Sex differences in brain atrophy in dementia with Lewy bodies.

INTRODUCTION: Sex influences neurodegeneration, but it has been poorly investigated in dementia with Lewy bodies (DLB). We investigated sex differences in brain atrophy in DLB using magnetic resonance imaging (MRI). METHODS: We included 436 patients from the European-DLB consortium and the Mayo Clinic. Sex differences and sex-by-age interactions were assessed through visual atrophy rating scales (n = 327; 73 ± 8 years, 62% males) and automated estimations of regional gray matter volume and cortical thickness (n = 165; 69 ± 9 years, 72% males). RESULTS: We found a higher likelihood of frontal atrophy and smaller volumes in six cortical regions in males and thinner olfactory cortices in females. There were significant sex-by-age interactions in volume (six regions) and cortical thickness (seven regions) across the entire cortex. DISCUSSION: We demonstrate that males have more widespread cortical atrophy at younger ages, but differences tend to disappear with increasing age, with males and females converging around the age of 75. HIGHLIGHTS: Male DLB patients had higher odds for frontal atrophy on radiological visual rating scales. Male DLB patients displayed a widespread pattern of cortical gray matter alterations on automated methods. Sex differences in gray matter measures in DLB tended to disappear with increasing age.

(Dis-)Connected Dots in Dementia with Lewy Bodies-A Systematic Review of Connectivity Studies.

Studies on dementia with Lewy bodies (DLB) have mainly focused on the degeneration of distinct cortical and subcortical regions related to the deposition of Lewy bodies. In view of the proposed trans-synaptic spread of the α-synuclein pathology, investigating the disease only in this segregated fashion would be detrimental to our understanding of its progression. In this systematic review, we summarize findings on structural and functional brain connectivity in DLB, as connectivity measures may offer better insights on how the brain is affected by the spread of the pathology. Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we searched Web of Science, PubMed, and SCOPUS for relevant articles published up to November 1, 2021. Of 1215 identified records, we selected and systematically reviewed 53 articles that compared connectivity features between patients with DLB and healthy controls. Structural and functional magnetic resonance imaging, positron emission tomography, single-positron emission computer tomography, and electroencephalography assessments of patients revealed widespread abnormalities within and across brain networks in DLB. Frontoparietal, default mode, and visual networks and their connections to other brain regions featured the most consistent disruptions, which were also associated with core clinical features and cognitive impairments. Furthermore, graph theoretical measures revealed disease-related decreases in local and global network efficiency. This systematic review shows that structural and functional connectivity characteristics in DLB may be particularly valuable at early stages, before overt brain atrophy can be observed. This knowledge may help improve the diagnosis and prognosis in DLB as well as pinpoint targets for future disease-modifying treatments. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Research diagnostic criteria for mild cognitive impairment with Lewy bodies: A systematic review and meta-analysis.

INTRODUCTION: Operationalized research criteria for mild cognitive impairment with Lewy bodies (MCI-LB) were published in 2020. The aim of this systematic review and meta-analysis was to review the evidence for the diagnostic clinical features and biomarkers in MCI-LB set out in the criteria. METHODS: MEDLINE, PubMed, and Embase were searched on 9/28/22 for relevant articles. Articles were included if they presented original data reporting the rates of diagnostic features in MCI-LB. RESULTS: Fifty-seven articles were included. The meta-analysis supported the inclusion of the current clinical features in the diagnostic criteria. Evidence for striatal dopaminergic imaging and meta-iodobenzylguanidine cardiac scintigraphy, though limited, supports their inclusion. Quantitative electroencephalogram (EEG) and fluorodeoxyglucose positron emission tomography (PET) show promise as diagnostic biomarkers. DISCUSSION: The available evidence largely supports the current diagnostic criteria for MCI-LB. Further evidence will help refine the diagnostic criteria and understand how best to apply them in clinical practice and research. HIGHLIGHTS: A meta-analysis of the diagnostic features of MCI-LB was carried out. The four core clinical features were more common in MCI-LB than MCI-AD/stable MCI. Neuropsychiatric and autonomic features were also more common in MCI-LB. More evidence is needed for the proposed biomarkers. FDG-PET and quantitative EEG show promise as diagnostic biomarkers in MCI-LB.

No Effect of Anodal tDCS on Verbal Episodic Memory Performance and Neurotransmitter Levels in Young and Elderly Participants.

Healthy ageing is accompanied by cognitive decline that affects episodic memory processes in particular. Studies showed that anodal transcranial direct current stimulation (tDCS) to the left dorsolateral prefrontal cortex (DLPFC) may counteract this cognitive deterioration by increasing excitability and inducing neuroplasticity in the targeted cortical region. While stimulation gains are more consistent in initial low performers, relying solely on behavioural measures to predict treatment benefits does not suffice for a reliable implementation of this method as a therapeutic option. Hence, an exploration of the underlying neurophysiological mechanisms regarding the differential stimulation effect is warranted. Glutamatergic metabolites (Glx) and γ-aminobutyric acid (GABA) are involved in learning and memory processes and can be influenced with tDCS; wherefore, they present themselves as potential biomarkers for tDCS-induced behavioural gains, which are affiliated with neuroplasticity processes. In the present randomized, double-blind, sham-controlled, crossover study, 33 healthy young and 22 elderly participants received anodal tDCS to their left DLPFC during the encoding phase of a verbal episodic memory task. Using MEGA-PRESS edited magnetic resonance spectroscopy (MRS), Glx and GABA levels were measured in the left DLPFC before and after the stimulation period. Further, we tested whether baseline performance and neurotransmitter levels predicted subsequent gains. No beneficial group effects of tDCS emerged in either verbal retrieval performances or neurotransmitter concentrations. Moreover, baseline performance levels did not predict stimulation-induced cognitive gains, nor did Glx or GABA levels. Nevertheless, exploratory analyses suggested a predictive value of the Glx : GABA ratio, with lower ratios at baseline indicating greater tDCS-related gains in delayed recall performance. This highlights the importance of further studies investigating neurophysiological mechanisms underlying previously observed stimulation-induced cognitive benefits and their respective interindividual heterogeneity.

Gray matter asymmetries in aging and neurodegeneration: A review and meta-analysis.

Inter-hemispheric asymmetries are a common phenomenon of the human brain. Some evidence suggests that neurodegeneration related to aging and disease may preferentially affect the left-usually language- and motor-dominant-hemisphere. Here, we used activation likelihood estimation meta-analysis to assess gray matter (GM) loss and its lateralization in healthy aging and in neurodegeneration, namely, mild cognitive impairment (MCI), Alzheimer's dementia (AD), Parkinson's disease (PD), and Huntington's disease (HD). This meta-analysis, comprising 159 voxel-based morphometry publications (enrolling 4,469 patients and 4,307 controls), revealed that GM decline appeared to be asymmetric at trend levels but provided no evidence for increased left-hemisphere vulnerability. Regions with asymmetric GM decline were located in areas primarily affected by neurodegeneration. In HD, the left putamen showed converging evidence for more pronounced atrophy, while no consistent pattern was found in PD. In MCI, the right hippocampus was more atrophic than its left counterpart, a pattern that reversed in AD. The stability of these findings was confirmed using permutation tests. However, due to the lenient threshold used in the asymmetry analysis, further work is needed to confirm our results and to provide a better understanding of the functional role of GM asymmetries, for instance in the context of cognitive reserve and compensation. Hum Brain Mapp 38:5890-5904, 2017. © 2017 Wiley Periodicals, Inc.

Tuning noninvasive brain stimulation with MRI to cope with intersubject variability.

PURPOSE OF REVIEW: The review aims at highlighting the additional benefit that can be gained from combining noninvasive brain stimulation as well as repetitive sensory stimulation protocols with MRI techniques to account for the intersubject variability observed in those treatments. Potentially, this should help to identify predictive patterns in the individual receptiveness to the treatment. RECENT FINDINGS: Knowledge about the underlying physiological principles of excitability changes as induced by noninvasive brain stimulation or repetitive sensory stimulation is accumulating, revealing strong associations with plasticity processes at the synaptic level. In this context, MRI techniques, such as magnetic resonance spectroscopy and functional MRI, emerged as valuable tools for the qualitative assessment of baseline states and induced changes. Those physiological readouts can help explain the interindividual heterogeneity found in behavioural and/or clinical responses to the specific stimulation protocols. This knowledge will eventually translate, first, into the preliminary classification of study participants into treatment groups according to their neurophysiological baseline state and expected responses to a particular stimulation. Subsequently, this should also aid the optimization of stimulation protocols according to the classification outcome, resulting in retuned protocols for particular groups of study participants. SUMMARY: The consistent MRI-based monitoring of stimulation effects in the neural network promises a considerable gain for the customization of intervention protocols with improved therapeutic potential and rehabilitative predictions.

Differentiating Prodromal Dementia with Lewy Bodies from Prodromal Alzheimer's Disease: A Pragmatic Review for Clinicians.

This pragmatic review synthesises the current understanding of prodromal dementia with Lewy bodies (pDLB) and prodromal Alzheimer's disease (pAD), including clinical presentations, neuropsychological profiles, neuropsychiatric symptoms, biomarkers, and indications for disease management. The core clinical features of dementia with Lewy bodies (DLB)-parkinsonism, complex visual hallucinations, cognitive fluctuations, and REM sleep behaviour disorder are common prodromal symptoms. Supportive clinical features of pDLB include severe neuroleptic sensitivity, as well as autonomic and neuropsychiatric symptoms. The neuropsychological profile in mild cognitive impairment attributable to Lewy body pathology (MCI-LB) tends to include impairment in visuospatial skills and executive functioning, distinguishing it from MCI due to AD, which typically presents with impairment in memory. pDLB may present with cognitive impairment, psychiatric symptoms, and/or recurrent episodes of delirium, indicating that it is not necessarily synonymous with MCI-LB. Imaging, fluid and other biomarkers may play a crucial role in differentiating pDLB from pAD. The current MCI-LB criteria recognise low dopamine transporter uptake using positron emission tomography or single photon emission computed tomography (SPECT), loss of REM atonia on polysomnography, and sympathetic cardiac denervation using meta-iodobenzylguanidine SPECT as indicative biomarkers with slowing of dominant frequency on EEG among others as supportive biomarkers. This review also highlights the emergence of fluid and skin-based biomarkers. There is little research evidence for the treatment of pDLB, but pharmacological and non-pharmacological treatments for DLB may be discussed with patients. Non-pharmacological interventions such as diet, exercise, and cognitive stimulation may provide benefit, while evaluation and management of contributing factors like medications and sleep disturbances are vital. There is a need to expand research across diverse patient populations to address existing disparities in clinical trial participation. In conclusion, an early and accurate diagnosis of pDLB or pAD presents an opportunity for tailored interventions, improved healthcare outcomes, and enhanced quality of life for patients and care partners.

Grey matter networks in women and men with dementia with Lewy bodies.

Sex differences permeate many aspects of dementia with Lewy bodies (DLB), yet sex differences in patterns of neurodegeneration in DLB remain largely unexplored. Here, we test whether grey matter networks differ between sexes in DLB and compare these findings to sex differences in healthy controls. In this cross-sectional study, we analysed clinical and neuroimaging data of patients with DLB and cognitively healthy controls matched for age and sex. Grey matter networks were constructed by pairwise correlations between 58 regional volumes after correction for age, intracranial volume, and centre. Network properties were compared between sexes and diagnostic groups. Additional analyses were conducted on w-scored data to identify DLB-specific sex differences. Data from 119 (68.7 ± 8.4 years) men and 45 women (69.9 ± 9.1 years) with DLB, and 164 healthy controls were included in this study. Networks of men had a lower nodal strength compared to women. In comparison to healthy women, the grey matter networks of healthy men showed a higher global efficiency, modularity, and fewer modules. None of the network measures showed significant sex differences in DLB. Comparing DLB patients with healthy controls revealed global differences in women and more local differences in men. Modular analyses showed a more distinct demarcation between cortical and subcortical regions in men compared with women. While topologies of grey matter networks differed between sexes in healthy controls, those sex differences were diluted in DLB patients. These findings suggest a disease-driven convergence of neurodegenerative patterns in women and men with DLB, which may inform precision medicine in DLB.

Sex differences in grey matter networks in dementia with Lewy bodies.

Objectives: Sex differences permeate many aspects of dementia with Lewy bodies (DLB), including epidemiology, pathogenesis, disease progression, and symptom manifestation. However, less is known about potential sex differences in patterns of neurodegeneration in DLB. Here, we test whether grey matter networks also differ between female and male DLB patients. To assess the specificity of these sex differences to DLB, we additionally investigate sex differences in healthy controls (HCs). Methods: A total of 119 (68.7 ± 8.4 years) male and 45 female (69.9 ± 9.1 years) DLB patients from three European centres and the Mayo Clinic were included in this study. Additionally, we included 119 male and 45 female age-matched HCs from the Mayo Clinic. Grey matter volumes of 58 cortical, subcortical, cerebellar, and pontine brain regions derived from structural magnetic resonance images were corrected for age, intracranial volume, and centre. Sex-specific grey matter networks for DLB patients and HCs were constructed by correlating each pair of brain regions. Network properties of the correlation matrices were compared between sexes and groups. Additional analyses were conducted on W-scored data to identify DLB-specific findings. Results: Networks of male HCs and male DLB patients were characterised by a lower nodal strength compared to their respective female counterparts. In comparison to female HCs, the grey matter networks of male HCs showed a higher global efficiency, modularity, and a lower number of modules. None of the global and nodal network measures showed significant sex differences in DLB. Conclusions: The disappearance of sex differences in the structural grey matter networks of DLB patients compared to HCs may indicate a sex-dependent network vulnerability to the alpha-synuclein pathology in DLB. Future studies might investigate whether the differences in structural network measures are associated with differences in cognitive scores and clinical symptoms between the sexes.

Sex differences in brain atrophy in dementia with Lewy bodies.

Background and objectives: Sex is an important contributing factor to neuroimaging phenotypes in brain disorders. However, little is known about the contribution of sex differences to the neurodegeneration in dementia with Lewy bodies (DLB). We investigated sex differences in probable DLB patients by using both visual rating scales of lobar atrophy and automated estimations of regional atrophy. Methods: We included 442 probable DLB patients from the European-DLB consortium and the Mayo Clinic who have magnetic resonance imaging (MRI) data available. We assessed sex differences and the sex-by-age interaction in two largely independent samples through visual rating scales of lobar atrophy (n = 333; mean age 73 ± 8 years, 62% males) and automated regional estimations of gray matter (GM) volume and mean cortical thickness (CTh) (n = 165; mean age 69 ± 9 years, 72% males). We used binary logistic regression and ANOVA for statistical analysis. Results: We found a statistically significantly higher likelihood of frontal atrophy measured by the global cortical atrophy-frontal subscale (GCA-F) in males (40% of males had an abnormal GCA-F score versus 29% of females, P-value = 0.006). Using automated estimations, we found smaller GM volumes in 6 cortical regions in males compared with females, as well as smaller GM volume in the entorhinal cortex and thinner olfactory cortices in females, compared with males. The sex-by-age interaction showed statistically significant results in 6 cortical volumes and 7 mean CTh estimations (P-value ≤ 0.05), accentuated in the right middle frontal gyrus (FDR-adjusted P-value = 0.047). These cross-sectional interactions indicated that while females have statistically significantly less atrophy than males at younger ages, differences become non-significant at older ages, with females showing the same level of atrophy than males around the age of 75. Conclusions: This study demonstrates sex differences on brain atrophy in probable DLB. While male DLB patients have a more widespread pattern of cortical atrophy at younger ages, these sex differences tend to disappear with increasing age. Longitudinal studies will help establish these cross-sectional findings and inform on sex and age considerations to the use of MRI in clinical routine, as the field moves towards precision medicine.

Stimulating aged brains with transcranial direct current stimulation: Opportunities and challenges.

Ageing involves significant neurophysiological changes that are both systematic while at the same time exhibiting divergent trajectories across individuals. These changes underlie cognitive impairments in elderly while also affecting the response of aged brains to interventions like transcranial direct current stimulation (tDCS). While the cognitive benefits of tDCS are more variable in elderly, older adults also respond differently to stimulation protocols compared to young adults. The age-related neurophysiological changes influencing the responsiveness to tDCS remain to be addressed in-depth. We review and discuss the premise that, in comparison to the better calibrated brain networks present in young adults, aged systems perform further away from a homoeostatic set-point. We argue that this age-related neurophysiological deviation from the homoeostatic optimum extends the leeway for tDCS to modulate the aged brain. This promotes the potency of immediate tDCS effects to induce directional plastic changes towards the homoeostatic equilibrium despite the impaired plasticity induction in elderly. We also consider how age-related neurophysiological changes pose specific challenges for tDCS that necessitate proper adaptations of stimulation protocols. Appreciating the distinctive properties of aged brains and the accompanying adjustment of stimulation parameters can increase the potency and reliability of tDCS as a treatment avenue in older adults.

Anodal tDCS Enhances Verbal Episodic Memory in Initially Low Performers.

The left dorsolateral prefrontal cortex (DLPFC) is involved in encoding and retrieval of episodic memories, and thus, is frequently targeted in non-invasive brain stimulation paradigms, aiming for its functional modulation. Anodal transcranial direct current stimulation (tDCS), that boosts neuronal excitability in stimulated cortical areas, has been found to increase cognitive skills differentially, depending on the initial performance. We hypothesize that the benefit of tDCS on verbal episodic memory can be extrapolated from the participants' baseline performance. In the present randomized, double-blind, parallel group study, healthy young adults (n = 43) received either real anodal or sham tDCS over their left DLPFC during the encoding phase of a verbal episodic memory task. Forty words were presented visually thrice with immediate vocal retrieval after each block and an additional delayed recall. We conducted a moderation analysis to test the modulating effect of initial episodic memory retrieval, adjusted for primacy and recency effects, on delayed recall under real or sham stimulation. Despite the absence of a significantly beneficial tDCS effect at the group level, we found that the number of remembered midlist words in the first retrieval significantly moderated the stimulation effect in such a way that initially low performers experienced the highest gain from real stimulation. These results suggest that anodal tDCS to the left DLPFC improves memory functions only so far. While only marginal stimulation-induced gains occur in cognitively unimpaired populations, greater stimulation benefits might be expected in individuals with clinically relevant deficiencies in the verbal episodic memory domain.