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Background and purpose: Visual hallucinations are a common, potentially distressing experience of people with Lewy body disease (LBD). The underlying brain changes giving rise to visual hallucinations are not fully understood, although previous models have posited that alterations in the connectivity between brain regions involved in attention and visual processing are critical. Methods: Data from 41 people with LBD and visual hallucinations, 48 with LBD without visual hallucinations and 60 similarly aged healthy comparator participants were used. Connections were investigated between regions in the visual cortex and ventral attention, dorsal attention and default mode networks. Results: Participants with visual hallucinations had worse cognition and motor function than those without visual hallucinations. In those with visual hallucinations, reduced functional connectivity within the ventral attention network and from the visual to default mode network was found. Connectivity strength between the visual and default mode network correlated with the number of correct responses on a pareidolia task, and connectivity within the ventral attention network with visuospatial performance. Conclusions: Our results add to evidence of dysfunctional connectivity in the visual and attentional networks in those with LBD and visual hallucinations. [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 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]

Multiple system atrophy (MSA) is a neurodegenerative disease characterized by autonomic failure, ataxia, and/or parkinsonism. Its prominent pathological alterations can be investigated using diffusion magnetic resonance imaging (dMRI), a technique that exploits the characteristics of water random motion inside brain tissue. The aim of this report was to review currently available literature on the application of dMRI in MSA and to describe microstructural abnormalities, diagnostic applications, and pathophysiological correlates. Sixty-four published studies involving microstructural investigation using dMRI in MSA were included. Widespread microstructural abnormalities of white matter were described, especially in the middle cerebellar peduncle, corticospinal tract, and hemispheric fibers. Gray matter degeneration was identified as well, with diffuse involvement of subcortical structures, especially in the putamina. Diagnostic applications of dMRI were mostly explored for the differential diagnosis between MSA parkinsonism and Parkinson's disease. Recently, machine learning algorithms for image processing and disease classification have demonstrated high diagnostic accuracy, showing potential for translation into clinical practice. To a lesser extent, clinical correlates of microstructural abnormalities have also been investigated, and abnormalities related to motor, ocular, and cognitive impairments were described. dMRI in MSA has contributed to in vivo identification of known pathological abnormalities. Translation into clinical practice of the latest advancements for the differential diagnosis between MSA and other forms of parkinsonism seems feasible. Current limitations involve the possibility of correctly diagnosing MSA in the very early stages, when the clinical diagnosis is most uncertain. Furthermore, pathophysiological correlates of microstructural abnormalities remain understudied. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [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]

Background: Neurodegenerative diseases lead to memory disorders and cognitive impairments with major impacts on day‐to‐day function. Early detection of patients is essential for an efficient care approach, and differential diagnosis is essential for determining prognosis and tailoring management. Most research studies compare patients by pairwise comparison methods, but this does not correspond to daily clinical practice, in which clinicians need to distinguish many different possible types of dementia concomitantly. It has been shown that magnetic resonance imaging (MRI) can mark with good accuracy the different types of dementia, such as: Alzheimer's disease (AD), Frontotemporal dementia (FTD), Parkinson's disease (PD), dementia with Lewy bodies (DLB). Recently, Deep Learning approaches have started being used although differential diagnosis is still almost ignored. The aim of this study was to develop a Convolution Neural Network (CNN) to classify probable AD, FTD, DLB, PD and healthy elderly control (CN) subjects starting from Diffusion Tensor Imaging (DTI). Method: The cohort used in this study came from six different initiatives: ADNI1, NIFD2, NACC3, PDBP4, PPMI5 and Newcastle University6,7,8,9. We analysed a total of 108 CN, 110 AD, 135 FTD, 150 DLB, 132 PD. Demographic and neuropsychological characterization is shown in Table 1. The DTI scans were pre‐processed using the FMRIB software library (FSL) with eddy current correction, skull‐stripping and diffusion tensor calculation. We post‐processed the Fractional Anisotropy (FA) map using 3D CNN. The proposed CNN structure consisted of an image input layer, convolutional filters, several batch normalization with max‐pooling layers and, finally, the classification layer. A data augmentation approach was adopted that ultimately resulted in a dataset of 26'450 brain scans. A hold‐out validation (70% training set 30% test set) was performed. Result: We found excellent performance of the 3D CNN in discriminating the different neurodegenerative diseases. Figure 1 shows the confusion matrix with the following values for the area under the ROC curve in each class: 0.92 for CN, 0.90 for AD, 0.97 for DLB, 0.96 for FTD, 0.99 for PD. Conclusion: These results prove that Deep Learning and the 3D CCN method are suitable for clinical practice and provide additional clues that can help clinicians in diagnosis making. [ABSTRACT FROM AUTHOR]

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 [18F]‐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 [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]

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]

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: 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]

We performed a clinicopathological study to assess the burden of small vessel disease (SVD) type of pathological changes in elderly demented subjects, who had clinical evidence of autonomic dysfunction, either carotid sinus hypersensitivity or orthostatic hypotension or both or had exhibited unexpected repeated falls. Clinical and neuropathological diagnoses in 112 demented subjects comprised dementia with Lewy bodies (DLB), Parkinson's disease with dementia (PDD), Alzheimer's disease (AD), Mixed dementia (mostly AD‐DLB) and vascular dementia (VaD). Of these, 12 DLB subjects had no recorded unexpected falls in life and therefore no evidence of concomitant autonomic dysfunction. A further 17 subjects were assessed as aging controls without significant pathology or signs of autonomic dysfunction. We quantified brain vascular pathological changes and determined severities of neurodegenerative lesions including α‐synuclein pathology. We found moderate‐severe vascular changes and high‐vascular pathology scores (P < 0.01) in all neurodegenerative dementias and as expected in VaD compared to similar age controls. Arteriolosclerosis, perivascular spacing and microinfarcts were frequent in the basal ganglia and frontal white matter (WM) across all dementias, whereas small infarcts (<5 mm) were restricted to VaD. In a sub‐set of demented subjects, we found that vascular pathology scores were correlated with WM hyperintensity volumes determined by MRI in life (P < 0.02). Sclerotic index values were increased by ~50% in both the WM and neocortex in all dementias compared to similar age controls. We found no evidence for increased α‐synuclein deposition in subjects with autonomic dysfunction. Our findings suggest greater SVD pathological changes occur in the elderly diagnosed with neurodegenerative dementias including DLB and who develop autonomic dysfunction. SVD changes may not necessarily manifest in clinically overt symptoms but they likely confound motor or cognitive dysfunction. We propose dysautonomia promotes chronic cerebral hypoperfusion to impact upon aging‐related neurodegenerative disorders and characterize their end‐stage clinical syndromes. [ABSTRACT FROM AUTHOR]

Background: Amyloid deposition is common in dementia with Lewy bodies, but its pathophysiological significance is unclear.Objective: The objective of this study was to investigate the relationship between amyloid deposition and clinical profile, gray matter volume, and brain perfusion in dementia with Lewy bodies.Methods: Dementia with Lewy bodies (n = 37), Alzheimer's disease (n = 20), and controls (n = 20) underwent a thorough clinical assessment, 3T MRI, and early- and late-phase 18 F-Florbetapir PET-CT to assess cortical perfusion and amyloid deposition, respectively. Amyloid scans were visually categorized as positive or negative. Image analysis was carried out using statistical parametric mapping (SPM) 8.Results: There were no significant differences between amyloid-positive and amyloid-negative dementia with Lewy bodies cases in age (P = .78), overall cognitive impairment (P = .83), level of functional impairment (P = .80), or any other clinical or cognitive scale. There were also no significant differences in hippocampal or gray matter volumes. However, amyloid-positive dementia with Lewy bodies cases had lower medial temporal lobe perfusion (P = .03) than amyloid-negative cases, although a combination of medial temporal lobe perfusion, hippocampal volume, and cognitive measures was unable to accurately predict amyloid status in dementia with Lewy bodies.Conclusions: Amyloid deposition was not associated with differences in clinical or neuropsychological profiles in dementia with Lewy bodies, but was associated with imaging evidence of medial temporal lobe dysfunction. The presence of amyloid in dementia with Lewy bodies cannot be identified on the basis of clinical and other imaging features and will require direct assessment via PET imaging or CSF. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Abstract: Dementia with Lewy bodies (DLB) is a common form of dementia and is characterized by cognitive fluctuations, visual hallucinations, and Parkinsonism. The phenotypic expression of the disease may, in part, relate to alterations in functional connectivity within and between brain networks. This resting‐state study sought to clarify this in DLB, how networks differed from Alzheimer's disease (AD), and whether they were related to clinical symptoms in DLB. Resting‐state networks were estimated using independent component analysis. We investigated functional connectivity changes in 31 DLB patients compared to 31 healthy controls and a disease comparator group of 29 AD patients using dual regression and FSLNets. Within‐network connectivity was generally decreased in DLB compared to controls, mainly in motor, temporal, and frontal networks. Between‐network connectivity was mainly intact; only the connection between a frontal and a temporal network showed increased connectivity in DLB. Differences between AD and DLB were subtle and we did not find any significant correlations with the severity of clinical symptoms in DLB. This study emphasizes the importance of reduced connectivity within motor, frontal, and temporal networks in DLB with relative sparing of the default mode network. The lack of significant correlations between connectivity measures and clinical scores indicates that the observed reduced connectivity within these networks might be related to the presence, but not to the severity of motor and cognitive impairment in DLB patients. Furthermore, our results suggest that AD and DLB may show more similarities than differences in patients with mild disease. [ABSTRACT FROM AUTHOR]

Abstract: A significant symptom of Lewy body dementia (LBD) is slow cognitive processing or bradyphrenia. In a previous fMRI task‐based study, we found slower responses in LBD, accompanied by greater deactivation in the default mode network. In this study, we investigated the timing and magnitude of the activations and deactivations with respect to reaction time to determine whether the slower responses in LBD were associated with delayed neuronal activity. Using fMRI, we examined the magnitude and latency of activations and deactivations during an event‐related attention task in 32 patients with LBD and 23 healthy controls using predefined regions of interest. Default mode network deactivations did not significantly differ in their timing between groups or task conditions, while the task‐related activations in the parietal, occipital, frontal, and motor cortex were all significantly later in the LBD group. Repeating the analysis with reaction time as a parametric modulator of activation magnitude produced similar findings, with the reaction time modulator being significant in a number of regions including the default mode network, suggesting that the increased deactivation in LBD is partly explained by slower task completion. Our data suggest that the default mode network deactivation is initiated at the start of the task, and remains deactivated until its end, with the increased magnitude of deactivation in LBD reflecting the more prolonged cognitive processing in these patients. These data add substantially to our understanding of the neural origins of bradyphrenia, which will be essential for determining optimum therapeutic strategies for cognitive impairment in LBD. Hum Brain Mapp 39:633–643, 2018. © 2017 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Mild cognitive impairment (MCI) is prevalent in 15%-40% of Parkinson's disease (PD) patients at diagnosis. In this investigation, we study brain intra- and inter-network alterations in resting state functional magnetic resonance imaging (rs-fMRI) in recently diagnosed PD patients and characterise them as either cognitive normal (PD-NC) or with MCI (PD-MCI). Patients were divided into two groups, PD-NC ( N = 62) and PD-MCI ( N = 37) and for comparison, healthy controls (HC, N = 30) were also included. Intra- and inter-network connectivity were investigated from participants' rs-fMRIs in 26 resting state networks (RSNs). Intra-network differences were found between both patient groups and HCs for networks associated with motor control (motor cortex), spatial attention and visual perception. When comparing both PD-NC and PD-MCI, intra-network alterations were found in RSNs related to attention, executive function and motor control (cerebellum). The inter-network analysis revealed a hyper-synchronisation between the basal ganglia network and the motor cortex in PD-NC compared with HCs. When both patient groups were compared, intra-network alterations in RSNs related to attention, motor control, visual perception and executive function were found. We also detected disease-driven negative synchronisations and synchronisation shifts from positive to negative and vice versa in both patient groups compared with HCs. The hyper-synchronisation between basal ganglia and motor cortical RSNs in PD and its synchronisation shift from negative to positive compared with HCs, suggest a compensatory response to basal dysfunction and altered basal-cortical motor control in the resting state brain of PD patients. Hum Brain Mapp 38:1702-1715, 2017. © 2016 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Background: Neuropsychiatric symptoms (NPS) in Lewy body diseases, including dementia with Lewy bodies (DLB) and Parkinson's disease (PD) dementia, occur frequently and at an early stage in disease progression. Such symptoms are significantly associated with quality of life, caregiver burden and functional limitations. Limited evidence exists, however, outlining the relationship between NPS and cognitive decline. Methods: Data from 217 participants were derived from three cohort studies. Patients diagnosed with either MCI with Lewy bodies (MCI‐LB, n = 67), PD‐MCI (n = 56) or Alzheimer's disease (MCI‐AD, n = 39) and a group of healthy older adults (n = 55) completed comprehensive neuropsychological and neuropsychiatric assessment and were followed up longitudinally for a median of three years. NPS identified at baseline by the Neuropsychiatric Inventory (NPI) were included as predictors in linear regressions and linear mixed effects models to assess the relationship between NPS and performance on a range of cognitive tests both at baseline and longitudinally. Results: At baseline, NPS were most prevalent and severe among the MCI‐LB group (49% with NPI score >4 in at least one symptom) and least prevalent in controls (7% with NPI score >4). Total NPI score was not related to baseline cognitive function in any domain in any group. Greater baseline total NPI score was associated with steeper rates of decline among PD‐MCI patients on a measure of processing speed (p =.01). Among healthy adults, only sleep disturbance was associated with steeper rates of decline on global cognition (p =.005). None of the patient groups showed any association between individual NPS and decline on a measure of global cognitive function. Conclusions: The lack of a significant relationship found between NPS and either global cognitive function or decline in global cognition seen among MCI patients suggests that at this prodromal stage of disease, NPS appear to be of limited clinical impact and indicates that the mechanisms of cognitive and neuropsychiatric symptoms may differ in early Lewy body disease. Future work will investigate these mechanisms using multimodal imaging data from this cohort. [ABSTRACT FROM AUTHOR]

Aims Complex visual hallucinations occur in 70% of dementia with Lewy bodies ( DLB) cases and significantly affect patient well-being. Visuo-cortical and retinal abnormalities have been recorded in DLB and may play a role in visual hallucinations. The present study aimed to investigate the lateral geniculate nucleus ( LGN), a visual relay centre between the retina and visual cortex, to see if changes to this structure underlie visual hallucinations in DLB. Methods Fifty-one [17 probable DLB, 19 control and 15 probable Alzheimer's disease ( AD)] cases were recruited for a functional magnetic resonance imaging study, in which patients' response to a flashing checkerboard stimulus was detected and measured in the LGN, before comparison across experimental groups. Additionally, post mortem LGN tissue was acquired for a cross-sectional study using 20 (six DLB, seven control and seven AD) cases and analysed using stereology. α-Synuclein, phosphorylated tau and amyloid-β pathology was also assessed in all cases. Results DLB cases did not significantly differ from controls on neuroimaging, morphometry or pathology. However, a significant increase in amyloid-β pathology, a reduction in number of parvocellular neurones and magnocellular gliosis was found in AD cases compared with control and DLB cases. Conclusions These findings suggest that the early visual system is relatively spared in DLB, which implies that upstream visual structures may be largely responsible for the generation of hallucinatory percepts. The significance of the degeneration of the LGN in AD cases is uncertain. [ABSTRACT FROM AUTHOR]

Background: The aim of this work was to investigate the cortical and white matter changes that underlie cognitive impairment in patients with incident Parkinson's disease (PD) disease using voxel-based morphometry and diffusion tensor imaging.Methods: Newly diagnosed nondemented PD (n = 125) and control subjects (n = 50) were recruited from the Incidence of Cognitive Impairment in Cohorts with Longitudinal Evaluation in Parkinson's Disease Study and completed cognitive assessments and 3T structural and diffusion tensor MR imaging. Voxel-based morphometry was performed to investigate the relationship between gray matter volume and cognitive ability. Microstructural white matter changes were assessed with diffusion tensor imaging measures of fractional anisotropy and mean diffusivity using tract-based spatial statistics.Results: Increased mean diffusivity was observed bilaterally in subjects with PD, relative to controls (P = 0.019). Increased mean diffusivity was associated with performance on the semantic fluency and Tower of London tasks in frontal and parietal white matter tracts, including the cingulum, superior longitudinal fasciculus, inferior longitudinal fasciculus, and inferior fronto-occipital fasciculus. There was no difference in total gray matter volume between groups; however, bilateral reductions in frontal and parietal gray matter volume were associated with reduced performance on measures of executive function in PD subjects.Conclusions: At the earliest stages of PD, regionally specific increases in central white matter mean diffusivity are present and suggest early axonal damage. Such changes are not accompanied by significant gray matter volume loss and are consistent with proposed models of pathological progression of the disease. Structural MRI, especially diffusion tensor imaging analysis, offers potential as a noninvasive biomarker reflecting cognitive impairment in PD. [ABSTRACT FROM AUTHOR]

Objective: Dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) are two dementias with overlapping phenotypes. Clinically, these are differentiated by the one-year precedence rule between the onset of dementia with respect to Parkinsonism. In this report we aimed to find differences between DLB and PDD in functional connectivity (FC) using resting state functional magnetic resonance imaging, which we hypothesised would reflect the underlying pathological differences between DLB and PDD.Methods: The study cohort comprised of 18 patients with DLB, 12 with PDD and 17 healthy control (HC) groups. Eight cortical and four subcortical seeds were chosen, and time series extracted to estimate correlation maps. We also implemented a voxel-based morphometry (VBM) analysis to assess regional grey matter differences. FC analysis was corrected for age, sex and regional grey matter differences.Results: The FC analysis showed greater alterations in DLB than in PDD for seeds placed within the fronto-parietal network (FPN), whilst in contrast, for the supplementary motor area seed FC alterations were more apparent in PDD than in DLB. However, when comparing DLB and PDD, no significant differences were found. In addition, VBM analysis revealed greater atrophy in PDD than HC and DLB in the bilateral motor cortices and precuneus respectively.Conclusions: PDD and DLB demonstrate similar FC alterations in the brain. However, attention- and motor-related seeds revealed subtle differences between both conditions when compared with HC, which may relate to the neuropathology and chronological precedence of core symptoms in the Lewy body dementias. [ABSTRACT FROM AUTHOR]

Background This study aimed to have international experts converge on a harmonized definition of whole hippocampus boundaries and segmentation procedures, to define standard operating procedures for magnetic resonance (MR)-based manual hippocampal segmentation. Methods The panel received a questionnaire regarding whole hippocampus boundaries and segmentation procedures. Quantitative information was supplied to allow evidence-based answers. A recursive and anonymous Delphi procedure was used to achieve convergence. Significance of agreement among panelists was assessed by exact probability on Fisher's and binomial tests. Results Agreement was significant on the inclusion of alveus/fimbria ( P = .021), whole hippocampal tail ( P = .013), medial border of the body according to visible morphology ( P = .0006), and on this combined set of features ( P = .001). This definition captures 100% of hippocampal tissue, 100% of Alzheimer’s disease-related atrophy, and demonstrated good reliability on preliminary intrarater (0.98) and inter-rater (0.94) estimates. Discussion Consensus was achieved among international experts with respect to hippocampal segmentation using MR resulting in a harmonized segmentation protocol. [ABSTRACT FROM AUTHOR]

The article discusses research which was conducted to investigate whether symptoms associated with carotid sinus hypersensitivity indicate cerebral hypoperfusion and whether patients with carotid sinus hypersensitivity are at a greater risk of white matter hyperintensities. Researchers evaluated 272 subjects. They found that symptoms during carotid sinus massage and not hemodynamic change are associated with white matter hyperintensity volume.

ABSTRACT Background Rapid eye movement sleep behavior disorder has poor prognostic implications for Parkinson's disease. The authors recruited 124 patients with early Parkinson's disease to compare clinical and neuroimaging findings based on the presence of this sleep disorder. Methods The presence of rapid eye movement sleep behavior disorder was assessed with the Mayo Sleep Questionnaire. Magnetic resonance imaging sequences were obtained for voxel-based morphometry and diffusion tensor imaging. Results Patients with sleep disorder had more advanced disease, but groups had similar clinical characteristics and cognitive performance. Those with sleep disorder had areas of reduced cortical grey matter volume and white matter changes compared with those who did not have sleep disorder. However, differences were slight and were not significant when the analyses were adjusted for multiple comparisons. Conclusions Rapid eye movement sleep behavior disorder was associated with subtle changes in white matter integrity and grey matter volume in patients with early Parkinson's disease. © 2013 Movement Disorder Society [ABSTRACT FROM AUTHOR]

Objectives Visuo-perceptual abnormalities are a prominent feature in dementia with Lewy bodies (DLB) and also occur in Alzheimer's disease (AD) to a lesser extent. We studied the progression of visuo-perceptual abnormalities over a 12-month period in DLB and AD by using a novel computerised test battery. Methods Following our previous work using the Newcastle Visual Perception (NEVIP) battery, we re-assessed 16 AD, 12 DLB and 28 similar-aged comparison participants 12 months after initial baseline assessment. Results DLB visual perception at follow-up showed worse performance than AD ( U = 43, p = 0.027); however, there were no significant changes in visuo-perceptual scores between baseline assessment and 12-month assessment within groups. A poor baseline score on the NEVIP predicted subsequent deterioration on the Bristol Activities of Daily Living Scale ( rs = −0.725, p = 0.014) in DLB participants but not in the AD group. Conclusions The NEVIP is a reliable test of visuo-perception, relatively independent of cognitive decline, with predictive value in identifying DLB participants at risk of functional decline. Visuo-perceptual dysfunction is a core feature of the disorder for some DLB patients and was stable over the 12-month period examined here. Copyright © 2012 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

ABSTRACT Dementia is a frequent and disabling complication of Parkinson's disease (PD). Clinicians and researchers lack a biomarker capable of tracking the structural and functional changes that underlie the evolution of cognitive dysfunction in PD. Magnetic resonance imaging (MRI) has been adopted as a biomarker in natural history and interventional studies of Alzheimer's disease (AD) and amnestic mild cognitive impairment (MCI), but its utility as a biomarker for PD and Parkinson's disease dementia (PDD) is unclear. In this review, the authors summarize the studies that have used MRI to investigate cognitive decline in PD, outline limitations of those studies, and suggest directions for future research. PD dementia is associated with extensive cortical atrophy, which may be quantified with structural MRI. More promisingly, patterns of atrophy may be present in those who have PD with MCI (PD-MCI). Subcortical white matter tract degeneration is detectable early in the disease with diffusion tensor imaging and may precede changes observed on conventional structural MRI. Although less well studied, other MR techniques, such as functional MRI, MR perfusion imaging with arterial spin labeling, and MR spectroscopy, have demonstrated differences in activation and metabolism between PD and PDD. In this review, the ability to compare studies was limited by the heterogeneity of study populations, cognitive testing methods, and imaging protocols. Future work should adopt agreed scan protocols, should be adequately powered, and should use carefully phenotyped patients to fully maximize the contribution of MRI as a biomarker for PDD. © 2013 Movement Disorder Society [ABSTRACT FROM AUTHOR]

Background Dementia with Lewy bodies (DLB) shares common clinical, neuropsychological and pathological features with other dementia subtypes, such as Alzheimer's disease (AD), making it difficult to differentiate in clinical practice. Despite the development of consensus diagnostic criteria, many cases are missed, and biomarkers to assist with diagnosis would represent important advances. Our aim was to review the literature to identify potential biomarkers that may distinguish DLB from other dementia subtypes, especially AD. Method The literature search was performed using Medline up to October 2010 for imaging studies [single-photon emission computed tomography (SPECT), positron emission tomography (PET), magnetic resonance imaging (MRI) and amyloid imaging] and cerebrospinal fluid (CSF) markers in DLB. Individual articles were examined for additional references. The abstracts of the identified articles were read to determine the most relevant papers, which became the basis for this review. Results The most robust evidence available was for striatal dopamine transporter activity visualised by 123I-labelled N-(3-fluoropropyl)-2β-carbomethoxy-3β-(4-iodophenyl)nortropane (123I-FP-CIT) SPECT. Several other imaging techniques have also reported promising results, such as [18F]fluorodopa PET, which assesses nigrostriatal integrity; [18F]fluorodeoxyglucose PET, which assesses metabolic deficits; and meta-iodobenzylguanidine imaging, which assesses sympathetic cardiac denervation. Data from studies using CSF measures of amyloid and tau, occipital hypoperfusion on SPECT and preservation of medial temporal lobe structures on MRI suggest that they may offer less diagnostic discrimination. Conclusion Several potential biomarkers have shown good diagnostic accuracy for DLB, but apart from FP-CIT SPECT, there is now a need for larger clinical multi-site studies, as well as for studies with pathological verification of diagnosis, before their use could be recommended for routine clinical practice. Copyright © 2011 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Introduction. White matter hyperintensities (WMHs) are a common finding on MRI scans of older people and are associated with vascular disease. We compared 3 methods for automatically segmenting WMHs from MRI scans. Method. An operator manually segmented WMHs on MRI images from a 3T scanner. The scans were also segmented in a fully automated fashion by three different programmes. The voxel overlap between manual and automated segmentation was compared. Results. Between observer overlap ratio was 63%. Using our previously described in-house software, we had overlap of 62.2%. We investigated the use of a modified version of SPM segmentation; however, this was not successful, with only 14% overlap. Discussion. Using our previously reported software, we demonstrated good segmentation of WMHs in a fully automated fashion. [ABSTRACT FROM AUTHOR]

We describe a fully automated method for hippocampal segmentation. The method uses SPM5 () software to segment the brain into grey/white matter, and spatially normalize the images to standard space. Grey matter pixels within a predefined hippocampal region in standard space are identified to segment the hippocampi. The method was validated on 36 subjects (9 each of Alzheimer's disease, dementia with Lewy bodies, vascular dementia, and healthy controls). The mean absolute difference in volume compared with manual segmentation was 11% (SD 9%). Linear regression between manual and automated volume gave V(auto) = V(manual) × 0.83 + 401 ml. The method provides an acceptable automated alternative to manual segmentation which may be of value in large studies. Hum Brain Mapp 2008. © 2007 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Background Both types of cerebral white matter hyperintensities, periventricular (PVL) and deep white matter lesions (DWML) have been previously associated with the development of depression in older subjects. However, it remains controversial as to whether PVL, DWML, or both are most strongly associated with depression and this was the aim of the current study. Methods In a pan-European multicentre study of 626 older subjects, we examined the relationship between PVL and DWML, depressive symptoms (GDS quintile), cognitive status (MMSE), hypertension and history of stroke. Results In univariate analysis we found that depressive symptoms as assessed by GDS were associated with both types of white matter lesions (Spearman rho = 0.12 p = 0.002 for DWML and rho = 0.09 p = 0.01 for PVL). Using ordinal logistic regression analysis the total DWML score (p = 0.041), rather than PVL (p = 0.9) was found to predict GDS scores. Conclusions DWML, but not PVL, were most strongly associated with depressive symptoms in this sample. As DWML (unlike PVL) are associated with vascular ischaemic damage, our findings are consistent with the ‘vascular depression’ hypothesis. Longitudinal studies are needed to clarify the time course of these relationships, in particular, whether modifying DWML alters the natural history of depression. Copyright © 2006 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background People with Parkinson's disease (PD) have an increased risk of developing dementia (PDD), which often has clinical features similar to dementia with Lewy bodies (DLB). Whilst perfusion studies have shown parieto-occipital hypoperfusion in DLB and PDD relative to controls, there have not been any longitudinal studies of perfusion changes in PDD and DLB. Methods In this study, we measured brain perfusion using Tc99m HMPAO SPECT over one year in 17 PDD, 18 DLB and 34 healthy subjects. We used SPM99 to compare perfusion changes in the two dementia groups against the control group. Results We did not see any reductions in perfusion in either of the dementia groups. However, in the DLB, but not PDD group, there was a significant increase in putamen perfusion relative to controls over the year. In both DLB and PDD groups, there was a correlation between striatal perfusion increase over the year, and worsening of parkinsonism. Perfusion changes were not secondary to changes in antiparkinsonian medication. Conclusion The increase in striatal perfusion may be a compensatory change related to decreasing striatal dopaminergic input from the substantia nigra in PDD and DLB, consistent with the increased predominance of rigidity over tremor symptoms in these groups compared with non-demented PD. Copyright © 2005 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background White matter hyperintensities have been associated with the development of depression in older subjects, though the details of this relationship are not fully understood. Methods In a pan-European multicentre study of 629 older subjects, we examined the relationship between MRI white matter hyperintensities (WMH), depressive symptoms and self perceived health quality of life (QOL). WMH were rated using a three-point scale. Results We found depressive symptoms as assessed by the geriatric depression 15-item scale to be associated with WMH rating (Spearman's rho 0.11, p = 0.008) and also with the Euro-QOL health score (Spearman's rho -0.5, p < 0.001). In a ordinal logistic regression model, QOL was found to strongly predict GDS score (p < 0.001) and severe vs mild WMH were associated with increased depression (p = 0.028). The relationship between history of severe depression and WMH score was examined, but there were no differences either between those with and without a history of severe depression, or those with an early vs late onset of depression. Conclusions The results suggest that WMH play a role in increasing depressive symptoms, even when perceived quality of life is controlled for as a possible mediating factor. Copyright © 2005 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background: There is a newly emergent ageing population of people living with HIV (PLWH) in Africa. However, there is little research into HIV‐associated neurocognitive disorder (HAND) in this population. Existing research suggests HAND is prevalent however the aetiology remains unclear. This study aims to determine whether HAND is truly prevalent and explore potential causes in PLWH on c‐ART using objective structural measures. Method: A systematic sample of PLWH aged ≥ 50 receiving combination antiretroviral treatment (cART) according to local guidelines were recruited from a HIV clinic in Kilimanjaro, Tanzania. Demographic data and comorbidities were self‐reported. HIV‐disease management data were obtained from detailed clinic data sheets. HIV viral load and CD4 count were measured. A detailed low‐literacy neurocognitive battery, informant history for functional impairment and neurological examination were conducted and HAND diagnosis made by consensus panel using AAN criteria. Cerebral atrophy (brain and ventricle volume) and WMH were measured using quantitative analysis of 1.5T MRI. Result: This cohort (n=91, 100% on cART, 64.8% female) had well‐managed HIV (75.9% suppressed viral load, median CD4 507 cells/ul). However, 66.7% had gross atrophy on their MRI scan, and HAND had a prevalence of 63.7%. The significant independent predictor (IP) of decreased brain volume was older age at HIV diagnosis (p=.001), and of increased ventricle volume was increased age (p<.0001), male gender (p<.0001) and increased frailty (p<.0001). The significant IPs of increased WMH volume were increased age (p<.0001) and smoking (p=.021). Only memory impairment independently predicted all structural measures. Conclusion: This is the first MRI study of older c‐ART treated PLWH in Africa. Despite c‐ART and good disease management, HAND was objectively prevalent and unrelated to measures of HIV disease severity. Cerebral atrophy and WMH were associated with factors of neurodegeneration. Cerebral atrophy was associated with male gender and older age at diagnosis. Association with older age at diagnosis may be 'legacy effect' of early CNS effect of the HIV virus rather than current management. [ABSTRACT FROM AUTHOR]