Lewy Body Disease Patients Research Articles

High prevalence of atrial conduction abnormalities in Lewy body disease - a marker of cardiac complications?

Increasing evidence suggests that Lewy body disease (LBD) is associated with clinically important cardiac complications, including sick sinus syndrome, atrial fibrillation and sudden cardiac death. The high prevalence of sick sinus syndrome and atrial fibrillation in LBD suggests the presence of disease-related atrial conduction disorders. To explore whether LBD is associated with atrial conduction disorders, electrocardiographic (ECG) P wave parameters were analyzed in a cohort of LBD patients (n = 74), using age-matched Alzheimer's disease (AD) patients (n = 25) as controls. P wave terminal force in V1 and P wave duration were found to be significantly greater in the LBD group than in the AD group. In addition, 43 (58%) individuals in the LBD exhibited pathological P wave terminal force (> 4000µV*ms) vs 3 (12%) in the AD group, and 60 (81%) in the LBD group exhibited pathological P wave duration (≥ 120ms), vs 13 (52%) in the AD group. The difference could not be explained by atrial fibrillation or atrial enlargement on echocardiogram. The clinical significance of pathological P wave parameters in LBD is unknown, but their presence suggests an atrial cardiomyopathy that could be due to cardiac alpha-synuclein deposition, autonomic dysfunction, or a combination thereof. Future research is warranted to elucidate whether this proposed disease-related atrial cardiomyopathy is related to cardiac alpha-synuclein deposition, whether it is causally related to cardiac complications in LBD, and whether pathological P wave parameters hold potential as a screening tool for cardiac complications in LBD.

Toward alpha‐synuclein seed amplification assay in clinical practice

AbstractINTRODUCTIONSeed amplification assays (SAAs) demonstrate remarkable diagnostic performance in alpha‐synucleinopathies. However, existing protocols lack accessibility in routine laboratories, mainly due to the requirement for in‐house production of recombinant alpha‐synuclein (aSyn). This study proposes a cerebrospinal fluid (CSF) aSyn‐SAA protocol using solely commercial reagents to facilitate its clinical implementation.METHODSRoutine clinical care CSF samples from 126 patients, comprising 47 with Lewy body diseases (LBD) (41 with dementia with Lewy bodies, six with Parkinson's disease), 37 without alpha‐synucleinopathy, and 42 with Alzheimer's disease (AD), underwent assessment for aSyn‐SAA activity.RESULTSCSF aSyn‐SAA showed a sensitivity of 72.3% and a specificity of 100% when distinguishing clinically diagnosed LBD patients from those without alpha‐synucleinopathy. In AD patients, 14.3% were tested positive for aSyn.DISCUSSIONThe commercial‐only CSF aSyn‐SAA protocol exhibited excellent specificity when applied to a real‐life cohort, signaling progress toward the accessibility of an aSyn biomarker in clinical settings.Highlights Diagnosis of LBD through aSyn‐SAA lacks accessibility. This commercial‐only aSyn‐SAA has satisfactory performance in a real‐life cohort. A negative aSyn‐SAA does not completely exclude a synucleinopathy. Some technical points must be considered when developing aSyn‐SAA. aSyn‐SAA must be confined to expert laboratories due to prion‐like risk management.

Alpha-synuclein seed amplification assay longitudinal outcomes in Lewy body disease spectrum.

Evidence from neuropathological cohorts indicates that a CSF α-synuclein (α-syn) seed amplification assay (SAA) may provide quantitative kinetic parameters correlating with α-syn pathology burden in patients with Lewy body disease (LBD). Studies are needed to assess their longitudinal trend during the pre-symptomatic and clinical disease phases and their correlation with measures of disease progression. We aimed to assess the baseline α-syn CSF SAA kinetic parameters, their longitudinal variations and associations with clinical outcomes in a cohort of longitudinally repeatedly sampled Lewy Body disease patients, including clinically unimpaired (asymptomatic LBD) and neurologically impaired individuals. Participants from the prospective BioFINDER-1 study with longitudinal CSF collections (n=718) were screened by α-syn SAA. CSF samples were tested in four replicates blinded to clinical diagnoses. The number of positive replicates (Nrep), the time needed by the fluorescence signal to reach the threshold (Lag) and the highest intensity of the fluorescent signal (Imax). were analysed at baseline (time of first positive SAA) in all participants and longitudinally in those with at least two α-syn positive CSF samples available. One hundred ninety-six individuals (whole cohort) showing α-syn seeding activity were included. Of those, 170 participants tested positive by SAA in all available samples, while 26 converted from a negative to a positive test result during follow-up (LBD-converters), suggesting an early LBD stage. At baseline, LBD-converters showed lower Nrep (p=0.001) and a longer Lag (p=0.001) than subjects displaying α-syn seeding activity from the first available sample. Nrep increased longitudinally in the whole cohort (β=0.09, 95% confidence interval (95%CI) 0.06-0.12, p<0.001), in asymptomatic LBD (β=0.15, 95%CI 0.09-0.21, p<0.001) and Parkinson's disease individuals without dementia (β=0.07, 95%CI 0.02-0.12, p=0.01). The Lag decreased longitudinally in asymptomatic LBD (β=-0.24, 95%CI -0.42 - -0.06, p=0.008). Baseline Nrep predicted the subsequent appearance of dementia in the whole cohort (Hazard ratio (HR) 1.57, 95%CI 1.19-2.07, p=0.001) and the Parkinson's disease subgroup (HR 1.83, 95%CI 1.17-2.85, p=0.008). The difference between the Lag at each sampling and that at baseline was negatively associated with the appearance of dementia in the whole cohort (HR 0.76, 95%CI 0.59-0.99, p=0.04) and Parkinson's disease subgroup (HR 0.69, 95%CI 0.50-0.95, p=0.02). α-syn SAA parameters Nrep and Lag showed associations with the LBD stage and the development of dementia. Furthermore, their longitudinal variation is coherent with pathology progression over time. These data support the use of SAA kinetic parameters to monitor disease progression and therapeutic response.

Corticotropin-releasing hormone as a candidate biomarker for parkinsonian disorders.

Disease-specific fluid biomarkers are in demand for parkinsonian syndromes (PS). Corticotropin-releasing hormone (CRH) was proposed as a biomarker for Lewy body disease. As such, this project aimed to confirm CRH as a potential biomarker for different PS. CRH and misfolded α-synuclein (αSyn) were measured in CSF. The primary cohort included Lewy body disease patients (i.e. Parkinson's disease or dementia with Lewy bodies, n = 77), atypical PS (n = 37) and non-parkinsonian neurodegenerative diseases (n = 164), as well as controls (n = 354). A replication cohort included Lewy body disease (n = 27), atypical PS (n = 58) and controls (n = 58). CRH was downregulated in αSyn positive Lewy body disease, αSyn positive controls and in all atypical PS compared with αSyn negative controls (P = 3.3e-05, P = 3.1e-10, P = 2.9e-03). CRH was also decreased in αSyn positive Lewy body disease compared with αSyn negative non-PS (P = 2e-03) and correlated with cognitive impairment and inflammation in αSyn positive Lewy body disease. We show that CRH is a promising biomarker for Lewy body disease and atypical PS and its association with inflammation and cognitive decline. Reductions in CRH in Lewy body disease and other PS suggest this decrease may relate to dopaminergic degeneration instead of αSyn pathology.

α-synuclein seed amplification assay sensitivity may be associated with cardiac MIBG abnormality among patients with Lewy body disease.

Although α-synuclein seed amplification assays (α-syn SAA) are promising, its sensitivity may be affected by heterogeneity among patients with Lewy body disease (LBD). We evaluated whether α-syn SAA sensitivity is affected by patient heterogeneity, using 123I-meta-iodobenzylguanidine (MIBG) cardiac scintigraphy in early drug-naïve patients. Thirty-four patients with clinically established or probable Parkinson's disease (PD) and seven with dementia with Lewy bodies (DLB) or prodromal DLB were included. While 85.2% of patients with abnormal cardiac MIBG were α-syn SAA positive, only 14.3% were positive among those with normal scans. Logistic regression analysis showed that MIBG positivity was the only significant variable associated with α-syn SAA positivity (odds ratio 74.2 [95% confidence interval 6.1-909]). Although α-syn SAA is sensitive for LBD in patients with abnormal MIBG, the sensitivity may be lower in those with normal MIBG. Further studies are necessary to evaluate the association between patient heterogeneity and α-syn SAA sensitivity.

In vivo detection of Alzheimer's and Lewy body disease concurrence: Clinical implications and future perspectives.

The recent introduction of seed amplification assays (SAAs) detecting misfolded α-synuclein, a pathology-specific marker for Lewy body disease (LBD), has allowed the in vivo identification and phenotypic characterization of patients with co-occurring Alzheimer's disease (AD) and LBD since the early clinical or even preclinical stage. We reviewed studies with an in vivo biomarker-based diagnosis of AD-LBD copathology. Studies in large cohorts of cognitively impaired individuals have shown that cerebrospinal fluid (CSF) biomarkers detect the coexistence of AD and LB pathology in approximately 20%-25% of them, independently of the primary clinical diagnosis. Compared to those with pure AD, AD-LBD patients showed worse global cognition, especially in attentive/executive and visuospatial functions, and worse motor functions. In cognitively unimpaired individuals, concurrent AD-LBD pathologies predicted longitudinal cognitive progression with faster worsening of global cognition, memory, and attentive/executive functions. Future research studies aiming for a better precision medicine approach should develop SAAs further to reach a quantitative evaluation or staging of each underlying pathology using a single biofluid sample. α-Synuclein seed amplification assays (SAAs) provide a specific marker for Lewy body disease (LBD). SAAs allow for the in vivo identification of co-occurring LBD in patients with Alzheimer's disease (AD). AD-LBD coexist in 20-25% of cognitively impaired elderly individuals, and ∼8% of those asymptomatic. Compared to pure AD, AD-LBD causes a faster worsening of cognitive functions. AD-LBD is associated with worse attentive/executive, memory, visuospatial and motor functions.

Unfolded protein response markers Grp78 and eIF2alpha are upregulated with increasing alpha-synuclein levels in Lewy body disease.

Endoplasmic reticulum stress followed by the unfolded protein response is one of the cellular mechanisms contributing to the progression of α-synuclein pathology in Parkinson's disease and other Lewy body diseases. We aimed to investigate the activation of endoplasmic reticulum stress and its correlation with α-synuclein pathology in human post-mortem brain tissue. We analysed brain tissue from 45 subjects-14 symptomatic patients with Lewy body disease, 19 subjects with incidental Lewy body disease, and 12 healthy controls. The analysed brain regions included the medulla, pons, midbrain, striatum, amygdala and entorhinal, temporal, frontal and occipital cortex. We analysed activation of endoplasmic reticulum stress via levels of the unfolded protein response-related proteins (Grp78, eIF2α) and endoplasmic reticulum stress-regulating neurotrophic factors (MANF, CDNF). We showed that regional levels of two endoplasmic reticulum-localised neurotrophic factors, MANF and CDNF, did not change in response to accumulating α-synuclein pathology. The concentration of MANF negatively correlated with age in specific regions. eIF2α was upregulated in the striatum of Lewy body disease patients and correlated with increased α-synuclein levels. We found the upregulation of chaperone Grp78 in the amygdala and nigral dopaminergic neurons of Lewy body disease patients. Grp78 levels in the amygdala strongly correlated with soluble α-synuclein levels. Our data suggest a strong but regionally specific change in Grp78 and eIF2α levels, which positively correlates with soluble α-synuclein levels. Additionally, MANF levels decreased in dopaminergic neurons in the substantia nigra. Our research suggests that endoplasmic reticulum stress activation is not associated with Lewy pathology but rather with soluble α-synuclein concentration and disease progression.

Clinical and diagnostic implications of Alzheimer's disease copathology in Lewy body disease.

Concomitant Alzheimer's disease (AD) pathology is a frequent event in the context of Lewy body disease (LBD), occurring in approximately half of all cases. Evidence shows that LBD patients with AD copathology show an accelerated disease course, a greater risk of cognitive decline and an overall poorer prognosis. However, LBD-AD cases may show heterogeneous motor and non-motor phenotypes with a higher risk of dementia and, consequently, be not rarely misdiagnosed. In this review, we summarize the current understanding of LBD-AD by discussing the synergistic effects of AD neuropathological changes and Lewy pathology and their clinical relevance. Furthermore, we provide an extensive overview of neuroimaging and fluid biomarkers under assessment for use in LBD-AD and their possible diagnostic and prognostic values. AD pathology can be predicted in vivo by means of CSF, MRI and PET markers, whereas the most promising technique to date for identifying Lewy pathology in different biological tissues is the α-synuclein seed amplification assay. Pathological imaging and CSF AD biomarkers are associated with a higher likelihood of cognitive decline in LBD but do not always mirror the neuropathological severity as in pure AD. Implementing the use of blood-based AD biomarkers might allow faster screening of LBD patients for AD copathology, thus improving the overall diagnostic sensitivity for LBD-AD. Finally, we discuss the literature on novel candidate biomarkers being exploited in LBD-AD to investigate other aspects of neurodegeneration, such as neuroaxonal injury, glial activation and synaptic dysfunction. The thorough characterization of AD copathology in LBD should be taken into account when considering differential diagnoses of dementia syndromes, to allow prognostic evaluation on an individual level, and to guide symptomatic and disease-modifying therapies.

Plasma pTau181 Reveals a Pathological Signature that Predicts Cognitive Outcomes in Lewy Body Disease.

To determine whether plasma phosphorylated-Tau181 (pTau181) could be used as a diagnostic biomarker of concurrent Alzheimer's disease neuropathologic change (ADNC) or amyloidosis alone, as well as a prognostic, monitoring, and susceptibility/risk biomarker for clinical outcomes in Lewy body disease (LBD). We studied 565 participants: 94 LBD with normal cognition, 83 LBD with abnormal cognition, 114 with Alzheimer's disease, and 274 cognitively normal. Plasma pTau181 levels were measured with the Lumipulse G platform. Diagnostic accuracy for concurrent ADNC and amyloidosis was assessed with Receiver Operating Characteristic curves in a subset of participants with CSF pTau181/Aβ42, and CSF Aβ42/Aβ40 or amyloid-β PET, respectively. Linear mixed effects models were used to examine the associations between baseline and longitudinal plasma pTau181 levels and clinical outcomes. Plasma pTau181 predicted concurrent ADNC and amyloidosis in LBD with abnormal cognition with 87% and 72% accuracy, respectively. In LBD patients with abnormal cognition, higher baseline plasma pTau181 was associated with worse baseline MoCAand CDR-SB, as well as accelerated decline in CDR-SB. Additionally, in this group, rapid increases in plasma pTau181 over 3 years predicted a faster decline in CDR-SB and memory. In LBD patients with normal cognition, there was no association between baseline or longitudinal plasma pTau181 levels and clinical outcomes; however, elevated pTau181 at baseline increased the risk of conversion to cognitive impairment. Our findings suggest that plasma pTau181 is a promising biomarker for concurrent ADNC and amyloidosis in LBD. Furthermore, plasma pTau181 holds potential as a prognostic, monitoring, and susceptibility/risk biomarker, predicting disease progression in LBD. ANN NEUROL 2024;96:526-538.

Cerebrospinal fluid/serum albumin ratio in patients with Lewy body disease: a systematic review and meta-analysis.

Abnormal cerebrospinal fluid (CSF)/serum albumin ratio (Qalb) levels have been observed in patients with cognitive impairment. Few studies have specifically focused on Lewy Body Disease (LBD), and the results were controversial. Thus, we conducted this systematic review and meta-analysis to investigate Qalb levels in patients with LBD by including data from different studies. We systematically searched PubMed, Embase, Cochrane Library, and Web of Science databases for a collection of studies containing studies comparing Qalb levels in patients with LBD and healthy controls (including healthy controls and other dementia subtypes). In the initial search, 86 relevant papers were retrieved. Standardized mean differences (SMD) in Qalb levels were calculated using a random effects model. A total of 13 eligible studies were included. Mean Qalb levels were significantly higher in patients with LBD compared to healthy older adults [standardized mean difference (SMD): 2.95, 95% confidence interval (CI): 0.89-5.00, Z = 2.81, p = 0.005]; and were significantly higher in patients with LBD than in patients with Alzheimer's disease (AD) (SMD: 1.13, 95% CI: 0.42-1.83, Z = 3.15, p = 0.002);whereas mean Qalb levels were significantly higher in patients with frontotemporal lobar degeneration (FTLD) compared to those with AD (SMD: 1.13, 95% CI,0.14-2.13, Z = 2.24, p = 0.03). Qalb levels were significantly elevated in LBD patients compared with normal older adults and were higher than those in AD patients and FTLD patients, which helped in the differential diagnosis of LBD from other neurodegenerative diseases. https://www.crd.york.ac.uk/prospero/, identifier CRD42024496616.

Distinct eye movement patterns to complex scenes in Alzheimer's disease and Lewy body disease.

Alzheimer's disease (AD) and Lewy body disease (LBD), the two most common causes of neurodegenerative dementia with similar clinical manifestations, both show impaired visual attention and altered eye movements. However, prior studies have used structured tasks or restricted stimuli, limiting the insights into how eye movements alter and differ between AD and LBD in daily life. We aimed to comprehensively characterize eye movements of AD and LBD patients on naturalistic complex scenes with broad categories of objects, which would provide a context closer to real-world free viewing, and to identify disease-specific patterns of altered eye movements. We collected spontaneous viewing behaviors to 200 naturalistic complex scenes from patients with AD or LBD at the prodromal or dementia stage, as well as matched control participants. We then investigated eye movement patterns using a computational visual attention model with high-level image features of object properties and semantic information. Compared with matched controls, we identified two disease-specific altered patterns of eye movements: diminished visual exploration, which differentially correlates with cognitive impairment in AD and with motor impairment in LBD; and reduced gaze allocation to objects, attributed to a weaker attention bias toward high-level image features in AD and attributed to a greater image-center bias in LBD. Our findings may help differentiate AD and LBD patients and comprehend their real-world visual behaviors to mitigate the widespread impact of impaired visual attention on daily activities.

Apathy in Lewy body disease and its effects on functional impairment over time.

Apathy strongly affects function in Alzheimer's disease and frontotemporal dementia, however its effect on function in Lewy Body Disease (LBD) has not been well-described. This study aims to (1) examine the prevalence and persistence of apathy in a large, national cohort of well-characterized patients with LBD, and (2) estimate the effect of apathy on function over time. Study included 676 participants with mild cognitive impairment (MCI) or dementia in the National Alzheimer's Coordinating Center Uniform Data Set. Participants were followed for an average of 3.4 ± 1.7 years and consistently had a primary diagnosis of LBD. Apathy was defined by clinician judgment, categorized into four mutually exclusive profiles: (1) never apathetic across all visits, (2) at least one but <50% of visits with apathy (intermittent apathy), (3) ≥50% but not all visits with apathy (persistent apathy), and (4) always apathy across all visits. Dementia severity was measured by baseline Clinical Dementia Rating score. Parkinsonism was defined by the presence of bradykinesia, resting tremor, rigidity, gait, and postural instability. Functional impairment was assessed using the Functional Assessment Questionnaire (FAQ). Baseline characteristics of the sample were: average age = 72.9 ± 6.9, years of education = 15.6 ± 3.4, Mini Mental State Exam (MMSE) = 24.4 ± 5.4, Geriatric Depression Scale (GDS) = 3.8 ± 3.2, FAQ = 12.0 ± 9.1. 78.8% were male and 89% were non-Hispanic white. Prevalence of apathy increased from 54.4% at baseline to 65.5% in year 4. 77% of participants had apathy at some point during follow-up. Independent of cognitive status and parkinsonian features, FAQ was significantly higher in participants with intermittent/persistent and always apathetic than never apathetic. Annual rate of decline in FAQ was faster in participants who were always apathetic than never apathy. In this large national longitudinal cohort of LBD patients with cognitive impairment, apathy was strongly associated with greater functional impairment at baseline and faster rate of decline over time. The magnitude of these effects were clinically important and were observed beyond the effects on function from participants' cognitive status and parkinsonism, highlighting the importance of specifically assessing for apathy in LBD.

Clinical Manifestations.

Visual hallucinations (VH) phenomenology in Lewy Body Disease (LBD) is heterogenous, including minor phenomena (passage, presence, illusions) and complex hallucinations. Neural substrates and mechanisms involved are still unclear. Here we investigated grey matter (GM) alterations associated with minor (MVH) and complex VH (CVH). LBD patients (n = 28) with VH and Healthy controls (HC-n = 20) underwent MRI. We administered the North East Visual Hallucinations Interview (NEVHI), a semi-structured interview assessing the phenomenology of VH, their duration and frequency. VH were clustered in MVH and CVH and treated as a patient's trait. First we compared GM volume of LBD and HC. Then, multiple regressions were performed to disclose alterations associated with the duration, frequency and severity of MVH and CVH, including the opposite VH domain, total intracranial volume (TIV) and MMSE as nuisance regressors. We found a decreased GM volume in the bilateral fusiform gyrus (FG), in the left posterior cingulate and in the right inferior frontal gyrus in LBD compared to HC. We also found that CVH duration was negatively associated with GM volume in the left FG. We did not find any association with MVH phenomenology. LBD patients showed GM alterations in ventral-visual-stream, default-mode-network and inhibitory regions compared to HC. Although the LBD versus HC comparison is not specific to VH, the regions identified have been implicated in VH in previous studies suggesting they may represent structural hallmarks of functional alterations in networks contributing to VH. When the association with VH phenomenology was tested, we did not find GM alterations associated with MVH. It is likely that these phenomena might be not associated with structural alterations but with functional alterations within visual networks. CVH were instead associated with decreased GM in FG. The atrophy in the FG may lead to a spontaneous activation of this region that sustain CVH duration, accounting for VH content (D'Antonio et al., 2022). These alterations may represent the predisposing condition to VH in LBD. According to the hodotopic model, VH phenomenology may help identify brain regions implicated and might reveal the substrates for cortical region/network dysfunctions occurring during VH state (ffytche et al., 2008).

White matter hyperintensities in cognitive impairment with Lewy body disease: a multicentre study.

White matter hyperintensities (WMHs) are associated with cognitive deficits and worse clinical outcomes in dementia, but rare studies have been carried out of cognitive impairment in Lewy body disease (CI-LB) patients. The objective was to investigate the associations between WMHs and clinical manifestations in patients with CI-LB. In this retrospective multicentre cohort study, 929 patients (486 with dementia with Lewy bodies [DLB], 262 with Parkinson's disease dementia [PDD], 74 with mild cognitive impairment [MCI] with Lewy bodies [MCI-LB] and 107 with Parkinson's disease with MCI [PD-MCI]) were analysed from 22 memory clinics between January 2018 and June 2022. Demographic and clinical data were collected by reviewing medical records. WMHs were semi-quantified according to the Fazekas method. Associations between WMHs and clinical manifestations were investigated by multivariate linear or logistic regression models. Dementia with Lewy bodies patients had the highest Fazekas scores compared with PDD, MCI-LB and PD-MCI. Multivariable regressions showed the Fazekas score was positively associated with the scores of Unified Parkinson's Disease Rating Scale Part III (p = 0.001), Hoehn-Yahn stage (p = 0.004) and total Neuropsychiatric Inventory (p = 0.001) in MCI-LB and PD-MCI patients. In patients with DLB and PDD, Fazekas scores were associated with the absence of rapid eye movement sleep behaviour disorder (p = 0.041) and scores of Unified Parkinson's Disease Rating Scale Part III (p < 0.001), Hoehn-Yahn stage (p < 0.001) and the Montreal Cognitive Assessment (p = 0.014). White matter hyperintensity burden of DLB was higher than for PDD, MCI-LB and PD-MCI. The greater WMH burden was significantly associated with poorer cognitive performance, worse motor function and more severe neuropsychiatric symptoms in CI-LB.

Neuropsychological correlates of visual hallucinatory phenomena in Lewy body disease

AbstractObjectivesVisual hallucinations (VH) ranging from minor to complex, are the most common psychiatric feature of Lewy Body Disease (LBD). Despite their high prevalence and poor prognostic implications instigating extensive research, the precise mechanisms underlying VH remain unclear. Cognitive impairment (CI) is a risk factor and a consistent correlate of VH in LBD. To help shed light on their underlying mechanisms, this study investigates the pattern of CI across the spectrum of VH in LBD.Methods30 LBD patients with minor VH (MVH), 13 with complex VH (CVH) and 32 without VH were retrospectively compared on the domains of higher‐order visual processing, memory, language and executive functioning. The VH groups were further stratified to investigate whether phenomenological subtypes have distinct cognitive correlates.ResultsLBD patients with CVH were impaired on the visuo‐spatial and executive functioning domains relative to controls. LBD patients with MVH were also impaired on the visuo‐spatial domain. No differences emerged in cognitive domains affected between patient groups endorsing specific hallucinatory phenomena.ConclusionA pattern of CI indicating fronto‐subcortical dysfunction in combination with posterior cortical involvement is implicated in the genesis of CVH. Moreover, this posterior cortical dysfunction may precede the occurrence of CVH as indicated by selective visuo‐spatial deficits in LBD patients with MVH.

Illusory responses across the Alzheimer’s disease spectrum and Lewy body disease spectrum

AbstractBackgroundPareidolias are specific illusions of faces and objects perceived in formless visual stimuli. In studies using a noise pareidolia task in patients with clinical dementia, Dementia with Lewy Bodies patients report more illusory responses than Alzheimer’s disease patients, which correlates with severity of visual hallucinations (Yokoi et al., 2014). However, it is unknown whether illusory responses occur in earlier stages of disease or in non‐hallucinating patients across the Lewy body disease (LBD) spectrum, such as Parkinson’s Disease with and without cognitive impairment.MethodWe studied the National Alzheimer’s Coordinating Center Noise Pareidolia Task‐Short Form from the LBD Module in 300 participants from the Stanford Alzheimer’s Disease Research Center and Pacific Udall Center who completed comprehensive motor and cognitive assessments with consensus diagnostic adjudication. We included 51 Alzheimer’s disease‐spectrum (AD‐s), 38 LBD with cognitive impairment (LB‐abnlCog), 65 LBD with no cognitive impairment (LB‐nlCog), and 146 Controls. Pairwise between‐group comparisons examined the impact of diagnosis on number of illusory responses. Ordinal regression analysis compared the number of illusory responses on the Noise Pareidolia Task across diagnosis groups, adjusting for age, sex, and education. Analyses were repeated after removing participants with reported hallucinations or delusions.ResultSee Table 1 for diagnosis group demographic characteristics. LB‐abnlCog were more than 10 times more likely than Controls and about 4–5 times more likely than AD‐s and LB‐nlCog participants to endorse illusory responses. The probability of endorsing one or more illusory response was 61% in the LB‐abnlCog group, compared to 26% in AD‐s, 25% in LB‐nlCog and 12% in Control participants (Figure 1). In LBD participants without hallucinations or delusions, 52% of those with mild cognitive impairment and 67% with dementia endorsed at least one illusory response.ConclusionIllusory responses are common in cognitively impaired LBD patients, including those without any reported psychosis. The Noise Pareidolia Task does not distinguish between Alzheimer’s disease and Lewy body patients until there is measurable cognitive impairment in the LBD patients, suggesting that early, unobtrusive pareidolias might arise in conjunction with cognitive decline in LBD.

Visuoconstruction Errors in pathologically confirmed Alzheimer’s disease versus Alzheimer’s disease with Lewy Body disease patients

AbstractBackgroundClinical differentiation of Alzheimer’s disease (AD) versus Lewy Body Disease (LBD; including mixed AD‐LBD) is challenging, as both diseases overlap in cognitive symptoms. This can lead to misdiagnosis with detrimental consequences to the patient’s health. While autopsy‐based studies reveal that visuoconstruction tends to be more preserved in AD versus LBD and mixed AD‐LBD, it is well established that patients with AD also have visuoconstructional difficulties. To this end, this study examined performance on three visuoconstruction tasks and qualitatively coded errors on overlapping pentagons to characterize the types of constructional difficulties in pathologically confirmed AD versus LBD and mixed AD‐LBD.MethodClinical and autopsy data were available for 30 individuals (19 AD; 11 LBD /mixed AD‐LBD). Overlapping pentagons were given a final score of either 0 or 1. Pentagons were then scored across six parameters: presence of two figures, overlapping figures, 5 sides on each figure, the correct overlap of figures (diamond in the middle), presence of overwriting, and closing‐in to stimulus. Copy of a cube and a circle/diamond figure was also scored as 0 or 1. Chi‐square analyses were used to examine the frequency of impairment on each visuoconstruction score among the pure AD versus LBD/mixed AD‐LBD groups.ResultThe combined LBD and mixed AD‐LBD group was more frequently impaired on circle‐diamond (p = .002), pentagons total score (p = .001), and two pentagons sub‐scores, including the presence of 5‐sides on each figure (p = .006) and the correct pentagon overlap (p = .006). The groups were impaired with equal frequency on the remaining pentagons sub‐scores, and on the cube copy (53% of AD and 37% of LBD/mixed AD‐LBD; p = .39).ConclusionAs expected, the combined LBD and mixed AD‐LBD group was more frequently impaired on several visuoconstruction tasks in comparison to the pure AD group. Specific pentagons errors were most sensitive to group differences. Of note, both groups were impaired with equal frequency on cube copy, suggesting that the three‐dimensional component of the task best captures the visuospatial difficulties characteristic of AD. Qualitative assessment of visuoconstruction may aid in differential diagnosis.

Diverse limbic comorbidities cause limbic and temporal atrophy in lewy body disease

BackgroundIn contrast to Alzheimer's disease (AD)-related pathology, the influence of comorbid limbic-predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC) or argyrophilic grains (AG) on structural imaging in Lewy body disease (LBD) has seldom been evaluated. ObjectiveThis study aimed to investigate whether non-AD limbic comorbidities, including LATE-NC and AG, cause cortical atrophy in LBD. MethodsSeventeen patients with pathologically confirmed LBD with lower Braak neurofibrillary tangle stage (<IV) and 10 healthy controls (HC) were included. Based on the presence of comorbid LATE-NC or AG, LBD patients were subdivided into nine patients with these proteinopathies (mixed LBD [mLBD]) and eight without (pure LBD [pLBD]). In addition to clinical feature evaluation, gray matter atrophy on voxel-based morphometry was compared between the two LBD and HC groups. ResultsThe mean age at antemortem magnetic resonance imaging of the mLBD patients was higher than that of the pLBD patients (84.3 ± 3.9 vs. 76.5 ± 10.5; p = .046). Irrespective of the presence or absence of comorbid LATE-NC or AG, all patients were clinically diagnosed with probable dementia with Lewy bodies or Parkinson's disease with dementia, respectively. Compared to the pLBD group, the mLBD group showed more conspicuous cortical atrophy of the bilateral hippocampus, amygdala, and temporal pole. ConclusionsNon-AD limbic comorbidities, including LATE-NC and AG, are associated with limbic and temporal atrophy in older patients with LBD. Therefore, the possibility of non-AD limbic comorbidities should be considered in the diagnosis of elderly patients with dementia with clinical symptoms of LBD and medial temporal atrophy.

Neuropathological studies of serotonergic and noradrenergic systems in Lewy body disease patients with delusion or depression.

AimThe association between psychiatric symptoms in Lewy body disease (LBD) and the noradrenergic and serotonergic systems is still controversial. This study investigated the quantitative relationships of depression and delusion with these systems.MethodsWe studied 24 postmortem tissues from individuals with a pathological diagnosis of LBD with sufficient clinical history. The numbers of neurons and Lewy bodies (LBs) in the locus coeruleus (LC) and dorsal raphe nucleus (DRN) were counted, and the density of neurons in the DRN was analyzed. In addition, the densities of tryptophan hydroxylase‐positive neurites and norepinephrine transporter‐positive neurites in the amygdala and dorsal prefrontal cortex were measured. Finally, we divided the cases into two groups: with or without depressive mood, and with or without delusion. Quantitative histological data were compared between the groups.ResultsThe group with depressive mood had a significantly smaller number of neurons in the LC compared with the group without depressive mood. The group with delusion had a significantly larger number of LBs in the DRN compared with the group without delusion. The density of norepinephrine transporter‐positive neurites in the dorsal prefrontal cortex was significantly correlated with the number of neurons in the LC.ConclusionsThe accumulation of LBs in the DRN of individuals with LBD was associated with delusion, whereas a decrease in the number of neurons in the LC was associated with depressive mood. These neurodegenerative changes involved the serotonergic and noradrenergic systems and may be associated with the formation of delusion and depression, respectively, in LBD.

Specific Cerebrospinal Fluid SerpinA1 Isoform Pattern in Alzheimer's Disease.

SerpinA1 (α1-antitrypsin) is a soluble glycoprotein, the cerebrospinal fluid (CSF) isoforms of which showed disease-specific changes in neurodegenerative disorders that are still unexplored in Alz-heimer’s disease (AD). By means of capillary isoelectric focusing immunoassay, we investigated six serpinA1 isoforms in CSF samples of controls (n = 29), AD-MCI (n = 29), AD-dem (n = 26) and Lewy body disease (LBD, n = 59) patients and correlated the findings with CSF AD core biomarkers (Aβ42/40 ratio, p-tau, t-tau). Four CSF serpinA1 isoforms were differently expressed in AD patients compared to controls and LBD patients, especially isoforms 2 and 4. AD-specific changes were found since the MCI stage and significantly correlated with decreased Aβ42/40 (p < 0.05) and in-creased p-tau and t-tau levels in CSF (p < 0.001). Analysis of serpinA1 isoform provided good di-agnostic accuracy in discriminating AD patients versus controls (AUC = 0.80) and versus LBD patients (AUC = 0.92), with best results in patients in the dementia stage (AUC = 0.97). SerpinA1 isoform expression is altered in AD patients, suggesting a common, albeit disease-specific, in-volvement of serpinA1 in most neurodegenerative disorders.