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Background: Predicting which individuals may convert to dementia from mild cognitive impairment (MCI) remains difficult in clinical practice. Electroencephalography (EEG) is a widely available investigation but there is limited research exploring EEG connectivity differences in patients with MCI who convert to dementia. Methods: Participants with a diagnosis of MCI due to Alzheimer's disease (MCI‐AD) or Lewy body disease (MCI‐LB) underwent resting state EEG recording. They were followed up annually with a review of the clinical diagnosis (n = 66). Participants with a diagnosis of dementia at year 1 or year 2 follow up were classed as converters (n = 23) and those with a diagnosis of MCI at year 2 were classed as stable (n = 43). We used phase lag index (PLI) to estimate functional connectivity as well as analysing dominant frequency (DF) and relative band power. The Network‐based statistic (NBS) toolbox was used to assess differences in network topology. Results: The converting group had reduced DF (U = 285.5, p = 0.005) and increased relative pre‐alpha power (U = 702, p = 0.005) consistent with previous findings. PLI showed reduced average beta band synchrony in the converting group (U = 311, p = 0.014) as well as significant differences in alpha and beta network topology. Logistic regression models using regional beta PLI values revealed that right central to right lateral (Sens = 56.5%, Spec = 86.0%, −2LL = 72.48, p = 0.017) and left central to right lateral (Sens = 47.8%, Spec = 81.4%, −2LL = 71.37, p = 0.012) had the best classification accuracy and fit when adjusted for age and MMSE score. Conclusion: Patients with MCI who convert to dementia have significant differences in EEG frequency, average connectivity and network topology prior to the onset of dementia. The MCI group is clinically heterogeneous and have underlying physiological differences that may be driving the progression of cognitive symptoms. EEG connectivity could be useful to predict which patients with MCI‐AD and MCI‐LB convert to dementia, regardless of the neurodegenerative aetiology. [ABSTRACT FROM AUTHOR]

Background: Multimorbidity, the presence of two or more health conditions, has been identified as a possible risk factor for clinical dementia. It is unclear whether this is due to worsening brain health and underlying neuropathology, or other factors. In some cases, conditions may reflect the same disease process as dementia (e.g. Parkinson's disease, vascular disease), in others, conditions may reflect a prodromal stage of dementia (e.g. depression, anxiety and psychosis). Aims: To assess whether multimorbidity in later life was associated with more severe dementia-related neuropathology at autopsy. Method: We examined ante-mortem and autopsy data from 767 brain tissue donors from the UK, identifying physical multimorbidity in later life and specific brain-related conditions. We assessed associations between these purported risk factors and dementia-related neuropathological changes at autopsy (Alzheimer's-disease related neuropathology, Lewy body pathology, cerebrovascular disease and limbic-predominant age-related TDP-43 encephalopathy) with logistic models. Results: Physical multimorbidity was not associated with greater dementia-related neuropathological changes. In the presence of physical multimorbidity, clinical dementia was less likely to be associated with Alzheimer's disease pathology. Conversely, conditions which may be clinical or prodromal manifestations of dementia-related neuropathology (Parkinson's disease, cerebrovascular disease, depression and other psychiatric conditions) were associated with dementia and neuropathological changes. Conclusions: Physical multimorbidity alone is not associated with greater dementia-related neuropathological change; inappropriate inclusion of brain-related conditions in multimorbidity measures and misdiagnosis of neurodegenerative dementia may better explain increased rates of clinical dementia in multimorbidity [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]

Age‐related hearing loss frequently precedes or coexists with mild cognitive impairment and dementia. The role specific neuropathologies play in this association, as either a cause or a consequence, is unclear. We therefore aimed to investigate whether specific dementia related neuropathologies were associated with hearing impairment in later life. We analysed data on ante‐mortem hearing impairment with post‐mortem neuropathological data for 442 participants from the Brains for Dementia Research Cohort. Binary logistic regression models were used to estimate the association of hearing impairment with the presence of each dementia‐related neuropathology overall, and with specific staged changes. All analyses adjusted for age and sex, and several sensitivity analyses were conducted to test the robustness of findings. Presence and density of neuritic plaques were associated with higher odds of hearing impairment ante‐mortem (OR = 3.65, 95% CI 1.78–7.46 for frequent density of plaques). Presence of any LB disease was likewise associated with hearing impairment (OR = 2.10, 95% CI 1.27–3.48), but this did not increase with higher cortical pathology (OR = 1.53, 95% CI 0.75–3.11). Nonspecific amyloid deposition, neurofibrillary tangle staging, overall AD neuropathology level, and cerebrovascular disease were not clearly associated with increased risks of hearing impairment. Our results provide some support for an association between dementia‐related neuropathology and hearing loss and suggest that hearing loss may be associated with a high neuritic plaque burden and more common in Lewy body disease. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Degeneration of cortical cholinergic projections from the nucleus basalis of Meynert (NBM) is characteristic of dementia with Lewy bodies (DLB) and Alzheimer's disease (AD), whereas involvement of cholinergic projections from the pedunculopontine nucleus (PPN) to the thalamus is less clear. METHODS: We studied both cholinergic projection systems using a free water‐corrected diffusion tensor imaging (DTI) model in the following cases: 46 AD, 48 DLB, 35 mild cognitive impairment (MCI) with AD, 38 MCI with Lewy bodies, and 71 controls. RESULTS: Free water in the NBM‐cortical pathway was increased in both dementia and MCI groups compared to controls and associated with cognition. Free water along the PPN‐thalamus tract was increased only in DLB and related to visual hallucinations. Results were largely replicated in an independent cohort. DISCUSSION: While NBM‐cortical projections degenerate early in AD and DLB, the thalamic cholinergic input from the PPN appears to be more selectively affected in DLB and might associate with visual hallucinations. Highlights: Free water in the NBM‐cortical cholinergic pathways is increased in AD and DLB.NBM‐cortical pathway integrity is related to overall cognitive performance.Free water in the PPN‐thalamus cholinergic pathway is only increased in DLB, not AD.PPN‐thalamus pathway integrity might be related to visual hallucinations in DLB. [ABSTRACT FROM AUTHOR]

Background: Promoting physical activity, such as habitual walking behaviors, in people with cognitive impairment may support their ability to remain independent with a good quality of life for longer. However, people with cognitive impairment participate in less physical activity compared to cognitively unimpaired older adults. The local area in which people live may significantly impact abilities to participate in physical activity. For example, people who live in more deprived areas may have less safe and walkable routes. Objective: To examine this further, this study aimed to explore associations between local area deprivation and physical activity in people with cognitive impairment and cognitively unimpaired older adults (controls). Methods: 87 participants with cognitive impairment (mild cognitive impairment or dementia) and 27 older adult controls from the North East of England were included in this analysis. Participants wore a tri-axial wearable accelerometer (AX3, Axivity) on their lower backs continuously for seven days. The primary physical activity outcome was daily step count. Individuals' neighborhoods were linked to UK government area deprivation statistics. Hierarchical Bayesian models assessed the association between local area deprivation and daily step count in people with cognitive impairment and controls. Results: Key findings indicated that there was no association between local area deprivation and daily step count in people with cognitive impairment, but higher deprivation was associated with lower daily steps for controls. Conclusion: These findings suggest that cognitive impairment may be associated with lower participation in physical activity which supersedes the influence of local area deprivation observed in normal aging. [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: The early degeneration of the cholinergic nucleus basalis of Meynert (NBM) and its cortical projections is a hallmark of both dementia with Lewy bodies (DLB) and Alzheimer's disease (AD). In addition to the NBM, the other major cholinergic projection system originates in the pedunculopontine nucleus (PPN) and provides innervation to the thalamus. Given that visual hallucinations are a hallmark of DLB, but not AD, and have recently been attributed to thalamic degeneration, we tested whether the PPN projection system is differentially altered in DLB compared to AD. Methods: NBM‐cortical and PPN‐thalamus white matter pathways were tracked using diffusion‐weighted imaging data from 46 patients with AD, 48 with DLB, 35 with mild cognitive impairment (MCI) with AD, 38 with MCI with Lewy bodies, and 71 control participants. A free‐water corrected DTI model was estimated. Free water fraction along the cholinergic pathways was compared between groups controlling for age, sex, and free water fraction from a white matter control mask. Multiple linear regression was applied to test associations with cognitive function, core Lewy body symptoms with a focus on visual hallucinations, and changes in cognition using longitudinal follow‐up data. Results: Free water fraction in the NBM lateral pathway was increased in both dementia and MCI groups compared to controls and this was associated with performance on overall cognition and phonemic fluency tests as well as with longitudinal changes in cognition (Figure 1). Free water fraction along the PPN‐thalamus tract was increased only in DLB patients while it appeared relatively spared in AD and this increase in the Lewy body patients was related to the presence of visual hallucinations (Figure 2). These results were largely replicated in an independent validation cohort (34 AD, 34 DLB, 35 controls). Conclusion: Our cross‐validated findings show that the cholinergic input to the thalamus from the PPN is selectively affected in DLB and contributes to visual hallucinations. [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]

Background: Alzheimer's disease (AD) co‐pathology is common in dementia with Lewy bodies and is associated with increased decline. Plasma pTau181 is a blood‐based biomarker that can detect AD co‐pathology. Objectives: We investigated whether pTau181 was associated with cognitive decline in mild cognitive impairment with Lewy bodies (MCI‐LB) and MCI with AD (MCI‐AD). Methods: We assessed plasma pTau181 using a single‐molecule array (Simoa) immunoassay at baseline and follow‐up in a longitudinal cohort of MCI‐LB, MCI‐AD, and controls. Results: One hundred forty‐six subjects (56 probable MCI‐LB, 22 possible MCI‐LB, 44 MCI‐AD, and 24 controls) were reviewed for up to 5.7 years. Probable MCI‐LB had significantly higher pTau181 (22.2% mean increase) compared with controls and significantly lower (24.4% mean decrease) levels compared with MCI‐AD. Receiver operating characteristic analyses of pTau181 in discriminating probable MCI‐LB from controls showed an area under the curve (AUC) of 0.68 (83% specificity, 57% sensitivity); for discriminating MCI‐AD from healthy controls, AUC was 0.8 (83.3% specificity, 72.7% sensitivity). pTau181 concentration was less useful in discriminating between probable MCI‐LB and MCI‐AD: AUC of 0.64 (71.4% specificity, 52.3% sensitivity). There was an association between pTau181 and cognitive decline in MCI‐AD but not in MCI‐LB. In a subset with repeat samples there was a nonsignificant 3% increase per follow‐up year in plasma pTau181. The rate of change in pTau181 was not significantly different in different diagnostic subgroups. Conclusions: pTau181 was not associated with an increased decline assessed using either baseline or repeat pTau181. pTau181 partially discriminated probable MCI‐LB from controls and MCI‐AD from controls but was not useful in distinguishing probable MCI‐LB from MCI‐AD. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

Objectives: Impaired olfaction may be a biomarker for early Lewy body disease, but its value in mild cognitive impairment with Lewy bodies (MCI-LB) is unknown. We compared olfaction in MCI-LB with MCI due to Alzheimer's disease (MCI-AD) and healthy older adults. We hypothesized that olfactory function would be worse in probable MCI-LB than in both MCI-AD and healthy comparison subjects (HC). Design: Cross-sectional study assessing olfaction using Sniffin' Sticks 16 (SS-16) in MCI-LB, MCI-AD, and HC with longitudinal follow-up. Differences were adjusted for age, and receiver operating characteristic (ROC) curves were used for discriminating MCI-LB from MCI-AD and HC. Setting: Participants were recruited from Memory Services in the North East of England. Participants: Thirty-eight probable MCI-LB, 33 MCI-AD, 19 possible MCI-LB, and 32HC. Measurements: Olfaction was assessed using SS-16 and a questionnaire. Results: Participants with probable MCI-LB had worse olfaction than both MCI-AD (age-adjusted mean difference (B) = 2.05, 95% CI: 0.62–3.49, p = 0.005) and HC (B = 3.96, 95% CI: 2.51–5.40, p < 0.001). The previously identified cutoff score for the SS-16 of ≤ 10 had 84% sensitivity for probable MCI-LB (95% CI: 69–94%), but 30% specificity versus MCI-AD. ROC analysis found a lower cutoff of ≤ 7 was better (63% sensitivity for MCI-LB, with 73% specificity vs MCI-AD and 97% vs HC). Asking about olfactory impairments was not useful in identifying them. Conclusions: MCI-LB had worse olfaction than MCI-AD and normal aging. A lower cutoff score of ≤ 7 is required when using SS-16 in such patients. Olfactory testing may have value in identifying early LB disease in memory services. [ABSTRACT FROM AUTHOR]

Objectives: Orthostatic hypotension is a common feature of normal ageing, and age-related neurodegenerative diseases, in particular the synucleinopathies including dementia with Lewy bodies. Orthostatic hypotension and other abnormal cardiovascular responses may be early markers of Lewy body disease. We aimed to assess whether abnormal blood pressure and heart rate responses to orthostatic challenge and Valsalva manoeuvre would be more common in mild cognitive impairment with Lewy bodies (MCI-LB) than MCI due to Alzheimer's disease (MCI-AD).Methods: MCI patients (n = 89) underwent longitudinal clinical assessment with differential classification of probable MCI-LB, possible MCI-LB, or MCI-AD, with objective autonomic function testing at baseline. Blood pressure and heart rate responses to active stand and Valsalva manoeuvre were calculated from beat-to-beat cardiovascular data, with abnormalities defined by current criteria, and age-adjusted group differences estimated with logistic models.Results: Orthostatic hypotension and abnormal heart rate response to orthostatic challenge were not more common in probable MCI-LB than MCI-AD. Heart rate abnormalities were likewise not more common in response to Valsalva manoeuvre in probable MCI-LB. An abnormal blood pressure response to Valsalva (delayed return to baseline/absence of overshoot after release of strain) was more common in probable MCI-LB than MCI-AD. In secondary analyses, magnitude of blood pressure drop after active stand and 10-s after release of Valsalva strain were weakly correlated with cardiac sympathetic denervation.Conclusions: Probable MCI-LB may feature abnormal blood pressure response to Valsalva, but orthostatic hypotension is not a clear distinguishing feature from MCI-AD. [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]

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]

Electroencephalographic (EEG) abnormalities are greater in mild cognitive impairment (MCI) with Lewy bodies (MCI-LB) than in MCI due to Alzheimer's disease (MCI-AD) and may anticipate the onset of dementia. We aimed to assess whether quantitative EEG (qEEG) slowing would predict a higher annual hazard of dementia in MCI across these etiologies. MCI patients (n = 92) and healthy comparators (n = 31) provided qEEG recording and underwent longitudinal clinical and cognitive follow-up. Associations between qEEG slowing, measured by increased theta/alpha ratio, and clinical progression from MCI to dementia were estimated with a multistate transition model to account for death as a competing risk, while controlling for age, cognitive function, and etiology classified by an expert consensus panel.Over a mean follow-up of 1.5 years (SD = 0.5), 14 cases of incident dementia and 5 deaths were observed. Increased theta/alpha ratio on qEEG was associated with increased annual hazard of dementia (hazard ratio = 1.84, 95% CI: 1.01-3.35). This extends previous findings that MCI-LB features early functional changes, showing that qEEG slowing may anticipate the onset of dementia in prospectively identified MCI. [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]

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]

Background: Mobility‐related ambulatory activity (e.g., walking) is essential to healthy cognitive and functional ageing. Wearable technology (e.g., accelerometers/inertial measurement units; IMUs) allows us to objectively and continuously capture digital mobility outcomes (DMOs), e.g. volume, pattern and variability of walking activities. Continuous digital mobility assessment has been shown as feasible and acceptable to older adults with and without dementia. However, interpretation of DMOs is limited as we do not yet understand the impact of different social and environmental contexts on walking activity. For example, DMOs may be influenced by the volume of walking that one's partner participates in, or by the walkability of their local area. Understanding the impact of social and environmental contexts on DMOs will support development of socio‐ecological strategies to support mobility in ageing. We aim to conduct a feasibility study in older adults with the following objectives: (1). Objectively assess DMOs in older adult dyads using digital mobility tools (i.e., IMUs/GPS); (2). Identify key social and environmental influences on DMOs through mixed‐methods exploration; (3). Develop a novel analytical approach combining DMOs with GPS data to assess independence/interdependence in dyads' walking activities. Method: We will recruit 20 older adult dyads in North‐East England for an observational cross‐sectional study. Walking activities will be recorded continuously for seven days using an IMU attached to participants' lower backs. DMOs include volume (e.g., daily steps), pattern (e.g. mean bout length) and variability (of bout length) of walking activities. Simultaneously, participants will carry a GPS device (i.e., smartphone) to monitor excursions outside the home. Questionnaires will capture information on cognition, function, falls risk, exercise motivation, wellbeing, relationship mutuality, spatial navigation, and walkability of local area. Participants will complete a "mobility diary" for the assessment period (e.g., daily journeys, motivations/perceptions/familiarity of journeys). Result: Preliminary results will be presented regarding associations between social/environmental contexts with DMOs via flexible Bayesian statistical models and thematic qualitative analysis. Conclusion: This study will assess the feasibility of the protocol and analysis strategies, with intentions of developing further research to examine the impact of social and environmental influences on DMOs in people with dementia and their carers. [ABSTRACT FROM AUTHOR]

Background: Depression and cognition have a complex bidirectional relationship in adulthood and later life. This association is likely heterogeneous, differing between individuals. Further complicating this association is the possible influence of unseen neuropathological changes: any associations between depression and cognitive symptoms may differ in normal and pathological ageing. We therefore aimed to examine the longitudinal coupling between depressive and cognitive symptoms in later life across multiple ageing cohorts drawing from population settings, memory services, and from a national dementia brain bank. Method: Repeated data on cognitive performance and self‐ or informant‐reported depressive symptoms were drawn from multiple cohorts: three population ageing studies, CFAS (n = 17,807), Whitehall II (n = 8249) and ELSA (n = 17,980); MEMENTO (n = 2306), a clinical cohort of people with subjective/mild cognitive impairment (S/MCI); BDR (n = 584), a clinico‐pathological cohort with autopsy‐confirmed dementia‐related neurological disease. Intercept and growth parameters for depressive and cognitive symptoms, and correlations between these, were estimated with bivariate latent growth models. Result: The relationships between depressive and cognitive symptoms differed substantially between cohorts across the ageing continuum. In early ageing and S/MCI, worse cognitive performance was associated with worsening depression over time (r = 0.12, p = 0.022), whereas in clinical dementia groups and those with autopsy‐confirmed neurological disease, worse cognitive performance was associated with improving depression over time (r = ‐0.30, p = 0.008 and r = ‐0.49, p = 0.023, respectively). Conclusion: Age‐related associations between cognitive and depressive symptoms may differ between specific ageing populations. When attempting to understand the relationship between depressive and cognitive trajectories, researchers should consider the position of the given sample along this healthy‐pathological ageing continuum. [ABSTRACT FROM AUTHOR]

Background: Blood‐based biomarkers of Alzheimer's disease (AD) may help to rule AD in, with particular promise at the mild cognitive impairment (MCI) stage when potential disease‐modifying treatments may be most effective. However, AD is not the only common cause of cognitive impairment: Lewy body disease and other non‐AD pathologies are common and under‐recognised. Reliance on AD‐specific biomarkers alone may therefore contribute to missed diagnosis of non‐AD aetiologies. We aimed to examine the utility of emerging AD plasma biomarkers in identifying disease‐specific MCI due to AD (MCI‐AD), MCI with Lewy bodies (MCI‐LB) and in disease‐general MCI. We also aimed to compare these with alternative disease‐general biomarkers of neurodegeneration, and examined any change over time. Method: In a longitudinal study, plasma samples were collected 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 Simoa assays for Alzheimer's disease (Aβ42, Aβ40, ptau‐181) and neurodegeneration (GFAP and NfL) biomarkers. MCI cases were differentially classified as MCI‐AD or MCI‐LB by an expert panel of old age psychiatrists, based on current consensus diagnostic criteria, and including Lewy body disease‐specific imaging biomarkers. Age‐adjusted mixed effects models assessed any longitudinal changes over time in each biomarker, and associations with severity of cognitive impairment as assessed by the Addenbrooke's Cognitive Examination – Revised. Result: GFAP performed comparably to AD‐specific biomarkers in identifying any‐cause MCI (GFAP AUC = 0.75; ptau‐181 = 0.73), while maintaining good accuracy in identifying MCI‐AD specifically. AD biomarkers did not reliably distinguish MCI‐AD from MCI‐LB. Severity of cognitive impairment in any‐cause MCI and MCI‐AD was most strongly correlated with the disease‐nonspecific neurodegenerative biomarker NfL (r = 0.48, p = 0.005; cf. GFAP r = 0.23, p = 0.121), which progressively increased over time. Conclusion: Given the high prevalence of unrecognised non‐AD pathologies at autopsy (>1/3 cases in UK brain banks), blood biomarkers of neurodegeneration may be a useful alternative to AD‐specific biomarkers in screening for neurodegenerative disease in MCI. As AD biomarkers do not reliably differentiate MCI‐AD from MCI‐LB, there is a need for disease‐specific biomarkers of synucleinopathies. [ABSTRACT FROM AUTHOR]

Background: Neuropsychiatric symptoms are a common feature of many dementia syndromes, and are frequently associated with poor clinical prognosis, reduction in quality of life, earlier institutionalisation, greater disability, and increased caregiver distress, particularly during later stages of disease. It has also been postulated that NPS may occur during prodromal stages of dementia, preceding or alongside early cognitive symptoms. Clinical profiles of dementia are both heterogenous and intersecting, which may reflect that up to 90% of cases have multiple pathologies post‐mortem. Comprehensive clinicopathological studies of neuropsychiatric symptoms in dementia are lacking, thus this study sought to investigate potential neuropsychiatric profiles resulting from mixed underlying pathology. Method: This analysis aimed to identify pathological correlations of neuropsychiatric symptoms and included 840 post‐mortem brains donated to the Brains for Dementia Research project, a longitudinal study with post‐mortem neuropathological assessment across several brain banks, between 2008 and 2020. Patterns of neuropsychiatric symptoms were compared between pathology subtypes using clinical data including the Neuropsychiatric Inventory (NPI‐Q) and Clinical Dementia Rating scale, and neuropathological assessment of degenerative pathologies and vascular features. Confirmatory factor analysis was used to identify latent variables for psychosis, mood, and behaviour. Associations between pathological variables assessed at autopsy and neuropsychiatric features during life were explored using bivariate and multivariate statistical methods. Result: Almost 80% of the 494 dementia cases included had at least one neuropsychiatric symptom across the course of disease. Apathy (51.2%) and aggression (41.7%) were the most prevalent neuropsychiatric features across all dementia subtypes. Preliminary results indicate that different underlying pathologies, including neurodegenerative pathologies (amyloid, neurofibrillary tangles, Lewy bodies, TDP‐43 inclusions) and vascular features may be associated with increased likelihood of specific neuropsychiatric symptoms, such as psychosis, mood and behaviour, during life. Co‐occurring substantial AD and Lewy body pathology was associated with the presence of anxiety, depression, and aberrant motor activity during life. AD in the absence of substantial Lewy body pathology, was associated with agitation, apathy, and disinhibition. Lewy body pathology, in the absence of substantial AD pathology, was associated with hallucinations, depression and sleep disturbances. Conclusion: The interaction of multiple pathologies may contribute to differing neuropsychiatric profiles during life. [ABSTRACT FROM AUTHOR]

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]

Leading theory hypothesizes that age deficits in decision making may rise as the complexity of decision-related information increases. This suggests that older adults would benefit relative to young adults from simplification of information used to inform decision making. Participants indicated political, nutritional and medical preferences and then chose between politicians, foods and medicines. The amount of information presented was systematically varied but age differences were largely similar for simple and complex trials. Paradoxically, the data showed that decisions based on simpler information could be less aligned with participant's preferences than decisions based on more complex information. Further analyses suggested that participants may have been responding purely on the basis of their most valued preferences and that when information about those preferences was not presented, decision making became poorer. Contrary to our expectations, simplification of information by exclusion may therefore hinder decision making and may not particularly help older adults. [ABSTRACT FROM AUTHOR]

Background: Empowering people with cognitive impairment (PwCI) to maintain physical activity (PA) supports functional independence. PwCI participate in less PA than recommended; disease‐specific factors (e.g. cognitive changes) do not sufficiently explain this. In older adults, most habitual PA takes place in the home or local neighbourhoods. Targeting PA in both the home and local community may be more impactful than creating external opportunities (e.g. exercise classes). Regular participation in PA requires time, money, security, and access. Area deprivation may contribute to inequalities in PA participation through environmental factors; less deprived areas may have safer walkable routes and more immediate socialisation opportunities which support PA. Understanding the complex relationship between local area deprivation and PA may support personalised care for PwCI. We aimed to explore associations between local area deprivation in the North East of England and PA in PwCI and cognitively‐intact older adults (controls). Method: We recruited 82 PwCI (mild cognitive impairment, dementia) and 26 controls. Daily step count was measured using an accelerometer worn on the lower back continuously for seven days. We derived mean daily step counts for each individual day. Individuals' neighbourhoods were linked to UK government area deprivation statistics. Hierarchical Bayesian models assessed the association between area deprivation and daily step count in PwD and healthy older adults. Result: Preliminary results indicated that greater area deprivation is associated with lower daily steps for cognitively‐healthy older adults (12,308 (8,302‐19,111) steps/day for controls in least deprived areas, vs 9,349 (5,178‐17,444) steps/day in most deprived areas), but not for PwCI (9,018 (7,042‐11,565) steps/day for PwCI in least deprived areas vs 9,124 (6,553‐12,435) steps/day in most deprived areas), who had consistently low step counts across neighbourhoods (Figure 1). Conclusion: Cognitive impairment may impose a barrier to maintenance of habitual PA which supersedes the positive or negative influences of area deprivation on PA in cognitively healthy older adults. Findings are limited by lack of regional diversity and statistical power; further research should examine area deprivation across the whole of the UK to ensure accurate representation of area deprivation. PA interventions should consider multiple socio‐ecological factors, including personal, organisational, environmental and policy‐related components. [ABSTRACT FROM AUTHOR]

Background: Visual hallucinations (VH) are a common symptom in dementia with Lewy bodies (DLB); however, their cognitive underpinnings remain unclear. Hallucinations have been related to cognitive slowing in DLB and may arise due to impaired sensory input, dysregulation in top-down influences over perception, or an imbalance between the two, resulting in false visual inferences. Methods: Here we employed a drift diffusion model yielding estimates of perceptual encoding time, decision threshold, and drift rate of evidence accumulation to (i) investigate the nature of DLB-related slowing of responses and (ii) their relationship to visuospatial performance and visual hallucinations. The EZ drift diffusion model was fitted to mean reaction time (RT), accuracy and RT variance from two-choice reaction time (CRT) tasks and data were compared between groups of mild cognitive impairment (MCI-LB) LB patients (n = 49) and healthy older adults (n = 25). Results: No difference was detected in drift rate between patients and controls, but MCI-LB patients showed slower non-decision times and boundary separation values than control participants. Furthermore, non-decision time was negatively correlated with visuospatial performance in MCI-LB, and score on visual hallucinations inventory. However, only boundary separation was related to clinical incidence of visual hallucinations. Conclusions: These results suggest that a primary impairment in perceptual encoding may contribute to the visuospatial performance, however a more cautious response strategy may be related to visual hallucinations in Lewy body disease. Interestingly, MCI-LB patients showed no impairment in information processing ability, suggesting that, when perceptual encoding was successful, patients were able to normally process information, potentially explaining the variability of hallucination incidence. [ABSTRACT FROM AUTHOR]

Clinical parkinsonism is a core diagnostic feature for mild cognitive impairment with Lewy bodies (MCI-LB) but can be challenging to identify. A five-item scale derived from the Unified Parkinson's Disease Rating Scale (UPDRS) has been recommended for the assessment of parkinsonism in dementia. This study aimed to determine whether the five-item scale is effective to identify parkinsonism in MCI. Participants with MCI from two cohorts (n = 146) had a physical examination including the UPDRS and [123I]-FP-CIT SPECT striatal dopaminergic imaging. Participants were classified as having clinical parkinsonism (P+) or no parkinsonism (P-), and with abnormal striatal dopaminergic imaging (D+) or normal imaging (D-). The five-item scale was the sum of UPDRS tremor at rest, bradykinesia, action tremor, facial expression, and rigidity scores. The ability of the scale to differentiate P+D+ and P-D- participants was examined. The five-item scale had an AUROC of 0.92 in Cohort 1, but the 7/8 cut-off defined for dementia had low sensitivity to identify P+D+ participants (sensitivity 25%, specificity 100%). Optimal sensitivity and specificity was obtained at a 3/4 cut-off (sensitivity 83%, specificity 88%). In Cohort 2, the five-item scale had an AUROC of 0.97, and the 3/4 cut-off derived from Cohort 1 showed sensitivity of 100% and a specificity of 82% to differentiate P+D+ from P-D- participants. The five-item scale was not effective in differentiating D+ from D- participants. The five-item scale is effective to identify parkinsonism in MCI, but a lower threshold must be used in MCI compared with dementia. • A five-item scale derived from the UPDRS can help identify parkinsonism in dementia. • The scale was tested in mild cognitive impairment (MCI). • It accurately identified MCI with parkinsonism and abnormal dopaminergic imaging. • A lower threshold is required in MCI compared with dementia. • The scale may help identify parkinsonism in clinical and research settings. [ABSTRACT FROM AUTHOR]