Functional and structural brain network correlates of visual hallucinations in Lewy body dementia.

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.

Gait-Related Metabolic Covariance Networks at Rest in Parkinson's Disease.

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.

Frontal white matter lesions in Alzheimer's disease are associated with both small vessel disease and AD-associated cortical pathology.

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 (Aß) 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 Aß 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.

Spatial Covariance of Cholinergic Muscarinic M1 /M4 Receptors in Parkinson's Disease.

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 M1 /M4 receptors in PD and their relationship with cognition and motor symptoms. METHODS: Some 19 PD and 24 older adult controls underwent 123 I-iodo-quinuclidinyl-benzilate (QNB) (M1 /M4 receptor) and 99m Tc-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 M1 /M4 spatial covariance patterns associated with PD. RESULTS: A cholinergic M1 /M4 pattern that converged onto key hubs of the default, auditory-visual, salience, and sensorimotor networks fully discriminated PD patients from controls (F1,41  = 135.4, P < 0.001). In PD, we derived M1 /M4 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 M1 /M4 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 M1 /M4 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 M1 /M4 binding within default and frontal executive networks could be an indicator of future cognitive decline. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Accuracy of dopaminergic imaging as a biomarker for mild cognitive impairment with Lewy bodies.

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

Concomitant neurodegenerative pathologies contribute to the transition from mild cognitive impairment to dementia.

INTRODUCTION: 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. METHODS: Data came from 670 cases from the Brains for Dementia research program. Cases were categorized into PurP, mixed SevP, or a main disease with additional LowP; 508 cases had a clinical dementia rating. RESULTS: 69.9% of cases had LowP, 22.7% had PurP, and 7.5% had mixed SevP. Additional LowP increased the likelihood of having mild dementia versus mild cognitive impairment (MCI) by almost 20-fold (odds ratio = 19.5). DISCUSSION: Most aged individuals have multiple brain pathologies. The presence of one additional LowP can significantly worsen cognitive decline, increasing the risk of transitioning from MCI to dementia 20-fold. Multimorbidity should be considered in dementia research and clinical studies.

Cortical thinning in dementia with Lewy bodies and Parkinson disease dementia.

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

Diagnostic accuracy of dopaminergic imaging in prodromal dementia with Lewy bodies.

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

Neuropsychiatric symptoms and cognitive profile in mild cognitive impairment with Lewy bodies.

BACKGROUND: The accurate clinical characterisation of mild cognitive impairment (MCI) is becoming increasingly important. The aim of this study was to compare the neuropsychiatric symptoms and cognitive profile of MCI with Lewy bodies (MCI-LB) with Alzheimer's disease MCI (MCI-AD). METHODS: Participants were ⩾60 years old with MCI. Each had a thorough clinical and neuropsychological assessment and 2ß-carbomethoxy-3ß-(4-iodophenyl)-N-(3-fluoropropyl)-nortropane single photon emission computed tomography FP-CIT SPECT). MCI-LB was diagnosed if two or more diagnostic features of dementia with Lewy bodies were present (visual hallucinations, cognitive fluctuations, motor parkinsonism, rapid eye movement sleep behaviour disorder or positive FP-CIT SPECT). A Lewy body Neuropsychiatric Supportive Symptom Count (LBNSSC) was calculated based on the presence or absence of the supportive neuropsychiatric symptoms defined by the 2017 DLB diagnostic criteria: non-visual hallucinations, delusions, anxiety, depression and apathy. RESULTS: MCI-LB (n = 41) had a higher LBNSSC than MCI-AD (n = 24; 1.8 ± 1.1 v. 0.7 ± 0.9, p = 0.001). 67% of MCI-LB had two or more of those symptoms, compared with 16% of MCI-AD (Likelihood ratio = 4.2, p < 0.001). MCI-LB subjects scored lower on tests of attention, visuospatial function and verbal fluency. However, cognitive test scores alone did not accurately differentiate MCI-LB from MCI-AD. CONCLUSIONS: MCI-LB is associated with neuropsychiatric symptoms and a cognitive profile similar to established DLB. This supports the concept of identifying MCI-LB based on the presence of core diagnostic features of DLB and abnormal FP-CIT SPECT imaging. The presence of supportive neuropsychiatric clinical features identified in the 2017 DLB diagnostic criteria was helpful in differentiating between MCI-LB and MCI-AD.

Parietal white matter lesions in Alzheimer's disease are associated with cortical neurodegenerative pathology, but not with small vessel disease.

Cerebral white matter lesions (WML) encompass axonal loss and demyelination, and the pathogenesis is assumed to be small vessel disease (SVD)-related ischemia. However, WML may also result from the activation of Wallerian degeneration as a consequence of cortical Alzheimer's disease (AD) pathology, i.e. hyperphosphorylated tau (HPτ) and amyloid-beta (Aß) deposition. WML seen in AD have a posterior predominance compared to non-demented individuals but it is unclear whether the pathological and molecular signatures of WML differ between these two groups. We investigated differences in the composition and aetiology of parietal WML from AD and non-demented controls. Parietal WML tissue from 55 human post-mortem brains (AD, n = 27; non-demented controls, n = 28) were quantitatively assessed for axonal loss and demyelination, as well as for cortical HPτ and Aß burden and SVD. Biochemical assessment included Wallerian degeneration protease calpain and the myelin-associated glycoprotein (MAG) to proteolipid protein (PLP) ratio (MAG:PLP) as a measure of hypoperfusion. WML severity was associated with both axonal loss and demyelination in AD, but only with demyelination in controls. Calpain was significantly increased in WML tissue in AD, whereas MAG:PLP was significantly reduced in controls. Calpain levels were associated with increasing amounts of cortical AD-pathology but not SVD. We conclude that parietal WML seen in AD differ in their pathological composition and aetiology compared to WML seen in aged controls: WML seen in AD may be associated with Wallerian degeneration that is triggered by cortical AD-pathology, whereas WML in aged controls are due to ischaemia. Hence, parietal WML as seen on MRI should not invariably be interpreted as a surrogate biomarker for SVD as they may be indicative of cortical AD-pathology, and therefore, AD should also be considered as the main underlying cause for cognitive impairment in cases with parietal WML.

Structural grey matter changes in the substantia innominata in Alzheimer's disease and dementia with Lewy bodies: a DARTEL-VBM study.

OBJECTIVES: Several cholinergic nuclei, and in particular the nucleus basalis of Meynert, are localised to the substantia innominata in the basal forebrain. These nuclei provide major cholinergic innervation to the cerebral cortex and hippocampus, and have an essential role in cognitive function. The aim of this study was to investigate volumetric grey matter (GM) changes in the substantia innominata from structural T1 images in Alzheimer's disease (AD), dementia with Lewy bodies (DLB) and healthy older participants using voxel-based morphometry. METHODS: Participants (41 DLB, 47 AD and 39 controls) underwent 3 T T1 magnetic resonance imaging and cognitive assessments. Voxel-based morphometry analysis used SPM8 with a substantia innominata brain mask to define the subspace for voxel GM analyses. Group differences, and selected behavioural and clinical correlates, were assessed. RESULTS: Compared with that in controls, bilateral GM loss in the substantia innominata was apparent in both AD and DLB. Relative to controls, significant bilateral GM loss in the substantia innominata was observed in DLB and AD. In DLB, significant associations were also observed between substantia innominata GM volume loss, and the levels of cognitive impairment and severity of cognitive fluctuations. CONCLUSIONS: Relative to that controls, atrophy of the substantia innominata was apparent in DLB and AD, and is associated with specific clinical manifestations in DLB. © 2016 The Authors. International Journal of Geriatric Psychiatry Published by John Wiley & Sons Ltd.

The influence of hippocampal atrophy on the cognitive phenotype of dementia with Lewy bodies.

OBJECTIVE: The level of hippocampal atrophy in dementia with Lewy bodies (DLB) is typically less than that observed in Alzheimer's disease (AD). However, it is not known how the cognitive phenotype of DLB is influenced by hippocampal atrophy or the atrophy of adjacent medial temporal lobe structures. METHODS: Dementia with Lewy bodies (n = 65), AD (n = 76) and control (n = 63) participants underwent 3T magnetic resonance imaging and cognitive Cambridge Cognitive Examination and Mini-Mental State Examination (CAMCOG and MMSE) assessments. Hippocampal volume, and parahippocampal, entorhinal and temporal pole cortical thickness, was compared between groups. Regression models were used to investigate whether hippocampal volume and cortical thickness associated with global cognition and cognitive subdomains. RESULTS: Dementia with Lewy bodies, AD and control participants showed significantly different hippocampal, parahippocampal and entorhinal cortical thinning, where atrophy was greatest in AD and intermediate in DLB. Temporal pole thickness was reduced in DLB and AD compared with control participants. In DLB, but not AD, hippocampal volume associated with total CAMCOG, CAMCOG memory and MMSE scores. In DLB, parahippocampal, entorhinal and temporal pole thickness associated with total CAMCOG and CAMCOG memory scores, parahippocampal thickness associated with MMSE scores, and entorhinal thickness associated with CAMCOG executive function scores. CONCLUSIONS: In this large sample, these results are in agreement with other studies indicating that hippocampal atrophy is less severe in DLB than AD. Hippocampal atrophy and medial temporal lobe cortical thickness were associated with the severity of cognitive symptoms, suggesting that atrophy in these structures, as a potential proxy of AD pathology, may partly mediate specific DLB cognitive symptoms. © 2017 The Authors. International Journal of Geriatric Psychiatry Published by John Wiley & Sons Ltd.

Computational meta-analysis of statistical parametric maps in major depression.

OBJECTIVE: Several neuroimaging meta-analyses have summarized structural brain changes in major depression using coordinate-based methods. These methods might be biased toward brain regions where significant differences were found in the original studies. In this study, a novel voxel-based technique is implemented that estimates and meta-analyses between-group differences in grey matter from individual MRI studies, which are then applied to the study of major depression. METHODS: A systematic review and meta-analysis of voxel-based morphometry studies were conducted comparing participants with major depression and healthy controls by using statistical parametric maps. Summary effect sizes were computed correcting for multiple comparisons at the voxel level. Publication bias and heterogeneity were also estimated and the excess of heterogeneity was investigated with metaregression analyses. RESULTS: Patients with major depression were characterized by diffuse bilateral grey matter loss in ventrolateral and ventromedial frontal systems extending into temporal gyri compared to healthy controls. Grey matter reduction was also detected in the right parahippocampal and fusiform gyri, hippocampus, and bilateral thalamus. Other areas included parietal lobes and cerebellum. There was no evidence of statistically significant publication bias or heterogeneity. CONCLUSIONS: The novel computational meta-analytic approach used in this study identified extensive grey matter loss in key brain regions implicated in emotion generation and regulation. Results are not biased toward the findings of the original studies because they include all available imaging data, irrespective of statistically significant regions, resulting in enhanced detection of additional areas of grey matter loss.

An evidence-based algorithm for the utility of FDG-PET for diagnosing Alzheimer's disease according to presence of medial temporal lobe atrophy.

BACKGROUND: Imaging biomarkers for Alzheimer's disease include medial temporal lobe atrophy (MTLA) depicted on computed tomography (CT) or magnetic resonance imaging (MRI) and patterns of reduced metabolism on fluorodeoxyglucose positron emission tomography (FDG-PET). AIMS: To investigate whether MTLA on head CT predicts the diagnostic usefulness of an additional FDG-PET scan. METHOD: Participants had a clinical diagnosis of Alzheimer's disease (n = 37) or dementia with Lewy bodies (DLB; n = 30) or were similarly aged controls (n = 30). We visually rated MTLA on coronally reconstructed CT scans and, separately and blind to CT ratings, abnormal appearances on FDG-PET scans. RESULTS: Using a pre-defined cut-off of MTLA ⩾5 on the Scheltens (0-8) scale, 0/30 controls, 6/30 DLB and 23/30 Alzheimer's disease had marked MTLA. FDG-PET performed well for diagnosing Alzheimer's disease v DLB in the low-MTLA group (sensitivity/specificity of 71%/79%), but in the high-MTLA group diagnostic performance of FDG-PET was not better than chance. CONCLUSIONS: In the presence of a high degree of MTLA, the most likely diagnosis is Alzheimer's disease, and an FDG-PET scan will probably not provide significant diagnostic information. However, in cases without MTLA, if the diagnosis is unclear, an FDG-PET scan may provide additional clinically useful diagnostic information.

Imaging in Dementia With Lewy Bodies: An Overview.

Dementia with Lewy bodies (DLB) while common in older age can present a diagnostic challenge to clinicians and is often misdiagnosed as Alzheimer disease (AD). Imaging studies have improved our understanding of the neurobiological changes in DLB during life and how they differ from AD. This has led to significant advances in the development of new techniques, such as dopaminergic imaging, which can aid the clinical diagnosis. Other functional imaging methods also show promise in helping to assess the influence of differing pathologies in DLB, most notably, AD-related and vascular pathology during life. This article will provide an overview of the main imaging findings in DLB.

Depressive symptoms are associated with daytime sleepiness and subjective sleep quality in dementia with Lewy bodies.

OBJECTIVE: Sleep problems and depression are common symptoms in dementia with Lewy bodies (DLB), where patients typically experience subjectively poor sleep quality, fatigue and excessive daytime sleepiness. However, whilst sleep disturbances have been linked to depression, this relationship has not received much attention in DLB. The present cross-sectional study addresses this by examining whether depressive symptoms are specifically associated with subjective sleep quality and daytime sleepiness in DLB, and by examining other contributory factors. METHODS: DLB patients (n = 32) completed the Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS) and the 15-item Geriatric Depression Scale (GDS-15). Motor and cognitive functioning was also assessed. Pearson correlations were used to assess the relationship between GDS-15, ESS and PSQI scores. RESULTS: GDS-15 scores were positively associated with both ESS (r = 0.51, p < 0.01) and PSQI (r = 0.59, p < 0.001) scores. CONCLUSIONS: Subjective poor sleep and daytime sleepiness were associated with depressive symptoms in DLB. Given the cross-sectional nature of the present study, the directionality of this relationship cannot be determined, although this association did not appear to be mediated by sleep quality or daytime sleepiness. Nevertheless, these findings have clinical relevance; daytime sleepiness or poor sleep quality might indicate depression in DLB, and subsequent work should examine whether the treatment of depression can reduce excessive daytime sleepiness and improve sleep quality in DLB patients. Alternatively, more rigorous screening for sleep problems in DLB might assist the treatment of depression. © 2015 The Authors. International Journal of Geriatric Psychiatry published by John Wiley & Sons, Ltd.

Subcortical volume changes in dementia with Lewy bodies and Alzheimer's disease. A comparison with healthy aging.

BACKGROUND: Differentiating Alzheimer's disease (AD) and dementia with Lewy bodies (DLB), two of the commonest forms of dementia in older age, remains a diagnostic challenge. To assist with better understanding of the differences between the conditions during life, we assessed limbic and subcortical brain volumes in AD, DLB, and healthy older individuals using magnetic resonance imaging (MRI), with the hypothesis that when compared with controls, subcortical volumes would be reduced to a greater extent in DLB than in AD. METHODS: One hundred participants (35 healthy controls, 32 AD, and 33 DLB) underwent 3 Tesla T1 weighted MR scanning. Volumes were automatically segmented for each participant using FreeSurfer, then expressed as a percentage of their total intracranial volumes. Group effects were assessed using multivariate analysis of covariance, controlling for age and gender. RESULTS: Significant group effects were apparent among subcortical brain volumes (F 28,162 = 4.8, p < 0.001; Wilk's Λ = 0.30, partial η 2 = 0.45), while univariate tests showed differences in all volumetric measures (p AD, p < 0.008). CONCLUSIONS: For similar levels of dementia severity, DLB appears to have greater involvement of subcortical brain atrophy than AD. Further investigation of the subcortical brain structures in DLB is warranted to fully understand their neurobiological role in this disease.

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

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

Neuropathologically mixed Alzheimer's and Lewy body disease: burden of pathological protein aggregates differs between clinical phenotypes.

Multiple different pathological protein aggregates are frequently seen in human postmortem brains and hence mixed pathology is common. Mixed dementia on the other hand is less frequent and neuropathologically should only be diagnosed if criteria for more than one full blown disease are met. We quantitatively measured the amount of hyperphosphorylated microtubule associated tau (HP-τ), amyloid-ß protein (Aß) and α-synuclein (α-syn) in cases that were neuropathologically diagnosed as mixed Alzheimer's disease (AD) and neocortical Lewy body disease (LBD) but clinically presented either as dementia due to AD or LBD, the latter including dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD). Our study group consisted of 28 cases (mean age, 76.11 SE: ±1.29 years; m:f, 17:11) of which 19 were neuropathologically diagnosed as mixed AD/DLB. Clinically, 8 mixed AD/DLB cases were diagnosed as AD (cAD), 8 as DLB (cDLB) and 3 as PDD (cPDD). In addition, we investigated cases that were both clinically and neuropathologically diagnosed as either AD (pure AD; n = 5) or DLB/neocortical LBD (pure DLB; n = 4). Sections from neocortical, limbic and subcortical areas were stained with antibodies against HP-τ, Aß and α-syn. The area covered by immunopositivity was measured using image analysis. cAD cases had higher HP-τ loads than both cDLB and cPDD and the distribution of HP-τ in cAD was similar to the one observed in pure AD whilst cDLB showed comparatively less hippocampal HP-τ load. cPDD cases showed lower HP-τ and Aß loads and higher α-syn loads. Here, we show that in neuropathologically mixed AD/DLB cases both the amount and the topographical distribution of pathological protein aggregates differed between distinct clinical phenotypes. Large-scale clinicopathological correlative studies using a quantitative methodology are warranted to further elucidate the neuropathological correlate of clinical symptoms in cases with mixed pathology.

Assessment of regional gray matter loss in dementia with Lewy bodies: a surface-based MRI analysis.

OBJECTIVE: To compare magnetic resonance imaging (MRI) patterns of cortical thinning in subjects with dementia with Lewy bodies (DLB), Alzheimer's disease (AD), and normal aging and investigate the relationship between cortical thickness and clinical measures. METHODS: Study participants (31 DLB, 30 AD, and 33 healthy comparison subjects) underwent 3-Tesla T1-weighted MRI and completed clinical and cognitive assessments. We used the FreeSurfer analysis package to measure cortical thickness and investigated the patterns of cortical thinning across groups. RESULTS: Cortical thinning in AD was found predominantly in the temporal and parietal areas extending into the frontal lobes (N = 63, df = 59, t >3.3, p <0.005, FDR-corrected). In DLB, cortical thinning was less diffuse with focal areas of cortical change predominantly affecting posterior structures (inferior parietal, posterior cingulate, and fusiform gyrus) (N = 64, df = 60, t >3.6, p <0.005, FDR-corrected). The average reduction in cortical thickness in medial temporal lobe structures was less in DLB (6%-10%) than in AD (15%-24%), and similar to the reduction in cortical thickness observed in other regions including inferior parietal, precuneus, and posterior cingulate (6%-9%). Associations between cortical thickness and clinical measures (MMSE and verbal fluency) were also observed in DLB (N = 31, df = 27, t >2.8, p <0.01 uncorrected). CONCLUSION: Cortical thickness may be a sensitive measure for characterising gray matter loss in DLB and highlights important structural imaging differences between the conditions.