Dementia With Lewy Bodies Research Articles

Mixed Dementia Alzheimer and Lewy body with congenital diseases: Case Study

Objectives: Dementia due to Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) are the diseases that appear together, especially in elderly people. Still, clinical identification of dementia is difficult in such circumstances. Therefore, we conducted a case study with a comprehensive prospective clinical assessment and complete mental, physical, and psychiatric examination to diagnose such mixed cases clinically and for curative management of mixed dementia of Alzheimer's disease (AD) and dementia with Lewy bodies (DLB). Case: a 76 years old woman have anxiety that fluctuated. The history of medical disorders, physical examination and supporting examinations, was found that the patient had hypertension, dyslipidemia, hypothyroidism in treatment, Barrett's esophagus in therapy, osteoarthritis genu dextra, history of malnutrition, breast cancer and hysterectomy. The patient was advised to administer antipsychotics because the patient's agitation was severe and the caregiver's distress was high. The patient improved with pharmacological therapy and family monitoring support. Conclusion: The diagnosis of mixed dementia patients (Alzheimer's disease (AD) and dementia with Lewy bodies (DLB)) with a medical history of congenital disease has overlapping symptoms so that very selective drug treatment is needed so as not to worsen the condition of other diseases. The supportive role of the family can help cure mixed Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) by creating a logbook of daily behavior and symptoms that appear in the patient.

Pathobiology of Cognitive Impairment in Parkinson Disease: Challenges and Outlooks.

Cognitive impairment (CI) is a characteristic non-motor feature of Parkinson disease (PD) that poses a severe burden on the patients and caregivers, yet relatively little is known about its pathobiology. Cognitive deficits are evident throughout the course of PD, with around 25% of subtle cognitive decline and mild CI (MCI) at the time of diagnosis and up to 83% of patients developing dementia after 20 years. The heterogeneity of cognitive phenotypes suggests that a common neuropathological process, characterized by progressive degeneration of the dopaminergic striatonigral system and of many other neuronal systems, results not only in structural deficits but also extensive changes of functional neuronal network activities and neurotransmitter dysfunctions. Modern neuroimaging studies revealed multilocular cortical and subcortical atrophies and alterations in intrinsic neuronal connectivities. The decreased functional connectivity (FC) of the default mode network (DMN) in the bilateral prefrontal cortex is affected already before the development of clinical CI and in the absence of structural changes. Longitudinal cognitive decline is associated with frontostriatal and limbic affections, white matter microlesions and changes between multiple functional neuronal networks, including thalamo-insular, frontoparietal and attention networks, the cholinergic forebrain and the noradrenergic system. Superimposed Alzheimer-related (and other concomitant) pathologies due to interactions between α-synuclein, tau-protein and β-amyloid contribute to dementia pathogenesis in both PD and dementia with Lewy bodies (DLB). To further elucidate the interaction of the pathomechanisms responsible for CI in PD, well-designed longitudinal clinico-pathological studies are warranted that are supported by fluid and sophisticated imaging biomarkers as a basis for better early diagnosis and future disease-modifying therapies.

Prosopagnosia: face blindness and its association with neurological disorders.

Loss of facial recognition or prosopagnosia has been well-recognized for over a century. It has been categorized as developmental or acquired depending on whether the onset is in early childhood or beyond, and acquired cases can have degenerative or non-degenerative aetiologies. Prosopagnosia has been linked to involvement of the fusiform gyri, mainly in the right hemisphere. The literature on prosopagnosia comprises case reports and small case series. We aim to assess demographic, clinical and imaging characteristics and neurological and neuropathological disorders associated with a diagnosis of prosopagnosia in a large cohort. Patients were categorized as developmental versus acquired; those with acquired prosopagnosia were further subdivided into degenerative versus non-degenerative, based on neurological aetiology. We assessed regional involvement on [18F] fluorodeoxyglucose-PET and MRI of the right and left frontal, temporal, parietal and occipital lobes. The Intake and Referral Center at the Mayo Clinic identified 487 patients with possible prosopagnosia, of which 336 met study criteria for probable or definite prosopagnosia. Ten patients, 80.0% male, had developmental prosopagnosia including one with Niemann-Pick type C and another with a forkhead box G1 gene mutation. Of the 326 with acquired prosopagnosia, 235 (72.1%) were categorized as degenerative, 91 (27.9%) as non-degenerative. The most common degenerative diagnoses were posterior cortical atrophy, primary prosopagnosia syndrome, Alzheimer's disease dementia and semantic dementia, with each diagnosis accounting for >10% of this group. The most common non-degenerative diagnoses were infarcts (ischaemic and haemorrhagic), epilepsy-related and primary brain tumours, each accounting for >10%. We identified a group of patients with non-degenerative transient prosopagnosia in which facial recognition loss improved or resolved over time. These patients had migraine-related prosopagnosia, posterior reversible encephalopathy syndrome, delirium, hypoxic encephalopathy and ischaemic infarcts. On [18F] fluorodeoxyglucose-PET, the temporal lobes proved to be the most frequently affected regions in 117 patients with degenerative prosopagnosia, while in 82 patients with non-degenerative prosopagnosia, MRI revealed the right temporal and right occipital lobes as most affected by a focal lesion. The most common pathological findings in those with degenerative prosopagnosia were frontotemporal lobar degeneration with hippocampal sclerosis and mixed Alzheimer's and Lewy body disease pathology. In this large case series of patients diagnosed with prosopagnosia, we observed that facial recognition loss occurs across a wide range of acquired degenerative and non-degenerative neurological disorders, most commonly in males with developmental prosopagnosia. The right temporal and occipital lobes, and connecting fusiform gyrus, are key areas. Multiple different pathologies cause degenerative prosopagnosia.

Characterization of de novo Dementia with Lewy Body with different duration of rapid eye movement sleep behavior disorder

BackgroundCognitive disorder, parkinsonism, autonomic dysfunction (AuD) and rapid eye movement sleep behavior disorder (RBD) can occur prior to or simultaneously with Dementia with Lewy Body (DLB) onset. RBD is generally linked with progressive neurodegenerative traits. However, associations between RBD with DLB, RBD without DLB, and RBD duration effects on DLB symptoms remain unclear. ObjectivesTo examine DLB symptom frequency and subtypes in RBD, and explore the effects of different RBD onset times on symptoms in de novo DLB patients. MethodsIn this multicenter investigation, we consecutively recruited 271 de novo DLB patients. All had standardized clinical and comprehensive neuropsychological evaluations. Subgroup analyses, performed based on the duration of RBD confirmed by polysomnography before the DLB diagnosis, we compared the proportion of patients with cognitive impairment, parkinsonism, and AuD features between groups. ResultsParkinsonism and AuD incidences were significantly elevated in DLB patients with RBD when compared with patients without RBD. Subgroup analyses indicated no significant differences in parkinsonism between DLB patients who developed RBD ≥10 years prior to the DLB diagnosis and DLB patients without RBD. The incidence of non-tremor-predominant parkinsonism and AuD was significantly higher in DLB patients whose RBD duration before the DLB diagnosis was <10 years when compared with DLB patients without RBD. ConclusionsWe identified significant symptom and phenotypic variability between DLB patients with and without RBD. Also, different RBD duration effects before the DLB diagnosis had a significant impact on symptomatic phenotypes, suggesting the existence of a slowly progressive DLB neurodegenerative subtype.

Sex differences in brain atrophy in dementia with Lewy bodies.

Sex influences neurodegeneration, but it has been poorly investigated in dementia with Lewy bodies (DLB). We investigated sex differences in brain atrophy in DLB using magnetic resonance imaging (MRI). We included 436 patients from the European-DLB consortium and the Mayo Clinic. Sex differences and sex-by-age interactions were assessed through visual atrophy rating scales (n=327; 73±8 years, 62% males) and automated estimations of regional gray matter volume and cortical thickness (n=165; 69±9 years, 72% males). We found a higher likelihood of frontal atrophy and smaller volumes in six cortical regions in males and thinner olfactory cortices in females. There were significant sex-by-age interactions in volume (six regions) and cortical thickness (seven regions) across the entire cortex. We demonstrate that males have more widespread cortical atrophy at younger ages, but differences tend to disappear with increasing age, with males and females converging around the age of 75. Male DLB patients had higher odds for frontal atrophy on radiological visual rating scales. Male DLB patients displayed a widespread pattern of cortical gray matter alterations on automated methods. Sex differences in gray matter measures in DLB tended to disappear with increasing age.

BIOMARKERS IN CNS-ORIGINATING EXTRACELLULAR VESICLES: A DIAGNOSTIC META-ANALYSIS FOR PARKINSONIAN DISORDERS

Abstract Parkinsonian disorders, including Parkinson’s disease (PD), multiple system atrophy (MSA), dementia with Lewy bodies (DLB), progressive supranuclear palsy (PSP), and corticobasal syndrome (CBS), present overlapping early symptoms, complicating accurate diagnosis. Predicting the conversion of prodromal conditions like REM behavior disorder (RBD) to PD, MSA, or DLB is also complex. Extracellular vesicles (EVs), small structures released by cells, carry cell-state-specific biomarkers that can cross the blood-brain barrier, providing a window into the brain’s biochemistry. Blood-isolated CNS-originating EVs have become a popular diagnostic tool. Yet, challenges remain in replicating and validating these findings. We conducted a PRISMA-guided systematic review and meta-analysis of 15 studies involving 1,455 persons with PD, 206 with MSA, 21 with DLB, 172 with PSP, 152 with CBS, 189 with RBD, and 1,045 healthy controls (HCs). Diagnostic accuracy for distinguishing persons with PD from HCs was moderate but showed high heterogeneity and significant publication bias. This indicates that studies with non-significant or lower effect sizes were less likely to be published. Differentiating persons with PD from those with PSP or CBS is limited due to the small number of involved studies. Our analyses suggest that biomarkers from CNS-originating EVs may not reliably differentiate persons with MSA or RBD from HCs due to variable accuracy and high heterogeneity. Our findings highlight the moderate diagnostic accuracy of EV biomarkers in differentiating Parkinsonian disorders, emphasizing substantial heterogeneity and significant publication bias. The need for larger, more standardized, and unbiased studies is underscored to validate the utility of EV biomarkers as diagnostic tools.

Different dysregulations of CYFIP1 and CYFIP2 in distinct types of dementia

In humans, the cytoplasmic FMR1 interacting protein (CYFIP) family consists of two members, namely CYFIP1 and CYFIP2. Both CYFIP1 and CYFIP2 function in the WAVE regulatory complex (WRC), which regulates actin polymerization. Additionally, these two proteins form a posttranscriptional regulatory complex with the fragile X mental retardation protein (FMRP), which suppresses mRNA translation. Thus, CYFIP1 and CYFIP2 are important signalling regulators at synapses, and mutations in their genes are associated with neurodevelopmental and neuropsychiatric disorders, including intellectual disabilities. Moreover, dysregulation of the CYFIP protein family is involved in Alzheimer’s disease (AD). However, the relevance of the CYFIP family in other dementias is largely unknown. Here, we compared CYFIP1/2 protein levels in the post-mortem hippocampus from patients with AD, dementia with Lewy bodies (DLB), vascular dementia (VaD) and frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP). Consistent with previous findings, CYFIP2 was reduced in AD hippocampus. In DLB and VaD hippocampus, the protein level of CYFIP2 and CYFIP1 was unaltered. Finally, an increase in the protein level of both CYFIP1 and CYFIP2 was noted in FTLD-TDP hippocampus. These findings reveal that the protein levels of the CYFIP family is distinct in different types of dementia, suggesting that the pathogenesis of these neurodegenerative disorders has divergent impacts on hippocampal synaptic function.

Multimodal lifestyle engagement patterns support cognitive stability beyond neuropathological burden

BackgroundModifiable lifestyle behaviors account for a large proportion of dementia risk. However, the combined contributions of multidomain lifestyle patterns to cognitive aging are poorly understood, as most studies have examined individual lifestyle behaviors in isolation and without neuropathological characterization. This study examined data-driven patterns of lifestyle behaviors across multiple domains among older adults and tested their associations with disease-specific neuropathological burden and cognitive decline.MethodsParticipants included 2059 older adults enrolled in the longitudinal Memory and Aging Project (MAP) at the Rush Alzheimer’s Disease Center; none of whom had dementia at baseline (73% no cognitive impairment (NCI), 27% mild cognitive impairment [MCI]). All participants completed cognitive testing annually. Lifestyle factors were measured during at least one visit and included (1) actigraphy-measured physical activity, as well as self-reported (2) sleep quality, (3) life space, (4) cognitive activities, (5) social activities, and (6) social network. A subset of participants (n = 791) had autopsy data for which burden of Alzheimer’s disease (AD), cerebrovascular disease (CVD), Lewy body disease, and hippocampal sclerosis/TDP-43 was measured. Latent profile analysis across all 2059 participants identified distinct subgroups (i.e., classes) of lifestyle patterns. Linear mixed-effects models examined relationships between lifestyle classes and global cognitive trajectories, with and without covarying for all neuropathologies. Classes were also compared on rates of incident MCI/dementia.ResultsFive classes were identified: Class 1Low Life Space (lowest lifestyle engagement), Class 2PA (high physical activity), Class 3Low Avg (low to average lifestyle engagement), Class 4Balanced (high average lifestyle engagement), and Class 5Social (large social network). Classes 4Balanced and 5Social had the lowest AD burden, and Class 2PA had the lowest CVD burden. Classes 2–5 had significantly less steep global cognitive decline compared to Class 1Low Life Space, with comparable effect sizes before and after covarying for neuropathological burden. Classes 4Balanced and 5Social exhibited the lowest rates of incident MCI/dementia.ConclusionsLifestyle behavior patterns among older adults account for differential rates of cognitive decline and clinical progression. Those with at least average engagement across all lifestyle domains exhibit greater cognitive stability after adjustment for neuropathology, highlighting the importance of engagement in multiple healthy lifestyle behaviors for later life cognitive health.

Pathology-specific patterns of cerebellar atrophy in neurodegenerative disorders.

Associations of cerebellar atrophy with specific neuropathologies in Alzheimer's disease and related dementias (ADRD) have not been systematically analyzed. This study examined cerebellar gray matter volume across major pathological subtypes of ADRD. Cerebellar gray matter volume was examined using voxel-based morphometry in 309 autopsy-proven ADRD cases and 80 healthy controls. ADRD subtypes included AD, mixed Lewy body disease and AD (LBD-AD), and frontotemporal lobar degeneration (FTLD). Clinical function was assessed using the Clinical Dementia Rating (CDR) scale. Distinct patterns of cerebellar atrophy were observed in all ADRD subtypes. Significant cerebellar gray matter changes appeared in the early stages of most subtypes and the very early stages of AD, LBD-AD, FTLD-TDP type A, and progressive supranuclear palsy. Cortical atrophy positively predicted cerebellar atrophy across all subtypes. Our findings establish pathology-specific profiles of cerebellar atrophy in ADRD and propose cerebellar neuroimaging as a non-invasive biomarker for differential diagnosis and disease monitoring. Cerebellar atrophy was examined in 309 patients with autopsy-proven neurodegeneration. Distinct patterns of cerebellar atrophy are found in all pathological subtypes of Alzheimer's disease and related dementias (ADRD). Cerebellar atrophy is seen in early-stage (Clinical Dementia Rating [CDR] ≤1) AD, Lewy body dementia (LBD), frontotemporal lobar degeneration with tau-positive inclusion (FTLD-tau), and FTLD-transactive response DNA binding protein (FTLD-TDP). Cortical atrophy positively predicts cerebellar atrophy across all neuropathologies.

Dementia with Lewy bodies: old and new knowledge-Part 2: treatment

The treatment of patients with dementia with Lewy bodies (DLB) is multifaceted, as motor symptoms, cognitive symptoms, behavioral and psychological symptoms can occur in different constellations. In addition, the use of certain medications is limited (e.g., neuroleptics). To summarize the main recent findings on the treatment of DLB. To date, there is no approved therapeutic option for the treatment of patients with DLB in Germany; moreover, the evidence base for pharmacological and non-pharmacological treatment is sparse. The currently consented treatment options are based on the treatment of motor symptoms in the same way as the treatment of Parkinson's disease and for behavioral symptoms based on the treatment for Alzheimer's disease. The treatment of DLB with its various symptoms is difficult and often can only be adequately achieved for the patient in close cooperation with aspecialist.

Evoked potential response in patients with idiopathic Parkinson’s disease and atypical parkinsonian syndromes: A comparative study

Patients with idiopathic Parkinson&amp;rsquo;s disease (IPD) and atypical parkinsonian syndromes (APSs) suffer from a range of disorders, especially in balance and locomotion, which necessitate visual, auditory, and somatosensory inputs. In this study, IPD patients, APS patients, and healthy controls (HCs) (n = 50 per group) underwent a series of assessments for visual evoked potentials (VEP), brainstem auditory evoked response (BAER), and short-latency somatosensory evoked potentials (SSEP). Results showed that VEP P100 latency was prolonged in multiple system atrophy-cerebellar type (MSA-C), multiple system atrophy-parkinsonian type (MSA-P), and corticobasal ganglionic degeneration (CBD) patients. The latency of peaks III and V was prolonged in IPD, MSA-C, dementia with Lewy bodies (DLB), and Parkinson&amp;rsquo;s disease dementia (PDD). BAER I-III and I-V interpeak latency were prolonged in IPD, DLB, and PDD, whereas BAER I-III, III-V, and I-V interpeak latencies were increased and the V/I amplitude ratio was decreased in MSA-C. The central sensory conduction time (N20-N13) was increased in MSA-P and MSA-C in SSEP. IPD patients had prolonged VEP P100 latency (P &lt; 0.001), lower VEP N75-P100 amplitude (P &lt; 0.001), prolonged BAER I, II, II, IV, V peak latencies (P &lt; 0.001), I-III, I-V interpeak latencies (P &lt; 0.001), lower BAER V/I amplitude ratio (P &lt; 0.001), and prolonged SSEP N13, N20, central sensory conduction time (N20-N13) (P &lt; 0.001) than HCs. IPD patients also had prolonged BAER I, II, II, IV, V peak latencies (P &lt; 0.001), prolonged I-III, I-V interpeak latencies (P &lt; 0.001), and shorter SSEP N13, N20, central sensory conduction time (N20-N13) (P &lt; 0.001) than APS patients. Moreover, APS patients had prolonged VEP P100 and N145 latencies (P &lt; 0.001) and decreased N75-N145 amplitude (P &lt; 0.001) compared to HCs. APS patients also had prolonged BAER II, II, IV, V peak latencies (P &lt; 0.001), prolonged I-III, III-V, I-V interpeak latencies (P &lt; 0.001), decreased V/I amplitude ratio, and prolonged SSEP N13, N20, central sensory conduction time (N20-N13) (P &lt; 0.001) than HCs. Postural instability and gait disorder (PIGD) IPD had significantly prolonged BAER III, V peak latencies (P &lt; 0.05), and prolonged III-V interpeak latencies (P &lt; 0.05) compared to tremor-dominant IPD. Overall, the IPD and APS patients had significant VEP, BAER, and SSEP abnormalities of demyelination and axonal variety in the visual, auditory, and somatosensory pathways. The changes were also correlated with the disease duration and severity. Although the diseases are predominantly motor disorders with significant non-motor components, these electrophysiological abnormalities might open a new avenue to assess the non-motor symptoms.

Dementia with Lewy bodies: old and new knowledge - Part 1: clinical aspects and diagnostics

Dementia with Lewy bodies (DLB) is the second most common neurodegenerative dementia after Alzheimer's disease. Patients with DLB often have apoor prognosis, with worse outcomes than patients with Alzheimer's disease in terms of important parameters, such as quality of life, caregiver burden, health-related costs, frequency of hospital and nursing home admissions, shorter time to severe dementia, and lower survival. The DLB is frequently misdiagnosed and often undertreated. Therefore, it is critical to diagnose DLB as early as possible to ensure optimal care and treatment. The aim of this review article is to summarize the main recent findings on diagnostic tools, epidemiology and genetics of DLB. Precise clinical diagnostic criteria exist for DLB that enable an etiologic assignment. Imaging techniques are used as standard in DLB, especially also to exclude non-neurodegenerative causes. In particular, procedures in nuclear medicine have ahigh diagnostic value. The diagnosis is primarily based on clinical symptoms, although the development of in vivo neuroimaging and biomarkers is changing the scope of clinical diagnosis as well as research into this devastating disease.

Dementia subtypes, cognitive decline and survival among older adults attending a memory clinic in Cape Town, South Africa: a retrospective study

BackgroundThere are no published longitudinal studies from Africa of people with dementia seen in memory clinics. The aim of this study was to determine the proportions of the different dementia subtypes, rates of cognitive decline, and predictors of survival in patients diagnosed with dementia and seen in a memory clinic.MethodsData were collected retrospectively from clinic records of patients aged ≥ 60 seen in the memory clinic at Groote Schuur Hospital, Cape Town, South Africa over a 10-year period. Diagnostic and Statistical Manual of Mental Disorders (DSM–5) criteria were used to identify patients with Major Neurocognitive Disorders (dementia). Additional diagnostic criteria were used to determine the specific subtypes of dementia. Linear regression analysis was used to determine crude rates of cognitive decline, expressed as mini-mental state examination (MMSE) points lost per year. Changes in MMSE scores were derived using mixed effects modelling to curvilinear models of cognitive change, with time as the dependent variable. Multivariable cox survival analysis was used to determine factors at baseline that predicted mortality.ResultsOf the 165 patients who met inclusion criteria, 117(70.9%) had Major Neurocognitive Disorder due to Alzheimer’s disease (AD), 24(14.6%) Vascular Neurocognitive Disorder (VND), 6(3.6%) Dementia with Lewy Bodies (DLB), 5(3%) Parkinson disease-associated dementia (PDD), 3(1.8%) fronto-temporal dementia, 4(2.4%) mixed dementia and 6(3.6%) other types of dementia. The average annual decline in MMSE points was 2.2(DLB/PDD), 2.1(AD) and 1.3(VND). Cognitive scores at baseline were significantly lower in patients with 8 compared to 13 years of education and in those with VND compared with AD. Factors associated with shorter survival included age at onset greater than 65 (HR = 1.82, 95% C.I. 1.11, 2.99, p = 0.017), lower baseline MMSE (HR = 1.05, 95% C.I. 1.01, 1.10, p = 0.029), Charlson’s comorbidity scores of 3 to 4 (HR = 1.88, 95% C.I. 1.14, 3.10, p = 0.014), scores of 5 or more (HR = 1.97, 95% C.I. 1.16, 3.34, p = 0.012) and DLB/PDD (HR = 3.07, 95% C.I. 1.50, 6.29, p = 0.002). Being female (HR = 0.59, 95% C.I.0.36, 0.95, p = 0.029) was associated with longer survival.ConclusionsKnowledge of dementia subtypes, the rate and factors affecting cognitive decline and survival outcomes will help inform decisions about patient selection for potential future therapies and for planning dementia services in resource-poor settings.

Development and validation of an expanded antibody toolset that captures alpha-synuclein pathological diversity in Lewy body diseases

The abnormal aggregation and accumulation of alpha-synuclein (aSyn) in the brain is a defining hallmark of synucleinopathies. Various aSyn conformations and post-translationally modified forms accumulate in pathological inclusions and vary in abundance among these disorders. Relying on antibodies that have not been assessed for their ability to detect the diverse forms of aSyn may lead to inaccurate estimations of aSyn pathology in human brains or disease models. To address this challenge, we developed and characterized an expanded antibody panel that targets different sequences and post-translational modifications along the length of aSyn, and that recognizes all monomeric, oligomeric, and fibrillar aSyn conformations. Next, we profiled aSyn pathology across sporadic and familial Lewy body diseases (LBDs) and reveal heterogeneous forms of aSyn pathology, rich in Serine 129 phosphorylation, Tyrosine 39 nitration and N- and C-terminal tyrosine phosphorylations, scattered both to neurons and glia. In addition, we show that aSyn can become hyperphosphorylated during processes of aggregation and inclusion maturation in neuronal and animal models of aSyn seeding and spreading. The validation pipeline we describe for these antibodies paves the way for systematic investigations into aSyn pathological diversity in the human brain, peripheral tissues, as well as in cellular and animal models of synucleinopathies.

A deep learning model for the detection of various dementia and MCI pathologies based on resting-state electroencephalography data: A retrospective multicentre study

Dementia and mild cognitive impairment (MCI) represent significant health challenges in an aging population. As the search for noninvasive, precise and accessible diagnostic methods continues, the efficacy of electroencephalography (EEG) combined with deep convolutional neural networks (DCNNs) in varied clinical settings remains unverified, particularly for pathologies underlying MCI such as Alzheimer's disease (AD), dementia with Lewy bodies (DLB) and idiopathic normal-pressure hydrocephalus (iNPH). Addressing this gap, our study evaluates the generalizability of a DCNN trained on EEG data from a single hospital (Hospital #1). For data from Hospital #1, the DCNN achieved a balanced accuracy (bACC) of 0.927 in classifying individuals as healthy (n = 69) or as having AD, DLB, or iNPH (n = 188). The model demonstrated robustness across institutions, maintaining bACCs of 0.805 for data from Hospital #2 (n = 73) and 0.920 at Hospital #3 (n = 139). Additionally, the model could differentiate AD, DLB, and iNPH cases with bACCs of 0.572 for data from Hospital #1 (n = 188), 0.619 for Hospital #2 (n = 70), and 0.508 for Hospital #3 (n = 139). Notably, it also identified MCI pathologies with a bACC of 0.715 for Hospital #1 (n = 83), despite being trained on overt dementia cases instead of MCI cases. These outcomes confirm the DCNN's adaptability and scalability, representing a significant stride toward its clinical application. Additionally, our findings suggest a potential for identifying shared EEG signatures between MCI and dementia, contributing to the field's understanding of their common pathophysiological mechanisms.

α-Synuclein emulsifies TDP-43 prion-like domain—RNA liquid droplets to promote heterotypic amyloid fibrils

Many neurodegenerative diseases including frontotemporal lobar degeneration (FTLD), Lewy body disease (LBD), multiple system atrophy (MSA), etc., show colocalized deposits of TDP-43 and α-synuclein (αS) aggregates. To understand whether these colocalizations are driven by specific molecular interactions between the two proteins, we previously showed that the prion-like C-terminal domain of TDP-43 (TDP-43PrLD) and αS synergistically interact to form neurotoxic heterotypic amyloids in homogeneous buffer conditions. However, it remains unclear if αS can modulate TDP-43 present within liquid droplets and biomolecular condensates called stress granules (SGs). Here, using cell culture and in vitro TDP-43PrLD – RNA liquid droplets as models along with microscopy, nanoscale AFM-IR spectroscopy, and biophysical analyses, we uncover the interactions of αS with phase-separated droplets. We learn that αS acts as a Pickering agent by forming clusters on the surface of TDP-43PrLD – RNA droplets. The aggregates of αS on these clusters emulsify the droplets by nucleating the formation of heterotypic TDP-43PrLD amyloid fibrils, structures of which are distinct from those derived from homogenous solutions. Together, these results reveal an intriguing property of αS to act as a Pickering agent while interacting with SGs and unmask the hitherto unknown role of αS in modulating TDP-43 proteinopathies.

Neuronally Derived Extracellular Vesicle α-Synuclein as a Serum Biomarker for Individuals at Risk of Developing Parkinson Disease

Nonmotor symptoms of Parkinson disease (PD) often predate the movement disorder by decades. Currently, there is no blood biomarker to define this prodromal phase. To investigate whether α-synuclein in neuronally derived serum-extracellular vesicles identifies individuals at risk of developing PD and related dementia. This retrospective, cross-sectional multicenter study of serum samples included the Oxford Discovery, Marburg, Cologne, and Parkinson's Progression Markers Initiative cohorts. Participants were recruited from July 2013 through August 2023 and samples were analyzed from April 2022 through September 2023. The derivation group (n = 170) included participants with isolated rapid eye movement sleep behavior disorder (iRBD) and controls. Two validation groups were used: the first (n = 122) included participants with iRBD and controls and the second (n = 263) included nonmanifest GBA1N409S gene carriers, participants with iRBD or hyposmia, and available dopamine transporter single-photon emission computed tomography, healthy controls, and patients with sporadic PD. Overall the study included 199 participants with iRBD, 20 hyposmic participants with available dopamine transporter single-photon emission computed tomography, 146 nonmanifest GBA1N409S gene carriers, 21 GBA1N409S gene carrier patients with PD, 50 patients with sporadic PD, and 140 healthy controls. In the derivation group and validation group 1, participants with polysomnographically confirmed iRBD were included. In the validation group 2, at-risk participants with available Movement Disorder Society prodromal markers and serum samples were included. Among 580 potential participants, 4 were excluded due to alternative diagnoses. Clinical assessments, imaging, and serum collection. L1CAM-positive extracellular vesicles (L1EV) were immunocaptured from serum. α-Synuclein and syntenin-1 were measured by electrochemiluminescence. Area under the receiver operating characteristic (ROC) curve (AUC) with 95% CIs evaluated biomarker performance. Probable prodromal PD was determined using the updated Movement Disorder Society research criteria. Multiple linear regression models assessed the association between L1EV α-synuclein and prodromal markers. Among 576 participants included, the mean (SD) age was 64.30 (8.27) years, 394 were male (68.4%), and 182 were female (31.6%). A derived threshold of serum L1EV α-synuclein distinguished participants with iRBD from controls (AUC = 0.91; 95% CI, 0.86-0.96) and those with more than 80% probability of having prodromal PD from participants with less than 5% probability (AUC = 0.80; 95% CI, 0.71-0.89). Subgroup analyses revealed that specific combinations of prodromal markers were associated with increased L1EV α-synuclein levels. Across all cohorts, L1EV α-synuclein differentiated participants with more than 80% probability of having prodromal PD from current and historic healthy control populations (AUC = 0.90; 95% CI, 0.87-0.93), irrespective of initial diagnosis. L1EV α-synuclein was increased in at-risk participants with a positive cerebrospinal fluid seed amplification assay and was above the identified threshold in 80% of cases (n = 40) that phenoconverted to PD or related dementia. L1EV α-synuclein in combination with prodromal markers should be considered in the stratification of those at high risk of developing PD and related Lewy body diseases.

Within and between‐network functional connectivity disruptions in posterior cortical atrophy and dementia with Lewy bodies

AbstractBackgroundPosterior cortical atrophy (PCA) and dementia with Lewy bodies (DLB) show overlapping patterns of hypometabolism affecting posterior regions of the brain. Both syndromes show disruptions in functional connectivity, but it is unknown how patterns of disruption within and between networks compare between PCA and DLB.MethodThirty amyloid‐positive PCA, 27 amyloid‐positive DLB (DLB+), 24 amyloid‐negative DLB (DLB‐) patients and 30 cognitively normal amyloid‐negative (CN) individuals were recruited at Mayo Clinic, Rochester, MN, and underwent structural and resting state functional MRI. Spatially preprocessed data was analyzed using the CONN functional connectivity toolbox to explore nine networks: visual, sensorimotor, dorsal‐attention, cerebellar, frontoparietal, memory, language, salience, and default mode networks (DMN). Multivariate linear regression models corrected for multiple comparisons and adjusted for age and sex were fit to analyze within‐network connectivity (Fisher’s R‐to‐Z transformations). Between‐network connectivity was assessed with group level difference maps (two‐sample t‐test) corrected for false discovery rate at p&lt;0.05.ResultMultivariate linear regression models showed reduced within‐network connectivity across all DMN components, sensorimotor, and dorsal‐attention networks, with trends for the visual network in PCA compared to CN. Both DLB‐ and DLB+ showed reduced within‐network connectivity for the cerebellar network, with DLB+ showing reduced connectivity in the posterior‐DMN, memory, and salience networks compared to CN. DLB‐ showed increased connectivity in dorsal‐attention and DMN, while DLB+ showing reduced connectivity in the memory network compared to PCA. Between‐network analysis showed an increase in cerebellar‐to‐sensorimotor connectivity in all three groups, with increase in cerebellar‐to‐dorsal‐attention connectivity in DLB‐ and PCA compared to CN. DLB‐ showed a decrease in posterior‐DMN‐to‐sensorimotor connectivity, while PCA showed reduced connectivity between all DMN components and dorsal‐attention‐to‐sensorimotor connectivity compared to CN. There was an increase in connectivity between all DMN components and a reduction in dorsal‐DMN‐to‐sensorimotor connectivity in both DLB‐ and DLB+ compared to PCA.ConclusionPCA was associated with connectivity disruptions across all DMN components, sensorimotor, dorsal‐attention and visual networks, while both DLB groups showed disruptions in cerebellar networks, with DLB+ showing further disruptions in posterior‐DMN, memory and salience networks. These findings suggest that both PCA and DLB have unique brain network disruptions, with amyloid status influencing connectivity in DLB.

Validation of Cerebrospinal Fluid Alpha‐synuclein Assay against Autopsy in Non‐Parkinson’s Disease Neurodegenerative Syndromes

AbstractBackgroundAlpha‐synuclein (αSyn) is the underlying neuropathology in both Parkinson’s Disease (PD) and non‐PD neurodegenerative syndromes, e.g. dementia with Lewy bodies (DLB). Importantly, αSyn is also a common co‐pathology, especially in Alzheimer’s disease (AD), where autopsy studies reveal comorbid αSyn in &gt;50% of cases. A seeded aggregation amplification (SAA) assay (SynTap) has been shown to be highly sensitive and specific for pathogenic αSyn seeds in patients with PD and DLB, with lower performance in amygdalar‐predominant Lewy Body disease (LBD). Here we evaluated the antemortem CSF performance of SynTap in patients with non‐PD syndromes, with specific attention to performance in brainstem‐predominant αSyn and patients with atypical PD, e.g. progressive supranuclear palsy Richardson’s syndrome (PSP‐RS, N = 6) and corticobasal syndrome (CBS, N = 11).MethodPatients were evaluated through observational studies at the UCSF Alzheimer’s Disease Research Center and neuropathologic evaluation was performed by the Neurodegenerative Disease Brain Bank. Antemortem CSF samples were tested with SynTap. Operators were blinded to diagnosis, and all samples were run as a single batch. Sensitivity and specificity were compared, and clinical correlations were examined across pathological groups and clinical diagnoses, using antemortem clinical records.ResultOverall, in 56 patients, SynTap was 59% sensitive and 96% specific for autopsy‐confirmed αSyn pathology of any type. SynTap had perfect performance for diffuse (4/4) and transitional (5/5) LBD, and correctly identified 3/3 cases where LBD was primary. Consistent with prior reports, sensitivity was low in amygdalar‐predominant LBD (6/14, 43%), and lower in brainstem‐predominant LBD (1/6, 17%). A false positive result was present in 1/27 cases (4%). In the PSP‐RS cohort, SynTap positively identified 1 case caused by diffuse LBD and AD, and was true negative in 5/5. Within CBS, SynTap positively identified 1/1 case with diffuse LBD co‐pathology, 1/2 cases with brainstem‐predominant LBD, but missed 1 case with amygdalar‐predominant LBD.ConclusionSynTap best identifies αSyn pathology in patients with diffuse and transitional LBD, though specificity is high in the entire cohort. The etiology of low sensitivity in amygdalar‐ and brainstem‐predominant LBD co‐pathology requires further elucidation. The test may aid diagnostically in atypical PD syndromes, but results should be carefully considered, given the possibility of co‐pathology.

Discrimination between dementia with Lewy bodies and Alzheimer’s disease based on biofluid monoamines, biomarker values and cognitive parameters

AbstractBackgroundDespite disease‐specific symptoms, differentiation between Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB) remains challenging, especially in early, prodromal stages. This is fueled by overlapping pathology in both diseases (Slaets et al., 2013). Monoamine neurotransmitters are significantly altered between DLB and AD and are capable of distinguishing DLB from AD, when added to the panel of cerebrospinal fluid (CSF) dementia biomarkers (Aβ1‐40, Aβ1‐42, T‐tau, P‐tau) and as standalone biomarkers (Janssens et al., 2018). Additionally, cognitive and behavioral differences linked to monoaminergic changes between DLB, AD patients and non‐demented control individuals, have been previously described (Engelborghs et al., 2006, Vermeiren et al., 2015).This study aimed to further explore these dissimilarities for improving discrimination between prodromal and advanced DLB and AD stages.MethodMonoamine neurotransmitter levels were measured in CSF and plasma of 160 prodromal AD (proAD), prodromal DLB (proDLB), AD and DLB patients and 40 non‐demented individuals, using ultra‐high‐performance liquid chromatography. CSF biomarker levels were determined through ELISA. A battery of cognitive and behavioral tests was performed. Monoaminergic, biomarker, cognitive and demographic data were integrated in stepwise regression models to discriminate between (prodromal) DLB and AD.ResultSignificant serotonergic differences in CSF between DLB and AD, as well as noradrenergic, dopaminergic and serotonergic differences in plasma between DLB and AD and with non‐demented individuals were noted. CSF dementia biomarkers levels differed significantly between proAD, proDLB, DLB and AD stages and with non‐demented individuals. There were no CSF, plasma monoamines or CSF biomarker changes between proDLB versus DLB, and proAD versus AD stages. Cognitive functioning differed significantly between prodromal and advanced DLB and AD stages and with non‐demented individuals. Stepwise regression identified that models including plasma and CSF serotonergic components, as well as cognitive tests were the most accurate at discriminating between proDLB versus DLB, proAD versus AD, proDLB versus proAD and DLB versus AD, with area under the curve (AUC), sensitivity and specificity values &gt; 0.9.ConclusionThese findings support differentially affected monoaminergic, pathological biomarker levels and cognitive abilities between (prodromal) AD and DLB, and with non‐demented individuals. In addition, this study provides robust models for discrimination between (prodromal) DLB and AD.