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.

Longitudinal Free-Water Changes in Dementia with Lewy Bodies.

BACKGROUND: Diffusion-weighted magnetic resonance imaging (dMRI) examines tissue microstructure integrity in vivo. Prior dementia with Lewy bodies (DLB) diffusion tensor imaging studies yielded mixed results. OBJECTIVE: We employed free-water (FW) imaging to assess DLB progression and correlate with clinical decline in DLB. METHODS: Baseline and follow-up MRIs were obtained at 12 and/or 24 months for 27 individuals with DLB or mild cognitive impairment with Lewy bodies (MCI-LB). FW was analyzed using the Mayo Clinic Adult Lifespan Template. Primary outcomes were FW differences between baseline and 12 or 24 months. To compare FW change longitudinally, we included 20 cognitively unimpaired individuals from the Alzheimer's Disease Neuroimaging Initiative. RESULTS: We followed 23 participants to 12 months and 16 participants to 24 months. Both groups had worsening in Montreal Cognitive Assessment (MoCA) and Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) scores. We found significant FW increases at both time points compared to baseline in the insula, amygdala, posterior cingulum, parahippocampal, entorhinal, supramarginal, fusiform, retrosplenial, and Rolandic operculum regions. At 24 months, we found more widespread microstructural changes in regions implicated in visuospatial processing, motor, and cholinergic functions. Between-group analyses (DLB vs. controls) confirmed significant FW changes over 24 months in most of these regions. FW changes were associated with longitudinal worsening of MDS-UPDRS and MoCA scores. CONCLUSIONS: FW increased in gray and white matter regions in DLB, likely due to neurodegenerative pathology associated with disease progression. FW change was associated with clinical decline. The findings support dMRI as a promising tool to track disease progression in DLB. © 2024 International Parkinson and Movement Disorder Society.

Sex differences in dementia with Lewy bodies: Focused review of available evidence and future directions.

In this review, we summarize the current knowledge on sex differences in dementia with Lewy bodies (DLB) relating to epidemiology, clinical features, neuropathology, biomarkers, disease progression, and caregiving. While many studies show a higher DLB prevalence in men, this finding is inconsistent and varies by study approach. Visual hallucinations may be more common and occur earlier in women with DLB, whereas REM sleep behavior disorder may be more common and occur earlier in men. Several studies report a higher frequency of parkinsonism in men with DLB, while the frequency of fluctuations appears similar between sexes. Women tend to be older, have greater cognitive impairment at their initial visit, and are delayed in meeting DLB criteria compared to men. Women are also more likely to have Lewy body disease with co-existing AD-related pathology than so-called "pure" Lewy body disease, while men may present with either. Research is mixed regarding the impact of sex on DLB progression. Biomarker and treatment research assessing for sex differences is lacking. Women provide the majority of caregiving in DLB but how this affects the caregiving experience is uncertain. Gaining a better understanding of sex differences will be instrumental in aiding future development of sex-specific strategies in DLB for early diagnosis, care, and drug development.

Lewy Body Dementias: Controversies and Drug Development.

Lewy body dementia (LBD) is one of the most common neurodegenerative dementias. Clinical trials for symptomatic and disease-modifying therapies in LBD remain a national research priority, but there are many challenges in both past and active drug developments in LBD. This review highlights the controversies in picking the appropriate populations, interventions, target selections, and outcome measures, which are all critical components of clinical trial implementation in LBD. The heterogeneity of LBD neuropathology and clinical presentations, limited understanding of core features such as cognitive fluctuations, and lack of validated LBD-specific outcome measures and biomarkers represent some of the major challenges in LBD trials.

Emerging Neuroimaging Biomarkers Across Disease Stage in Parkinson Disease: A Review.

Importance: Imaging biomarkers in Parkinson disease (PD) are increasingly important for monitoring progression in clinical trials and also have the potential to improve clinical care and management. This Review addresses a critical need to make clear the temporal relevance for diagnostic and progression imaging biomarkers to be used by clinicians and researchers over the clinical course of PD. Magnetic resonance imaging (diffusion imaging, neuromelanin-sensitive imaging, iron-sensitive imaging, T1-weighted imaging), positron emission tomography/single-photon emission computed tomography dopaminergic, serotonergic, and cholinergic imaging as well as metabolic and cerebral blood flow network neuroimaging biomarkers in the preclinical, prodromal, early, and moderate to late stages are characterized. Observations: If a clinical trial is being carried out in the preclinical and prodromal stages, potentially useful disease-state biomarkers include dopaminergic imaging of the striatum; metabolic imaging; free-water, neuromelanin-sensitive, and iron-sensitive imaging in the substantia nigra; and T1-weighted structural magnetic resonance imaging. Disease-state biomarkers that can distinguish atypical parkinsonisms are metabolic imaging, free-water imaging, and T1-weighted imaging; dopaminergic imaging and other molecular imaging track progression in prodromal patients, whereas other established progression biomarkers need to be evaluated in prodromal cohorts. Progression in early-stage PD can be monitored using dopaminergic imaging in the striatum, metabolic imaging, and free-water and neuromelanin-sensitive imaging in the posterior substantia nigra. Progression in patients with moderate to late-stage PD can be monitored using free-water imaging in the anterior substantia nigra, R2* of substantia nigra, and metabolic imaging. Cortical thickness and gyrification might also be useful markers or predictors of progression. Dopaminergic imaging and free-water imaging detect progression over 1 year, whereas other modalities detect progression over 18 months or longer. The reliability of progression biomarkers varies with disease stage, whereas disease-state biomarkers are relatively consistent in individuals with preclinical, prodromal, early, and moderate to late-stage PD. Conclusions and Relevance: Imaging biomarkers for various stages of PD are readily available to be used as outcome measures in clinical trials and are potentially useful in multimodal combination with routine clinical assessment. This Review provides a critically important template for considering disease stage when implementing diagnostic and progression biomarkers in both clinical trials and clinical care settings.

An Update on Botulinum Toxin in Neurology.

Botulinum neurotoxin (BoNT) is an effective treatment for many neurologic disorders. This article gives a comprehensive overview of the clinical applications of BoNT across the field of neurology.

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.

Dysarthria and Speech Intelligibility Following Parkinson's Disease Globus Pallidus Internus Deep Brain Stimulation.

BACKGROUND: Although earlier studies reported variable speech changes following subthalamic nucleus (STN) deep brain stimulation (DBS) in Parkinson's disease (PD) patients, the effects of globus pallidus internus (GPi) DBS on speech performance in PD remain largely unknown. OBJECTIVE: We aimed to characterize speech changes following PD GPi-DBS. METHODS: We retrospectively analyzed clinical and speech outcomes of 25 PD patients treated with bilateral GPi-DBS at a single center. Outcome measures included the Unified Parkinson's Disease Rating Scale (UPDRS), speech subsystem domains (respiratory, laryngeal, resonance, orofacial, rate, prosody, rhythm, and naturalness), and overall speech intelligibility. Scores at baseline were compared with those at 6 months, 1 year, and the longest clinical follow-up available. RESULTS: In the off-medication state, activities of daily living and motor function based on UPDRS II and III significantly improved postoperatively. We observed unique patterns of speech changes in patients with PD following GPi-DBS in the short- (n = 25) and longer-term (n = 8) follow-up periods. Velopharyngeal (resonance), laryngeal components, and prosody worsened after bilateral GPi-DBS (p < 0.015). Speech intelligibility did not worsen after GPi-DBS in the short-term, but there was a trend to deteriorate at long-term follow-up (e.g., one year and beyond). We observed worsening of hypokinetic dysarthria in individual patients. Also, a minority of patients developed stuttering, spastic dysarthria, or ataxic dysarthria. CONCLUSION: Bilateral GPi-DBS worsened several modalities of parkinsonian speech without compromising overall speech intelligibility. GPi-DBS can potentially worsen or induce hypokinetic dysarthria, stuttering, spastic dysarthria, or ataxic dysarthria. GPi-DBS may have different and variable effects on speech function when compared to STN-DBS.

Ataxia and tolerance after thalamic deep brain stimulation for essential tremor.

BACKGROUND: Deep brain stimulation (DBS) of the ventral intermediate nucleus (VIM) thalamus is highly effective to treat medication-refractory essential tremor (ET). Complications of stimulation-induced ataxia and tolerance have been reported in limited series, ranging from 5 to 40%. OBJECTIVE: We analyzed a large single-center cohort of ET patients treated with thalamic DBS to assess rates of ataxia and tolerance. METHODS: Retrospective study of all ET patients that underwent VIM DBS at Mayo Clinic from 2010 to 2014. Demographic, clinical and DBS data were extracted. Risk factors, complications and time to onset of tolerance and ataxia were examined. RESULTS: One hundred and thirteen ET patients (51% male) of mean age 68 ± 10 years and mean ET duration 27 ± 18 years underwent DBS during the study period. Of these, 98 (87%) had follow-up of ≥6 months (mean 4.0 ± 1.5 years) and were included for analysis. Complications of isolated ataxia (26%), isolated tolerance (4%), both tolerance and ataxia (9%), or neither (61%) were identified. Development of ataxia was about 3 times more common than tolerance (35% vs. 13%). The mean time to ataxia was 5.5 ± 0.3 years postoperatively. Risk factors for ataxia were baseline ataxic features, older age, and shorter ET disease duration. Small sample size limited calculation of risk factors and onset time for tolerance. CONCLUSIONS: Stimulation-related ataxia occurred in one-third of ET patients, while tolerance was less common. Presence of baseline ataxia, age, and disease duration may aid counseling of stimulation-related ataxia risk. Larger studies are warranted to confirm these findings and further assess risk factors for tolerance.

High-dose Botulinum Toxin Therapy: Safety, Benefit, and Endurance of Efficacy.

Background: Botulinum neurotoxin therapy (BoNT) is a powerful tool for treating many neurologic disorders. The U.S. Food and Drug Administration (FDA)-approved maximum onabotulinum toxin A (OnaA) dose is 400 units (U) per visit, but higher doses are commonly necessary, particularly when treating multiple body regions. Methods: We collected demographics, OnaA dose, body regions injected and indications, patient-reported efficacy via 7-point Clinical Global Impression Scale (CGIS), and duration of benefit. Results: Sixty-eight patients were identified receiving OnaA >400 U/session. Dystonia (n = 44) and spasticity (n = 24) were the most common indications for high-dose OnaA. Mean duration of benefit was 9 weeks (standard deviation [SD] 3). More than 70% of patients self-reported "very much improved" or "much improved" at 6 month, 1 year, and last visit. No serious adverse effects were reported. Discussion: The majority of patients tolerated >400 U OnaA with continued benefit. OnaA doses >400 U may be safe and effective in appropriate patients.

Clinical outcome of brainstem arteriovenous malformations after incomplete nidus obliteration.

PURPOSE: Brainstem arteriovenous malformations (AVMs) present a formidable therapeutic challenge, and a variety of surgical and non-surgical treatment strategies can be used to obliterate the AVM nidus, eliminating its risk of hemorrhage. However, complete obliteration of brainstem AVMs is often not possible. We aimed to investigate the natural history of brainstem AVMs with incomplete nidus obliteration after initial treatment. METHODS: Data from consecutive patients who presented to our institution during the study period with a brainstem AVM and residual nidus after treatment were retrospectively reviewed. We evaluated patients for the incidence of AVM rupture and calculated the risk of rupture after treatment resulted in incomplete nidus obliteration. RESULTS: A total of 14 patients were included, five of whom suffered rupture after incomplete nidus obliteration (36%). Annual risk of rupture was 4.9% (95% CI: 1.60-11.5) per patient over a median follow-up of 72 months. The most common treatment modality of these patients was SRS-alone (n = 6), and two (33%) patients who underwent this treatment later ruptured after 103 and 130 months. Of the five patients who ruptured after treatment, 80% had already ruptured once, and 80% had an intranidal and/or feeding artery aneurysm. CONCLUSIONS: Brainstem AVMs with incomplete nidus obliteration are at high risk of future rupture. Patients with brainstem AVMs who have a residual nidus after treatment should be counselled about the risk of AVM rupture and be recommended to undergo close follow-up imaging studies to monitor the nidus.