Postprandial hypotension is more common than orthostatic hypotension in older adults with dementia with lewy bodies: a cross-sectional study.

Cardiovascular autonomic dysfunction is one of the supportive clinical features in dementia with Lewy bodies (DLB). This study aimed to investigate the frequency of postural and postprandial hypotension in people with DLB. The study group comprised 125 patients with DLB (76 females; mean age 78.4 ± 7.1 years) and 122 controls (88 females; mean age 74.4 ± 6.9 years). Postprandial blood pressure changes were assessed by ambulatory 24-hour blood pressure monitorization. Postural blood pressure changes were assessed via the head-up tilt table test. The frequency of postprandial hypotension (PPH) and orthostatic hypotension (OH) was higher in patients with DLB compared to controls (89.4% vs 51.7%; p < 0.001, and 45.5% vs 27.9%; p = 0.004, respectively) whereas the frequency of supine hypertension (SH), and orthostatic hypertension (OHT) was similar. However, SH in non-hypertensive participants was higher in DLB patients than in controls (48.9%, 25.7%; p = 0.035). PPH and OH were independently associated with a diagnosis of DLB (odds ratio [OR]:10.26 confidence interval [CI]%95 3.02-34.82; p < 0.001, and OR:2.22 CI%95 1.2-4.12; p = 0.012, respectively) after adjustment for age, number of medications, use of anti-psychotics drugs, angiotensin receptor blockers, and beta blockers. In conclusion, the study demonstrated that PPH was the most common finding of cardiovascular autonomic dysfunction, followed by OH and SH in older patients with DLB. Given the potential complications of postural blood pressure changes and PPH in such patients, cardiovascular autonomic dysfunction should be evaluated in patients with DLB.

Clinical application of whole genome sequencing in young onset dementia: challenges and opportunities.

INTRODUCTION: Young onset dementia (YOD) by its nature is difficult to diagnose. Despite involvement of multidisciplinary neurogenetics services, patients with YOD and their families face significant diagnostic delays. Genetic testing for people with YOD currently involves a staggered, iterative approach. There is currently no optimal single genetic investigation that simultaneously identifies the different genetic variants resulting in YOD. AREAS COVERED: This review discusses the advances in clinical genomic testing for people with YOD. Whole genome sequencing (WGS) can be employed as a 'one stop shop' genomic test for YOD. In addition to single nucleotide variants, WGS can reliably detect structural variants, short tandem repeat expansions, mitochondrial genetic variants as well as capture single nucleotide polymorphisms for the calculation of polygenic risk scores. EXPERT OPINION: WGS, when used as the initial genetic test, can enhance the likelihood of a precision diagnosis and curtail the time taken to reach this. Finding a clinical diagnosis using WGS can reduce invasive and expensive investigations and could be cost effective. These advances need to be balanced against the limitations of the technology and the genetic counseling needs for these vulnerable patients and their families.

Alpha tACS Improves Cognition and Modulates Neurotransmission in Dementia with Lewy Bodies.

BACKGROUND: Dementia with Lewy bodies (DLB) is characterized by a marked shift of electroencephalographic (EEG) power and dominant rhythm, from the α toward the θ frequency range. Transcranial alternate current stimulation (tACS) is a non-invasive brain stimulation technique that allows entrainment of cerebral oscillations at desired frequencies. OBJECTIVES: Our goal is to evaluate the effects of occipital α-tACS on cognitive functions and neurophysiological measures in patients with DLB. METHODS: We conducted a double-blind, randomized, sham-controlled, cross-over clinical trial in 14 participants with DLB. Participants were randomized to receive either α-tACS (60 minutes of 3 mA peak-to-peak stimulation at 12 Hz) or sham stimulation applied over the occipital cortex. Clinical evaluations were performed to assess visuospatial and executive functions, as well as verbal episodic memory. Neurophysiological assessments and EEG recordings were conducted at baseline and following both α-tACS and sham stimulations. RESULTS: Occipital α-tACS was safe and well-tolerated. We observed a significant enhancement in visuospatial abilities and executive functions, but no improvement in verbal episodic memory. We observed an increase in short latency afferent inhibition, a neurophysiological marker indirectly and partially dependent on cholinergic transmission, coinciding with an increase in α power and a decrease in Δ power following α-tACS stimulation, effects not seen with sham stimulation. CONCLUSIONS: This study demonstrates that occipital α-tACS is safe and enhances visuospatial and executive functions in patients with DLB. Improvements in indirect markers of cholinergic transmission and EEG changes indicate significant neurophysiological engagement. These findings justify further exploration of α-tACS as a therapeutic option for DLB patients. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Cognitive dysfunction in animal models of human lewy-body dementia.

Cognitive impairments are a common feature of synucleinopathies such as Parkinson's Disease Dementia and Dementia with Lewy Bodies. These pathologies are characterized by accumulation of Lewy bodies and Lewy neurites as well as neuronal cell death. Alpha-synuclein is the main proteinaceous component of Lewy bodies and Lewy neurites. To model these pathologies in vivo, toxins that selectively target certain neuronal populations or different means of inducing alpha-synuclein aggregation can be used. Alpha-synuclein accumulation can be induced by genetic manipulation, viral vector overexpression or the use of preformed fibrils of alpha-synuclein. In this review, we summarize the cognitive impairments associated with different models of synucleinopathies and relevance to observations in human diseases.

Rapid iPSC inclusionopathy models shed light on formation, consequence, and molecular subtype of α-synuclein inclusions.

The heterogeneity of protein-rich inclusions and its significance in neurodegeneration is poorly understood. Standard patient-derived iPSC models develop inclusions neither reproducibly nor in a reasonable time frame. Here, we developed screenable iPSC "inclusionopathy" models utilizing piggyBac or targeted transgenes to rapidly induce CNS cells that express aggregation-prone proteins at brain-like levels. Inclusions and their effects on cell survival were trackable at single-inclusion resolution. Exemplar cortical neuron α-synuclein inclusionopathy models were engineered through transgenic expression of α-synuclein mutant forms or exogenous seeding with fibrils. We identified multiple inclusion classes, including neuroprotective p62-positive inclusions versus dynamic and neurotoxic lipid-rich inclusions, both identified in patient brains. Fusion events between these inclusion subtypes altered neuronal survival. Proteome-scale α-synuclein genetic- and physical-interaction screens pinpointed candidate RNA-processing and actin-cytoskeleton-modulator proteins like RhoA whose sequestration into inclusions could enhance toxicity. These tractable CNS models should prove useful in functional genomic analysis and drug development for proteinopathies.

Plasma biomarkers of amyloid, tau, axonal, and neuroinflammation pathologies in dementia with Lewy bodies.

BACKGROUND: Increasing evidence supports the use of plasma biomarkers of amyloid, tau, neurodegeneration, and neuroinflammation for diagnosis of dementia. However, their performance for positive and differential diagnosis of dementia with Lewy bodies (DLB) in clinical settings is still uncertain. METHODS: We conducted a retrospective biomarker study in two tertiary memory centers, Paris Lariboisière and CM2RR Strasbourg, France, enrolling patients with DLB (n = 104), Alzheimer's disease (AD, n = 76), and neurological controls (NC, n = 27). Measured biomarkers included plasma Aß40/Aß42 ratio, p-tau181, NfL, and GFAP using SIMOA and plasma YKL-40 and sTREM2 using ELISA. DLB patients with available CSF analysis (n = 90) were stratified according to their CSF Aß profile. RESULTS: DLB patients displayed modified plasma Aß ratio, p-tau181, and GFAP levels compared with NC and modified plasma Aß ratio, p-tau181, GFAP, NfL, and sTREM2 levels compared with AD patients. Plasma p-tau181 best differentiated DLB from AD patients (ROC analysis, area under the curve [AUC] = 0.80) and NC (AUC = 0.78), and combining biomarkers did not improve diagnosis performance. Plasma p-tau181 was the best standalone biomarker to differentiate amyloid-positive from amyloid-negative DLB cases (AUC = 0.75) and was associated with cognitive status in the DLB group. Combining plasma Aß ratio, p-tau181 and NfL increased performance to identify amyloid copathology (AUC = 0.79). Principal component analysis identified different segregation patterns of biomarkers in the DLB and AD groups. CONCLUSIONS: Amyloid, tau, neurodegeneration and neuroinflammation plasma biomarkers are modified in DLB, albeit with moderate diagnosis performance. Plasma p-tau181 can contribute to identify Aß copathology in DLB.

Factors Associated With Increased Health Care Utilization for Patients With Dementia With Lewy Bodies: A Narrative Review.

Numerous studies have demonstrated that dementia is associated with increased utilization of health care services, which in turn results in increased costs of care. Dementia with Lewy bodies (DLB) is associated with greater costs of care relative to other forms of dementia due to higher rates of hospitalization and nursing home placement directly related to neuropsychiatric symptoms, parkinsonism, increased susceptibility to delirium, and elevated rates of caregiver burden. There is a critical need for researchers to identify potentially modifiable factors contributing to increased costs of care and poor clinical outcomes for patients with DLB, which may include comorbidities, polypharmacy/contraindicated medications, and access to specialty care. Previous research has utilized Medicare claims data, limiting the ability to study patients with early-onset (ie, prior to age 65) DLB. Integrated health systems offer the ability to combine electronic medical record data with Medicare, Medicaid, and commercial claims data and may therefore be ideal for utilization research in this population. The goals of this narrative review are to 1) synthesize and describe the current literature on health care utilization studies for patients with DLB, 2) highlight the current gaps in the literature, and 3) provide recommendations for stakeholders, including researchers, health systems, and policymakers. It is important to improve current understanding of potentially modifiable factors associated with increased costs of care among patients with DLB to inform public health policies and clinical decision-making, as this will ultimately improve the quality of patient care.

The Clinical Role of Heart Rate Variability Assessment in Cognitively Impaired Patients and Its Applicability in Community Care Settings: A Systematic Review of the Literature.

Heart rate variability (HRV) correlates well with a person's overall physiological function. Clinically, HRV is successfully used in acute care to identify impending infections, but little is known about its potential in the management of chronic diseases like cognitive decline/dementia. The aim of this study was to identify the best available knowledge about HRV in cognitively impaired populations that might be applied to improve clinical practice in community settings. We conducted a systematic literature search in PubMed, Embase, and Cochrane databases published from January 2009 to August 2022. Eligible studies were selected using Covidence and each study underwent qualitative assessment using the Mixed Method Appraisal Tool. At each stage of selection, each study was reviewed independently by two members of the team, and any disputes were discussed along the way. The literature identified that the brain regions controlling HRV are also those affected by dementias of Alzheimer's type (AD) and Lewy body types (DLB). HRV was impaired in both types, with DLB showing greater impairment in all HRV parameters compared to AD. No studies explored the temporal changes of HRV or its use in the clinical management of people with cognitive impairment (CI). The current lack of standardization of HRV recording and analysis limits its use in clinical practice. HRV may emerge as a potentially useful tool to identify people with early/preclinical memory impairment and help to differentiate AD from DLB. Longitudinal HRV measurement is emerging as a useful way to monitor disease progression and treatment response, and continuous HRV measurement may prove useful in the early identification of sepsis and its complications in patients no longer able to communicate their illness experiences.

Genetic evidence for causal association between migraine and dementia: a mendelian randomization study.

BACKGROUND: There is an association between migraine and dementia, however, their causal relationship remains unclear. This study employed bidirectional two-sample Mendelian randomization (MR) to investigate the potential causal relationship between migraine and dementia and its subtypes: Alzheimer's disease (AD), vascular dementia (VaD), frontotemporal dementia (FTD), and dementia with Lewy bodies (DLB). METHODS: Summary-level statistics data were obtained from publicly available genome-wide association studies (GWAS) for both migraine and five types of dementia. Single nucleotide polymorphisms (SNPs) associated with migraine and each dementia subtype were selected. MR analysis was conducted using inverse variance weighting (IVW) and weighted median (WM) methods. Sensitivity analyses included Cochran's Q test, MR pleiotropy residual sum and outlier (MR-PRESSO) analysis, the intercept of MR-Egger, and leave-one-out analysis. RESULTS: Migraine showed a significant causal relationship with AD and VaD, whereas no causal relationship was observed with all-cause dementia, FTD, or DLB. Migraine may be a potential risk factor for AD (odds ratio [OR]: 1.09; 95% confidence interval [CI]: 0.02-0.14; P = 0.007), while VaD may be a potential risk factor for migraine (OR: 1.04; 95% CI: 0.02-0.06; P = 7.760E-5). Sensitivity analyses demonstrated the robustness of our findings. CONCLUSION: Our study suggest that migraine may have potential causal relationships with AD and VaD. Migraine may be a risk factor for AD, and VaD may be a risk factor for migraine. Our study contributes to unraveling the comprehensive genetic associations between migraine and various types of dementia, and our findings will enhance the academic understanding of the comorbidity between migraine and dementia.

Neuropathologic findings in a patient with hemiparkinsonism and hemiatrophy syndrome.

The first postmortem neuropathological findings of a hemiparkinsonism and hemiatrophy (HPHA) patient are presented. A 50-year-old man developed resting tremors affecting the right hand and leg, followed by mild clumsiness of the right hand. On examination, he exhibited muscle atrophy of the right leg extremity, accompanied by right-sided parkinsonism. Brain magnetic resonance imaging was normal. Based on the clinical and radiological findings, HPHA syndrome was diagnosed, showing a good response to L-DOPA. He gradually developed muscular atrophy of the right distal upper extremity. Thirteen years after the onset of the disease, left-sided parkinsonism appeared. The patient died of Trousseau's syndrome associated with a rapidly emerging pancreatic tumor. The total duration of the disease was 14 years. Neuropathologically, the substantia nigra showed markedly left-predominant neuronal loss, along with almost symmetrical Lewy body (LB) pathology. These findings indicated that the patient originally had fewer neurons in the left substantia nigra than in the right, probably caused by congenital or childhood cerebral injury, followed by the development of unilateral parkinsonism due to the progression of LB pathology. Despite our extensive neuropathological analysis, we could not specify the etiology or anatomical substrate responsible for the development of right upper and lower extremity atrophy. Further clinicopathological studies are needed to elucidate the pathoanatomical areas causing hemiparkinsonism and hemiatrophy.

Dementia with Lewy bodies and gait neural basis: a cross-sectional study.

BACKGROUND: Dementia with Lewy Bodies (DLB) is responsible for cognitive-behavioural disorders but also for gait disorders. The latter are thought to be related to parkinsonism, but the neural bases of these disorders are not well known, especially in the early stages. The aim of this study was to investigate by volumetric Magnetic Resonance Imaging the neuronal basis of gait disorders in DLB patients, compared to Healthy Elderly Controls and Alzheimer's Disease patients. METHODS: Clinical examination with motor assessment including 10-meter walking speed, one-leg balance and Timed Up and Go test, a comprehensive neuropsychological evaluation and 3D brain Magnetic Resonance Imaging were performed on 84 DLB patients, 39 Alzheimer's Disease patients and 22 Healthy Elderly Controls. We used Statistical Parametric Mapping 12 to perform a one-sample t-test to investigate the correlation between each gait score and gray matter volume (P ≤ 0.05 corrected for family-wise error). RESULTS: We found a correlation for DLB patients between walking speed and gray matter decrease (P < 0.05, corrected for family-wise error) in caudate nuclei, anterior cingulate cortex, mid-cingulate cortex, hippocampi, supplementary motor area, right cerebellar cortex and left parietal operculum. We found no correlation with Timed Up and Go test and one-leg balance. CONCLUSION: Gait disorders are underpinned by certain classical regions such as the cerebellum and the supplementary motor area. Our results suggest there may be a motivational and emotional component of voluntary gait in DLB subjects, underpinned by the cingulate cortex, a spatial orientation component, underpinned by hippocampi and suggest the involvement of brain processing speed and parkinsonism, underpinned by the caudate nuclei. TRIAL REGISTRATION: The study protocol has been registered on ClinicalTrials.gov. (NCT01876459) on June 12, 2013.

Post hoc analysis of the characteristics and treatment needs of patients with dementia with Lewy bodies (DLB) and their caregivers and their physicians' awareness of those treatment needs according to the duration after diagnosis of DLB.

OBJECTIVES: To investigate the differences in patient/caregiver characteristics, their treatment needs, and the attending physician's understanding of those treatment needs according to the duration after diagnosis of dementia with Lewy bodies (DLB). METHODS: This was a post hoc analysis of a multicenter, cross-sectional, questionnaire survey study. A total of 263 patient-caregiver pairs were reclassified into two groups according to the median duration after diagnosis of DLB as follows: short (<24 months; S-group) and long (≥24 months; L-group) post-DLB diagnosis duration. Treatment need was defined as the symptom domain that caused the patient or caregiver the most distress. Concordance rates between patient-physician and caregiver-physician were calculated for physicians' understanding of treatment needs. RESULTS: In this analysis, 126 pairs (32 physicians) and 137 pairs (34 physicians) were classified as the S- and L-groups, respectively. Patient and caregiver characteristics were broadly similar between groups (mean age for patients 78.7 ± 6.6 vs. 79.8 ± 6.7, for caregivers 64.7 ± 12.9 vs. 64.9 ± 12.8; number of male/female for patients 61/65 vs. 67/70, for caregivers 34/92 vs. 38/99), but the prevalence of parkinsonism (82.5% vs. 66.7%) and autonomic dysfunction (49.6% vs. 33.3%), severity of parkinsonism (MDS-UPDRS Part III total scores, 29.2 ± 22.6 vs. 18.0 ± 16.4; Part II total score, 14.6 ± 12.0 vs. 7.6 ± 7.9), and caregiver burden (J-ZBI_8 score, 9.1 ± 6.7 vs. 7.5 ± 5.8) were higher in the L-group than the S-group. Regarding treatment needs, the invalid answer rates for patients were 34.9% and 46.8%, and those for caregivers were 28.6% and 34.9% in the S- and L groups, respectively. Patients' treatment needs did not significantly differ (p = 0.056), but S-group patients were more likely to select cognitive impairment (p = 0.045) as their treatment need, whereas L-group patients were more likely to select parkinsonism (p = 0.003). Caregivers' treatment needs significantly differed (p = 0.032) between groups. S-group caregivers were more likely to select cognitive impairment (p = 0.001), whereas L-group caregivers were more likely to select other symptom domains such as parkinsonism (S-group vs. L-group: 10.3% vs. 16.7%), psychiatric symptoms (20.6% vs. 24.6%), sleep-related disorder (4.0% vs. 7.1%), and autonomic dysfunction (4.8% vs. 9.5%). Concordance rates between patient-physician and caregiver-physician were low in both groups. CONCLUSIONS: There were some differences in characteristics according to the duration after diagnosis of DLB. Cognitive dysfunction may be a particular concern for patients and caregivers soon after diagnosis of DLB. Treatment needs of patients and caregivers for parkinsonism, psychiatric symptoms, sleep-related disorder, or autonomic dysfunction were different according to the duration after diagnosis of DLB. Physicians' perception of patients'/caregivers' treatment needs was poor regardless of the duration after diagnosis of DLB. CLINICAL TRIAL REGISTRATION: UMIN Clinical Trials Registry (UMIN000041844).

Developing a person-centered stated preference survey for dementia with Lewy bodies: value of a personal and public involvement process.

Introduction: The development of high-quality stated preference (SP) surveys requires a rigorous design process involving engagement with representatives from the target population. However, while transparency in the reporting of the development of SP surveys is encouraged, few studies report on this process and the outcomes. Recommended stages of instrument development includes both steps for stakeholder/end-user engagement and pretesting. Pretesting typically involves interviews, often across multiple waves, with improvements made at each wave; pretesting is therefore resource intensive. The aims of this paper are to report on the outcomes of collaboration with a Lewy body dementia research advisory group during the design phase of a SP survey. We also evaluate an alternative approach to instrument development, necessitated by a resource constrained context. Method: The approach involved conducting the stages of end-user engagement and pretesting together during a public involvement event. A hybrid approach involving a focus group with breakout interviews was employed. Feedback from contributors informed the evolution of the survey instrument. Results: Changes to the survey instrument were organized into four categories: attribute modifications; choice task presentation and understanding; information presentation, clarity and content; and best-best scaling presentation. The hybrid approach facilitated group brainstorming while still allowing the researcher to assess the feasibility of choice tasks in an interview setting. However, greater individual exploration and the opportunity to trial iterative improvements across waves was not feasible with this approach. Discussion: Involvement of the research advisory group resulted in a more person-centered survey design. In a context constrained by time and budget, and with consideration of the capacity and vulnerability of the target population, the approach taken was a feasible and pragmatic mechanism for improving the design of a SP survey.

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.

Excitatory synaptic structural abnormalities produced by templated aggregation of α-syn in the basolateral amygdala.

Parkinson's disease (PD) and Dementia with Lewy bodies (DLB) are characterized by neuronal α-synuclein (α-syn) inclusions termed Lewy Pathology, which are abundant in the amygdala. The basolateral amygdala (BLA), in particular, receives projections from the thalamus and cortex. These projections play a role in cognition and emotional processing, behaviors which are impaired in α-synucleinopathies. To understand if and how pathologic α-syn impacts the BLA requires animal models of α-syn aggregation. Injection of α-syn pre-formed fibrils (PFFs) into the striatum induces robust α-syn aggregation in excitatory neurons in the BLA that corresponds with reduced contextual fear conditioning. At early time points after aggregate formation, cortico-amygdala excitatory transmission is abolished. The goal of this project was to determine if α-syn inclusions in the BLA induce synaptic degeneration and/or morphological changes. In this study, we used C57BL/6 J mice injected bilaterally with PFFs in the dorsal striatum to induce α-syn aggregate formation in the BLA. A method was developed using immunofluorescence and three-dimensional reconstruction to analyze excitatory cortico-amygdala and thalamo-amygdala presynaptic terminals closely juxtaposed to postsynaptic densities. The abundance and morphology of synapses were analyzed at 6- or 12-weeks post-injection of PFFs. α-Syn aggregate formation in the BLA did not cause a significant loss of synapses, but cortico-amygdala and thalamo-amygdala presynaptic terminals and postsynaptic densities with aggregates of α-syn show increased volumes, similar to previous findings in human DLB cortex, and in non-human primate models of PD. Transmission electron microscopy showed that asymmetric synapses in mice with PFF-induced α-syn aggregates have reduced synaptic vesicle intervesicular distances, similar to a recent study showing phospho-serine-129 α-syn increases synaptic vesicle clustering. Thus, pathologic α-syn causes major alterations to synaptic architecture in the BLA, potentially contributing to behavioral impairment and amygdala dysfunction observed in synucleinopathies.

Undetected Association Between Fatty Acids and Dementia with Lewy Bodies: A Bidirectional Two-Sample Mendelian Randomization Study.

Background: Although observational studies indicated connections between fatty acids (FAs) and Alzheimer's disease and dementia, uncertainty persists regarding how these relationships extend to dementia with Lewy bodies (DLB). Objective: To explore the potential causal relationships between FAs and the development of DLB, thus clarifying these associations using genetic instruments to infer causality. Methods: We applied a two-sample Mendelian randomization (MR) and multivariable Mendelian randomization (MVMR) approach. Genetic data were obtained from a DLB cohort, comprising 2,591 cases and 4,027 controls of European descent. Eight FAs, including linoleic acid, docosahexaenoic acid, monounsaturated fatty acid, omega-3 fatty acid, omega-6 fatty acid, polyunsaturated fatty acid, saturated fatty acid, and total fatty acid, were procured from a comprehensive GWAS of metabolic biomarkers of UK Biobank, conducted by Nightingale Health in 2020 (met-d), involving 114,999 individuals. Our analysis included inverse-variance weighted, MR-Egger, weighted-median, simple mode, and weighted-mode MR estimates. Cochran's Q-statistics, MR-PRESSO, and MR-Egger intercept test were used to quantify the heterogeneity and horizontal pleiotropy of instrumental variables. Results: Only linoleic acid showed a significant genetic association with the risk of developing DLB in the univariate MR. The odds ratio for linoleic acid was 1.337 with a 95% confidence interval of 1.019-1.756 (pIVW = 0.036). Results from the MVMR showed that no FAs were associated with the incidence of DLB. Conclusions: The results did not support the hypothesis that FAs could reduce the risk of developing DLB. However, elucidating the relationship between FAs and DLB risk holds potential implications for informing dietary recommendations and therapeutic approaches in DLB.

Identification of retinal oligomeric, citrullinated, and other tau isoforms in early and advanced AD and relations to disease status.

This study investigates various pathological tau isoforms in the retina of individuals with early and advanced Alzheimer's disease (AD), exploring their connection with disease status. Retinal cross-sections from predefined superior-temporal and inferior-temporal subregions and corresponding brains from neuropathologically confirmed AD patients with a clinical diagnosis of either mild cognitive impairment (MCI) or dementia (n = 45) were compared with retinas from age- and sex-matched individuals with normal cognition (n = 30) and non-AD dementia (n = 4). Retinal tau isoforms, including tau tangles, paired helical filament of tau (PHF-tau), oligomeric-tau (Oligo-tau), hyperphosphorylated-tau (p-tau), and citrullinated-tau (Cit-tau), were stereologically analyzed by immunohistochemistry and Nanostring GeoMx digital spatial profiling, and correlated with clinical and neuropathological outcomes. Our data indicated significant increases in various AD-related pretangle tau isoforms, especially p-tau (AT8, 2.9-fold, pS396-tau, 2.6-fold), Cit-tau at arginine residue 209 (CitR209-tau; 4.1-fold), and Oligo-tau (T22+, 9.2-fold), as well as pretangle and mature tau tangle forms like MC-1-positive (1.8-fold) and PHF-tau (2.3-fold), in AD compared to control retinas. MCI retinas also exhibited substantial increases in Oligo-tau (5.2-fold), CitR209-tau (3.5-fold), and pS396-tau (2.2-fold). Nanostring GeoMx analysis confirmed elevated retinal p-tau at epitopes: Ser214 (2.3-fold), Ser396 (2.6-fold), Ser404 (2.4-fold), and Thr231 (1.8-fold), particularly in MCI patients. Strong associations were found between retinal tau isoforms versus brain pathology and cognitive status: a) retinal Oligo-tau vs. Braak stage, neurofibrillary tangles (NFTs), and CDR cognitive scores (ρ = 0.63-0.71), b) retinal PHF-tau vs. neuropil threads (NTs) and ABC scores (ρ = 0.69-0.71), and c) retinal pS396-tau vs. NTs, NFTs, and ABC scores (ρ = 0.67-0.74). Notably, retinal Oligo-tau strongly correlated with retinal Aß42 and arterial Aß40 forms (r = 0.76-0.86). Overall, this study identifies and quantifies diverse retinal tau isoforms in MCI and AD patients, underscoring their link to brain pathology and cognition. These findings advocate for further exploration of retinal tauopathy biomarkers to facilitate AD detection and monitoring via noninvasive retinal imaging.

Experimental models of Parkinson's disease: Challenges and Opportunities.

Parkinson's disease (PD) is a widespread neurodegenerative disorder occurs due to the degradation of dopaminergic neurons present in the substantia nigra pars compacta (SNpc). Millions of people are affected by this devastating disorder globally, and the frequency of the condition increases with the increase in the elderly population. A significant amount of progress has been made in acquiring more knowledge about the etiology and the pathogenesis of PD over the past decades. Animal models have been regarded to be a vital tool for the exploration of complex molecular mechanisms involved in PD. Various animals used as models for disease monitoring include vertebrates (zebrafish, rats, mice, guinea pigs, rabbits and monkeys) and invertebrate models (Drosophila, Caenorhabditis elegans). The animal models most relevant for study of PD are neurotoxin induction-based models (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 6-Hydroxydopamine (6-OHDA) and agricultural pesticides (rotenone, paraquat), pharmacological models (reserpine or haloperidol treated rats), genetic models (α-synuclein, Leucine-rich repeat kinase 2 (LRRK2), DJ-1, PINK-1 and Parkin). Several non-mammalian genetic models such as zebrafish, Drosophila and Caenorhabditis elegance have also gained popularity in recent years due to easy genetic manipulation, presence of genes homologous to human PD, and rapid screening of novel therapeutic molecules. In addition, in vitro models (SH-SY5Y, PC12, Lund human mesencephalic (LUHMES) cells, Human induced pluripotent stem cell (iPSC), Neural organoids, organ-on-chip) are also currently in trend providing edge in investigating molecular mechanisms involved in PD as they are derived from PD patients. In this review, we explain the current situation and merits and demerits of the various animal models.

Metallomic analysis of brain tissues distinguishes between cases of dementia with Lewy bodies, Alzheimer's disease, and Parkinson's disease dementia.

Background: Dementia with Lewy bodies (DLB) can be difficult to distinguish from Alzheimer's disease (AD) and Parkinson's disease dementia (PDD) at different stages of its progression due to some overlaps in the clinical and neuropathological presentation of these conditions compared with DLB. Metallomic changes have already been observed in the AD and PDD brain-including widespread decreases in Cu levels and more localised alterations in Na, K, Mn, Fe, Zn, and Se. This study aimed to determine whether these metallomic changes appear in the DLB brain, and how the metallomic profile of the DLB brain appears in comparison to the AD and PDD brain. Methods: Brain tissues from ten regions of 20 DLB cases and 19 controls were obtained. The concentrations of Na, Mg, K, Ca, Zn, Fe, Mn, Cu, and Se were determined using inductively coupled plasma-mass spectrometry (ICP-MS). Case-control differences were evaluated using Mann-Whitney U tests. Results were compared with those previously obtained from AD and PDD brain tissue, and principal component analysis (PCA) plots were created to determine whether cerebral metallomic profiles could distinguish DLB from AD or PDD metallomic profiles. Results: Na was increased and Cu decreased in four and five DLB brain regions, respectively. More localised alterations in Mn, Ca, Fe, and Se were also identified. Despite similarities in Cu changes between all three diseases, PCA plots showed that DLB cases could be readily distinguished from AD cases using data from the middle temporal gyrus, primary visual cortex, and cingulate gyrus, whereas DLB and PDD cases could be clearly separated using data from the primary visual cortex alone. Conclusion: Despite shared alterations in Cu levels, the post-mortem DLB brain shows very few other similarities with the metallomic profile of the AD or PDD brain. These findings suggest that while Cu deficiencies appear common to all three conditions, metal alterations otherwise differ between DLB and PDD/AD. These findings can contribute to our understanding of the underlying pathogenesis of these three diseases; if these changes can be observed in the living human brain, they may also contribute to the differential diagnosis of DLB from AD and/or PDD.

"¿Cómo qué, cómo qué? cómo qué?" Single-language echolalia in a bilingual female with progressive supranuclear palsy: a case report.

The case study explores bilingualism and neurodegenerative disorders, specifically progressive supranuclear palsy (PSP) with speech and language disorder (PSP-SL). It features a 78-year-old Mexican American woman who exhibits echolalia only in response to Spanish. This selective impairment suggests unevenly affected language control mechanisms despite her proficiency in both languages. Cognitive function is evaluated with neuropsychological tests; she's diagnosed with PSP-SL, depression, and anxiety. Echolalia in response to one language implies complex phonological retrieval mechanisms. Such observations prompt further inquiry into bilingual language control and processing mechanisms. The case supports evidence that bilingualism may attenuate neurodegeneration effects, suggesting better inhibitory control over disinhibited speech through enhanced executive functioning benefits.