INTRODUCTION:Predicting conversion to dementia in mild cognitive impairment with Lewy bodies (MCI-LB) remains challenging. Furthermore, there is limited research combining predictive markers in MCI-LB. We explored the utility of Lewy body and Alzheimer's disease biomarkers for the prediction of future decline in MCI-LB. METHODS:Eighty-seven participants were included (35 MCI-AD, 15 possible MCI-LB, 37 probable MCI-LB). Baseline assessment involved MRI, EEG, bloods and cognitive testing. Follow up was completed yearly with review of diagnosis and repeat cognitive testing. We evaluated the relationship between baseline biomarkers and dementia-free survival time. We also investigated biomarker effects on future cognitive decline using annualised change in ACE-R. The value of combining biomarkers with baseline cognitive test score was assessed using forward selection. RESULTS:In probable MCI-LB, shorter dementia-free survival time was strongly associated with smaller hippocampal volume (hazard ratio = 2.36, 95% CI 1.41 - 3.94) and smaller posterior cortical volume (hazard ratio = 2.62, 95% CI 1.35 - 5.10). Reduced EEG dominant frequency, increased relative delta and theta power, reduced insula volume, increased plasma tau, and increased plasma GFAP were also associated with an increased hazard ratio. Posterior atrophy, hippocampal atrophy, and GFAP were significant predictors of ACE-R decline. Combining blood and MRI biomarkers improved model quality for dementia-free survival (GFAP and hippocampal atrophy) and cognitive test decline (AB ratio and posterior atrophy). CONCLUSION:Blood, EEG and MRI biomarkers of dementia with Lewy bodies, neurodegeneration and Alzheimer's co-pathology demonstrate utility for prognosis in MCI-LB. Combining biomarkers across modalities improves prognostic accuracy.

Alzheimer's disease (AD) is neuropathologically defined by deposits of misfolded hyperphosphorylated tau (HP-tau) and amyloid-β. Lewy body (LB) dementia, which includes dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD), is characterized pathologically by α-synuclein aggregates. HP-tau and amyloid-β can also occur as co-pathologies in LB dementia, and a diagnosis of mixedAD/DLB can be made if present in sufficient quantities. We hypothesized that the spread of these abnormal proteins selectively affects vulnerable areas, resulting in pathologic regional covariance that differentially associates with pre-mortem clinical characteristics. Our aims were to map regional quantitative pathology (HP-tau, amyloid-β, α-synuclein) and investigate the spatial distributions from tissue microarray post-mortem samples across healthy aging, AD and LB dementia. The study involved 159 clinico-pathologically diagnosed human post-mortem brains (48 controls, 47 AD, 25 DLB, 20 mixedAD/DLB, 19 PDD). The burden of HP-tau, amyloid-β and α-synuclein was quantitatively assessed in cortical and subcortical areas. Principal components (PC) analysis was applied across all cases to determine the pattern nature of HP-tau, amyloid-β and α-synuclein. Further analyses explored the relationships of these pathological patterns with cognitive and symptom variables. Cortical (tauPC1) and temporo-limbic (tauPC2) patterns were observed for HP-tau. For amyloid-β, a cortical-subcortical pattern (amylPC1) was identified. For α-synuclein, four patterns emerged: 'posterior temporal-occipital' (synPC1), 'anterior temporal-frontal' (synPC2), 'parieto-cingulate-insula' (synPC3), and 'frontostriatal-amygdala' (synPC4). Distinct synPC scores were apparent among DLB, mixedAD/DLB and PDD, and may relate to different spreading patterns of α-synuclein pathology. In dementia, cognitive measures correlated with tauPC1,tauPC2 and amylPC1 pattern scores (P ≤ 0.02), whereas such variables did not relate to α-synuclein parameters in these or combined LB dementia cases. Mediation analysis then revealed that in the presence of amylPC1, tauPC1 had a direct effect on global cognition in dementia (n = 65, P = 0.04), while tauPC1 mediated the relationship between amylPC1 and cognition through the indirect pathway (amylPC1 → tauPC1 → global cognition) (P < 0.05). Last, in synucleinopathies, synPC1 and synPC4 pattern scores were associated with visual hallucinations and motor impairment, respectively (P = 0.02). In conclusion, distinct patterns of α-synuclein pathology were apparent in LB dementia, which could explain some of the disease heterogeneity and differing spreading patterns among these conditions. Visual hallucinations and motor severity were associated with specific α-synuclein topographies in LB dementia that may be important to the clinical phenotype and could, after necessary testing/validation, be integrated into semiquantitative routine pathological assessment.

BACKGROUND:Delirium is an acute neuropsychiatric condition linked to increased dementia risk, yet its mechanisms remain unclear. Previous studies reported cerebral hypometabolism. Spatial covariance of 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) was applied to acutely unwell inpatients with and without delirium (Delirium, Conunwell) to derive a delirium-specific metabolic pattern (DP). DP expression was evaluated in healthy older adults (Conhealthy) and patients with delirium superimposed on dementia (DSD) and tracked longitudinally with symptom resolution. METHODS:Seventy participants were included (30 Conhealthy, 10 Conunwell, 13 Delirium, 17 DSD). Voxel principal components (PCs) identified intercorrelated metabolic patterns. RESULTS:The DP distinguished Conunwell from Delirium, with relative hypometabolism in default, frontoparietal, visual, and frontostriatal networks, and relative hypermetabolism in sensorimotor and limbic hubs. Delirium and DSD demonstrated higher DP expression than controls. In participants with follow-up, recovery was paralleled by reduced DP expression. DISCUSSION:Delirium exhibited a metabolic profile of network dysfunction that may be modifiable and clinically responsive. HIGHLIGHTS:Derivation of a DP, primarily attributable to delirium itself, rather than acute illness or dementia. The DP revealed metabolic dysfunction spanning large-scale networks, consistent with the proposed model of delirium as global brain failure. DP expression was elevated in delirium, both with and without dementia, compared to healthy and acutely unwell controls. In participants with follow-up, clinical recovery was paralleled by a reduction in DP expression. The delirium pattern reflected clinically responsive and modifiable network dysfunction.

Cholinergic dysfunction, particularly involving nicotinic acetylcholine receptors (nAChRs), contributes to cognitive and psychiatric symptoms in dementia with Lewy bodies (DLB), yet spatial covariance patterns remain unexplored. We aimed to characterise these patterns using 123I-5-iodo-3-[2(S)-2-azetidinylmethoxy] pyridine (5IA-85380) SPECT (α4β2 nAChR assessment) and examine their association with cognitive function. Fifteen DLB and 16 healthy controls underwent 1235IA-85380 and rCBF 99mTc-exametazime SPECT scanning. Voxel principal components analysis (PCA), generated PC images representing common intercorrelated voxels across subjects. Linear regression identified α4β2 nAChR and rCBF patterns distinguishing DLB from controls. A distinct α4β2 nAChR pattern differentiated DLB from controls (F1,29 = 165.1, p < 0.001), that was dissimilar to rCBF changes. This pattern was characterised by decreased uptake in temporal pole, inferior frontal cortex, amygdala, olfactory cortex, insula, anterior/mid cingulate, and putamen, alongside preserved/increased uptake in sensorimotor cortex, fusiform and occipital lobe. These regions mapped onto default, salience, limbic, frontostriatal, sensorimotor and visual hubs. We then derived from patients, α4β2 nAChR patterns that correlated with CAMCOGtotal (r = – 0.52, p = 0.04), MMSE (r = – 0.68, p = 0.01) and CAMCOGmemory (r = – 0.70, p = 0.01), demonstrating a common topography of relative decreased binding in lateral/medial prefrontal, lateral temporal, fusiform, inferior parietal and thalamus along with relative preserved/increased binding in cingulate, insula, occipital and medial temporal regions: structures within a range of networks supporting executive, language, attention, motor and visual processing. These findings provide novel insights into the pathophysiology of DLB and may inform future therapeutic strategies targeting nAChRs.

Introduction: 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. Methods: 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. Results: 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. Conclusions: The five -item scale is effective to identify parkinsonism in MCI, but a lower threshold must be used in MCI compared with dementia.

Background and Objectives Progressive nigrostriatal pathway degeneration occurs in individuals with dementia with Lewy bodies (LB). Our objective was to investigate whether repeat 123[I]-N-(3-fluoropropyl)-2β-carboxymethoxy-3β-(4-iodophenyl) nortropane (FP-CIT) single photon emission computed tomography (SPECT) can identify progressive dopaminergic loss in mild cognitive impairment (MCI) with Lewy bodies (MCI-LB). Methods Individuals with MCI-LB and MCI due to Alzheimer disease (MCI-AD) underwent comprehensive clinical assessment, 123[I]-FP-CIT SPECT at baseline and annual reviews, and baseline cardiac 123 iodine metaiodobenzylguanidine (I-MIBG). Mixed-effects models were used to investigate changes in 123[I]-FP-CIT specific binding ratio (SBR) in the striatum for each diagnostic group compared with controls. The time interval to the development of a quantitatively abnormal 123[I]-FP-CIT SPECT in the possible and probable MCI-LB groups was determined as the time it took for these groups to reach a striatal uptake 2 SDs below aged-matched controls. Test-retest variation was assessed using baseline and repeat scans in controls. Results We recruited 20 individuals with MCI-AD, 11 with possible MCI-LB, 25 with probable MCI-LB, and 29 age-matched controls. The mean time between baseline and the final image was 1.6 years (SD = 0.9, range 1.0–4.3). The annual estimated change in SBR was 0.23 for controls (95% CI −0.07 to 0.53), −0.09 (−0.55 to 0.36) for MCI-AD, −0.50 (−1.03 to 0.04) for possible MCI-LB, and −0.48 (−0.89 to −0.06) for probable MCI-LB. The median annual percentage change in SBR in MCI-LB was −5.6% (95% CI −8.2% to −2.9%) and 2.1% (−3.5% to 8.0%) for MCI-AD. The extrapolated time for a normal scan to become abnormal was 6 years. Controls and MCI-AD showed no significant change in dopaminergic binding over time. The mean test-retest variation in controls was 12% (SD 5.5%), which cautions against overinterpretation of small changes on repeat scanning. Discussion Progressive dopaminergic loss in the striatum is detectable using 123[I]-FP-CIT SPECT in MCI-LB at a group level. In clinical practice, individual change in striatal 123[I]-FP-CIT uptake seems to be of limited diagnostic value because of high test-retest variation. Classification of Evidence This study provides Class II evidence that longitudinal declines in striatal uptake measured using 123[I]-FP-CIT SPECT are associated with MCI due to Lewy body disease but not MCI due to Alzheimer disease.

Abstract 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.

We investigated diagnostic characteristics of spatial covariance analysis (SCA) of FDG-PET and HMPAO-SPECT scans in the differential diagnosis of dementia with Lewy bodies (DLB) and Alzheimer's disease (AD), in comparison with visual ratings and region of interest (ROI) analysis. Sixty-seven patients (DLB 29, AD 38) had both HMPAO-SPECT and FDG-PET scans. Spatial covariance patterns were used to separate AD and DLB in an initial derivation group (DLB n=15, AD n=19), before being forward applied to an independent group (DLB n=14, AD n=19). Visual ratings were by consensus, with ROI analysis utilising medial occipital/medial temporal uptake ratios. SCA of HMPAO-SPECT performed poorly (AUC 0.59±0.10), whilst SCA of FDG-PET (AUC 0.83±0.07) was significantly better. For FDG-PET, SCA showed similar diagnostic performance to ROI analysis (AUC 0.84±0.08) and visual rating (AUC 0.82±0.08). In contrast to ROI analysis, there was little concordance between SCA and visual ratings of FDG-PET scans. We conclude that SCA of FDG-PET outperforms that of HMPAO-SPECT. SCA of FDG-PET also performed similarly to the other analytical approaches, despite the limitations of a relatively small SCA derivation group. Compared to visual rating, SCA of FDG-PET relies on different sources of group variance to separate DLB from AD.

Objective cognitive impairment is a feature of Lewy body dementia (LBD), and computerised attentional tasks are commonly used as outcome measures in interventional trials. However, the reliability of these measures, in the absence of interventions, are unknown. This study examined the reliability of these attentional measures at short-term and longer-term follow-up stages. LBD patients (n = 36) completed computerised attentional tasks [simple and choice reaction time, and digit vigilance (SRT, CRT, DV)] at short-term (Day 0–Day 5) and longer-term (4 and 12 weeks) follow-up. Intra-class correlations (ICCs) were calculated to assess test–retest reliability. At short-term, the reciprocal SRT, CRT and DV mean reaction time to correct answers, the reciprocal DV coefficient of variation, and reciprocal power of attention (PoA) all showed excellent levels of reliability (all ICCs > 0.90). The reciprocal PoA showed the highest level of reliability (ICC = 0.978). At longer-term follow-up, only the reciprocal PoA had excellent levels of reliability (ICC = 0.927). Reciprocal SRT, CRT and DV reaction time to correct answers, and the CRT coefficient of variation values, showed good levels of test–retest reliability (ICCs ≥ 0.85). Contrary to expectations, most attentional measures demonstrated high levels of test–retest reliability at both short-term and longer-term follow-up time points. The reciprocal PoA composite measure demonstrated excellent levels of test–retest reliability, both in the short-term and long-term. This indicates that objective attentional tasks are suitable outcome measures in LBD studies and that the composite PoA measure may offer the highest levels of reliability.

Objective: To investigate the potential therapeutic benefits and tolerability of inhibitory transcranial direct current stimulation (tDCS) on the remediation of visual hallucinations in Charles Bonnet syndrome (CBS). Participants: Sixteen individuals diagnosed with CBS secondary to visual impairment caused by eye disease experiencing recurrent visual hallucinations. Intervention: All participants received 4 consecutive days of active and placebo cathodal stimulation (current density: 0.29 mA/cm2) to the visual cortex (Oz) over 2 defined treatment weeks, separated by a 4-week washout period. Main Outcome Measures: Ratings of visual hallucination frequency and duration following active and placebo stimulation, accounting for treatment order, using a 2 x 2 repeated-measures model. Secondary outcomes included impact ratings of visual hallucinations and electrophysiological measures. Results: When compared with placebo treatment, active inhibitory stimulation of visual cortex resulted in a significant reduction in the frequency of visual hallucinations measured by the North East Visual Hallucinations Interview, with a moderate-to-large effect size. Impact measures of visual hallucinations improved in both placebo and active conditions, suggesting support and education for CBS may have therapeutic benefits. Participants who demonstrated greater occipital excitability on electroencephalography assessment at the start of treatment were more likely to report a positive treatment response. Stimulation was found to be tolerable in all participants, with no significant adverse effects reported, including no deterioration in preexisting visual impairment. Conclusions: Findings indicate that inhibitory tDCS of visual cortex may reduce the frequency of visual hallucinations in people with CBS, particularly individuals who demonstrate greater occipital excitability prior to stimulation. tDCS may offer a feasible intervention option for CBS with no significant side effects, warranting larger-scale clinical trials to further characterize its efficacy. Ophthalmology 2022;129:1368-1379 (c) 2022 by the American Academy of Ophthalmology. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

BACKGROUND:Gait impairments are characteristic motor manifestations and significant predictors of poor quality of life in Parkinson's disease (PD). Neuroimaging biomarkers for gait impairments in PD could facilitate effective interventions to improve these symptoms and are highly warranted. OBJECTIVE:The aim of this study was to identify neural networks of discrete gait impairments in PD. METHODS:Fifty-five participants with early-stage PD and 20 age-matched healthy volunteers underwent quantitative gait assessment deriving 12 discrete spatiotemporal gait characteristics and [18 F]-2-fluoro-2-deoxyglucose-positron emission tomography measuring resting cerebral glucose metabolism. A multivariate spatial covariance approach was used to identify metabolic brain networks that were related to discrete gait characteristics in PD. RESULTS:In PD, we identified two metabolic gait-related covariance networks. The first correlated with mean step velocity and mean step length (pace gait network), which involved relatively increased and decreased metabolism in frontal cortices, including the dorsolateral prefrontal and orbital frontal, insula, supplementary motor area, ventrolateral thalamus, cerebellum, and cuneus. The second correlated with swing time variability and step time variability (temporal variability gait network), which included relatively increased and decreased metabolism in sensorimotor, superior parietal cortex, basal ganglia, insula, hippocampus, red nucleus, and mediodorsal thalamus. Expression of both networks was significantly elevated in participants with PD relative to healthy volunteers and were not related to levodopa dosage or motor severity. CONCLUSIONS:We have identified two novel gait-related brain networks of altered glucose metabolism at rest. These gait networks could serve as a potential neuroimaging biomarker of gait impairments in PD and facilitate development of therapeutic strategies for these disabling symptoms. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Cerebral white matter lesions (WML) encompass axonal loss and demyelination and are assumed to be associated with small vessel disease (SVD)-related ischaemia. However, our previous study in the parietal lobe white matter revealed that WML in Alzheimer’s disease (AD) are linked with degenerative axonal loss secondary to the deposition of cortical AD pathology. Furthermore, neuroimaging data suggest that pathomechanisms for the development of WML differ between anterior and posterior lobes with AD-associated degenerative mechanism driving posterior white matter disruption, and both AD-associated degenerative and vascular mechanisms contributed to anterior matter disruption. In this pilot study, we used human post-mortem brain tissue to investigate the composition and aetiology of frontal WML from AD and non-demented controls to determine if frontal WML are SVD-associated and to reveal any regional differences in the pathogenesis of WML. Frontal WML tissue sections from 40 human post-mortem brains (AD, n = 19; controls, n = 21) were quantitatively assessed for demyelination, axonal loss, cortical hyperphosphorylated tau (HPτ) and amyloid-beta (Aβ) burden, and arteriolosclerosis as a measure of SVD. Biochemical assessment included Wallerian degeneration-associated protease calpain and the myelin-associated glycoprotein to proteolipid protein ratio as a measure of ante-mortem ischaemia. Arteriolosclerosis severity was found to be associated with and a significant predictor of frontal WML severity in both AD and non-demented controls. Interesting, frontal axonal loss was also associated with HPτ and calpain levels were associated with increasing Aβ burden in the AD group, suggestive of an additional degenerative influence. To conclude, this pilot data suggest that frontal WML in AD may result from both increased arteriolosclerosis and AD-associated degenerative changes. These preliminary findings in combination with previously published data tentatively indicate regional differences in the aetiology of WML in AD, which should be considered in the clinical diagnosis of dementia subtypes: posterior WML maybe associated with degenerative mechanisms secondary to AD pathology, while anterior WML could be associated with both SVD-associated and degenerative mechanisms.

Abstract Background Mild cognitive impairment with Lewy bodies (MCI-LB) is the commonest prodromal phenotype of Dementia with Lewy Bodies (DLB) and may be challenging to differentiate from MCI due to Alzheimer’s disease (MCI-AD). Preservation of medial temporal lobe structures on MRI is recognised as a supportive biomarker consistent with underlying Lewy body disease rather Alzheimer’s disease (AD). We investigated whether whole hippocampal volume and differing hippocampal subfield atrophy patterns, could be used as a surrogate biomarker of underlying ad pathology, allowing for differentiation of MCI-LB from MCI-AD. Methods Participants were recruited to the following groups’: healthy controls (HC), MCI-LB and MCI-ad, all ≥60 years. Alongside detailed clinical, neuropsychological assessments, all participants underwent 3 T MRI, 123I-FP-CIT SPECT and 123I-MIBG myocardial scintigraphy. Using Freesurfer (v.6.0), a fully automated hippocampal subfield segmentation of the MRI data was performed. Results Groups consisted of 31 HC (mean age, 73.7 yrs; mean Mini-Mental state Examination [MMSE] score, 28.4), 34 MCI-LB (mean age, 74.7 yrs; mean MMSE score, 26.6) and 29 MCI-ad (mean age, 75.4 yrs; mean MMSE score, 27.1). There was no significant difference in whole hippocampal volume between MCI-LB and MCI-ad(Mean (SD) in mm3: MCI-LB 6025 (961) vs MCI-ad 5407 (882), p = 0.12) or between MCI-LB and HC (Mean (SD) in mm3: MCI-LB 6025 (961) vs HC 6355 (962), p = 0.11). Whole hippocampal volume was significantly smaller in MCI-ad compared with HC (p < 0.001). Comparison between MCI-LB and MCI-ad, showed absolute hippocampal subfield volumes were all lower in MCI-ad. However, the magnitude of the differences were small and no significant difference in hippocampal subfield volumes were noted between these groups, with the exception of the hippocampal tail being significantly smaller in MCI-ad compared to MCI-LB (p = 0.04). Conclusion In a well-characterised cohort, whole hippocampal and hippocampal subfield volumes were similarly atrophied in MCI-LB and MCI-ad and did not distinguish between the groups.

Background Parkinson's disease (PD) is associated with cholinergic dysfunction, although the role of M1 and M4 receptors remains unclear. Objective To investigate spatial covariance patterns of cholinergic muscarinic M-1/M-4 receptors in PD and their relationship with cognition and motor symptoms. Methods Some 19 PD and 24 older adult controls underwent I-123-iodo-quinuclidinyl-benzilate (QNB) (M-1/M-4 receptor) and Tc-99m-exametazime (perfusion) single-photon emission computed tomography (SPECT) scanning. We implemented voxel principal components analysis, producing a series of images representing patterns of intercorrelated voxels across individuals. Linear regression analyses derived specific M-1/M-4 spatial covariance patterns associated with PD. Results A cholinergic M-1/M-4 pattern that converged onto key hubs of the default, auditory-visual, salience, and sensorimotor networks fully discriminated PD patients from controls (F-1,F-41 = 135.4, P < 0.001). In PD, we derived M-1/M-4 patterns that correlated with global cognition (r = -0.62, P = 0.008) and motor severity (r = 0.53, P = 0.02). Both patterns emerged with a shared topography implicating the basal forebrain as well as visual, frontal executive, and salience circuits. Further, we found a M-1/M-4 pattern that predicted global cognitive decline (r = 0.46, P = 0.04) comprising relative decreased binding within default and frontal executive networks. Conclusions Cholinergic muscarinic M-1/M-4 modulation within key brain networks were apparent in PD. Cognition and motor severity were associated with a similar topography, inferring both phenotypes possibly rely on related cholinergic mechanisms. Relative decreased M-1/M-4 binding within default and frontal executive networks could be an indicator of future cognitive decline. (c) 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

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.

BackgroundDopaminergic imaging is an established biomarker for dementia with Lewy bodies, but its diagnostic accuracy at the mild cognitive impairment (MCI) stage remains uncertain.AimsTo 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.MethodWe 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.ResultsAt 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.ConclusionsIt 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.

Objective To provide evidence that cardiac I-123-metaiodobenzylguanidine sympathetic innervation imaging (MIBG) scintigraphy differentiates probable mild cognitive impairment with Lewy bodies (MCI-LB) from mild cognitive impairment due to Alzheimer disease (MCI-AD), we scanned patients with MCI and obtained consensus clinical diagnoses of their MCI subtype. We also performed baseline FP-CIT scans to compare the accuracy of MIBG and FP-CIT. Methods We conducted a prospective cohort study into the accuracy of cardiac MIBG scintigraphy in the diagnosis of MCI-LB. Follow-up clinical assessment was used to diagnose MCI-AD (no core features of MCI-LB and normal FP-CIT), probable MCI-LB (2 or more core features, or 1 core feature with abnormal FP-CIT), or possible MCI-LB (1 core feature or abnormal FP-CIT). For the comparison between MIBG and FP-CIT, only core clinical features were used for diagnosis. Results We recruited 95 people with mild cognitive impairment. Cardiac MIBG was abnormal in 22/37 probable and 2/15 possible MCI-LB cases and normal in 38/43 MCI-AD cases. The sensitivity in probable MCI-LB was 59% (95% confidence interval [CI], 42%-75%), specificity 88% (75%-96%), and accuracy 75% (64%-84%). The positive likelihood ratio was 5.1 and negative likelihood ratio 0.46. With symptom-only diagnoses, the accuracies were 79% for MIBG (95% CI, 68%-87%) and 76% for FP-CIT (95% CI, 65%-85%). Conclusions Cardiac MIBG appears useful in early disease, with an abnormal scan highly suggestive of MCI-LB. Validation in a multicenter setting is justified. Classification of Evidence This study provides Class I evidence that cardiac MIBG distinguishes MCI-LB from MCI-AD.

The aged brain frequently exhibits multiple pathologies, rather than a single hallmark pathology (pure pathology [PurP]), ranging from low/intermediate levels of additional pathology (LowP) to mixed severe pathology (mixed SevP). We investigated the frequency of PurP, LowP, and mixed SevP, and the impact of additional LowP on cognition.

AbstractBackgroundUsing the UK's Brains for Dementia Research (BDR) program, we investigated the frequency of neuropathological dementia diagnosis, the proportion of pure, mixed or concomitant pathologies and the pathological substrates for cognitive impairment.MethodAll cases (n = 673) underwent standardised neuropathological assessment outlined in [1]. Cases were classed as ‘pure’, ‘mixed’ or ‘concomitant’. 473 cases had clinical dementia rating (CDR) scores: binary linear regression was employed to estimate the odds of increasing CDR score due to the presence of pathologies and multiple pathologies.Result142 cases (21.1%) were diagnosed as controls and 531 fulfilled the criteria for a neurodegenerative disease: Alzheimer’s disease (n = 221) > Lewy body disease (n = 65) > vascular dementia (n = 50). Only 23.5% were classified as ‘pure’, 63.1% as ‘concomitant’ and 13.4% as ‘mixed’. 147 (28.9%) had no cognitive impairment and 301 had dementia. Higher burdens of hyperphosphorylated‐ τ (Hpτ), amyloid‐β and α‐synuclein burden had a three‐fold increase on the risk of being demented (OR = <3.4; 95% CI 2.1, 5.5). Regarding the conversion from mild cognitive impairment to dementia, Hpτ had a two‐fold increase on risk (OR = 1.75; 95% CI 1.16, 2.6) and the presence of multiple pathologies had a nine‐fold increase on risk (OR = 8.8; 95% CI 3.19, 24.3).ConclusionThe majority of the BDR cohort contains multiple pathologies. Increasing burden of Hpτ and multiple pathologies greatly increases the odds of dementia. (1) Francis et al, (2018) DOI 10.3233/JAD‐180699.