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The prodromal phase of dementia with Lewy bodies (DLB) includes (1) mild cognitive impairment (MCI), (2) delirium-onset, and (3) psychiatric-onset presentations. The purpose of our review is to determine whether there is sufficient information yet available to justify development of diagnostic criteria for each of these. Our goal is to achieve evidence-based recommendations for the recognition of DLB at a predementia, symptomatic stage. We propose operationalized diagnostic criteria for probable and possible mild cognitive impairment with Lewy bodies, which are intended for use in research settings pending validation for use in clinical practice. They are compatible with current criteria for other prodromal neurodegenerative disorders including Alzheimer and Parkinson disease. Although there is still insufficient evidence to propose formal criteria for delirium-onset and psychiatric-onset presentations of DLB, we feel that it is important to characterize them, raising the index of diagnostic suspicion and prioritizing them for further investigation.

The Dementia with Lewy Bodies (DLB) Consortium has refined its recommendations about the clinical and pathologic diagnosis of DLB, updating the previous report, which has been in widespread use for the last decade. The revised DLB consensus criteria now distinguish clearly between clinical features and diagnostic biomarkers, and give guidance about optimal methods to establish and interpret these. Substantial new information has been incorporated about previously reported aspects of DLB, with increased diagnostic weighting given to REM sleep behavior disorder and 123iodine-metaiodobenzylguanidine (MIBG) myocardial scintigraphy. The diagnostic role of other neuroimaging, electrophysiologic, and laboratory investigations is also described. Minor modifications to pathologic methods and criteria are recommended to take account of Alzheimer disease neuropathologic change, to add previously omitted Lewy-related pathology categories, and to include assessments for substantia nigra neuronal loss. Recommendations about clinical management are largely based upon expert opinion since randomized controlled trials in DLB are few. Substantial progress has been made since the previous report in the detection and recognition of DLB as a common and important clinical disorder. During that period it has been incorporated into DSM-5, as major neurocognitive disorder with Lewy bodies. There remains a pressing need to understand the underlying neurobiology and pathophysiology of DLB, to develop and deliver clinical trials with both symptomatic and disease-modifying agents, and to help patients and carers worldwide to inform themselves about the disease, its prognosis, best available treatments, ongoing research, and how to get adequate support.

Background: Attention deficits are notable in Lewy body dementia (LBD) and in Alzheimer's disease (AD). In this study, we combined functional magnetic resonance imaging (fMRI) and electroencephalograph (EEG) to detect neural correlates of attention dysfunctions in LBD and AD. Methods: We recruited 33 patients with LBD, 15 patients with AD and 19 elderly healthy controls. The participants performed the modified Attention Network Task (ANT) to investigate the attention dysfunctions. Results: We found that LBD had alerting attention deficits and AD showed apparent orienting attention dysfunctions, while LBD and AD maintained relatively normal executive/conflict attention. Based on source-level EEG analyses, LBD had frontal-central deficits for alerting attention while AD showed inferior frontal and precentral impairments for orienting attention. In addition, the insular and inferior frontal areas were hyper-activated in LBD and AD for executive/conflict attention. Apart from these areas, LBD showed activity in the complementary temporal-central-occipital network for the modified ANT task. Furthermore, the oscillational sources for the ANT effects indicated that the alpha and theta bands were partly impaired in dementia patients. Conclusions: In summary, using source-localised EEG, we found that attention dysfunctions in LBD and AD engaged different neural networks. [ABSTRACT FROM AUTHOR]

Background: In multifactorial diseases, alterations in the concentration of metabolites can identify novel pathological mechanisms at the intersection between genetic and environmental influences. This study aimed to profile the plasma metabolome of patients with dementia with Lewy bodies (DLB) and Alzheimer’s disease (AD), two neurodegenerative disorders for which our understanding of the pathophysiology is incomplete. In the clinical setting, DLB is often mistaken for AD, highlighting a need for accurate diagnostic biomarkers. We therefore also aimed to determine the overlapping and differentiating metabolite patterns associated with each and establish whether identification of these patterns could be leveraged as biomarkers to support clinical diagnosis. Methods: A panel of 630 metabolites (Biocrates MxP Quant 500) and a further 232 metabolism indicators (biologically informative sums and ratios calculated from measured metabolites, each indicative for a specific pathway or synthesis; MetaboINDICATOR) were analyzed in plasma from patients with probable DLB (n  =  15; age 77.6  ±  8.2  years), probable AD (n  =  15; 76.1  ±  6.4  years), and age-matched cognitively healthy controls (HC; n  =  15; 75.2  ±  6.9  years). Metabolites were quantified using a reversed-phase ultraperformance liquid chromatography column and triple-quadrupole mass spectrometer in multiple reaction monitoring (MRM) mode, or by using flow injection analysis in MRM mode. Data underwent multivariate (PCA analysis), univariate and receiving operator characteristic (ROC) analysis. Metabolite data were also correlated (Spearman r) with the collected clinical neuroimaging and protein biomarker data. Results: The PCA plot separated DLB, AD and HC groups (R2  =  0.518, Q2  =  0.348). Significant alterations in 17 detected metabolite parameters were identified (q≤  0.05), including neurotransmitters, amino acids and glycerophospholipids. Glutamine (Glu; q  =  0.045) concentrations and indicators of sphingomyelin hydroxylation (q  =  0.039) distinguished AD and DLB, and these significantly correlated with semi-quantitative measurement of cardiac sympathetic denervation. The most promising biomarker differentiating AD from DLB was Glu:lysophosphatidylcholine (lysoPC a 24:0) ratio (AUC  =  0.92; 95%CI 0.809–0.996; sensitivity  =  0.90; specificity  =  0.90). Discussion: Several plasma metabolomic aberrations are shared by both DLB and AD, but a rise in plasma glutamine was specific to DLB. When measured against plasma lysoPC a C24:0, glutamine could differentiate DLB from AD, and the reproducibility of this biomarker should be investigated in larger cohorts. [ABSTRACT FROM AUTHOR]

Background: Blood biomarkers of Alzheimer's disease (AD) may allow for the early detection of AD pathology in mild cognitive impairment (MCI) due to AD (MCI-AD) and as a co-pathology in MCI with Lewy bodies (MCI-LB). However not all cases of MCI-LB will feature AD pathology. Disease-general biomarkers of neurodegeneration, such as glial fibrillary acidic protein (GFAP) or neurofilament light (NfL), may therefore provide a useful supplement to AD biomarkers. We aimed to compare the relative utility of plasma A β 42/40, p -tau181, GFAP and NfL in differentiating MCI-AD and MCI-LB from cognitively healthy older adults, and from one another. Methods: Plasma samples were analysed for 172 participants (31 healthy controls, 48 MCI-AD, 28 possible MCI-LB and 65 probable MCI-LB) at baseline, and a subset (n = 55) who provided repeated samples after ≥1 year. Samples were analysed with a Simoa 4-plex assay for A β 42, A β 40, GFAP and NfL, and incorporated previously-collected p -tau181 from this same cohort. Results: Probable MCI-LB had elevated GFAP (p < 0.001) and NfL (p = 0.012) relative to controls, but not significantly lower A β 42/40 (p = 0.06). GFAP and p -tau181 were higher in MCI-AD than MCI-LB. GFAP discriminated all MCI subgroups, from controls (AUC of 0.75), but no plasma-based marker effectively differentiated MCI-AD from MCI-LB. NfL correlated with disease severity and increased with MCI progression over time (p = 0.011). Conclusion: Markers of AD and astrocytosis/neurodegeneration are elevated in MCI-LB. GFAP offered similar utility to p -tau181 in distinguishing MCI overall, and its subgroups, from healthy controls. [ABSTRACT FROM AUTHOR]

Background: In recent years, MRS has benefited from increased MRI field strengths, new acquisition protocols and new processing techniques. This review aims to determine how this has altered our understanding of MRS neurometabolic markers in neurodegenerative dementias. Methods: Our systematic review of human in vivo MRS literature since 2002 pertains to Alzheimer's disease (AD), dementia with Lewy bodies (DLB), Parkinson's disease dementia, frontotemporal dementia (FTD), prodromal and 'at‐risk' states. Studies using field strengths of 3 T or more were included. Results: Of 85 studies, AD and/or mild cognitive impairment (MCI) were the most common conditions of interest (58 papers, 68%). Only 14 (16%) studies included other dementia syndromes and 13 (15%) investigated 'at‐risk' cohorts. Earlier findings of lower N‐acetylaspartate and higher myo‐inositol were confirmed. Additionally, lower choline and creatine in AD and MCI were reported, though inconsistently. Previously challenging‐to‐measure metabolites (glutathione, glutamate and gamma‐aminobutyric acid) were reportedly lower in AD, FTD and DLB compared with controls. Discussion: Increasing field strength alongside targeted acquisition protocols has revealed additional metabolite changes. Most studies were small and regional metabolite differences between dementia types may not have been captured due to the predominant placement of voxels in the posterior cingulate cortex. The standard of data collection, quality control and analysis is improving due to greater consensus regarding acquisition and processing techniques. Ongoing harmonization of techniques, creation of larger and longitudinal cohorts, and placement of MRS voxels in more diverse regions will strengthen future research. [ABSTRACT FROM AUTHOR]

Background and purpose: Mild cognitive impairment with Lewy bodies (MCI‐LB) is associated with a range of cognitive, motor, neuropsychiatric, sleep, autonomic, and visual symptoms. We investigated the cumulative frequency of symptoms in a longitudinal cohort of MCI‐LB compared with MCI due to Alzheimer disease (MCI‐AD) and analysed the ability of a previously described 10‐point symptom scale to differentiate MCI‐LB and MCI‐AD, in an independent cohort. Methods: Participants with probable MCI‐LB (n = 70), MCI‐AD (n = 51), and controls (n = 34) had a detailed clinical assessment and annual follow‐up (mean duration = 1.7 years). The presence of a range of symptoms was ascertained using a modified version of the Lewy Body Disease Association Comprehensive LBD Symptom Checklist at baseline assessment and then annually. Results: MCI‐LB participants experienced a greater mean number of symptoms (24.2, SD = 7.6) compared with MCI‐AD (11.3, SD = 7.4) and controls (4.2, SD = 3.1; p < 0.001 for all comparisons). A range of cognitive, parkinsonian, neuropsychiatric, sleep, and autonomic symptoms were significantly more common in MCI‐LB than MCI‐AD, although when present, the time of onset was similar between the two groups. A previously defined 10‐point symptom scale demonstrated very good discrimination between MCI‐LB and MCI‐AD (area under the receiver operating characteristic curve = 0.91, 95% confidence interval = 0.84–0.98), replicating our previous finding in a new cohort. Conclusions: MCI‐LB is associated with the frequent presence of a particular profile of symptoms compared to MCI‐AD. Clinicians should look for evidence of these symptoms in MCI and be aware of the potential for treatment. The presence of these symptoms may help to discriminate MCI‐LB from MCI‐AD. [ABSTRACT FROM AUTHOR]

Background: Previous studies have shown reduced survival in Lewy body dementia (LBD) compared to Alzheimer’s disease (AD), but the reasons for this are not known. We identified cause of death categories accounting for the reduced survival in LBD. Methods: We linked cohorts of patients with dementia with Lewy bodies (DLB), Parkinson’s disease dementia (PDD) and AD, with proximal cause of death data. We examined mortality by dementia group and hazard ratios for each death category by dementia group in males and females separately. In a specific focus on the dementia group with the highest mortality rate versus reference, we examined cumulative incidence to identify the main causes of death accounting for the excess deaths. Results: Hazard ratios for death were higher in PDD and DLB compared to AD, for both males and females. PDD males had the highest hazard ratio for death across the dementia comparison groups (HR 2.7, 95% CI 2.2–3.3). Compared with AD, hazard ratios for “nervous system” causes of death were significantly elevated in all LBD groups. Additional significant cause‐of‐death categories included aspiration pneumonia, genitourinary causes, other respiratory causes, circulatory and a “symptoms and signs” category in PDD males; other respiratory causes in DLB males; mental disorders in PDD females; and aspiration pneumonia, genitourinary and other respiratory causes in DLB females. Conclusion: Further research and cohort development is required to investigate differences by age group, to extend cohort follow‐up to the whole population and to investigate the risk‐balance of interventions which may differ by dementia group. [ABSTRACT FROM AUTHOR]

Drug repositioning and repurposing has proved useful in identifying new treatments for many diseases, which can then rapidly be brought into clinical practice. Currently, there are few effective pharmacological treatments for Lewy body dementia (which includes both dementia with Lewy bodies and Parkinson's disease dementia) apart from cholinesterase inhibitors. We reviewed several promising compounds that might potentially be disease-modifying agents for Lewy body dementia and then undertook an International Delphi consensus study to prioritise compounds. We identified ambroxol as the top ranked agent for repurposing and identified a further six agents from the classes of tyrosine kinase inhibitors, GLP-1 receptor agonists, and angiotensin receptor blockers that were rated by the majority of our expert panel as justifying a clinical trial. It would now be timely to take forward all these compounds to Phase II or III clinical trials in Lewy body dementia. [ABSTRACT FROM AUTHOR]

Objective: The present study aimed to clarify the neuropsychological profile of the emergent diagnostic category of Mild Cognitive Impairment with Lewy bodies (MCI-LB) and determine whether domain-specific impairments such as in memory were related to deficits in domain-general cognitive processes (executive function or processing speed). Method: Patients (n = 83) and healthy age- and sex-matched controls (n = 34) underwent clinical and imaging assessments. Probable MCI-LB (n = 44) and MCI-Alzheimer's disease (AD) (n = 39) were diagnosed following National Institute on Aging-Alzheimer's Association (NIA-AA) and dementia with Lewy bodies (DLB) consortium criteria. Neuropsychological measures included cognitive and psychomotor speed, executive function, working memory, and verbal and visuospatial recall. Results: MCI-LB scored significantly lower than MCI-AD on processing speed [Trail Making Test B: p =.03, g =.45; Digit Symbol Substitution Test (DSST): p =.04, g =.47; DSST Error Check: p <.001, g =.68] and executive function [Trail Making Test Ratio (A/B): p =.04, g =.52] tasks. MCI-AD performed worse than MCI-LB on memory tasks, specifically visuospatial (Modified Taylor Complex Figure: p =.01, g =.46) and verbal (Rey Auditory Verbal Learning Test: p =.04, g =.42) delayed recall measures. Stepwise discriminant analysis correctly classified the subtype in 65.1% of MCI patients (72.7% specificity, 56.4% sensitivity). Processing speed accounted for more group-associated variance in visuospatial and verbal memory in both MCI subtypes than executive function, while no significant relationships between measures were observed in controls (all ps >.05) Conclusions: MCI-LB was characterized by executive dysfunction and slowed processing speed but did not show the visuospatial dysfunction expected, while MCI-AD displayed an amnestic profile. However, there was considerable neuropsychological profile overlap and processing speed mediated performance in both MCI subtypes. [ABSTRACT FROM AUTHOR]

Visual hallucinations are a common feature of Lewy body dementia. Previous studies have shown that visual hallucinations are highly specific in differentiating Lewy body dementia from Alzheimer's disease dementia and Alzheimer-Lewy body mixed pathology cases. Computational models propose that impairment of visual and attentional networks is aetiologically key to the manifestation of visual hallucinations symptomatology. However, there is still a lack of experimental evidence on functional and structural brain network abnormalities associated with visual hallucinations in Lewy body dementia. We used EEG source localization and network based statistics to assess differential topographical patterns in Lewy body dementia between 25 participants with visual hallucinations and 17 participants without hallucinations. Diffusion tensor imaging was used to assess structural connectivity between thalamus, basal forebrain and cortical regions belonging to the functionally affected network component in the hallucinating group, as assessed with network based statistics. The number of white matter streamlines within the cortex and between subcortical and cortical regions was compared between hallucinating and not hallucinating groups and correlated with average EEG source connectivity of the affected subnetwork. Moreover, modular organization of the EEG source network was obtained, compared between groups and tested for correlation with structural connectivity. Network analysis showed that compared to non-hallucinating patients, those with hallucinations feature consistent weakened connectivity within the visual ventral network, and between this network and default mode and ventral attentional networks, but not between or within attentional networks. The occipital lobe was the most functionally disconnected region. Structural analysis yielded significantly affected white matter streamlines connecting the cortical regions to the nucleus basalis of Meynert and the thalamus in hallucinating compared to not hallucinating patients. The number of streamlines in the tract between the basal forebrain and the cortex correlated with cortical functional connectivity in non-hallucinating patients, while a correlation emerged for the white matter streamlines connecting the functionally affected cortical regions in the hallucinating group. This study proposes, for the first time, differential functional networks between hallucinating and not hallucinating Lewy body dementia patients, and provides empirical evidence for existing models of visual hallucinations. Specifically, the outcome of the present study shows that the hallucinating condition is associated with functional network segregation in Lewy body dementia and supports the involvement of the cholinergic system as proposed in the current literature. [ABSTRACT FROM AUTHOR]

Patients who have dementia with Lewy bodies and Alzheimer's disease show early degeneration of the cholinergic nucleus basalis of Meynert. However, how white matter projections between the nucleus basalis of Meynert and the cortex are altered in neurodegenerative disease is unknown. Tractography of white matter pathways originating from the nucleus basalis of Meynert was performed using diffusion-weighted imaging in 46 patients with Alzheimer's disease dementia, 48 with dementia with Lewy bodies, 35 with mild cognitive impairment with Alzheimer's disease, 38 with mild cognitive impairment with Lewy bodies and 71 control participants. Mean diffusivity of the resulting pathways was compared between groups and related to cognition, attention, functional EEG changes and dementia conversion in the mild cognitive impairment groups. We successfully tracked a medial and a lateral pathway from the nucleus basalis of Meynert. Mean diffusivity of the lateral pathway was higher in both dementia and mild cognitive impairment groups than controls (all P < 0.03). In the patient groups, increased mean diffusivity of this pathway was related to more impaired global cognition (β = -0.22, P = 0.06) and worse performance on an attention task (β = 0.30, P = 0.03). In patients with mild cognitive impairment, loss of integrity of both nucleus basalis of Meynert pathways was associated with increased risk of dementia progression [hazard ratio (95% confidence interval), medial pathway: 2.51 (1.24-5.09); lateral pathway: 2.54 (1.24-5.19)]. Nucleus basalis of Meynert volume was reduced in all clinical groups compared to controls (all P < 0.001), but contributed less strongly to cognitive impairment and was not associated with attention or dementia conversion. EEG slowing in the patient groups as assessed by a decrease in dominant frequency was associated with smaller nucleus basalis of Meynert volumes (β = 0.22, P = 0.02) and increased mean diffusivity of the lateral pathway (β = -0.47, P = 0.003). We show that degeneration of the cholinergic nucleus basalis of Meynert in Alzheimer's disease and dementia with Lewy bodies is accompanied by an early reduction in integrity of white matter projections that originate from this structure. This is more strongly associated with cognition and attention than the volume of the nucleus basalis of Meynert itself and might be an early indicator of increased risk of dementia conversion in people with mild cognitive impairment. [ABSTRACT FROM AUTHOR]

Background: Recently published diagnostic criteria for mild cognitive impairment with Lewy bodies (MCI-LB) include five neuropsychiatric supportive features (non-visual hallucinations, systematised delusions, apathy, anxiety and depression). We have previously demonstrated that the presence of two or more of these symptoms differentiates MCI-LB from MCI due to Alzheimer's disease (MCI-AD) with a likelihood ratio >4. The aim of this study was to replicate the findings in an independent cohort. Methods: Participants ⩾60 years old with MCI were recruited. Each participant had a detailed clinical, cognitive and imaging assessment including FP-CIT SPECT and cardiac MIBG. The presence of neuropsychiatric supportive symptoms was determined using the Neuropsychiatric Inventory (NPI). Participants were classified as MCI-AD, possible MCI-LB and probable MCI-LB based on current diagnostic criteria. Participants with possible MCI-LB were excluded from further analysis. Results: Probable MCI-LB (n = 28) had higher NPI total and distress scores than MCI-AD (n = 30). In total, 59% of MCI-LB had two or more neuropsychiatric supportive symptoms compared with 9% of MCI-AD (likelihood ratio 6.5, p < 0.001). MCI-LB participants also had a significantly greater delayed recall and a lower Trails A:Trails B ratio than MCI-AD. Conclusions: MCI-LB is associated with significantly greater neuropsychiatric symptoms than MCI-AD. The presence of two or more neuropsychiatric supportive symptoms as defined by MCI-LB diagnostic criteria is highly specific and moderately sensitive for a diagnosis of MCI-LB. The cognitive profile of MCI-LB differs from MCI-AD, with greater executive and lesser memory impairment, but these differences are not sufficient to differentiate MCI-LB from MCI-AD. [ABSTRACT FROM AUTHOR]

Background and purpose: Lewy body dementia (LBD), including dementia with Lewy bodies (DLB) and Parkinson's disease dementia, is a common form of neurodegenerative dementia. The frequency and influence of comorbid cerebrovascular disease is not understood but has potentially important clinical management implications. Methods: A systematic literature search was conducted (MEDLINE and Embase) for studies including participants with DLB and/or Parkinson's disease dementia assessing cerebrovascular lesions (imaging and pathological studies). They included white matter changes, cerebral amyloid angiopathy, cerebral microbleeds (CMB), macroscopic infarcts, microinfarcts and intracerebral haemorrhage. Results: Of 4411 articles, 63 studies were included. Cerebrovascular lesions commonly studied included white matter changes (41 studies) and CMB (18 studies). There was an increased severity of white matter changes on magnetic resonance imaging (visualized as white matter hyperintensities), but not neuropathology, in LBD compared to Parkinson's disease without dementia and age‐matched controls. CMB prevalence in DLB was highly variable but broadly similar to Alzheimer's disease (0%–48%), with a lobar predominance. No relationship was found between large cortical or small subcortical infarcts or intracerebral haemorrhage and the presence of LBD. Conclusion: The underlying mechanisms of white matter hyperintensities in LBD require further exploration, as their increased severity in LBD was not supported by neuropathological examination of white matter. CMB in LBD had a similar prevalence to Alzheimer's disease. There is a need for larger studies assessing the influence of cerebrovascular lesions on clinical symptoms, disease progression and outcomes. [ABSTRACT FROM AUTHOR]

Objectives: Autonomic symptoms are a common feature of the synucleinopathies, and may be a distinguishing feature of prodromal Lewy body disease. We aimed to assess whether the cognitive prodrome of dementia with Lewy bodies, mild cognitive impairment (MCI) with Lewy bodies (MCI-LB), would have more severe reported autonomic symptoms than cognitively healthy older adults, with MCI due to Alzheimer's disease (MCI-AD) also included for comparison. We also aimed to assess the utility of an autonomic symptom scale in differentiating MCI-LB from MCI-AD.Methods: Ninety-three individuals with MCI and 33 healthy controls were assessed with the Composite Autonomic Symptom Score 31-item scale (COMPASS). Mild cognitive impairment patients also underwent detailed clinical assessment and differential classification of MCI-AD or MCI-LB according to current consensus criteria. Differences in overall COMPASS score and individual symptom sub-scales were assessed, controlling for age.Results: Age-adjusted severity of overall autonomic symptomatology was greater in MCI-LB (Ratio = 2.01, 95% CI: 1.37-2.96), with higher orthostatic intolerance and urinary symptom severity than controls, and greater risk of gastrointestinal and secretomotor symptoms. MCI-AD did not have significantly higher autonomic symptom severity than controls overall. A cut-off of 4/5 on the COMPASS was sensitive to MCI-LB (92%) but not specific to this (42% specificity vs. MCI-AD and 52% vs. healthy controls).Conclusions: Mild cognitive impairment with Lewy bodies had greater autonomic symptom severity than normal ageing and MCI-AD, but such autonomic symptoms are not a specific finding. The COMPASS-31 may therefore have value as a sensitive screening test for early-stage Lewy body disease. [ABSTRACT FROM AUTHOR]

Background: Mild cognitive impairment (MCI) may gradually worsen to dementia, but often remains stable for extended periods of time. Little is known about the predictors of decline to help explain this variation. We aimed to explore whether this heterogeneous course of MCI may be predicted by the presence of Lewy body (LB) symptoms in a prospectively-recruited longitudinal cohort of MCI with Lewy bodies (MCI-LB) and Alzheimer's disease (MCI-AD). Methods: A prospective cohort (n = 76) aged ⩾60 years underwent detailed assessment after recent MCI diagnosis, and were followed up annually with repeated neuropsychological testing and clinical review of cognitive status and LB symptoms. Latent class mixture modelling identified data-driven sub-groups with distinct trajectories of global cognitive function. Results: Three distinct trajectories were identified in the full cohort: slow/stable progression (46%), intermediate progressive decline (41%) and a small group with a much faster decline (13%). The presence of LB symptomology, and visual hallucinations in particular, predicted decline v. a stable cognitive trajectory. With time zeroed on study end (death, dementia or withdrawal) where available (n = 39), the same subgroups were identified. Adjustment for baseline functioning obscured the presence of any latent classes, suggesting that baseline function is an important parameter in prospective decline. Conclusions: These results highlight some potential signals for impending decline in MCI; poorer baseline function and the presence of probable LB symptoms – particularly visual hallucinations. Identifying people with a rapid decline is important but our findings are preliminary given the modest cohort size. [ABSTRACT FROM AUTHOR]

Objectives: Previous research has identified that dementia with Lewy bodies (DLB) has abnormal pareidolic responses which are associated with severity of visual hallucinations (VH), and the pareidolia test accurately classifies DLB with VH. We aimed to assess whether these findings would also be evident at the earlier stage of mild cognitive impairment (MCI) with Lewy bodies (MCI‐LB) in comparison to MCI due to AD (MCI‐AD) and cognitively healthy comparators. Methods: One‐hundred and thirty‐seven subjects were assessed prospectively in a longitudinal study with a mean follow‐up of 1.2 years (max = 3.7): 63 MCI‐LB (22% with VH) and 40 MCI‐AD according to current research diagnostic criteria, and 34 healthy comparators. The pareidolia test was administered annually as a repeated measure. Results: Probable MCI‐LB had an estimated pareidolia rate 1.2–6.7 times higher than MCI‐AD. Pareidolia rates were not associated with concurrent VH, but had a weak association with total score on the North East Visual Hallucinations Inventory. The pareidolia test was not an accurate classifier of either MCI‐LB (Area under curve (AUC) = 0.61), or VH (AUC = 0.56). There was poor sensitivity when differentiating MCI‐LB from controls (41%) or MCI‐AD (27%), though specificity was better (91% and 89%, respectively). Conclusions: Whilst pareidolic responses are specifically more frequent in MCI‐LB than MCI‐AD, sensitivity of the pareidolia test is poorer than in DLB, with fewer patients manifesting VH at the earlier MCI stage. However, the high specificity and ease of use may make it useful in specialist clinics where imaging biomarkers are not available. Key Points: Pareidolia responses to ambiguous visual stimuli may be a surrogate for visual hallucinationsPareidolias are more common in dementia with Lewy bodies than in Alzheimer's disease (AD)We found an increased rate of pareidolias in mild cognitive impairment (MCI) with Lewy bodies than in AD or healthy comparatorsMisperceptions in the pareidolia test are reasonably specific to MCI with Lewy bodies, but these may lack sensitivity at early stages [ABSTRACT FROM AUTHOR]

Objectives: Dementia with Lewy bodies (DLB) is a major cause of degenerative dementia, yet the diagnosis is often missed or mistaken for Alzheimer's disease (AD). We assessed whether the revised Addenbrooke's Cognitive Examination (ACE‐R), a brief test for dementia, differentiates DLB from AD. Methods: We first compared baseline ACE‐R performance in 76 individuals with DLB, 40 individuals with AD and 66 healthy controls. We then investigated the diagnostic accuracy of a simple standardised 'memory/visuospatial' ratio calculated from the ACE‐R subscores. Finally, as a comparison a logistic regression machine learning algorithm was trained to classify between DLB and AD. Results: Individuals with AD had poorer memory (p = 0.001) and individuals with DLB had poorer visuospatial function (p = 0.005). Receiver operating characteristics curves confirmed that the ACE‐R total score could differentiate dementia from non‐dementia cases with 98% accuracy, but could not discriminate between dementia types (50%, or chance‐level accuracy). However, a 'memory/visuospatial' ratio ≥1.1 differentiated DLB from AD with 82% sensitivity, 68% specificity and 77% mean accuracy. The machine learning classifier did not improve the overall diagnostic accuracy (74%) of the simple ACE‐R subscores ratio. Conclusions: The ACE‐R‐based 'memory/visuospatial' ratio, but not total score, demonstrates good clinical utility for the differential diagnosis of DLB from AD. [ABSTRACT FROM AUTHOR]

Background: Dopaminergic imaging is an established biomarker for dementia with Lewy bodies, but its diagnostic accuracy at the mild cognitive impairment (MCI) stage remains uncertain.Aims: To provide robust prospective evidence of the diagnostic accuracy of dopaminergic imaging at the MCI stage to either support or refute its inclusion as a biomarker for the diagnosis of MCI with Lewy bodies.Method: We conducted a prospective diagnostic accuracy study of baseline dopaminergic imaging with [123I]N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane single-photon emission computerised tomography (123I-FP-CIT SPECT) in 144 patients with MCI. Images were rated as normal or abnormal by a panel of experts with access to striatal binding ratio results. Follow-up consensus diagnosis based on the presence of core features of Lewy body disease was used as the reference standard.Results: At latest assessment (mean 2 years) 61 patients had probable MCI with Lewy bodies, 26 possible MCI with Lewy bodies and 57 MCI due to Alzheimer's disease. The sensitivity of baseline FP-CIT visual rating for probable MCI with Lewy bodies was 66% (95% CI 52-77%), specificity 88% (76-95%) and accuracy 76% (68-84%), with positive likelihood ratio 5.3.Conclusions: It is over five times as likely for an abnormal scan to be found in probable MCI with Lewy bodies than MCI due to Alzheimer's disease. Dopaminergic imaging appears to be useful at the MCI stage in cases where Lewy body disease is suspected clinically. [ABSTRACT FROM AUTHOR]

Objective: To use arterial spin labelling to investigate differences in perfusion in mild cognitive impairment with Lewy bodies (MCI-LB) compared to Alzheimer type MCI (MCI-AD) and healthy controls. Methods: We obtained perfusion images on 32 MCI-LB, 30 MCI-AD and 28 healthy subjects of similar age. Perfusion relative to cerebellum was calculated, and we aimed to examine differences in relative perfusion between MCI-LB and the other groups. This included whole brain voxelwise comparisons, as well as using predefined region-of-interest ratios of medial occipital to medial temporal, and posterior cingulate to precuneus. Differences in occipital perfusion in eyes open vs eyes closed conditions were also examined. Results: Compared to controls, the MCI-LB showed reduced perfusion in the precuneus, parietal, occipital and fusiform gyrus regions. In our predefined regions, the ratio of perfusion in occipital/medial temporal was significantly lower, and the posterior cingulate/precuneus ratio was significantly higher in MCI-LB compared to controls. Overall, the occipital perfusion was greater in the eyes open vs closed condition, but this did not differ between groups. Conclusion: We found patterns of altered perfusion in MCI-LB which are similar to those seen in dementia with Lewy bodies, with reduction in posterior parietal and occipital regions, but relatively preserved posterior cingulate. [ABSTRACT FROM AUTHOR]

Background: Lewy body dementia, comprising both dementia with Lewy bodies and Parkinson's disease dementia, is challenging to manage because of a complex symptom profile and lack of clear evidence‐based management guidelines. Objectives: We assessed the feasibility of undertaking a cluster randomized study of the introduction of an evidence‐based management toolkit for Lewy body dementia, assessing the outcomes for patients and carers as secondary measures. Methods: We randomized 23 memory/dementia, movement disorder, or nonspecialist secondary care services to the management toolkit or usual care. People with dementia with Lewy bodies or Parkinson's disease dementia underwent assessments of cognition, motor and neuropsychiatric symptoms, and global outcome at baseline and 3 and 6 months. Healthcare, personal and social care costs, and carer‐related outcomes of carer stress, depression, and anxiety were also examined. Results: A total of 131 participants were recruited (target 120), for whom 6‐month data were available on 108 (83%). There was a benefit of being in the intervention arm for carers (reduced Zarit Burden Scale [P < 0.01], reduced depressive symptoms [P < 0.05]), who also reported less marked patient deterioration on the global outcome measure (P < 0.05). There were no significant differences in other outcomes or in costs between groups. Conclusions: The introduction of an evidence‐based management toolkit for Lewy body dementia was feasible and associated with some benefits, especially for carers. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

Objective: Dementia with Lewy bodies (DLB) is a common cause of dementia, but atrophy is mild compared to Alzheimer's disease. We propose that DLB is associated instead with severe synaptic loss, and we test this hypothesis in vivo using positron emission tomography (PET) imaging of 11C-UCB-J, a ligand for presynaptic vesicle protein 2A (SV2A), a vesicle membrane protein ubiquitously expressed in synapses. Methods: We performed 11C-UCB-J PET in two DLB patients (an amyloid-negative male and an amyloid-positive female in their 70s) and 10 similarly aged healthy controls. The DLB subjects also underwent PET imaging of amyloid (11C-PiB) and tau (18F-AV-1451). 11C-UCB-J binding was quantified using non-displaceable binding potential (BPND) determined from dynamic imaging. Changes in 11C-UCB-J binding were correlated with MRI regional brain volume, 11C-PiB uptake and 18F-AV-1451 binding. Results: Compared to controls, both patients had decreased 11C-UCB-J binding, especially in parietal and occipital regions (FDR-corrected p < 0.05). There were no significant correlations across regions between 11C-UCB-J binding and grey matter, tau (18F-AV1451) or amyloid (11C-PiB) in either patient. Conclusions: Quantitative imaging of in vivo synaptic density in DLB is a promising approach to understanding the mechanisms of DLB, over and above changes in grey matter volume and concurrent amyloid/tau deposition. [ABSTRACT FROM AUTHOR]

The physical, cognitive and neuropsychiatric challenges associated with dementia with Lewy bodies make people particularly vulnerable to COVID-19. Dementia with Lewy bodies (DLB) represents at least 4.2% of community-based dementia, and 7.5% of cases in clinical dementia populations.5 Under-diagnosis is however common, meaning the true figure is likely to be higher.6 This form of dementia presents with several distinct cognitive, neuropsychiatric, sleep, autonomic and motor symptoms. Compared with AD, caregiver burden in family caregivers of people with DLB is rated 30% higher on the Relative Stress Scale35 and a major depressive disorder in the caregiver is significantly more likely.36 The COVID-19 pandemic is likely to create multiple further difficulties. Diagnosis and management of dementia with Lewy bodies: fourth consensus report of the DLB consortium. [Extracted from the article]

Objectives: We conducted a prospective longitudinal study of plasma cytokines during the Mild Cognitive Impairment (MCI) stage of Lewy body disease and Alzheimer's disease, hypothesizing that cytokine levels would decrease over time and that this would be correlated with decline in cognition.Methods: Older (≥60) people with MCI were recruited from memory services in healthcare trusts in North East England, UK. MCI was diagnosed as due to Alzheimer's disease (MCI-AD) or Lewy body disease (MCI-LB). Baseline and repeat annual clinical and cognitive assessments were undertaken and plasma samples were obtained at the same time. Cytokine assays were performed on all samples using the Meso Scale Discovery V-Plex Plus Proinflammatory Panel 1, which included IFNγ, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13 and TNFα.Results: Fifty-six patients (21 MCI-AD, 35 MCI-LB) completed prospective evaluations and provided samples up to 3 years after baseline. Six cytokines (IFNγ, IL-1β, IL-2, IL-4, IL-6 and IL-10) showed highly significant (P < .002) decreases over time. AD and LB did not differ in rate of decrease nor were there any effects related to age or general morbidity. Decrease in five of these cytokines (IFNγ, IL-1β, IL-2, IL-4, and IL-10) was highly correlated with decrease in cognition (P < .003).Conclusions: Peripheral inflammation decreased in both disease groups during MCI suggesting this may be a therapeutic window for future anti-inflammatory agents. [ABSTRACT FROM AUTHOR]

Background: Regional cerebral hypoperfusion is characteristic of Alzheimer's disease (AD). Previous studies report conflicting findings in cognitively normal individuals at high risk of AD. Understanding early preclinical perfusion alterations may improve understanding of AD pathogenesis and lead to new biomarkers and treatment targets.Methods: 3T arterial spin labelling MRI scans from 162 participants in the PREVENT-Dementia cohort were analysed (cognitively normal participants aged 40-59, stratified by future dementia risk). Cerebral perfusion was compared vertex-wise according to APOE ε4 status and family history (FH). Correlations between individual perfusion, age and cognitive scores (COGNITO battery) were explored.Results: Regional hyperperfusion was found in APOE ε4+group (left cingulate and lateral frontal and parietal regions p<0.01, threshold-free cluster enhancement, TFCE) and in FH +group (left temporal and parietal regions p<0.01, TFCE). Perfusion did not correlate with cognitive test scores.Conclusions: Regional cerebral hyperperfusion in individuals at increased risk of AD in mid-life may be a very early marker of functional brain change related to AD. Increased perfusion may reflect a functional 'compensation' mechanism, offsetting the effects of early neural damage or may itself be risk factor for accelerating spread of degenerative pathology. [ABSTRACT FROM AUTHOR]

Background: We investigated the structural changes associated with Alzheimer's disease, dementia with Lewy bodies and Parkinson disease dementia by means of cortical thickness analysis. Methods: Two hundred and forty-five participants: 76 Alzheimer's disease, 65 dementia with Lewy bodies, 29 Parkinson disease dementia and 76 cognitively normal controls underwent 3-T T1-weighted magnetic resonance imaging and clinical and cognitive assessments. We implemented FreeSurfer to obtain cortical thickness estimates to contrast patterns of cortical thinning across groups and their clinical correlates. Results: In Alzheimer's disease and dementia with Lewy bodies, a largely similar pattern of regional cortical thinning was observed relative to controls apart from a more severe loss within the entorhinal and parahippocampal structures in Alzheimer's disease. In Parkinson disease dementia, regional cortical thickness was indistinguishable from controls and dementia with Lewy bodies, suggesting an 'intermediate' pattern of regional cortical change. In terms of global cortical thickness, group profiles were controls > Parkinson disease dementia > dementia with Lewy bodies > Alzheimer's disease (F3, 241 ⩽ 123.2, p < 0.001), where percentage wise, the average difference compared to controls were −1.8%, −5.5% and −6.4%, respectively. In these samples, cortical thinning was also associated with cognitive decline in dementia with Lewy bodies but not in Parkinson disease dementia and Alzheimer's disease. Conclusion: In a large and well-characterised cohort of people with dementia, regional cortical thinning in dementia with Lewy bodies was broadly similar to Alzheimer's disease. There was preservation of the medial temporal lobe structures in dementia with Lewy bodies compared with Alzheimer's disease, supporting its inclusion as a supportive biomarker in the revised clinical criteria for dementia with Lewy bodies. However, there was less global cortical thinning in Parkinson disease dementia, with no significant regional difference between Parkinson disease dementia and controls. These findings highlight the overlap across the Alzheimer's disease/Parkinson disease dementia spectrum and the potential for differing mechanisms underlying neurodegeneration and cognition in dementia with Lewy bodies and Parkinson disease dementia. [ABSTRACT FROM AUTHOR]

Background: Lewy body dementia (LBD), which includes dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD), is characterised by marked deficits within the cholinergic system which are more severe than in Alzheimer's disease (AD) and are mainly caused by degeneration of the nucleus basalis of Meynert (NBM) whose widespread cholinergic projections provide the main source of cortical cholinergic innervation. EEG alpha reactivity, which refers to the reduction in alpha power over occipital electrodes upon opening the eyes, has been suggested as a potential marker of cholinergic system integrity. Methods: Eyes-open and eyes-closed resting state EEG data were recorded from 41 LBD patients (including 24 patients with DLB and 17 with PDD), 21 patients with AD, and 40 age-matched healthy controls. Alpha reactivity was calculated as the relative reduction in alpha power over occipital electrodes when opening the eyes. Structural MRI data were used to assess volumetric changes within the NBM using a probabilistic anatomical map. Results: Alpha reactivity was reduced in AD and LBD patients compared to controls with a significantly greater reduction in LBD compared to AD. Reduced alpha reactivity was associated with smaller volumes of the NBM across all groups (ρ = 0.42, pFDR = 0.0001) and in the PDD group specifically (ρ = 0.66, pFDR = 0.01). Conclusions: We demonstrate that LBD patients show an impairment in alpha reactivity upon opening the eyes which distinguishes this form of dementia from AD. Furthermore, our results suggest that reduced alpha reactivity might be related to a loss of cholinergic drive from the NBM, specifically in PDD. [ABSTRACT FROM AUTHOR]

The diagnosis of dementia with Lewy bodies (DLB) versus Alzheimer's disease (AD) can be difficult especially early in the disease process. However, one inexpensive and non‐invasive biomarker which could help is electroencephalography (EEG). Previous studies have shown that the brain network architecture assessed by EEG is altered in AD patients compared with age‐matched healthy control people (HC). However, similar studies in Lewy body diseases, that is, DLB and Parkinson's disease dementia (PDD) are still lacking. In this work, we (a) compared brain network connectivity patterns across conditions, AD, DLB and PDD, in order to infer EEG network biomarkers that differentiate between these conditions, and (b) tested whether opting for weighted matrices led to more reliable results by better preserving the topology of the network. Our results indicate that dementia groups present with reduced connectivity in the EEG α band, whereas DLB shows weaker posterior–anterior patterns within the β‐band and greater network segregation within the θ‐band compared with AD. Weighted network measures were more consistent across global thresholding levels, and the network properties reflected reduction in connectivity strength in the dementia groups. In conclusion, β‐ and θ‐band network measures may be suitable as biomarkers for discriminating DLB from AD, whereas the α‐band network is similarly affected in DLB and PDD compared with HC. These variations may reflect the impairment of attentional networks in Parkinsonian diseases such as DLB and PDD. [ABSTRACT FROM AUTHOR]

Background: The peak width of skeletonized mean diffusivity (PSMD) has been proposed as a fully automated imaging marker of relevance to cerebral small vessel disease (SVD). We assessed PSMD in relation to conventional SVD markers, global measures of neurodegeneration, and cognition. Methods: 145 participants underwent 3T brain MRI and cognitive assessment. 112 were patients with mild cognitive impairment, Alzheimer's disease, progressive supranuclear palsy, dementia with Lewy bodies, or frontotemporal dementia. PSMD, SVD burden [white matter hyperintensities (WMH), enlarged perivascular spaces (EPVS), microbleeds, lacunes], average mean diffusivity (MD), gray matter (GM), white matter (WM), and total intracranial volume were quantified. Robust linear regression was conducted to examine associations between variables. Dominance analysis assessed the relative importance of markers in predicting various outcomes. Regional analyses examined spatial overlap between PSMD and WMH. Results: PSMD was associated with global and regional SVD measures, especially WMH and microbleeds. Dominance analysis demonstrated that among SVD markers, WMH was the strongest predictor of PSMD. Furthermore, PSMD was more closely associated to WMH than with GM and WM volumes. PSMD was associated with WMH across all regions, and correlations were not significantly stronger in corresponding regions (e.g., frontal PSMD and frontal WMH) compared to non-corresponding regions. PSMD outperformed all four conventional SVD markers and MD in predicting cognition, but was comparable to GM and WM volumes. Discussion: PSMD was robustly associated with established SVD markers. This new measure appears to be a marker of diffuse brain injury, largely due to vascular pathology, and may be a useful and convenient metric of overall cerebrovascular burden. [ABSTRACT FROM AUTHOR]

An introduction is presented in which the editor discusses several articles published within issue on topics related to recognition and diagnosis of Lewy body dementia.

Background: Inflammation appears to play a role in the progression of neurodegenerative diseases. However, little is known about inflammation during early stages of cognitive decline or whether this differs in different disease groups. We sought to investigate this by assessing the inflammatory profile in patients with Parkinson disease with the early stages of cognitive impairment (PD-MCI), patients with prodromal Alzheimer disease (MCI-AD), prodromal Lewy body disease (MCI-LB), and controls.Methods: We obtained venous blood samples from participants with PD-MCI (n = 44), PD-normal cognition (n = 112), MCI-LB (n = 38), MCI-AD (n = 21), and controls (n = 84). We measured 10 cytokines using Meso Scale Discovery V-Plex Plus including interferon gamma, interleukin (IL)-10, IL-12p70, IL-13, IL-1beta, IL-2, IL-4, IL-6, IL-8, and tumour necrosis factor alpha. High-sensitivity C-reactive protein was measured.Results: There was a higher level of inflammation in patients with MCI-AD and MCI-LB compared with controls. PD noncognitively impaired had higher inflammatory markers than controls, but there was no difference between PD-MCI and controls. There was a decrease in inflammatory markers with increasing motor severity based on the Unified Parkinson's Disease Rating Scale.Conclusions: Inflammation may be involved in the onset of cognitive decline in patients with MCI-AD and MCI-LB but appears to be less prominent PD-MCI albeit in a small data set. This suggests that anti-inflammatory medications may have most benefit at the earliest stages of neurodegenerative diseases. For PD cases, this might be in advance of the development of MCI. [ABSTRACT FROM AUTHOR]

Background: Lewy body dementia (LBD) and Alzheimer's disease (AD) are common forms of degenerative dementia. While they are characterized by different clinical profiles, attentional deficits are a common feature. The objective of this study was to investigate how attentional problems in LBD and AD differentially affect different aspects of reaction time performance and to identify possible structural neural correlates. Methods: We studied reaction time data from an attention task comparing 39 LBD patients, 28 AD patients, and 22 age-matched healthy controls. Data were fitted to an ex-Gaussian model to characterize different facets of the reaction time distribution (mean reaction time, reaction time variability, and the subset of extremely slow responses). Correlations between ex-Gaussian parameters and grey and white matter volume were assessed by voxel-based morphometry. Results: Both dementia groups showed an increase in extremely slow responses. While there was no difference between AD and controls with respect to mean reaction time and variability, both were significantly increased in LBD patients compared to controls and AD. There were widespread correlations between mean reaction time and variability and grey matter loss in AD, but not in LBD. Conclusions: This study shows that different aspects of reaction time performance are differentially affected by AD and LBD, with a difference in structural neural correlates underlying the observed behavioural deficits. While impaired attentional performance is linked to brain atrophy in AD, in LBD it might be related to functional or microstructural rather than macrostructural changes. [ABSTRACT FROM AUTHOR]

Introduction: Lewy body disease is postulated, by the Braak model, to originate in the enteric nervous system, before spreading to the central nervous system. Therefore, a high prevalence of gastroparesis symptoms would be expected in prodromal dementia with Lewy bodies (DLB) and be highest in those with a dopaminergic deficit on imaging. The aim of this study was to explore whether gastroparesis symptoms are an early diagnostic marker of prodromal DLB and explore the relationship between symptoms and dopaminergic imaging findings on FP-CIT SPECT.Methods: We recruited 75 patients over 60 with mild cognitive impairment (MCI), 48 with MCI with suspected Lewy body disease (MCI-LB) and 27 with MCI with suspected Alzheimer's disease (MCI-AD). All patients completed the Gastroparesis Cardinal Symptom Index (GSCI) questionnaire and also underwent FP-CIT [123 I-N-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)] dopaminergic imaging.Results: At least one symptom suggestive of gastroparesis was reported in 48% (n = 23) MCI-LB vs 37% MCI-AD (n = 10) (P = 0.36). Rates of definite symptoms of gastroparesis, as defined by a GCSI total score ≥ 1.90, were rare and rates in MCI-LB were not different from MCI-AD (6% vs 0%, p = 0.55). After adjusting for gender differences between groups, no difference in gastroparesis symptom prevalence (2.27 vs 0.81 P = 0.05) or severity score (0.62 vs 0.28, p = 0.28) was noted between normally and abnormally visually rated FP-CIT SPECT scans.Conclusion: The GCSI is not a useful tool for differentiating MCI-LB from MCI-AD. A low rate of definite gastroparesis was detected in prodromal DLB. No association was found between gastroparesis symptoms and FP-CIT SPECT findings. [ABSTRACT FROM AUTHOR]

Lewy body dementia includes dementia with Lewy bodies and Parkinson's disease dementia and is characterized by transient clinical symptoms such as fluctuating cognition, which might be driven by dysfunction of the intrinsic dynamic properties of the brain. In this context we investigated whole-brain dynamics on a subsecond timescale in 42 Lewy body dementia compared to 27 Alzheimer's disease patients and 18 healthy controls using an EEG microstate analysis in a cross-sectional design. Microstates are transiently stable brain topographies whose temporal characteristics provide insight into the brain's dynamic repertoire. Our additional aim was to explore what processes in the brain drive microstate dynamics. We therefore studied associations between microstate dynamics and temporal aspects of large-scale cortical-basal ganglia-thalamic interactions using dynamic functional MRI measures given the putative role of these subcortical areas in modulating widespread cortical function and their known vulnerability to Lewy body pathology. Microstate duration was increased in Lewy body dementia for all microstate classes compared to Alzheimer's disease (P < 0.001) and healthy controls (P < 0.001), while microstate dynamics in Alzheimer's disease were largely comparable to healthy control levels, albeit with altered microstate topographies. Correspondingly, the number of distinct microstates per second was reduced in Lewy body dementia compared to healthy controls (P < 0.001) and Alzheimer's disease (P < 0.001). In the dementia with Lewy bodies group, mean microstate duration was related to the severity of cognitive fluctuations (ρ = 0.56, PFDR = 0.038). Additionally, mean microstate duration was negatively correlated with dynamic functional connectivity between the basal ganglia (r = - 0.53, P = 0.003) and thalamic networks (r = - 0.38, P = 0.04) and large-scale cortical networks such as visual and motor networks in Lewy body dementia. The results indicate a slowing of microstate dynamics and disturbances to the precise timing of microstate sequences in Lewy body dementia, which might lead to a breakdown of the intricate dynamic properties of the brain, thereby causing loss of flexibility and adaptability that is crucial for healthy brain functioning. When contrasted with the largely intact microstate dynamics in Alzheimer's disease, the alterations in dynamic properties in Lewy body dementia indicate a brain state that is less responsive to environmental demands and might give rise to the apparent slowing in thinking and intermittent confusion which typify Lewy body dementia. By using Lewy body dementia as a probe pathology we demonstrate a potential link between dynamic functional MRI fluctuations and microstate dynamics, suggesting that dynamic interactions within the cortical-basal ganglia-thalamic loop might play a role in the modulation of EEG dynamics. [ABSTRACT FROM AUTHOR]

The hippocampus has a critical role in cognition and human memory and is one of the most studied structures in the brain. Despite more than 400 years of research, little is known about the Ammon's horn region cornu ammonis 2 (CA2) subfield in comparison to other subfield regions (CA1, CA3, and CA4). Recent findings have shown that CA2 plays a bigger role than previously thought. Here, we review understanding of hippocampus and CA2 ontogenesis, together with basic and clinical findings about the potential role of this region in neurodegenerative disease. The CA2 has widespread anatomical connectivity, unique signaling molecules, and intrinsic electrophysiological properties. Experimental studies using in vivo models found that the CA2 region has a role in cognition, especially in social memory and object recognition. In models of epilepsy and hypoxia, the CA2 exhibits higher resilience to cell death and hypoxia in comparison with neighboring regions, and while hippocampal atrophy remains poorly understood in Parkinson's disease (PD) and dementia with Lewy bodies (DLB), findings from postmortem PD brain demonstrates clear accumulation of α-synuclein pathology in CA2, and the CA2-CA3 region shows relatively more atrophy compared with other hippocampal subfields. Taken together, there is a growing body of evidence suggesting that the CA2 can be an ideal hallmark with which to differentiate different neurodegenerative stages of PD. Here, we summarize these recent data and provide new perspectives/ideas for future investigations to unravel the contribution of the CA2 to neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Positron emission tomography (PET) with radiotracers that bind to synaptic vesicle glycoprotein 2 A (SV2A) enables quantification of synaptic density in the living human brain. Assessing the regional distribution and severity of synaptic density loss will contribute to our understanding of the pathological processes that precede atrophy in neurodegeneration. In this systematic review, we provide a discussion of in vivo SV2A PET imaging research for quantitative assessment of synaptic density in various dementia conditions: amnestic Mild Cognitive Impairment and Alzheimer's disease, Frontotemporal dementia, Progressive supranuclear palsy and Corticobasal degeneration, Parkinson's disease and Dementia with Lewy bodies, Huntington's disease, and Spinocerebellar Ataxia. We discuss the main findings concerning group differences and clinical-cognitive correlations, and explore relations between SV2A PET and other markers of pathology. Additionally, we touch upon synaptic density in healthy ageing and outcomes of radiotracer validation studies. Studies were identified on PubMed and Embase between 2018 and 2023; last searched on the 3rd of July 2023. A total of 36 studies were included, comprising 5 on normal ageing, 21 clinical studies, and 10 validation studies. Extracted study characteristics were participant details, methodological aspects, and critical findings. In summary, the small but growing literature on in vivo SV2A PET has revealed different spatial patterns of synaptic density loss among various neurodegenerative disorders that correlate with cognitive functioning, supporting the potential role of SV2A PET imaging for differential diagnosis. SV2A PET imaging shows tremendous capability to provide novel insights into the aetiology of neurodegenerative disorders and great promise as a biomarker for synaptic density reduction. Novel directions for future synaptic density research are proposed, including (a) longitudinal imaging in larger patient cohorts of preclinical dementias, (b) multi-modal mapping of synaptic density loss onto other pathological processes, and (c) monitoring therapeutic responses and assessing drug efficacy in clinical trials. • SV2A PET enables quantification of synaptic density in the living human brain. • Topology of synaptic density loss differs among various neurodegenerative disorders. • Synaptic density loss links to disease-related in cognitive decline. • SV2A PET imaging is a promising biomarker for synaptic density loss. [ABSTRACT FROM AUTHOR]

Visual hallucinations are common in dementia with Lewy bodies (DLB), although their etiology is unclear. This study aimed to investigate the relationship between severity and frequency of hallucinations and regional brain glucose metabolism. We performed brain FDG-PET scanning on 28 subjects with DLB (mean age 76). The neuropsychiatric index (NPI) was used to assess frequency and severity of hallucinations. We used the SPM package to investigate voxelwise correlations between NPI hallucination score (severity x frequency) and FDG uptake relative to the cerebellum. There was a bilateral medial occipital region where reduced FDG was associated with increased hallucination severity and frequency. We conclude that the reduced occipital metabolism frequently seen in DLB is associated with frequency and severity of visual hallucinations. Further studies are required to investigate whether this is the result of deficits in top-down or bottom-up visual processing pathways. [ABSTRACT FROM AUTHOR]

Dementia with Lewy bodies (DLB) is the underlying aetiology of 10-15% of all cases of dementia and as such is a clinically important diagnosis. In the past few years, substantial advances have been made in understanding the genetics and pathology of this condition. For example, research has expanded our knowledge of the proteinaceous inclusions that characterize the disease, has provided an appreciation of the role of disease-associated processes such as inflammation and has revealed an association between DLB and genes such as GBA. These insights might have broader relevance to other neurodegenerative conditions and are beginning to be translated into clinical trials. In this Review, we provide clinical insights for the basic scientist and a basic science foundation for the clinician. We discuss the history of the condition; the definition of DLB; the relationship between DLB and other neurodegenerative conditions; current understanding of the pathology, genetics, clinical presentation and diagnosis of DLB; options for treatment; and potential future directions for research. [ABSTRACT FROM AUTHOR]

Background: Dopaminergic imaging has high diagnostic accuracy for dementia with Lewy bodies (DLB) at the dementia stage. We report the first investigation of dopaminergic imaging at the prodromal stage. Methods: We recruited 75 patients over 60 with mild cognitive impairment (MCI), 33 with probable MCI with Lewy body disease (MCI-LB), 15 with possible MCI-LB and 27 with MCI with Alzheimer's disease. All underwent detailed clinical, neurological and neuropsychological assessments and FP-CIT [123I-N-fluoropropyl-2 β -carbomethoxy-3 β -(4-iodophenyl)] dopaminergic imaging. FP-CIT scans were blindly rated by a consensus panel and classified as normal or abnormal. Results: The sensitivity of visually rated FP-CIT imaging to detect combined possible or probable MCI-LB was 54.2% [95% confidence interval (CI) 39.2–68.6], with a specificity of 89.0% (95% CI 70.8–97.6) and a likelihood ratio for MCI-LB of 4.9, indicating that FP-CIT may be a clinically important test in MCI where any characteristic symptoms of Lewy body (LB) disease are present. The sensitivity in probable MCI-LB was 61.0% (95% CI 42.5–77.4) and in possible MCI-LB was 40.0% (95% CI 16.4–67.7). Conclusions: Dopaminergic imaging had high specificity at the pre-dementia stage and gave a clinically important increase in diagnostic confidence and so should be considered in all patients with MCI who have any of the diagnostic symptoms of DLB. As expected, the sensitivity was lower in MCI-LB than in established DLB, although over 50% still had an abnormal scan. Accurate diagnosis of LB disease is important to enable early optimal treatment for LB symptoms. [ABSTRACT FROM AUTHOR]

Background: Dementia with Lewy bodies (DLB) is the second most common degenerative dementia in older people. However, rates of misdiagnosis are high, and little is known of its natural history and outcomes. Very few previous studies have been able to access routine clinical information for large, unbiased DLB cohorts in order to establish initial presentation, neuropsychological profile, and mortality.Objective: To examine in detail, symptom patterns at presentation and their association with outcomes, including mortality, in a large naturalistic DLB cohort from a secondary care sample.Methods: A retrospective cohort design was used to identify a DLB cohort (n = 251) from Cambridgeshire and Peterborough NHS Foundation Trust (CPFT). Information relating to first consultation, diagnosis, and DLB diagnostic features were extracted.Results: A wide range of presenting complaints and differential initial diagnoses were identified for the cohort. Along with memory loss (27.1%) and hallucinations (25.4%), low mood (25.1%) was noted as a key presenting complaint among the DLB cohort. Rates of REM sleep disorder were considerably lower (8.4%) than would be expected. Deficits in non-amnestic cognitive domains were associated with reduced mortality compared with amnestic-only presentations.Conclusion: Individuals later diagnosed with DLB present initially to secondary care with a wide range of symptoms and complaints, some of which are not immediately suggestive of a DLB diagnosis. More examinations of large cohorts such as this are needed to further elucidate the complex presentation and clinical course of DLB, and to confirm whether amnestic-only presentation confers a worse outcome. [ABSTRACT FROM AUTHOR]