Lewy body pathology modifies risk factors for cerebral amyloid angiopathy when comorbid with Alzheimer's disease pathology.

INTRODUCTION: Cerebral amyloid angiopathy (CAA) often accompanies dementia-associated pathologies and is important in the context of anti-amyloid monoclonal therapies and risk of hemorrhage. METHODS: We conducted a retrospective neuropathology-confirmed study of 2384 participants in the National Alzheimer Coordinating Center cohort (Alzheimer's disease [AD], n = 1175; Lewy body pathology [LBP], n = 316; and mixed AD and LBP [AD-LBP], n = 893). We used logistic regression to evaluate age, sex, education, APOE ε4, neuritic plaques, and neurofibrillary tangles (NFTs) in CAA risk. RESULTS: APOE ε4 increased CAA risk in all three groups, while younger age and higher NFT stages increased risk in AD and AD-LBP. In AD-LBP, male sex and lower education were additional risk factors. The odds of APOE ε4 carrier homozygosity related to CAA was higher in LBP (25.69) and AD-LBP (9.50) than AD (3.17). DISCUSSION: AD and LBPs modify risk factors for CAA and should be considered in reviewing the risk of CAA. HIGHLIGHTS: Lewy body pathology modifies risk factors for cerebral amyloid angiopathy (CAA) when present along with Alzheimer's disease (AD) neuropathology. In the context of anti-amyloid monoclonal therapies and their associated risks for hemorrhage, the risk of underlying CAA in mixed dementia with Lewy body pathology needs to be considered.

Effects of a combined transcranial magnetic stimulation (TMS) and cognitive training intervention in patients with Alzheimer's disease.

INTRODUCTION: This clinical trial evaluates the efficacy and safety of a 6-week course of daily neuroAD™ therapy. METHODS: 131 subjects between 60 and 90 years old, unmedicated for Alzheimer's disease (AD), or on stable doses of an acetylcholinesterase inhibitor and/or memantine, with Mini-Mental State Examination scores between 18 and 26, clinical dementia rating scale scores of 1 or 2, enrolled for a prospective, randomized, double-blind, sham-controlled, multicenter clinical trial. Structural brain MRIs were obtained for transcranial magnetic stimulation targeting. Baseline Alzheimer's disease assessment scale-cognitive (ADAS-Cog) and Clinical Global Impression of Change were assessed. 129 participants were randomized to active treatment plus standard of care (SOC) or sham treatments plus SOC. RESULTS: Subjects with baseline ADAS-Cog ≤ 30 (~85% of study population) showed a statistically significant benefit favoring active over sham. Responder analysis showed 31.7% participants in the active group with ≤ -4 point improvement on ADAS-Cog versus 15.4% in the sham group. DISCUSSION: neuroAD™ Therapy System provides a low-risk therapeutic benefit for patients with milder AD (baseline ADAS-Cog ≤30) beyond pharmacologic SOC.

Color Vision Impairment Differentiates Alzheimer Dementia From Dementia With Lewy Bodies.

OBJECTIVE: Dementia with Lewy bodies (DLB) is frequently misdiagnosed for Alzheimer dementia (AD), especially in its earlier stages. We characterized color vision impairment (CVI) in patients with DLB versus patients with AD to determine its usefulness in improving accuracy of early diagnosis. METHODS: We retrospectively reviewed charts of patients with AD, DLB, and patients with mild cognitive impairment suspected to be in the prodromal phase of DLB (pro-DLB) or prodromal phase of AD (pro-AD). All patients underwent an online 15-hue color vision arrangement test. RESULTS: Fifty-two patients were included in this study with a median age of 77 years, of which 44% were female. No significant differences in gender, age, or Montreal Cognitive Assessment existed among patients with AD (n = 15), pro-AD (n = 5), pro-DLB (n = 8), and DLB (n = 24). Of the 52 patients, 4 (2 AD, 1 DLB, and 1 pro-AD) had CVI history from a young age and were excluded from final analyses. New-onset CVI prevalence differed significantly based on diagnosis: patients with pro-AD (20%), patients with AD (15%), patients with pro-DLB (38%), and patients with DLB (78%, P < .001). In a stepwise multivariate logistic regression analysis to determine factors associated with CVI, "diagnosis type" as a binary variable (DLB or pro-DLB vs AD or pro-AD) was the only variable retained in the model (odds ratio = 9.8 [95% CI: 2.3-42.1], P < .001). CONCLUSIONS: Color vision impairment in patients with DLB showed a prevalence similar to the core features of DLB (∼80%) and can be supportive to a diagnosis of DLB versus AD. Pending prospective confirmation of our findings, simple online color vision testing could be incorporated into multivariate diagnostic tools to possibly improve accuracy of early diagnosis of DLB.

The Skin and Lewy Body Disease.

This manuscript reviews the significant skin manifestations of Lewy body disease, including Parkinson's disease and dementia with Lewy bodies, and the diagnostic utility of skin biopsy. Besides classic motor and cognitive symptoms, non-motor manifestations, particularly dermatologic disorders, can play a crucial role in disease presentation and diagnosis. This review explores the intricate relationship between the skin and Lewy body disease. Seborrheic dermatitis, autoimmune blistering diseases (bullous pemphigoid and pemphigus), rosacea, and melanoma are scrutinized for their unique associations with Parkinson's disease, revealing potential links through shared pathophysiological mechanisms. Advances in diagnostic techniques allow the identification of promising biomarkers such as α-synuclein in samples obtained by skin punch biopsy. Understanding the dermatologic aspects of Lewy body disease not only contributes to its holistic characterization but also holds implications for innovative diagnostic approaches.

Relationships between plasma biomarkers, tau PET, FDG PET, and volumetric MRI in mild to moderate Alzheimer's disease patients.

INTRODUCTION: The "A/T/N" (amyloid/tau/neurodegeneration) framework provides a biological basis for Alzheimer's disease (AD) diagnosis and can encompass additional changes such as inflammation ("I"). A spectrum of T/N/I imaging and plasma biomarkers was acquired in a phase 2 clinical trial of rasagiline in mild to moderate AD patients. We evaluated these to understand biomarker distributions and relationships within this population. METHODS: Plasma biomarkers of pTau-181, neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), other inflammation-related proteins, imaging measures including fluorodeoxyglucose (FDG) positron emission tomography (PET), flortaucipir PET, and volumetric magnetic resonance imaging (MRI), and cognitive endpoints were analyzed to assess characteristics and relationships for the overall population (N = 47 at baseline and N = 21 for longitudinal cognitive comparisons) and within age-decade subgroups (57-69, 70-79, 80-90 years). RESULTS: Data demonstrate wide clinical and biomarker heterogeneity in this population influenced by age and sex. Plasma pTau-181 and GFAP correlate with tau PET, most strongly in left inferior temporal cortex (p = 0.0002, p = 0.0006, respectively). In regions beyond temporal cortex, tau PET uptake decreased with age for the same pTau-181 or GFAP concentrations. FDG PET and brain volumes correlate with tau PET in numerous regions (such as inferior temporal: p = 0.0007, p = 0.00001, respectively). NfL, GFAP, and all imaging modalities correlate with baseline MMSE; subsequent MMSE decline is predicted by baseline parahippocampal and lateral temporal tau PET (p = 0.0007) and volume (p = 0.0006). Lateral temporal FDG PET (p = 0.006) and volume (p = 0.0001) are most strongly associated with subsequent ADAS-cog decline. NfL correlates with FDG PET and baseline MMSE but not tau PET. Inflammation biomarkers are intercorrelated but correlated with other biomarkers in only the youngest group. DISCUSSION: Associations between plasma biomarkers, imaging biomarkers, and cognitive status observed in this study provide insight into relationships among biological processes in mild to moderate AD. Findings show the potential to characterize AD patients regarding likely tau pathology, neurodegeneration, prospective clinical decline, and the importance of covariates such as age. Highlights: Plasma pTau-181 and GFAP correlated with regional and global tau PET in mild to moderate AD.NfL correlated with FDG PET and cognitive endpoints but not plasma pTau-181 or tau PET.Volume and FDG PET showed strong relationships to tau PET, one another, and cognitive status.Temporal volumes most strongly predicted decline in both MMSE and ADAS-cog.Volume and plasma biomarkers can enrich for elevated tau PET with age a significant covariate.

Current Therapies and Drug Development Pipeline in Lewy Body Dementia: An Update.

The term Lewy body dementia refers to either of two related diagnoses: dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD). Clinical management of Lewy body dementia is challenging. The current treatment options focus on relieving symptoms; no disease-modifying therapies are available. There are currently no US Food and Drug Administration (FDA) approved drugs for the treatment of DLB, and there are only a few for PDD. Cholinesterase inhibitors are shown to be beneficial in improving cognitive symptoms in Lewy body dementia. Rivastigmine was approved by the FDA to treat PDD. Donepezil was approved in Japan as a treatment for DLB. Levodopa may provide modest benefit in treating motor symptoms and zonisamide in adjunct to low-dose levodopa helps with parkinsonism. Treatment of autonomic symptoms are based on symptomatic treatment with off-label agents. Our main objective in this article is to present an overview of the current pharmacological options available to treat the clinical features of DLB and PDD. When evaluating the existing management options for Lewy body dementia, it is difficult to fully separate PDD from DLB. However, we have attempted to identify whether the cited studies include patients with PDD and/or DLB. Moreover, we have provided an overview of the current drug pipeline in Lewy body dementia. All currently active trials are in phase I or II and most are focused on disease modification rather than symptomatic treatment. Phase II trial results for neflamapimod show promising results. Due to heterogeneity of symptoms and underlying pathophysiology, there is a need for new biomarker strategies and improved definitions of outcome measures for Lewy body dementia drug trials.

The Application of Zonisamide to Patients Suffering from Dementia with Lewy Bodies: Emerging Clinical Data.

Zonisamide is an anti-epileptic medication with multiple mechanisms of action and a favorable safety profile. Zonisamide may interact with Lewy body dementia pathophysiology through a mechanism unrelated to its original indication. Zonisamide has shown efficacy as adjunct therapy for the management of motor symptoms in patients with Parkinson's disease (PD). Given that dementia with Lewy bodies (DLB) and PD are considered subtypes of a Lewy body disease spectrum, zonisamide was investigated for the treatment of parkinsonism in DLB. Phase II and phase III clinical trials were conducted in patients with DLB in Japan. In both studies, participants were randomized to receive 12 weeks of zonisamide 25 or 50 mg/day or placebo. Zonisamide significantly improved the Unified Parkinson's Disease Rating Scale Part III (UPDRS-III) without affecting the Mini-Mental State Examination (MMSE) or Neuropsychiatry Inventory-10 (NPI-10) scores at week 12. In 2018, zonisamide received Japanese regulatory approval for the additional indication of parkinsonism in DLB. This review discusses the emerging clinical data on zonisamide in the field of DLB.

An international, randomized, placebo-controlled, phase 2b clinical trial of intepirdine for dementia with Lewy bodies (HEADWAY-DLB).

INTRODUCTION: A phase 2b clinical trial, HEADWAY-DLB, was performed to assess treatment with intepirdine, a serotonin receptor antagonist, in patients with dementia with Lewy bodies (DLB). METHODS: HEADWAY-DLB was a multinational, double-blind, randomized, placebo-controlled study. Two hundred sixty-nine DLB patients were randomized to receive placebo, 70 mg/day intepirdine, or 35 mg/day intepirdine over 24 weeks. The primary endpoint was change from baseline to week 24 on the Unified Parkinson's Disease Rating Scale-Part III (UPDRS-III). RESULTS: Both intepirdine groups did not demonstrate significant benefits over placebo at 24 weeks on the UPDRS-III (35 mg/day: P = .1580, 70 mg/day: P = .6069). All other endpoints were not significant. Intepirdine was well tolerated, with a slightly higher incidence of gastrointestinal adverse events observed in the intepirdine groups versus placebo. DISCUSSION: Intepirdine treatment did not lead to improvements over placebo in patients with DLB. As one of the largest DLB studies to date, HEADWAY-DLB demonstrates that international trials for DLB are feasible within a reasonable timeframe.

Rasagiline effects on glucose metabolism, cognition, and tau in Alzheimer's dementia.

BACKGROUND: A Phase II proof of concept (POC) randomized clinical trial was conducted to evaluate the effects of rasagiline, a monoamine oxidase B (MAO-B) inhibitor approved for Parkinson disease, in mild to moderate Alzheimer's disease (AD). The primary objective was to determine if 1 mg of rasagiline daily for 24 weeks is associated with improved regional brain metabolism (fluorodeoxyglucose-positron emission tomography [FDG-PET]) compared to placebo. Secondary objectives included measurement of effects on tau PET and evaluation of directional consistency of clinical end points. METHODS: This was a double-blind, parallel group, placebo-controlled, community-based, three-site trial of 50 participants randomized 1:1 to receive oral rasagiline or placebo (NCT02359552). FDG-PET was analyzed for the presence of an AD-like pattern as an inclusion criterion and as a longitudinal outcome using prespecified regions of interest and voxel-based analyses. Tau PET was evaluated at baseline and longitudinally. Clinical outcomes were analyzed using an intention-to-treat (ITT) model. RESULTS: Fifty patients were randomized and 43 completed treatment. The study met its primary end point, demonstrating favorable change in FDG-PET differences in rasagiline versus placebo in middle frontal (P < 0.025), anterior cingulate (P < 0.041), and striatal (P < 0.023) regions. Clinical measures showed benefit in quality of life (P < 0.04). Digit Span, verbal fluency, and Neuropsychiatric Inventory (NPI) showed non-significant directional favoring of rasagiline; no effects were observed in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog) or activities of daily living. Rasagiline was generally well tolerated with low rates of adverse events and notably fewer neuropsychiatric symptoms in the active treatment group. DISCUSSION: These outcomes illustrate the potential benefits of rasagiline on clinical and neuroimaging measures in patients with mild to moderate AD. Rasagiline appears to affect neuronal activity in frontostriatal pathways, with associated clinical benefit potential warranting a more fully powered trial. This study illustrated the potential benefit of therapeutic repurposing and an experimental medicine proof-of-concept design with biomarkers to characterize patient and detect treatment response.

Dementia Care in the Time of COVID-19 Pandemic.

Patients with dementia are particularly vulnerable during the COVID-19 pandemic. The initial response to COVID-19 promoted behavioral changes in both society and healthcare, while a long-term solution is sought by prioritizing societal values. In addition, there has been disruption to clinical care and clinical research. This pandemic might have significantly changed the care for our patients with dementia toward increased acceptance of telemedicine by the patients and providers, and its utilization in both clinical care and research.

Clinical and Imaging Characteristics Associated with Color Vision Impairment in Lewy Body Disease.

BACKGROUND: Color vision impairment (CVI) has been reported in dementia with Lewy bodies (DLB) and prodromal Lewy body disease (pro-LBD). OBJECTIVE: In order to better characterize the diagnostic value of CVI testing, we compared the prevalence of CVI in patients with with Lewy body disease compared to Alzheimer's disease (AD), and we examined clinical and imaging characteristics associated with CVI in patients with DLB and suspected pro-LBD. METHODS: We retrospectively reviewed medical records, dopamine transporter (DaT-SPECT) imaging, and volumetric MRI from patients with AD, DLB, and suspected pro-LBD who underwent an online Farnsworth D-15 color vision test. RESULTS: 111 patients (62 DLB, 25 pro-LBD, and 24 AD) were included with a median age of 75 years. Newly diagnosed CVI was present in 67% of patients with DLB, 44% of patients with pro-LBD, and 18% of patients with AD. In patients with DLB, CVI was associated with lower Montreal Cognitive Assessment (MoCA) scores and lower sub-scores in visuospatial/executive function, naming, and language. In a multivariable logistic regression model, a diagnosis of DLB or pro-LBD compared to AD, and a lower composite MoCA score in visuospatial/executive function, naming, and language were associated with CVI controlling for age and gender. Among 17 DLB patients who underwent volumetric MRI, patients with CVI (n = 9) demonstrated lower normative volumetric percentiles in the right transverse superior temporal lobe. CONCLUSION: We provide further evidence that CVI can help differentiate DLB from AD, and we suggest that CVI may be an indicator of cognitive decline and disease progression in DLB.

Amygdala sign, a FDG-PET signature of dementia with Lewy Bodies.

BACKGROUND: Biomarkers are being used increasingly to support the diagnosis of dementia with Lewy bodies (DLB). Novel biomarkers that increase diagnostic specificity of DLB are needed. We assessed previously known FDG-PET occipital cortex hypometabolism, and cingulate island sign biomarkers of DLB against a novel amygdala signature. METHODS: Retrospective analysis of 49 patients evaluated at one tertiary memory clinic. All had a FDG-PET brain scan performed as part of their diagnostic work up evaluating three common neurodegenerative etiologies: Alzheimer dementia (AD), Frontotemporal dementia (FTD) and DLB. A consensus diagnosis of dementia was made based on accepted clinical criteria for AD, FTD and DLB. FDG-PET regional metabolism was delineated by automatic segmentation as well as manual tracing of amygdala and posterior cingulate volumes of interest. Mean normalized values calculated for regional FDG-PET signatures of DLB: occipital cortex hypometabolism and preservation of posterior cingulate and amygdala metabolism relative to whole brain metabolism were evaluated. RESULTS: Significant overlap between DLB and AD patients (occipital, parietal, temporal and frontal hypometabolism) and between DLB and FTD (frontal hypometabolism and the posterior cingulate sign) were identified. Right amygdala (p = 0.028) and right posterior cingulate (p = 0.035) mean normalized regional metabolism levels were preserved in DLB compared to AD. Among subjects at less advanced stages of dementia (MoCA>10), relative preservation of regional metabolism was notable across both left (p = 0.006) and right (p = 0.020) amygdala. CONCLUSION: Relative preservation of amygdala metabolism could complement previously described FDG-PET findings in earlier stages of DLB.

Movement disorder emergencies in the elderly: recognizing and treating an often-iatrogenic problem.

Movement disorder emergencies in the elderly--such as rigidity, dystonia, hyperkinetic movements, and psychiatric disturbances--are challenging to manage. Many case, are iatrogenic. In theory, some cases could be avoidedby anticipating them and by avoiding polypharmacy and potentially dangerous drug interactions.

5HT6 Antagonists in the Treatment of Alzheimer's Dementia: Current Progress.

Alzheimer's disease is an important condition with a considerable and unmet disease burden in large need of continued research and more treatment options. The 5HT6 antagonists are a new class of medications to be offered. Because they are pro-cholinergic, these medications are to be used as adjuncts to acetylcholinesterase inhibitors (such as donepezil), further increasing acetylcholine in the central nervous system (CNS). Early trials of the 5HT6 antagonists showed improvements in cognition and activities of daily living when used as adjuncts to current therapies for Alzheimer's dementia. However, recent phase III trials have failed to show a statistically significant improvement in cognitive function. This article will provide a comprehensive review of 5HT6 antagonists in drug development, including some that have been recently discontinued. We will discuss both the successes and failures of this drug class and provide rationale for their continued research and development.

Diagnosis and Management of Cognitive and Behavioral Changes in Dementia With Lewy Bodies.

OPINION STATEMENT: Proper diagnosis of dementia with Lewy bodies (DLB) in clinical practice remains suboptimal as many cases are misdiagnosed, usually as Alzheimer disease (AD) or Parkinson's disease (PD) and, in rare cases, psychosis. Therefore, it is important for patients with dementia to be thoroughly evaluated by a specialist who is familiar with current diagnostic tests and treatment options. New diagnostic criteria from the Dementia with Lewy Bodies Consortium have been developed to increase diagnostic sensitivity for DLB (Diagnosis and management of dementia with Lewy bodies: fourth consensus report of the DLB Consortium; McKeith et al.; Neurology, 89(1): 88-100). REM sleep behavior disorder (RBD) has been studied more thoroughly in correlation with DLB and is now considered a core feature. D2 receptor blocking antipsychotics, which can cause severe antipsychotic sensitivity, are now rarely prescribed for treatment. Therefore, severe antipsychotic sensitivity, which was a suggestive criterion for DLB diagnosis, is now listed as a supportive feature. Reduced DAT uptake in basal ganglia demonstrated by SPECT or PET imaging has high specificity (90%) for distinguishing DLB from AD. Reduced uptake on metaiodobenzylguanidine myocardial scintigraphy correlates with reduced postganglionic sympathetic cardiac innervation in Lewy body diseases, which can increase specificity for discriminating probable DLB from probable AD in milder cases of dementia. However, the latter is more commonly used in Japan and is not used in the USA. The evidence supporting the benefit of other therapeutic modalities is limited in DLB due to lack of extensive studies. There are no FDA-approved medications for the treatment of DLB, although some effective drugs have been used off label to treat various symptoms.

ALZ i-Connect.

Currently, there is not enough time or staff in the physician's office to provide education about Alzheimer's disease for newly diagnosed patients and their family members. The Alzheimer's Association Cleveland Area Chapter has implemented a novel approach for individuals to connect to helpful information about Alzheimer's disease and related dementias while at the physician's office. This project is being piloted at two memory assessment clinics of The Cleveland Clinic as a way to give assessment center staff the opportunity to connect families right away with the free support services available at the Association.

Utility of Montreal Cognitive Assessment in Differentiating Dementia With Lewy Bodies From Alzheimer's Dementia.

Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) are the 2 most common neurodegenerative dementias. Identification of patients with DLB is necessary to guide appropriate clinical management and medication trials. Patients with DLB are reported to perform poorly on tasks of visuospatial and executive function, compared to patients with AD who perform poorly on memory tasks. Using the Montreal Cognitive Assessment, we found that patients with DLB (n = 73) had statistically significant lower performance in clock drawing (visuospatial and executive function) and higher performance in delayed recall (memory) subscores compared to patients with AD (n = 57). This score pattern should raise suspicion for a DLB diagnosis at initial evaluation of patients with dementia.

The emerging role of bexarotene in the treatment of Alzheimer's disease: current evidence.

In 2012, a novel approach to the treatment of Alzheimer's disease was introduced, heralding a wave of excitement in the field of dementia. Bexarotene, a retinoid X receptor agonist, was shown to reverse neurodegeneration, improve cognition, and decrease levels of amyloid-ß in transgenic mice expressing familial Alzheimer disease mutations. Since then, there has been widespread discussion about bexarotene, as well as a number of follow-up studies. Bexarotene is a unique compound, as it is approved by the US Food and Drug Administration for other purposes and there are reasonable data to justify its mechanism of action in dementia. This review discusses these studies and the emerging role of bexarotene in the clinical field of Alzheimer's dementia.