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.

Does in-vehicle automation help individuals with Parkinson's disease? A preliminary analysis.

Introduction: PD is a progressive neurodegenerative disorder that affects, according to the ICF, body systems (cognitive, visual, and motor), and functions (e.g., decreased executive functions, decreased visual acuity, impaired contrast sensitivity, decreased coordination)-all which impact driving performance, an instrumental activity of daily living in the domain of "Activity" and "Participation" according to the ICF. Although there is strong evidence of impaired driving performance in PD, few studies have explored the real-world benefits of in-vehicle automation technologies, such as in-vehicle information systems (IVIS) and advanced driver assistance systems (ADAS), for drivers with PD. These technologies hold potential to alleviate driving impairments, reduce errors, and improve overall performance, allowing individuals with PD to maintain their mobility and independence more safely and for longer periods. This preliminary study aimed to fill the gap in the literature by examining the impact of IVIS and ADAS on driving safety, as indicated by the number of driving errors made by people with PD in an on-road study. Methods: Forty-five adults with diagnosed PD drove a 2019 Toyota Camry equipped with IVIS and ADAS features (Toyota Safety Sense 2.0) on a route containing highway and suburban roads. Participants drove half of the route with the IVIS and ADAS systems activated and the other half with the systems deactivated. Results: The results suggest that systems that assume control of the driving task, such as adaptive cruise control, were most effective in reducing driving errors. Furthermore, individual differences in cognitive abilities, particularly memory, were significantly correlated with the total number of driving errors when the systems were deactivated, but no significant correlations were present when the systems were activated. Physical capability factors, such as rigidity and bradykinesia, were not significantly correlated with driving error. Discussion: Taken together, these results show that in-vehicle driver automation systems can benefit drivers with PD and diminish the impact of individual differences in driver cognitive ability.

Group therapeutic singing improves clinical motor scores in persons with Parkinson's disease.

Background: Previous reports suggest that group therapeutic singing (GTS) may have a positive effect on motor symptoms in persons with Parkinson's disease (PD). Objective: To determine the effect of a single session of GTS on clinical motor symptoms. Methods: Clinical motor symptom assessment was completed immediately before and after 1 hour of GTS in 18 participants. Results: A significant decrease in average scores for gait and posture and tremor, but not speech and facial expression or bradykinesia was revealed. Conclusion: These results support the notion that GTS is a beneficial adjuvant therapy for persons with PD that warrants further research.

RCT protocol for driving performance in people with Parkinson's using autonomous in-vehicle technologies.

Introduction: Driving is an essential facilitator of independence, community participation, and quality of life. Drivers with Parkinson's Disease (PD) make more driving errors and fail on-road evaluations more than healthy controls. In-vehicle technologies may mitigate PD-related driving impairments and associated driving errors. Establishing a rigorous study protocol will increase the internal validity and the transparency of the scientific work. Methods: We present a protocol to assess the efficacy of autonomous in-vehicle technologies (Level 1) on the driving performance of drivers with PD via a randomized crossover design with random allocation. Drivers with a PD diagnosis based on established clinical criteria (N = 105), referred by neurologists, are exposed to two driving conditions (technology activated or not) on a standardized road course as they drove a 2019 Toyota Camry. The researchers collected demographic, clinical, on-road data observational and kinematic, and video data to understand several primary outcome variables, i.e., number of speeding, lane maintenance, signaling, and total driving errors. Discussion: The protocol may enhance participant adherence, decrease attrition, provide early and accurate identification of eligible participants, ensure data integrity, and improve the study flow. One limitation is that the protocol may change due to unforeseen circumstances and assumptions upon implementation. A strength is that the protocol ensures the study team executes the planned research in a systematic and consistent way.Following, adapting, and refining the protocol will enhance the scientific investigation to quantify the nuances of driving among those with PD in the era of automated in-vehicle technologies. Trial registration: ClinicalTrials.gov NCT04660500.

Connectomic analysis of unilateral dual-lead thalamic deep brain stimulation for treatment of multiple sclerosis tremor.

Tremor is a common symptom in multiple sclerosis and can present as a severe postural and action tremor, leading to significant disability. Owing to the diffuse and progressive nature of the disease, it has been challenging to characterize the pathophysiology underlying multiple sclerosis tremor. Deep brain stimulation of the ventralis intermedius and the ventralis oralis posterior thalamic nuclei has been used to treat medically refractory multiple sclerosis tremors with variable results. The aim of this study was to characterize multiple sclerosis tremor at the network level by applying modern connectomic techniques to data from a previously completed single-centre, randomized, single-blind prospective trial of 12 subjects who were treated with unilateral dual-lead (ventralis intermedius + ventralis oralis posterior) thalamic deep brain stimulation. Preoperative T1-weighted MRI and postoperative head CTs were used, along with applied programming settings, to estimate the volume of tissue activated for each patient. The volumes of tissue activated were then used to make voxel-wise and structural connectivity correlations with clinically observed tremor suppression. The volume of the tissue-activated analyses identified the optimal region of stimulation at the ventralis oralis posterior ventralis intermedius border intersecting with the dentato-rubro-thalamic tract. A regression model showed strong connectivity to the supplemental motor area was positively associated with tremor suppression (r = 0.66) in this cohort, whereas connectivity to the primary motor cortex was negatively associated with tremor suppression (r = -0.69), a finding opposite to that seen in ventralis intermedius deep brain stimulation for essential tremor. Comparing the structural connectivity to that of an essential tremor cohort revealed a distinct network that lies anterior to the essential tremor network. Overall, the volumes of tissue activated and connectivity observations converge to suggest that optimal suppression of multiple sclerosis tremor will likely be achieved by directing stimulation more anteriorly toward the ventralis oralis posterior and that a wide field of stimulation synergistically modulating the ventralis oralis posterior and ventralis intermedius nuclei may be more effective than traditional ventralis intermedius deep brain stimulation at suppressing the severe tremors commonly seen in complex tremor syndromes such as multiple sclerosis tremor.

RT-PCR negative COVID-19.

BACKGROUND: COVID-19 is a multi-system infection with emerging evidence-based antiviral and anti-inflammatory therapies to improve disease prognosis. However, a subset of patients with COVID-19 signs and symptoms have repeatedly negative RT-PCR tests, leading to treatment hesitancy. We used comparative serology early in the COVID-19 pandemic when background seroprevalence was low to estimate the likelihood of COVID-19 infection among RT-PCR negative patients with clinical signs and/or symptoms compatible with COVID-19. METHODS: Between April and October 2020, we conducted serologic testing of patients with (i) signs and symptoms of COVID-19 who were repeatedly negative by RT-PCR ('Probables'; N = 20), (ii) signs and symptoms of COVID-19 but with a potential alternative diagnosis ('Suspects'; N = 15), (iii) no signs and symptoms of COVID-19 ('Non-suspects'; N = 43), (iv) RT-PCR confirmed COVID-19 patients (N = 40), and (v) pre-pandemic samples (N = 55). RESULTS: Probables had similar seropositivity and levels of IgG and IgM antibodies as propensity-score matched RT-PCR confirmed COVID-19 patients (60.0% vs 80.0% for IgG, p-value = 0.13; 50.0% vs 72.5% for IgM, p-value = 0.10), but multi-fold higher seropositivity rates than Suspects and matched Non-suspects (60.0% vs 13.3% and 11.6% for IgG; 50.0% vs 0% and 4.7% for IgM respectively; p-values < 0.01). However, Probables were half as likely to receive COVID-19 treatment than the RT-PCR confirmed COVID-19 patients with similar disease severity. CONCLUSIONS: Findings from this study indicate a high likelihood of acute COVID-19 among RT-PCR negative with typical signs/symptoms, but a common omission of COVID-19 therapies among these patients. Clinically diagnosed COVID-19, independent of RT-PCR positivity, thus has a potential vital role in guiding treatment decisions.

Outcome Measures for Dementia With Lewy Body Clinical Trials: A Review.

BACKGROUND: Dementia with Lewy bodies (DLB) is one of the most common degenerative dementias. Clinical trials for individuals with DLB are increasing. We aimed to identify commonly used outcome measures for trials in DLB. METHODS: A pragmatic literature search of PubMed and clinicaltrials.gov identified interventional studies including populations with DLB. Studies were included if they enrolled participants with DLB and met the National Institutes of Health criteria for a clinical trial. Data were collected using standardized forms. Outcome measures were categorized according to core and supportive features of DLB. RESULTS: After de-duplication, 58 trials were identified. The most common cognitive outcome measures were the Mini Mental State Examination (n=24) and Cognitive Drug Research computerized Assessment System (n=5). The Clinician's Assessment of Fluctuations was the most commonly used measure for fluctuations (n=4). Over half of studies used the Neuropsychiatric Inventory to assess behavioral symptoms (n=31). The Unified Parkinson's Disease Rating Scale was frequently used for motor assessment (n=23). CONCLUSIONS AND RELEVANCE: Clinical trial outcomes used in DLB are rarely validated in this population and some lack face validity. There is a need to validate existing scales in DLB and develop DLB-specific outcome measures.

Wearable sensor-driven responsive deep brain stimulation for essential tremor.

BACKGROUND: Deep brain stimulation (DBS) is an effective surgical therapy for individuals with essential tremor (ET). However, DBS operates continuously, resulting in adverse effects such as postural instability or dysarthria. Continuous DBS (cDBS) also presents important practical issues including limited battery life of the implantable neurostimulator (INS). Collectively, these shortcomings impact optimal therapeutic benefit in ET. OBJECTIVE: The goal of the study was to establish a physiology-driven responsive DBS (rDBS) system to provide targeted and personalized therapy based on electromyography (EMG) signals. METHODS: Ten participants with ET underwent rDBS using Nexus-D, a Medtronic telemetry wand that acts as a direct conduit to the INS by modulating stimulation voltage. Two different rDBS paradigms were tested: one driven by one EMG (single-sensor) and another driven by two or more EMGs (multi-sensor). The feature(s) used in the rDBS algorithms was the pow2er in the participant's tremor frequency band derived from the sensors controlling stimulation. Both algorithms were trained on kinetic and postural data collected during DBS off and cDBS states. RESULTS: Using established clinical scales and objective measurements of tremor severity, we confirm that both rDBS paradigms deliver equivalent clinical benefit as cDBS. Moreover, both EMG-driven rDBS paradigms delivered less total electrical energy translating to an increase in the battery life of the INS. CONCLUSIONS: The results of this study verify that EMG-driven rDBS provides clinically equivalent tremor suppression compared to cDBS, while delivering less total electrical energy. Controlling stimulation using a dynamic rDBS paradigm can mitigate limitations of traditional cDBS systems.

Frequency of suicidal ideation and associated clinical features in Lewy body dementia.

INTRODUCTION: Neuropsychiatric disturbance is common in individuals with Lewy body dementia (LBD). Despite this, there is minimal research regarding suicide risks in this population. METHODS: This study was a retrospective review of a prospectively-collected database at a tertiary movement disorders clinic. Database participants with an LBD diagnosis at their most recent visit and at least one complete Beck Depression Inventory-II (BDI-II) were included. Additional measures included demographics and measures of cognition, psychiatric symptoms, motor function, and the Parkinson Disease Questionnaire-39. The frequency of suicidal ideation was assessed using question 9 of the BDI-II. Features associated with a BDI-II score greater than zero were assessed using logistic regression. RESULTS: The database included 95 individuals with LBD and at least one BDI-II (visit years 2010-2020). Most participants were older men who identified as white. Eighteen individuals (18.9%; 95% CI 12.3%-28.0%) reported thoughts of killing themselves without an intent to carry them out (BDI-II = 1). No participants reported a desire or plan to kill themselves. The presence of SI was associated with measures of depression, anxiety, and emotional well-being, but not with demographics, measures of disease severity, or other psychiatric concerns. CONCLUSION: These findings emphasize the importance of routine screening for psychiatric symptoms in LBD and intervention when such concerns are identified. Interventions could include pharmacologic (e.g. depression treatment) and non-pharmacologic (e.g. firearm screening) approaches. More research is needed to assess suicidal ideation and suicide risks in large and more diverse LBD populations. Prospective studies should include measures of additional potential contributors to suicidality.

The Effects of Group Therapeutic Singing on Cortisol and Motor Symptoms in Persons With Parkinson's Disease.

The inclusion of music into the treatment plan for persons with Parkinson's disease (PD) may be a viable strategy to target multiple motor symptoms. However, potential mechanisms to explain why music has an impact on multiple motor symptoms in persons with PD remain understudied. The purpose of this study was to examine the acute effects of 1 h of group therapeutic singing (GTS) on physiological measures of stress and clinical motor symptoms in persons with PD. We posit that improvement in motor symptoms after GTS may be related to stress reduction. Seventeen participants with PD completed 1 h of GTS and eight participants completed 1 h of a quiet reading (control session). Cortisol was collected via passive drool immediately before and after the singing and control session. The Unified Parkinson's Disease Rating Scale (UPDRS) Part-III (motor examination) was also video-recorded immediately before and after the singing and control session and scored by two raters masked to time and condition. Secondary outcome measures for quality of life, depression, and mood were collected. Results revealed no significant change in cortisol or motor UPDRS scores, as well as no significant relationship between cortisol and motor UPDRS scores. There was a trend for the singing group to report feeling less sad compared to the control group after the 1-h session (effect size = 0.86), and heart rate increased in the singing group while heart rate decreased in the control group after the 1-h session. These results suggest that an acute session of GTS is not unduly stressful and promotes the use of GTS for persons with PD. Multiple mechanisms may underlie the benefits of GTS for persons with PD. Further exploring potential mechanisms by which singing improves motor symptoms in persons with PD will provide greater insight on the therapeutic use of music for persons with PD.

Deep brain stimulation programming strategies: segmented leads, independent current sources, and future technology.

Introduction: Advances in neuromodulation and deep brain stimulation (DBS) technologies have facilitated opportunities for improved clinical benefit and side effect management. However, new technologies have added complexity to clinic-based DBS programming.Areas covered: In this article, we review basic basal ganglia physiology, proposed mechanisms of action and technical aspects of DBS. We discuss novel DBS technologies for movement disorders including the role of advanced imaging software, lead design, IPG design, novel programming techniques including directional stimulation and coordinated reset neuromodulation. Additional topics include the use of potential biomarkers, such as local field potentials, electrocorticography, and adaptive stimulation. We will also discuss future directions including optogenetically inspired DBS.Expert opinion: The introduction of DBS for the management of movement disorders has expanded treatment options. In parallel with our improved understanding of brain physiology and neuroanatomy, new technologies have emerged to address challenges associated with neuromodulation, including variable effectiveness, side-effects, and programming complexity. Advanced functional neuroanatomy, improved imaging, real-time neurophysiology, improved electrode designs, and novel programming techniques have collectively been driving improvements in DBS outcomes.

Case Report: Deep Brain Stimulation of the Nucleus Basalis of Meynert for Advanced Alzheimer's Disease.

Patients with advanced Alzheimer's disease (AD) experience cognitive impairment and physical disabilities in daily life. Currently, there are no treatments available to slow down the course of the disease, and limited treatments exist only to treat symptoms. However, deep brain stimulation of the nucleus basalis of Meynert (NBM-DBS) has been reported to improve cognitive function in individuals with AD. Here, we report the effects of NBM-DBS on cognitive function in a subject with severe AD. An 80-year-old male with severe AD (Clinical Dementia Rating scale: 3.0 points) underwent surgery for bilateral NBM-DBS electrode placement. After 10 weeks of stimulation, Mini-Mental State Examination (MMSE) assessment improved from a score of 5 to 9 points, and assessment using the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog) showed a marked reduction in total score from 43 to 33 points, suggesting cognitive benefits from NBM-DBS. The patient's postoperative course was complicated by a subdural effusion that occurred several days after surgery, with complete recovery. Interestingly, the subject also displayed abnormal thermoregulation with stimulation initiation and stimulation parameter modifications. NBM-DBS may serve as a potential therapy for severe AD patients. Clinical Trial Registration: ChiCTR1900022324.

Response to Telemedicine Visits From Patients With Parkinsonism During the COVID-19 Pandemic on Postvisit Surveys.

Parkinson's disease and parkinsonism are common chronic neurodegenerative disorders that tend to affect older adults and cause physical and sometimes cognitive limitations. Given that these limitations could impact successful telemedicine use, we aimed to investigate the experiences of patients with parkinsonism using telemedicine during the COVID-19 pandemic. A 19-item survey was emailed to patients with parkinsonism following telemedicine visits at a single US tertiary care parkinsonism specialty clinic. Seventy-four individuals responded, out of 270 invitations sent. Almost two-thirds (61.6%) of the respondents were comfortable with using technology in general, and almost all were very satisfied with their telemedicine experience. The most commonly reported benefits included cost and travel savings, ease of access to a specialist, and time savings. Issues with technology and previsit instructions were the most commonly identified challenges (28%). Urgent implementation, due to the pandemic, of telemedicine care for patients with parkinsonism was feasible and well received. The challenges most commonly reported by patients could be potentially alleviated by better education and support.

Clinical Care and Unmet Needs of Individuals With Dementia With Lewy Bodies and Caregivers: An Interview Study.

BACKGROUND: Patient-centered care requires understanding patient preferences and needs, but research on the clinical care preferences of individuals living with dementia and caregivers is sparse, particularly in dementia with Lewy bodies (DLB). METHODS: Investigators conducted telephone interviews with individuals living with DLB and caregivers from a Lewy body dementia specialty center. Interviews employed a semistructured questionnaire querying helpful aspects of care and unmet needs. Investigators used a qualitative descriptive approach to analyze transcripts and identify themes. RESULTS: Twenty individuals with DLB and 25 caregivers participated. Twenty-three of the caregivers were spouses, 2 were daughters. Aspects of clinical care valued by individuals with DLB and caregivers included clinician time, diagnosis, education, symptom management, communication, and caring staff. Unmet needs or challenges included patient/caregiver education, education of nonspecialist clinicians and community care providers, scheduling difficulties, caregiver support, financial concerns, assistance with advance care planning and finding local resources, and effective treatments for DLB symptoms. CONCLUSION AND RELEVANCE: Improving care for individuals with DLB and their families will require a multipronged strategy including education for nonspecialist care providers, increasing specialty care access, improved clinical care services, research to support disease prognosis and treatment decisions, and local and national strategies for enhanced caregiver support.

Mediterranean Diet Adherence in People With Parkinson's Disease Reduces Constipation Symptoms and Changes Fecal Microbiota After a 5-Week Single-Arm Pilot Study.

Introduction: Non-motor symptoms of Parkinson's disease (PD) such as gastrointestinal (GI) dysfunction are common, yet little is known about how modifying dietary intake impacts PD symptoms. The aim of this study in individuals with PD was to determine whether a Mediterranean diet intervention is feasible and affects GI function, intestinal permeability and fecal microbial communities. Methods: A single-arm, 5-week Mediterranean diet intervention study was conducted in eight people with PD. Daily and weekly questionnaires were administered to determine changes in GI symptoms. Urine and stool samples were collected at baseline and after 5 weeks to assess intestinal permeability and fecal microbial communities. Additionally, live-in partners of the participants with PD were matched as controls (n = 8) for baseline urine and stool samples. Results: Participants with PD increased intake of Mediterranean diet based on adherence scores from baseline to week 5 (4.4 ± 0.6 vs. 11.9 ± 0.7; P < 0.01 with >10 representing good adherence), which was linked with weight loss (77.4 kg vs. 74.9 kg, P = 0.01). Constipation syndrome scores decreased after 5 weeks (2.3 ± 0.5 vs. 1.5 ± 0.3; P = 0.04). Bilophila, was higher at baseline in PD (0.6 ± 0.1% vs. 0.2 ± 0.1% P = 0.02) and slightly decreased after the diet intervention (0.5 ± 0.1%; P = 0.01). Interestingly, the proportion of Roseburia was significantly lower in PD compared to controls (0.6 ± 0.2% vs. 1.6 ± 0.3%; P = 0.02) and increased at week 5 (0.9 ± 0.2%; P < 0.01). No differences were observed for markers of intestinal permeability between the control and PD groups or post-intervention. Conclusions: Short-term Mediterranean diet adherence is feasible in participants with PD; correlated with weight loss, improved constipation, and modified gut microbiota. Clinical Trial Registration: ClinicalTrials.gov, identifier: NCT03851861.

Advances and Future Directions of Neuromodulation in Neurologic Disorders.

"Deep brain stimulation is a safe and effective therapy for the management of a variety of neurologic conditions with Food and Drug Administration or humanitarian exception approval for Parkinson disease, dystonia, tremor, and obsessive-compulsive disorder. Advances in neurophysiology, neuroimaging, and technology have driven increasing interest in the potential benefits of neurostimulation in other neuropsychiatric conditions including dementia, depression, pain, Tourette syndrome, and epilepsy, among others. New anatomic or combined targets are being investigated in these conditions to improve symptoms refractory to medications or standard stimulation."

Brain Atrophy Following Deep Brain Stimulation: Management of a Moving Target.

Clinical vignette: A 51-year-old man with essential tremor (ET) had bilateral ventralis intermedius nucleus deep brain stimulation (VIM-DBS) placed to address refractory tremor. Despite well-placed DBS leads and adequate tremor response, he subsequently experienced worsening. Re-programming of the device and reconfirming the electrical thresholds for benefits and side effects were both performed. Six years following DBS implantation, repeat imaging revealed brain atrophy and a measured lead position change with a coincident change in clinical response. Clinical dilemma: What do we know about brain atrophy affecting lead placement and long-term DBS effectiveness? What are the potential strategies to combat narrowed therapeutic thresholds and to maximize DBS therapeutic benefit? Clinical solution: Decreasing the electrical field of stimulation and programming in a bipolar configuration are strategies to provide symptomatic tremor control and to minimize stimulation-induced side effects. Gaps in knowledge: Currently, effects of brain atrophy, and factors underpinning emergence of side effects and/or loss of benefit in chronic VIM-DBS remain largely unexplored.