and Meta-analysis.

BACKGROUND: Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions that lead to involuntary postures or repetitive movements. Genetic mutations are being increasingly recognized as a cause of dystonia. Deep brain stimulation (DBS) is one of the limited treatment options available. However, there are varying reports on its efficacy in genetic dystonias. This systematic review of the characteristics of genetic dystonias treated with DBS and their outcomes aims to aid in the evaluation of eligibility for such treatment. METHODS: We performed a PUBMED search of all papers related to genetic dystonias and DBS up until April 2022. In addition to performing a systematic review, we also performed a meta-analysis to assess the role of the mutation on DBS response. We included cases that had a confirmed genetic mutation and DBS along with pre-and post-operative BFMDRS. RESULTS: Ninety-one reports met our inclusion criteria and from them, 235 cases were analyzed. Based on our analysis DYT-TOR1A dystonia had the best evidence for DBS response and Rapid-Onset Dystonia Parkinsonism was among the least responsive to DBS. CONCLUSION: While our report supports the role of genetics in DBS selection and response, it is limited by the rarity of the individual genetic conditions, the reliance on case reports and case series, and the limited ability to obtain genetic testing on a large scale in real-time as opposed to retrospectively as in many cases.

Current opinions and practices in post-stroke movement disorders: Survey of movement disorders society members.

BACKGROUND: Post-stroke movement disorders (PSMD) encompass a wide array of presentations, which vary in mode of onset, phenomenology, response to treatment, and natural history. There are no evidence-based guidelines on the diagnosis and treatment of PSMD. OBJECTIVES: To survey current opinions and practices on the diagnosis and treatment of PSMD. METHODS: A survey was developed by the PSMD Study Group, commissioned by the International Parkinson's and Movement Disorders Society (MDS). The survey, distributed to all members, yielded a total of 529 responses, 395 (74.7%) of which came from clinicians with experience with PSMD. RESULTS: Parkinsonism (68%), hemiballismus/hemichorea (61%), tremor (58%), and dystonia (54%) were by far the most commonly endorsed presentation of PSMD, although this varied by region. Basal ganglia stroke (76% of responders), symptoms contralateral to stroke (75%), and a temporal relationship (59%) were considered important factors for the diagnosis of PSMD. Oral medication use depended on the phenomenology of the PSMD. Almost 50% of respondents considered deep brain stimulation and ablative surgeries as options for treatment. The lack of guidelines for the diagnosis and treatment was considered the most important gap to address. CONCLUSIONS: Regionally varying opinions and practices on PSMD highlight gaps in (and mistranslation of) epidemiologic and therapeutic knowledge. Multicenter registries and prospective community-based studies are needed for the creation of evidence-based guidelines to inform the diagnosis and treatment of patients with PSMD.

Integrity of the nucleus basalis of meynert and self-reported cognitive dysfunction during wearing-off periods in parkinson's disease.

BACKGROUND: Cognition in Parkinson's Disease can be impacted by the wearing-off phenomenon which results from changes in dopaminergic tone throughout the day. Given the well-established role of the cholinergic basal forebrain in cognition, we hypothesized that the Nucleus Basalis of Meynert may support cognitive processes during wearing-off periods. Specifically, we evaluated whether worsening of cognitive symptoms during wearing-off is more likely to occur with structural degeneration of the Nucleus Basalis of Meynert. METHODS: Cognitive wearing-off was evaluated via the Movement Disorders Society Non-Motor Fluctuation Assessment Questionnaire in 33 Parkinson's Disease participants undergoing evaluation for deep brain stimulation. Pre-operative diffusion MRIs were used to measure brain diffusion metrics of the Nucleus Basalis of Meynert and control regions (caudate and putamen). RESULTS: The number of cognitive symptoms which worsened during OFF periods positively correlated with mean diffusivity (ρ = 0.561, p = 0.0007) and generalized fractional anisotropy (ρ=-0.447, p = 0.009) within the Nucleus Basalis of Meynert but not in the caudate or putamen. Meanwhile, stable cognitive symptoms, and ON-state cognitive performance as measured by the DRS-2 did not correlate with Nucleus Basalis of Meynert metrics. Correlations were corrected for age, sex, scanner type, disease duration, education and LEDD. CONCLUSIONS: Our study suggests that reduced structural integrity of the Nucleus Basalis of Meynert is associated with worsening of participant-reported cognitive deficits during OFF periods, but not overall cognitive functioning in the ON-state. These findings support the hypothesis that structural integrity of the cholinergic Nucleus Basalis of Meynert may provide resilience to cognitive worsening during dopamine-related wearing-off.

The Rapid Access Memory Program for Addressing Concerns of Incipient Dementia in Academic Primary Care Settings.

BACKGROUND: Expedient diagnosis of incipient dementia is often hindered by time constraints in primary care visits, shortage of dementia specialists, and extended waitlists for comprehensive neuropsychological evaluations. METHODS: We developed the Rapid Access Memory Program (RAMP) to improve access of neuropsychological services for older adults presenting to our institutional primary care clinics with concerns of cognitive decline. RAMP provides abbreviated neurocognitive assessment, same-day patient feedback, expedited reporting to referring providers, and is financially self-supported. Here, we describe development of RAMP and clinical outcomes from the first 3 years. RESULTS: Of 160 patients seen, dementia was diagnosed in 30% and Mild Cognitive Impairment in 50%; Alzheimer's disease was the most common suspected etiology. New psychiatric diagnosis was made in about one-third (n = 54). Most frequent recommendations involved medication adjustments (initiating cholinesterase inhibitors, deprescribing anticholinergics), safety (driving, decision-making), and specialist referrals. Additionally, 27 (17%) subsequently enrolled in local research. CONCLUSIONS: Results support feasibility and utility of RAMP for connecting older adults in primary care with neuropsychological services.

Bridging the Gap: Association between Objective and Subjective Outcomes of Communication Performance in People with Parkinson's Disease Evaluated for Deep Brain Stimulation.

Background: Decrements in verbal fluency following deep brain stimulation (DBS) in people with Parkinson's disease (PwP) are common. As such, verbal fluency tasks are used in assessing DBS candidacy and target selection. However, the correspondence between testing performance and the patient's perception of communication abilities is not well-established. Methods: The Communication Participation Item Bank (CPIB) was administered to 85 PwP during pre-DBS neuropsychological evaluations. Central tendencies for CPIB responses and correlations between CPIB total scores, clinical and demographic factors, and language-based tasks were examined. Results: Most PwP indicated some degree of communication interference on the CPIB. Worse scores on semantic fluency and greater motor impairment were associated with more communication interference. Conclusions: Our findings suggest an incomplete correspondence between commonly used language-based tests and patient-reported outcomes of communication abilities. The need for a functional communication instrument that reflects the different aspects of communication abilities in functional contexts is emphasized.

Are Standardized Tests Sensitive to Early Cognitive Change in Parkinson's Disease?

Introduction: Cognitive deficits within the first years of Parkinson's disease (PD) diagnosis are commonly reported, and progression to dementia greatly impacts independence. Identifying measures sensitive to early changes is critical for trials of symptomatic therapies and neuroprotection. Methods: A sample of 253 newly diagnosed PD patients and 134 Health Controls (HC) completed a brief cognitive battery annually over a 5-year period through the Parkinson's Progression Markers Initiative (PPMI). The battery included standardized measures of memory, visuospatial functions, processing speed, working memory, and verbal fluency. Inclusion criterion for HCs was performance above a cutoff for possible Mild Cognitive Impairment (pMCI) on cognitive screening (MoCA ⩾ 27) The PD sample was therefore divided to match HCs on baseline cognitive testing (PD-normal n = 169; PD-pMCI n = 84). The multivariate approach to repeated measures examined rates of change between groups on cognitive measures. Results: An interaction indicating slightly greater decline over time in PD-normal relative to HCs was observed on a measure of working memory: letter-number sequencing. Differential rates of change were not observed on any other measures. Motor symptoms on the dominant right upper extremity accounted for performance differences on a test with writing demands (Symbol-Digit Modality Test). PD-pMCI performed worse than PD-normal on all cognitive measures at baseline, but did not decline faster. Discussion: Working memory appears to decline slightly faster in early PD compared to HCs, while other domains remain similar. Within PD, faster decline was not associated with lower baseline cognition. These findings have implications for clinical trial outcome selection and study design.

Utility of the 20-Item Noise Pareidolia Task (NPT-20) for Assessing Visuoperceptual Disturbances Associated with Complex Visual Hallucinations in Parkinson's Disease.

Background: Complex visual hallucinations (VH) are a common complication of Parkinson's disease (PD). Recent studies have demonstrated relevance of face pareidolia to VH in PD and Lewy body dementia (LBD). Objective: This study examined utility of the 20-item Noise Pareidolia Task (NPT-20) in assessing visuoperceptual disturbances associated with VH in PD. Methods: Retrospective chart review included 46 consecutive PD patients who completed NPT-20 during clinical neuropsychological evaluation. Results: About half the sample (43%) reported VH. PD with VH made significantly more false-positive pareidolia errors on the NPT-20 (p < 0.0001). A cut-off of 2 errors yielded 40% sensitivity, 100% specificity to VH; cut-off of 1 yielded 75% sensitivity, 81% specificity. NPT-20 was not associated with any other clinical or demographic factor. Across groups, NPT-20 evinced moderate correlations with visuospatial functioning and visual memory. Conclusions: Current findings support utility of the NPT-20 for evaluating visuoperceptual disturbances associated with VH in PD.

Priorities for research on neuromodulatory subcortical systems in Alzheimer's disease: Position paper from the NSS PIA of ISTAART.

The neuromodulatory subcortical system (NSS) nuclei are critical hubs for survival, hedonic tone, and homeostasis. Tau-associated NSS degeneration occurs early in Alzheimer's disease (AD) pathogenesis, long before the emergence of pathognomonic memory dysfunction and cortical lesions. Accumulating evidence supports the role of NSS dysfunction and degeneration in the behavioral and neuropsychiatric manifestations featured early in AD. Experimental studies even suggest that AD-associated NSS degeneration drives brain neuroinflammatory status and contributes to disease progression, including the exacerbation of cortical lesions. Given the important pathophysiologic and etiologic roles that involve the NSS in early AD stages, there is an urgent need to expand our understanding of the mechanisms underlying NSS vulnerability and more precisely detail the clinical progression of NSS changes in AD. Here, the NSS Professional Interest Area of the International Society to Advance Alzheimer's Research and Treatment highlights knowledge gaps about NSS within AD and provides recommendations for priorities specific to clinical research, biomarker development, modeling, and intervention. HIGHLIGHTS: Neuromodulatory nuclei degenerate in early Alzheimer's disease pathological stages. Alzheimer's pathophysiology is exacerbated by neuromodulatory nuclei degeneration. Neuromodulatory nuclei degeneration drives neuropsychiatric symptoms in dementia. Biomarkers of neuromodulatory integrity would be value-creating for dementia care. Neuromodulatory nuclei present strategic prospects for disease-modifying therapies.

Dementia with Lewy bodies: Impact of co-pathologies and implications for clinical trial design.

Dementia with Lewy bodies (DLB) is clinically defined by the presence of visual hallucinations, fluctuations, rapid eye movement (REM) sleep behavioral disorder, and parkinsonism. Neuropathologically, it is characterized by the presence of Lewy pathology. However, neuropathological studies have demonstrated the high prevalence of coexistent Alzheimer's disease, TAR DNA-binding protein 43 (TDP-43), and cerebrovascular pathologic cases. Due to their high prevalence and clinical impact on DLB individuals, clinical trials should account for these co-pathologies in their design and selection and the interpretation of biomarkers values and outcomes. Here we discuss the frequency of the different co-pathologies in DLB and their cross-sectional and longitudinal clinical impact. We then evaluate the utility and possible applications of disease-specific and disease-nonspecific biomarkers and how co-pathologies can impact these biomarkers. We propose a framework for integrating multi-modal biomarker fingerprints and step-wise selection and assessment of DLB individuals for clinical trials, monitoring target engagement, and interpreting outcomes in the setting of co-pathologies.

Gaps, Controversies, and Proposed Roadmap for Research in Poststroke Movement Disorders.

Poststroke movement disorders (PSMDs) are a common cause of secondary movement disorders. Although prior studies have highlighted the clinical spectrum and phenomenology of PSMDs, there are many knowledge gaps worth addressing. Some of the most important include lack of clinical definitions, variable stroke symptom latencies, and lack of biomarkers for vulnerability for or resilience against developing PSMDs. Collectively, the association between stroke localization and phenomenology is less than 30%, and the long-term clinical prognosis and treatment responses are highly variable. After summarizing the accumulated evidence regarding the phenomenology, pathophysiology, neuroimaging, and treatment of PSMDs, highlighting the many gaps and controversies including diagnostic challenges, we propose a roadmap for future research to fill these gaps and resolve the related controversies. More research is warranted concerning the phenomenology, classification, diagnostic criteria, and pathophysiology of PSMDs. Further, there is an urgent need for treatment guidelines for the management of PSMDs. © 2022 International Parkinson and Movement Disorder Society.

Clinical outcome measures in dementia with Lewy bodies trials: critique and recommendations.

The selection of appropriate outcome measures is fundamental to the design of any successful clinical trial. Although dementia with Lewy bodies (DLB) is one of the most common neurodegenerative conditions, assessment of therapeutic benefit in clinical trials often relies on tools developed for other conditions, such as Alzheimer's or Parkinson's disease. These may not be sufficiently valid or sensitive to treatment changes in DLB, decreasing their utility. In this review, we discuss the limitations and strengths of selected available tools used to measure DLB-associated outcomes in clinical trials and highlight the potential roles for more specific objective measures. We emphasize that the existing outcome measures require validation in the DLB population and that DLB-specific outcomes need to be developed. Finally, we highlight how the selection of outcome measures may vary between symptomatic and disease-modifying therapy trials.

A Modified Progressive Supranuclear Palsy Rating Scale for Virtual Assessments.

BACKGROUND: The reliability of the Progressive Supranuclear Palsy Rating Scale (PSPRS) using teleneurology has not been assessed. OBJECTIVES: To test whether removing items inadequately assessed by video would impact measurement of PSP severity and progression. METHODS: We performed secondary analyses of two data sets: the phase 2/3 trial of Davunetide in PSP and a large single-center cohort. We examined two modifications of the PSPRS: (1) removing neck rigidity, limb rigidity, and postural stability (25 items; mPSPRS-25) and (2) also removing three ocular motor items and limb dystonia (21 items; mPSPRS-21). Proportional agreement relative to the possible total scores was measured using the intraclass correlation coefficient, compared to the original PSPRS baseline values and change over 6 and 12 months. We examined the ability of both scales to predict survival in the single-center cohort using proportional hazards models. RESULTS: The mPSPRS-25 showed excellent agreement (0.99; P < 0.001) with the original PSPRS at baseline, 0.98 (P < 0.001) agreement in measuring change over 6 months, and 0.98 (P < 0.001) over 12 months. The mPSPRS-21 showed agreement of 0.94 (P < 0.001) with the original PSPRS at baseline, 0.92 (P < 0.001) at 6 months, and 0.95 (P < 0.001) at 12 months. Baseline and 6-month change in both modified scales were highly predictive of survival in the single-center cohort. CONCLUSIONS: Modified versions of the PSPRS which can be administered remotely show excellent agreement with the original scale and predict survival in PSP. The mPSPRS-21 should facilitate clinical care and research in PSP via teleneurology. © 2022 International Parkinson and Movement Disorder Society.

Executive function and dopamine response in Parkinson's disease freezing of gait.

BACKGROUND: This investigation examined whether aspects of attention and executive functioning differed between Parkinson's Disease (PD) patients with freezing of gait (FOG) based on responsiveness to dopamine. We also explored association of cognition with FOG severity and gait metrics. METHODS: Fifty-four individuals with PD completed the study protocol: 17 without freezing (PDC), 23 with dopa-responsive FOG (RFOG), and 14 with dopa-unresponsive (URFOG). Standardized neuropsychological tests assessed attention (focused and sustained), psychomotor speed, and set-switching (time and errors). FOG severity was measured using the new FOG Questionnaire (nFOG-Q). Metrics from timed up and go (TUG) tasks were obtained while "on" and "off" dopamine, with and without dual cognitive tasks. RESULTS: After controlling for clinical and demographic factors, analysis of covariance revealed a significant between-group difference for set-switching errors; planned contrasts revealed increased set-switching errors in URFOG relative to RFOG and PD control groups. Groups were not different in other cognitive domains. FOG severity was modestly associated with set-switching errors in RFOG but not URFOG. TUG performances while "on" were associated with set-switching errors in PD controls, and with focused attention in RFOG. CONCLUSION: PD patients with dopa-unresponsive FOG are more prone to set-switching errors than those who respond to treatment. Furthermore, executive function appears relevant to FOG severity only in patients who show dopamine response. Together, these findings suggest disruption of a common dopamine-mediated pathway for FOG and ability to monitor rules while alternating cognitive processes. Consideration of dopa-response could be useful in characterizing cohorts and treating FOG in PD.

Best Practices in the Clinical Management of Progressive Supranuclear Palsy and Corticobasal Syndrome: A Consensus Statement of the CurePSP Centers of Care.

Progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS; the most common phenotype of corticobasal degeneration) are tauopathies with a relentless course, usually starting in the mid-60s and leading to death after an average of 7 years. There is as yet no specific or disease-modifying treatment. Clinical deficits in PSP are numerous, involve the entire neuraxis, and present as several discrete phenotypes. They center on rigidity, bradykinesia, postural instability, gait freezing, supranuclear ocular motor impairment, dysarthria, dysphagia, incontinence, sleep disorders, frontal cognitive dysfunction, and a variety of behavioral changes. CBS presents with prominent and usually asymmetric dystonia, apraxia, myoclonus, pyramidal signs, and cortical sensory loss. The symptoms and deficits of PSP and CBS are amenable to a variety of treatment strategies but most physicians, including many neurologists, are reluctant to care for patients with these conditions because of unfamiliarity with their multiplicity of interacting symptoms and deficits. CurePSP, the organization devoted to support, research, and education for PSP and CBS, created its CurePSP Centers of Care network in North America in 2017 to improve patient access to clinical expertise and develop collaborations. The directors of the 25 centers have created this consensus document outlining best practices in the management of PSP and CBS. They formed a writing committee for each of 12 sub-topics. A 4-member Steering Committee collated and edited the contributions. The result was returned to the entire cohort of authors for further comments, which were considered for incorporation by the Steering Committee. The authors hope that this publication will serve as a convenient guide for all clinicians caring for patients with PSP and CBS and that it will improve care for patients with these devastating but manageable disorders.

Association of Orthostatic Hypotension With Cerebral Atrophy in Patients With Lewy Body Disorders.

OBJECTIVE: To evaluate whether orthostatic hypotension (OH) or supine hypertension (SH) is associated with brain atrophy and white matter hyperintensities (WMH), we analyzed clinical and radiologic data from a large multicenter consortium of patients with Parkinson disease (PD) and dementia with Lewy bodies (DLB). METHODS: Supine and orthostatic blood pressure (BP) and structural MRI data were extracted from patients with PD and DLB evaluated at 8 tertiary-referral centers in the United States, Canada, Italy, and Japan. OH was defined as a systolic/diastolic BP fall ≥20/10 mm Hg within 3 minutes of standing from the supine position (severe ≥30/15 mm Hg) and SH as a BP ≥140/90 mm Hg with normal sitting BP. Diagnosis-, age-, sex-, and disease duration-adjusted differences in global and regional cerebral atrophy and WMH were appraised with validated semiquantitative rating scales. RESULTS: A total of 384 patients (310 with PD, 74 with DLB) met eligibility criteria, of whom 44.3% (n = 170) had OH, including 24.7% (n = 42) with severe OH and 41.7% (n = 71) with SH. OH was associated with global brain atrophy (p = 0.004) and regional atrophy involving the anterior-temporal (p = 0.001) and mediotemporal (p = 0.001) regions, greater in severe vs nonsevere OH (p = 0.001). The WMH burden was similar in those with and without OH (p = 0.49). SH was not associated with brain atrophy (p = 0.59) or WMH (p = 0.72). CONCLUSIONS: OH, but not SH, was associated with cerebral atrophy in Lewy body disorders, with prominent temporal region involvement. Neither OH nor SH was associated with WMH.