Spectrum Of Lewy Body Disease Research Articles

Cognitive Speed in Neurodegenerative Disease: Comparing Mean Rate and Inconsistency Within and Across the Alzheimer's and Lewy Body Spectra in the COMPASS-ND Study.

Alzheimer's disease (AD) and Lewy body disease (LBD) are characterized by early and gradual worsening perturbations in speeded cognitive responses. Using simple and choice reaction time tasks, we compared two indicators of cognitive speed within and across the AD and LBD spectra: mean rate (average reaction time across trials) and inconsistency (within person variability). The AD spectrum cohorts included subjective cognitive impairment (SCI, n = 28), mild cognitive impairment (MCI, n = 121), and AD (n = 45) participants. The LBD spectrum included Parkinson's disease (PD, n = 32), mild cognitive impairment in PD (PD-MCI, n = 21), and LBD (n = 18) participants. A cognitively unimpaired (CU, n = 39) cohort served as common benchmark. We conducted multivariate analyses of variance and discrimination analyses. Within the AD spectrum, the AD cohort was slower and more inconsistent than the CU, SCI, and MCI cohorts. The MCI cohort was slower than the CU cohort. Within the LBD spectrum, the LBD cohort was slower and more inconsistent than the CU, PD, and PD-MCI cohorts. The PD-MCI cohort was slower than the CU and PD cohorts. In cross-spectra (corresponding cohort) comparisons, the LBD cohort was slower and more inconsistent than the AD cohort. The PD-MCI cohort was slower than the MCI cohort. Discrimination analyses clarified the group difference patterns. For both speed tasks, mean rate and inconsistency demonstrated similar sensitivity to spectra-related comparisons. Both dementia cohorts were slower and more inconsistent than each of their respective non-dementia cohorts.

Automated Analysis of REM Sleep without Atonia in the Lewy Body Disease Spectrum

AbstractBackgroundQuantitative rapid eye movement (REM) sleep without atonia (RSWA) recorded during polysomnography (PSG) represents loss of normal REM sleep atonia. RSWA is the neurophysiologic signature of REM sleep behavior disorder (RBD). Visually scored RSWA is a candidate biomarker for synucleinopathies. However, visual RSWA scoring requires expert scoring, limiting widespread application. We comparatively analyzed RSWA in DLB and iRBD using the automated Ferri REM Atonia Index (RAI).MethodWe quantitatively analyzed the RAI in 12 DLB and 20 iRBD patients, compared to 20 controls using Hypnolab Software for Sleep Analysis (SWS Soft, Inc, Colognola ai Colli, Italy). PSG data were converted to European Data Format (.EDF), and the submentalis surface electromyogram (EMG) signal was notch‐filtered at 60 Hertz and rectified. Automatically calculated RAI scores were comparatively analyzed across groups (DLB, iRBD, controls) using Kruskal Wallis H tests for group comparisons, and regression analyses determined relationships between diagnosis, age, and sex. Logistic regression ROC determined optimal RAI for distinguishing iRBD from DLB. When interpreting RAI, lower values represent greater amounts of RSWA, and higher values represent more normal REM atonia.ResultMean age was older in DLB than in iRBD or controls (72.6 vs. 68.7 vs. 66.5 years). All 12 DLB participants were men, the iRBD group had 18 men and 2 women, and controls were comprised of 16 men and 4 women. Mean RAI was lowest in DLB (0.46), intermediate in iRBD (0.71) and highest in controls (0.96), indicating a gradient in RSWA amounts from DLB patients (highest) to controls (lowest) (Figure). Regression demonstrated diagnosis independently predicted RAI, controlling for age and sex (adjusted R2 = 0.49, p = 0.0001). The RAI that optimally distinguished iRBD from DLB was 0.46 (specificity 85%, sensitivity 58%, AUC = 0.75).ConclusionThe RAI demonstrated a clear gradient throughout the Lewy body spectrum; highest (indicating lowest RSWA amounts) in controls, intermediate in iRBD, and lowest (indicating greatest RSWA) in DLB. The RAI is a promising, time efficient and broadly applicable candidate biomarker for DLB and iRBD. Automated quantitative RSWA could be a valuable tool for deep phenotyping throughout the Lewy body disease spectrum.

Decline in cognitive trajectories in the neuropathological spectrum of Lewy Body disease

AbstractBackgroundPathological Lewy body disease (LBD) may commonly present clinically as Parkinson’s disease dementia (PDD), Dementia with Lewy bodies (DLB) or Alzheimer’s disease dementia (ADD). Neuropathological definitions also include a group in which ADD is present, but the postmortem Lewy pathology does not meet threshold density and distribution levels for the neuropathological diagnosis of DLB (ADLB). Little is known about the cognitive profiles of patients with ADLB and despite common underlying pathology, studies delineating neuropsychological profiles in LBD are fraught with inconsistencies. We characterized the longitudinal cognitive trajectories defined by neuropsychological profiles in cases along the pathological spectrum of LBD.MethodCases from the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND) with a cognitive diagnosis of dementia at death and who at minimum, had two neuropsychological evaluations were included. Final neuropathological diagnosis was determined as LBD (neocortical or limbic LB ± AD), ADLB, and AD pathology only. LBD cases were categorized by their cognitive clinical syndromes as PDD and DLB. Global cognition was evaluated using MMSE. Neuropsychological domains of Memory, Executive function, language, attention, and visuospatial were evaluated. Mixed linear methods were used to predict longitudinal change for a given baseline MMSE.Result287 participants and 1874 participant‐years of data were included in this study. LBD (n = 115), and ADLB (52) groups were predominantly male, while AD (n = 114) group was primarily female. Baseline MMSE was similar across all pathologic groups. Linear mixed modelling methods showed faster decrease in memory domain scores (decreasing 0.22 units/year – 0.42 units/year faster, p = 0.01) in ADLB group compared to other groups. Significantly faster decline was noted in LBD and ADLB group in clock drawing (p<0.001), fluency scores (declining 1.02 unit/year faster p<0.001) compared to AD group. There was no difference between PDD and DLB clinical subgroups.ConclusionIn autopsy confirmed cases, ADLB had an accelerated trajectory of decline in memory tasks, while AD, and LBD appeared to have similar trajectories. In contrast, all groups with Lewy bodies progressed faster and showed accelerated decline compared to AD in measures of frontal‐subcortical functions. These results may inform antemortem classification of patients and diagnostic accuracy in these groups.

Morphological characteristics differentiate dementia with Lewy bodies from Parkinson disease with and without dementia.

Dementia with Lewy bodies (DLB) and Parkinson disease (PD) with and without dementia are entities of a spectrum of Lewy body diseases. About 26.3% of all PD patients develop dementia increasing up to 83%. Parkinson disease-dementia (PDD) and DLB share many clinical and morphological features that separate them from non-demented PD (PDND). Clinically distinguished by the temporal sequence of motor and cognitive symptoms, the pathology of PDD and DLB includes variable combinations of Lewy body (LB) and Alzheimer (AD) lesions, both being more severe in DLB, but much less frequent and less severe in PDND. The objective of this study was to investigate the morphological differences between these three groups. 290 patients with pathologically confirmed PD were reviewed. 190 of them had clinical dementia; 110 met the neuropathological criteria of PDD and 80 of DLB. The major demographic and clinical data were obtained from medical records. Neuropathology included semiquantitative assessment of LB and AD pathologies including cerebral amyloid angiopathy (CAA). PDD patients were significantly older than PDND and DLB ones (83.9 vs 77.9years, p < 0.05); the age of DLB patients was between them (80.0years), while the disease duration was shortest in DLB. Brain weight was lowest in DLB, which showed higher Braak LB scores (mean 5.2 vs 4.2) and highest Braak tau stages (mean 5.2 vs 4.4 and 2.3, respectively). Thal Aβ phases were also highest in DLB (mean 4.1 vs 3.0 and 1.8, respectively). Major findings were frequency and degree of CAA, being highest in DLB (95% vs 50% and 24%, with scores 2.9 vs 0.7 and 0.3, respectively), whereas other small vessel lesions showed no significant differences. Striatal Aβ deposits also differentiated DLB from the other groups. This and other studies of larger cohorts of PD patients indicate that the association of CAA and cortical tau-but less-LB pathologies are associated with more severe cognitive decline and worse prognosis that distinguish DLB from PDD and PDND. The particular impact of both CAA and tau pathology supports the concept of a pathogenic continuum ranging from PDND to DLB + AD within the spectrum of age-related synucleinopathies.

Illusory Responses across the Lewy Body Disease Spectrum.

This study was undertaken to study pareidolias, or perceived meaningful objects in a meaningless stimulus, in patients across the Lewy body (LB) disease spectrum, where most do not report hallucinations or delusions. We studied illusory responses on the Noise Pareidolia Task in 300 participants (38 cognitively impaired LB, 65 cognitively unimpaired LB, 51 Alzheimer disease spectrum [AD-s], 146 controls). Pairwise between-group comparisons examined how diagnosis impacts the number of illusory responses. Ordinal regression analysis compared the number of illusory responses across diagnosis groups, adjusting for age, sex, and education. Analyses were repeated after removing participants with reported hallucinations or delusions. Cognitively impaired LB participants were 12.3, 4.9, and 4.6 times more likely than control, cognitively unimpaired LB, and AD-s participants, respectively, to endorse illusory responses. After adjusting for age, sex, and education, the probability of endorsing 1 or more illusory responses was 61% in the cognitively impaired LB group, compared to 26% in AD-s, 25% in cognitively unimpaired LB, and 12% in control participants. All results were similar after repeated analysis only in participants without hallucinations or delusions. In LB without hallucinations or delusions, 52% with mild cognitive impairment and 66.7% with dementia endorsed at least 1 illusory response. We found illusory responses are common in cognitively impaired LB patients, including those without any reported psychosis. Our data suggest that, prior to the onset of hallucinations and delusions, the Noise Pareidolia Task can easily be used to screen for unobtrusive pareidolias in all LB patients. ANN NEUROL 2023;93:702-714.

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.

Are there morphological differences between Parkinson's disease-dementia and dementia with Lewy bodies?

Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB) are two major neurocognitive disorders in the spectrum of Lewy body diseases that overlap in many clinical and neuropathological features, although they show several differences. Clinically distinguished mainly based on the duration of parkinsonism prior to development of dementia, their morphology is characterized by a variable combination of Lewy body (LB) and Alzheimer's disease (AD) pathologies, the latter usually being more frequent and severe in DLB. ObjectiveThe aims of the study were to investigate essential neuropathological differences between PDD and DLB in a larger cohort of autopsy cases. Methods110 PDD autopsy cases were compared with 78 DLB cases. The major demographic, clinical (duration of illness, final MMSE) and neuropathological data were assessed retrospectively. Neuropathological studies used standardized methods and immunohistochemistry for phospho-tau, β-amyloid (Aß) and α-synuclein, with semiquantitative assessment of the major histological lesions. ResultsPDD patients were significantly older at death than DLB ones (mean 83.9 vs. 79.8 years), with a significantly longer disease duration (mean 9.2 vs. 6.7 years). Braak LB scores and particularly neuritic Braak stages were significantly higher in the DLB group (mean 5.1and 5.1 vs. 4.2 and 4.4, respectively), as were Thal Aβ phases (mean 4.1 vs. 3.0). Diffuse striatal Aβ plaques were considerable in 55% and moderate in 45% of DLB cases, but were extremely rare in PDD. The most significant differences concerned the frequency and degree of cerebral amyloid angiopathy (CAA), being significantly higher in DLB (98.7 vs. 50%, and mean degree of 2.9 vs. 0.72, respectively). Worse prognosis in DLB than in PDD was linked to both increased Braak neuritic stages and more severe CAA. InterpretationThese and other recent studies imply the association of CAA, more severe concomitant AD pathology, and striatal Aβ load with cognitive decline and more rapid disease process that distinguishes DLB from PDD, while the influence of other cerebrovascular diseases or co-pathologies in both disorders was not specifically examined. The importance of both CAA and tau pathology in DLB and much less in PDD supports the concept of a pathogenetic continuum from Parkinson's disease (PD) - > PDD - > DLB - > DLB + AD and subtypes of AD with LB pathology within the spectrum of age-related proteinopathies.

Association of β-Amyloid and Basal Forebrain With Cortical Thickness and Cognition in Alzheimer and Lewy Body Disease Spectra.

Cholinergic degeneration and β-amyloid contribute to brain atrophy and cognitive dysfunction in Alzheimer disease (AD) and Lewy body disease (LBD), but their relationship has not been comparatively evaluated. In this cross-sectional study, we recruited 28 normal controls (NC), 55 patients with AD mild cognitive impairment (MCI), 34 patients with AD dementia, 28 patients with LBD MCI, and 51 patients with LBD dementia. Participants underwent cognitive evaluation, brain MRI to measure the basal forebrain (BF) volume and global cortical thickness (CTh), and 18F-florbetaben (FBB) PET to measure the standardized uptake value ratio (SUVR). Using general linear models and path analyses, we evaluated the association of FBB-SUVR and BF volume with CTh or cognitive dysfunction in the AD spectrum (AD and NC) and LBD spectrum (LBD and NC), respectively. Covariates included age, sex, education, deep and periventricular white matter hyperintensities, intracranial volume, hypertension, diabetes, and hyperlipidemia. BF volume mediated the association between FBB-SUVR and CTh in both the AD and LBD spectra, while FBB-SUVR was associated with CTh independently of BF volume only in the LBD spectrum. Significant correlation between voxel-wise FBB-SUVR and CTh was observed only in the LBD group. FBB-SUVR was independently associated with widespread cognitive dysfunction in both the AD and LBD spectra, especially in the memory domain (standardized beta [B] for AD spectrum = -0.60, B for LBD spectrum = -0.33). In the AD spectrum, BF volume was associated with memory dysfunction (B = 0.18), and CTh was associated with language (B = 0.21) and executive (B = 0.23) dysfunction. In the LBD spectrum, however, BF volume and CTh were independently associated with widespread cognitive dysfunction. There is a common β-amyloid-related degenerative mechanism with or without the mediation of BF in the AD and LBD spectra, while the association of BF atrophy with cognitive dysfunction is more profound and there is localized β-amyloid-cortical atrophy interaction in the LBD spectrum.

Long‐term cognitive and motor decline across the spectrum of Lewy body disease

AbstractBackgroundThis study aims to compare the progression of motor and cognitive decline in dementia with Lewy bodies (DLB) compared with Parkinson’s disease (PD) using a large multicentre international consortium with up to 15 years of follow‐up.MethodLongitudinal data from 12 cohorts of patients with PD and DLB were included. The PD cohort (n=1108) included newly diagnosed patients from large, on‐going studies. The DLB cohort (n=290) included patients with probable DLB from the European DLB consortium (Table 1). The Mini Mental State Examination (MMSE) was used to explore cognitive functioning and UPDRS‐III for motor impairment. The differences in the rate of progression of MMSE and UPDRS‐III were analyzed with Linear Mixed Effects Model (LMEM) adjusted for baseline variables, with interactions for time. We used square root transformation of the number of errors to obtain an MMSE variable with normal distribution.ResultBoth DLB and PD groups presented motor and cognitive decline. The MMSE (figure 1A) showed a mean annual worsening of 2.35 points (95% CI 1.67‐3.03) for DLB patients and 1.05 points (95% CI 0.62‐1.47) for PD patients (P &lt;0.001). In PD the rate of decline increased with time and from the tenth year, the annual rate of decline of the transformed MMSE scores matched the rate in the DLB group. While DLB patients had lower UPDRS‐III scores at baseline, the rate of decline in UPDRS‐III (figure 1B) scores was faster in DLB compared to PD (P &lt;0.001). The annual increase in UPDRS III in DLB was 5.8 points (95% CI 5.71‐5.90), while in PD it was 1.9 points (95% CI 1.76‐1.97).ConclusionOur findings suggest that patients with DLB experience not only more rapid cognitive decline, but also accelerated motor deterioration compared to patients with PD. After ten years of follow‐up (and 12.9 years from the onset of symptoms), PD patients reach DLB's degree of yearly cognitive decline. This is the first large study to compare the natural history of PD and DLB and provides important information about the prognosis of these diseases.

Update on neuroimaging in non-Alzheimer's disease dementia: a focus on the Lewy body disease spectrum.

An accurate differential diagnosis between Alzheimer's disease (AD) and non-AD dementia is of paramount importance to study disease mechanisms, define prognosis, and select patients for disease-specific treatments. The purpose of the present review is to describe the most recent neuroimaging studies in Lewy body disease spectrum (LBDS), focusing on differences with AD. Different neuroimaging methods are used to investigate patterns of alterations, which can be helpful to distinguish LBDS from AD. Positron emission tomography radiotracers and advanced MRI structural and functional methods discriminate these two conditions with increasing accuracy. Prodromal disease stages can be identified, allowing an increasingly earlier diagnosis. Neuroimaging biomarkers can aid in obtaining the best diagnostic accuracy in LBDS. Despite the main role of neuroimaging in clinical setting is to exclude secondary causes of dementia, structural and metabolic imaging techniques give an essential help to study in-vivo pathophysiological mechanisms of diseases. The importance of neuroimaging in LBDS is given by the increasing number of imaging biomarker developed and studied in the last years.

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

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

Dementia with Lewy bodies and Parkinson’s disease dementia-two independent disorders or one clinical entity within a clinical spectrum of synucleinopathies?

Abstract Introduction: Introduction: Both dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD) are important dementia syndromes that overlap in their clinical features and clinical course, neuropathological abnormalities, and also therapeutic approach. Nevertheless it is still unclear whether DLB and PDD are two different disorders that require differentiation or are one clinical entity within a spectrum of Lewy body disease. Currently these disorders are mainly distinguished on the basis of the relative timing of the onset of symptoms of dementia and parkinsonism. The present paper presents current concepts on the pathogenesis of both disorders and their possible overlap. Material and methods: Online databases in the field of DLB and PDD were searched for to find potentially eligible articles. Only most recent articles published after the year 2000 were chosen. Results: The clinical features of DLB and PDD are similar and include dementia with hallucinations and cognitive fluctuations, as well as parkinsonian signs. Also cognitive deficits are similar in PDD and in DLB, with predominance of executive dysfunction, visual-spatial deficits and memory impairment. Neuropathological changes in both disorders involve the presence of Lewy bodies and Lewy neurites within brainstem, limbic and neocortex, as well as loss of midbrain dopamine cells, and loss of cholinergic neurons in the nuclei of ventral forebrain. Conclusions: Similarities in clinical manifestation, neuropsychological deficits and neuropathological abnormalities may suggest that both DLB and PDD are two different phenotypes of the same disorder. This review article presents current knowledge on similarities and differences between these two clinical entities and raises the question whether they require differentiation or not.

1127 Utility of Quantitative EEG During Sleep as a Potential Biomarker of Lewy Body Disease Progression

Abstract Introduction Sleep disturbances are common among patients with Lewy body disorders. Idiopathic REM sleep behavior disorder (iRBD) has been identified as a prodromal Lewy body condition with a significantly increased risk of conversion to either Parkinson’s disease (PD) or Dementia with Lewy Bodies (DLB). Pathological involvement of thalamic and brainstem structures involved in sleep regulation has been reported in these disorders, especially in later stages. We hypothesized that progression along the Lewy body disease spectrum may be associated with unique changes in spindle density and EEG power spectra during sleep reflecting involvement of these deep brain structures. Methods A cross-sectional design was used. 9 polysomnography confirmed iRBD, 18 early PD, 23 DLB and 13 controls underwent overnight polysomnography, neurological and neuropsychological assessment. Power spectrum analysis during NREM and REM sleep was undertaken using a previously validated quantitative EEG algorithm and compared between groups. Following artefact and outlier removal, results were analysed using the Cz derivation. Groups were statistically compared with a non-parametric Jonckheree-Terpstra test for ordered alternatives, controlling for age and sex. Results We found a significant and ordered reduction in power in the spindle frequency band (12-15 Hz) in NREM sleep across the Lewy body disease spectrum compared to controls (Controls &amp;gt; iRBD &amp;gt; early PD &amp;gt; DLB; TJT = 521.00, z = -2.902. p&amp;lt;0.001). In REM sleep we found a shift in power to slower frequencies with increased power in the theta (4.5-8 Hz) band in order of disease severity (DLB &amp;gt; early PD &amp;gt; iRBD &amp;gt; Controls; TJT = 950.00, z = 2.253. p=0.024). No differences were found across the other frequency bands in NREM or REM sleep. Conclusion There is a significant and progressive reduction in spindle density and corresponding slowing in REM sleep frequencies during sleep with clinical Lewy body staging. Thus, such measures have the potential to be useful biomarkers of progression towards Lewy body dementia from prodromal stages. Support This work was supported by a NHMRC Dementia Team Grant (#1095127), the NHMRC Postgraduate Scholarship and the University of Sydney Research Excellence Initiative 2020 grant.

Frontal and subcortical contribution to visual hallucinations in dementia with Lewy bodies and Parkinson’s disease

ABSTRACTObjectives: Visual hallucinations (VH) are common in Lewy body disease (LBD), and have been associated with cognitive and structural brain alterations. Evidence so far concerns mainly Parkinson’s disease (PD), but little is known about symptom-specific pathophysiological mechanisms across the LBD spectrum, especially related to the presence of dementia. The aim of the present pilot study was to investigate the neuroanatomical, and neuropsychological characteristics related to VH in two forms of LBD, namely dementia with Lewy bodies (DLB) and PD without dementia.Methods: Whole brain voxel-based morphometry (VBM) analyses on 3D MRI acquired structural brain scans, and neuropsychological testing were performed on 28 clinically diagnosed DLB (11 with VH, 17 NVH), and 24 PD (9 with VH, and 15 NVH) patients. In order to assess differences in gray matter (GM) regional volumes, and cognitive performance, hallucinating patients for each group were compared with corresponding non-hallucinating ones.Results: DLB patients with VH presented significantly worse visual attention deficits compared to those without, which persisted even when controlling for visual perception. Whole brain VBM analysis revealed decreased GM volume in DLB with VH in the right superior and medial frontal gyri, putamen, caudate nucleus and insula. Subcortical regional volumes were also significantly associated with visual attention performance. Hallucinating PD patients, instead, presented more severe executive dysfunction, but VBM showed no volumetric differences between the two PD subgroups. Post hoc region of interest analyses revealed striatal GM loss in PD with VH.Conclusion: Frontal and striatal GM atrophy may contribute to the emergence of VH in DLB, which may be fostered by the more severe attention deficits. Striatal GM loss and executive dysfunction, instead, appeared to underlie VH in PD without dementia.

Monoaminergic Markers Across the Cognitive Spectrum of Lewy Body Disease.

Lewy body disorders, including Parkinson's disease (PD), Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB), are characterized by profound central and peripheral monoaminergic dysfunction. To investigate whether these alterations depend on dementia status, we measured cerebrospinal fluid (CSF) and serum monoamine and metabolite levels across subgroups of the cognitive spectrum, and evaluated their marker potential afterwards. In total, 153 subjects were included, of which 43 healthy controls (HC), 28 PD patients with normal cognition (PD-NC), 26 patients with PD and mild cognitive impairment (PD-MCI), 18 PDD patients, and 38 DLB patients. The levels of monoamines and metabolites in paired CSF and serum samples were analyzed applying reversed-phase high-performance liquid chromatography with electrochemical detection. Firstly, when comparing subgroups, CSF 3-methoxy-4-hydroxyphenylglycol (MHPG) levels were found lowest in HC and PD-NC groups and significantly higher in PDD/DLB patients. In addition, CSF 5-hydroxyindoleacetic acid (5-HIAA) levels differed significantly between HC and PD-MCI/PDD, and DLB patients (P≤0.001), but not between HC and PD-NC patients. Secondly, when performing logistic regression, it was shown that particularly CSF/serum MHPG levels and the serum MHPG to noradrenaline (NA) ratio effectively differentiated between HC and (non-)pooled PD subgroups (AUC = 0.914-0.956), and PDD and DLB patients (AUC = 0.822), respectively. Furthermore, CSF 5-HIAA was the most discriminative parameter to differentiate between PD-NC and PD-MCI (AUC = 0.808), and, PD-NC and PDD subgroups (AUC = 0.916). Our data revealed that especially alterations of the noradrenergic neurotransmitter system could distinguish between Lewy body disorder subtypes, pinpointing CSF/serum MHPG and NA as potential stage markers across the cognitive spectrum.

Distinct patterns of amyloid-dependent tau accumulation in Lewy body diseases.

In addition to Lewy body pathology, amyloid-β plaques and neurofibrillary tangles that are characteristic for Alzheimer's disease are also frequently found in Lewy body diseases. The objective of this study was to investigate tau accumulation patterns in dementia with Lewy bodies and other Lewy body diseases using in vivo 18 F-AV-1451 PET. The study included 12 Parkinson's disease (PD) patients with normal cognition, 22 PD patients with cognitive impairment, and 18 dementia with Lewy bodies patients. In addition, 25 Alzheimer's disease patients and 25 healthy controls were included for comparison. All participants underwent 18 F-AV-1451 and 18 F-florbetaben PET scans, and cortical binding values were compared between the controls and each disease group. When compared with the controls, dementia with Lewy bodies patients showed slightly increased 18 F-AV-1451 binding in the primary sensorimotor and visual cortices and the parieto-temporal cortices, which failed to survive multiple comparisons. Amyloid-positive dementia with Lewy bodies patients showed significantly increased binding in the same regions when compared with controls, and even greater binding in the primary sensorimotor and visual cortices than Alzheimer's disease. Meanwhile, binding in the lateral and medial temporal cortices was less prominent than in Alzheimer's disease. In dementia with Lewy bodies, 18 F-AV-1451 binding in the occipital cortex correlated with 18 F-florbetaben binding. Amyloid-negative patients with normal cognition, patients with cognitive impairment, and dementia with Lewy bodies patients did not show increased 18 F-AV-1451 binding. Dementia with Lewy bodies patients may harbor 18 F-AV-1451 binding patterns distinct from Alzheimer's disease, with greater involvement of the primary cortices and less involvement of the temporal cortex. Tau burden increases in the Lewy body disease spectrum, and amyloid may play an important role in the accumulation of neocortical tau in Lewy body diseases. © 2017 International Parkinson and Movement Disorder Society.

Anomalies occurring in lipid profiles and protein distribution in frontal cortex lipid rafts in dementia with Lewy bodies disclose neurochemical traits partially shared by Alzheimer's and Parkinson's diseases

Lipid rafts are highly dynamic membrane microdomains intimately associated with cell signaling. Compelling evidence has demonstrated that alterations in lipid rafts are associated with neurodegenerative diseases such Alzheimer's disease, but at present, whether alterations in lipid raft microdomains occur in other types of dementia such dementia with Lewy bodies (DLB) remains unknown. Our analyses reveal that lipid rafts from DLB exhibit aberrant lipid profiles including low levels of n-3 long-chain polyunsaturated fatty acids (mainly docosahexaenoic acid), plasmalogens and cholesterol, and reduced unsaturation and peroxidability indexes. As a consequence, lipid raft resident proteins holding principal factors of the β-amyloidogenic pathway, including β-amyloid precursor protein, presenilin 1, β-secretase, and PrP, are redistributed between lipid rafts and nonraft domains in DLB frontal cortex. Meta-analysis discloses certain similarities in the altered composition of lipid rafts between DLB and Parkinson's disease which are in line with the spectrum of Lewy body diseases. In addition, redistribution of proteins linked to the β-amyloidogenic pathway in DLB can facilitate generation of β-amyloid, thus providing mechanistic clues to the intriguing convergence of Alzheimer's disease pathology, particularly β-amyloid deposition, in DLB.

Cerebrospinal Fluid Alzheimer's Disease Biomarkers Across the Spectrum of Lewy Body Diseases: Results from a Large Multicenter Cohort.

Concomitant Alzheimer's disease (AD) pathology is observed in Lewy body diseases (LBD), but the clinical impact is unknown. Only a few biomarker studies in LBD exist and have included small cohorts from single centers. We aimed to evaluate the prevalence of abnormal cerebrospinal fluid (CSF) AD biomarkers across the spectrum of LBD in a large multicenter cohort and to assess whether an AD biomarker profile was associated with demographic and clinical differences in dementia with Lewy bodies (DLB). We included 375 DLB patients, 164 Parkinson's disease (PD) patients without dementia, and 55 PD patients with dementia (PDD) from 10 centers. CSF amyloid-beta42 (Aβ42), total tau (t-tau), and phosphorylated tau (p-tau) values were dichotomized as abnormal or normal according to locally available cut-off values. A CSF AD profile was defined as abnormal Aβ42 combined with abnormal t-tau and/or p-tau. A substantial proportion of DLB patients had abnormal values for CSF Aβ42, t-tau, and p-tau, while abnormal values were uncommon in PD without dementia. Patients with PDD had values in between. A CSF AD profile was observed in 25% of DLB patients, compared with only 9% of PDD and 3% of PD without dementia. Within DLB, patients with a CSF AD profile were older, more often female, performed worse on the Mini-Mental State Examination, and had shorter disease duration compared with patients with normal CSF. A CSF AD profile is more common in DLB compared with PDD and PD, and is associated with more severe cognitive impairment in DLB.

Lewy Body Dementias: Dementia With Lewy Bodies and Parkinson Disease Dementia.

This article provides an overview of the clinical features, neuropathologic findings, diagnostic criteria, and management of dementia with Lewy bodies (DLB) and Parkinson disease dementia (PDD), together known as the Lewy body dementias. DLB and PDD are common, clinically similar syndromes that share characteristic neuropathologic changes, including deposition of α-synuclein in Lewy bodies and neurites and loss of tegmental dopamine cell populations and basal forebrain cholinergic populations, often with a variable degree of coexisting Alzheimer pathology. The clinical constellations of DLB and PDD include progressive cognitive impairment associated with parkinsonism, visual hallucinations, and fluctuations of attention and wakefulness. Current clinical diagnostic criteria emphasize these features and also weigh evidence for dopamine cell loss measured with single-photon emission computed tomography (SPECT) imaging and for rapid eye movement (REM) sleep behavior disorder, a risk factor for the synucleinopathies. The timing of dementia relative to parkinsonism is the major clinical distinction between DLB and PDD, with dementia arising in the setting of well-established idiopathic Parkinson disease (after at least 1 year of motor symptoms) denoting PDD, while earlier cognitive impairment relative to parkinsonism denotes DLB. The distinction between these syndromes continues to be an active research question. Treatment for these illnesses remains symptomatic and relies on both pharmacologic and nonpharmacologic strategies. DLB and PDD are important and common dementia syndromes that overlap in their clinical features, neuropathology, and management. They are believed to exist on a spectrum of Lewy body disease, and some controversy persists in their differentiation. Given the need to optimize cognition, extrapyramidal function, and psychiatric health, management can be complex and should be systematic.

Regional functional synchronizations in dementia with Lewy bodies and Alzheimer's disease.

Dementia with Lewy bodies (DLB) is a common cause of dementia in the elderly population after Alzheimer's disease (AD), and at early stages differential diagnosis between DLB and AD might be difficult due to their symptomatic overlap, e.g. cognitive and memory impairments. We aimed to investigate functional brain differences between both diseases in patients recently diagnosed. We investigated regional functional synchronizations using regional homogeneity (ReHo) in patients clinically diagnosed with DLB (n = 19) and AD (n = 18), and for comparisons we also included healthy controls (HC, n = 16). Patient groups were matched by age, education, and by the level of cognitive impairment (MMSE p-value = 0.36). Additionally, correlations between ReHo values and clinical scores were investigated. The DLB group showed lower ReHo in sensory-motor cortices and higher ReHo in left middle temporal gyrus when compared with HCs (p-value < 0.001 uncorrected). The AD group demonstrated lower ReHo in the cerebellum and higher ReHo in the left/right lingual gyri, precuneus cortex, and other occipital and parietal regions (p-value < 0.001 uncorrected). Our results agree with previous ReHo investigations in Parkinson's disease (PD), suggesting that functional alterations in motor-related regions might be a characteristic of the Lewy body disease spectrum. However, our results in AD contradict previously reported findings for this disease and ReHo, which we speculate are a reflection of compensatory brain responses at early disease stages. ReHo differences between patient groups were at regions related to the default mode and sensory-motor resting state networks which might reflect the aetiological divergences in the underlying disease processes between AD and DLB.