(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

In vivo 1H-magnetic resonance spectroscopy can detect metabolic changes in APP/PS1 mice after donepezil treatment

<p>Abstract</p> <p>Background</p> <p>Donepezil improves cognitive functions in AD patients. Effects on the brain metabolites N-acetyl-L-aspartate, choline and <it>myo-</it>inositol levels have been reported in clinical studies using this drug. The APP/PS1 mouse coexpresses the mutated forms of human β-amyloid precursor protein (APP) and mutated human presenilin 1 (PS1). Consequently, the APP/PS1 mouse model reflects important features of the neurochemical profile in humans. <it>In vivo </it>magnetic resonance spectroscopy (¹H-MRS) was performed in fronto-parietal cortex and hippocampus (ctx/hipp) and in striatum (str). Metabolites were quantified using the LCModel and the final analysis was done using multivariate data analysis. The aim of this study was to investigate if multivariate data analysis could detect changes in the pattern of the metabolic profile after donepezil treatment.</p> <p>Results</p> <p>Significant differences were observed in the metabolic pattern of APP/PS1 mice in both str and ctx/hipp before and after donepezil treatment using multivariate data analysis, evidencing a significant treatment effect. A treatment effect was also seen in wild type (wt) mice in str. A significant decrease in the metabolic ratio taurine/creatine (Tau/tCr) was related to donepezil treatment (p < 0.05) in APP/PS1 mice in both brain regions. Furthermore, a significant influence on the choline/creatine (tCho/tCr) level was observed in treated APP/PS1 mice compared to untreated in str (p = 0.011). Finally, there was an increase in glutamate/creatine (Glu/tCr) in str in wt mice treated with donepezil.</p> <p>Conclusion</p> <p>Multivariate data analysis can detect changes in the metabolic profile in APP/PS1 mice after donepezil treatment. Effects on several metabolites that are measurable <it>in vivo </it>using MR spectroscopy were observed. Changes in Tau/tCr and tCho/tCr could possibly be related to changed cholinergic activity caused by donepezil treatment.</p

Associations of Vascular Risk Factors and APOE Genotype With Perivascular Spaces Among Community‐Dwelling Older Adults

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Association between Subcortical Lesions and Behavioral and Psychological Symptoms in Patients with Alzheimer's Disease.

Background/Aims: The most devastating features of Alz-heimer's disease (AD) are often the behavioral and psychological symptoms in dementia (BPSD). There is controversy as to whether subcortical lesions contribute to BPSD. The aim of this study was to examine the relationship between BPSD and subcortical lesions (white-matter lesions and lacunes) in AD. Methods: CT or MRI from 259 patients with mild-to-moderate AD were assessed with the Age-Related White Matter Changes scale. Linear measures of global and temporal atrophy and Mini-Mental State Examination scores were used to adjust for AD pathology and disease severity in logistic regression models with the BPSD items delusions, hallucinations, agitation, depression, anxiety, apathy and irritability. Results: Lacunes in the left basal ganglia were asso-ciated with delusions (OR 2.57, 95% CI 1.21-5.48) and hallucinations (OR 3.33, 95% CI 1.38-8.01) and lacunes in the right basal ganglia were associated with depression (OR 2.13, 95% CI 1.01-4.51). Conclusion: Lacunes in the basal ganglia resulted in a 2- to 3-fold increased risk of delusions, hallucinations and depression, when adjusting for cognition and atrophy. This suggests that basal ganglia lesions can contribute to BPSD in patients with AD, independently of the AD process

Cerebral connectivity and psychotic personality traits: A diffusion tensor imaging study

This study aims to investigate the relationship between regional connectivity in the brain white matter and the presence of psychotic personality traits, in healthy subjects with psychotic traits. Thirteen healthy controls were administered the MMPI-2, to assess psychotic traits and, according to MMPI results, a dichotomization into a group of "high-psychotic” and "low-psychotic” was performed. Diffusion tensor imaging (DTI) was used as a non-invasive measure, in order to obtain information about the fractional anisotropy (FA), an intravoxel index of local connectivity and, by means of a voxelwise approach, the between-group differences of the FA values were calculated. The "high-psychotic” group showed higher FA in the left arcuate fasciculus. Subjects with low scores for psychotic traits had significantly higher FA in the corpus callosum, right arcuate fasciculus, and fronto-parietal fibers. In line with previous brain imaging studies of schizophrenia spectrum disorders, our results suggest that psychotic personality traits are related to altered connectivity and brain asymmetr

Cerebral inflammation is an underlying mechanism of early death in Alzheimer’s disease: a 13-year cause-specific multivariate mortality study

Introduction: Although Alzheimer’s disease (AD) is associated with early death, its life expectancy differs greatly between patients. A better understanding of this heterogeneity may reveal important disease mechanisms underlying the malignancy of AD. The aim of this study was to examine the relation between AD pathologies and early death in AD caused by dementia. Methods: At a memory clinic, 247 referred consecutive patients with AD were monitored during 12.6 ± 1.6 years. Multivariate Cox regression analyses were performed with baseline measures of amyloid beta (Aβ) pathology (APOE genotype, cerebrospinal fluid (CSF) Aβ42) tau pathology (CSF phosphorylated tau and total tau), cerebrovascular pathology (white-matter lesions and CSF/serum albumin ratio), neuroinflammatory pathology (CSF soluble vascular cell adhesion molecule-1, sVCAM-1), frontal, temporal, and central brain atrophies, global cognition, sex, and age. Comorbidities and medications also were analyzed. All continuous variables were transformed to z scores to compare hazard ratios (HRs) and 95% confidence intervals (CIs). Results: At follow-up, 89% of the patients had died. The mean survival time was 6.4 ± 3.0 years. The AD pathology that independently predicted an early death caused by dementia was cerebral inflammation (sVCAM-1; HR, 1.32; 95% CI, 1.07–1.64). Other independent predictors were lower global cognition (HR, 0.51; 95% CI, 0.43–0.61), frontal atrophy (HR, 1.38; 95% CI, 1.12–1.70), and medial temporal atrophy (HR, 1.23; 95% CI, 1.02–1.49). When examining death caused by dementia and related causes (vascular diseases and infections), age (HR, 1.23; 95% CI, 1.04–1.46) and cerebrovascular pathology (white-matter lesions: HR, 1.17; 95% CI, 1.01–1.36; and CSF/serum albumin ratio: HR, 1.16; 95% CI, 1.001–1.34) were also significant risk factors in addition to the previous variables. No comorbidity or medication was significant in the specific-cause models. Conclusions: This is the first study to link neuroinflammation independently to early death in AD and, hence, a rapidly progressing disease. Frontal and medial temporal atrophies and low cognition were also significant predictors. These are probably downstream biomarkers that reflect neuronal degeneration and late-stage disease. Our results suggest that inflammation, and not amyloid or tau pathology, is an independent underlying mechanism in the malignancy of AD

Meta-Review of CSF Core Biomarkers in Alzheimer’s Disease: The State-of-the-Art after the New Revised Diagnostic Criteria

Background: Current research criteria for Alzheimer’s disease (AD) include cerebrospinal fluid (CSF) biomarkers into the diagnostic algorithm. However, spreading their use to the clinical routine is still questionable. Objective: To provide an updated, systematic and critical review on the diagnostic utility of the CSF core biomarkers for AD. Data sources: MEDLINE, PreMedline, EMBASE, PsycInfo, CINAHL, Cochrane Library, and CRD. Eligibility criteria: (1a) Systematic reviews with meta-analysis; (1b) Primary studies published after the new revised diagnostic criteria; (2) Evaluation of the diagnostic performance of at least one CSF core biomarker. Results: The diagnostic performance of CSF biomarkers is generally satisfactory. They are optimal for discriminating AD patients from healthy controls. Their combination may also be suitable for mild cognitive impairment (MCI) prognosis. However, CSF biomarkers fail to distinguish AD from other forms of dementia. Limitations: (1) Use of clinical diagnosis as standard instead of pathological postmortem confirmation; (2) variability of methodological aspects; (3) insufficiently long follow-up periods in MCI studies; and (4) lower diagnostic accuracy in primary care compared with memory clinics. Conclusion: Additional work needs to be done to validate the application of CSF core biomarkers as they are proposed in the new revised diagnostic criteria. The use of CSF core biomarkers in clinical routine is more likely if these limitations are overcome. Early diagnosis is going to be of utmost importance when effective pharmacological treatment will be available and the CSF core biomarkers can also be implemented in clinical trials for drug development

Default Mode Network Complexity and Cognitive Decline in Mild Alzheimer’s Disease

The human resting-state is characterized by spatially coherent brain activity at a low temporal frequency. The default mode network (DMN), one of so-called resting-state networks, has been associated with cognitive processes that are directed toward the self, such as introspection and autobiographic memory. The DMN’s integrity appears to be crucial for mental health. For example, patients with Alzheimer’s disease or other psychiatric conditions show disruptions of functional connectivity within the brain regions of the DMN. However, in prodromal or early stages of Alzheimer’s disease, physiological alterations are sometimes elusive, despite manifested cognitive impairment. While functional connectivity assesses the signal correlation between brain areas, multi-scale entropy (MSE) measures the complexity of the blood-oxygen level dependent signal within an area and thus might show local changes before connectivity is affected. Hence, we investigated alterations of functional connectivity and MSE within the DMN in fifteen mild Alzheimer’s disease patients as compared to fourteen controls. Potential associations of MSE with functional connectivity and cognitive abilities [i.e., mini-mental state examination (MMSE)] were assessed. A moderate decrease of DMN functional connectivity between posterior cingulate cortex and right hippocampus in Alzheimer’s disease was found, whereas no differences were evident for whole-network functional connectivity. In contrast, the Alzheimer’s disease group yielded lower global DMN-MSE than the control group. The most pronounced regional effects were localized in left and right hippocampi, and this was true for most scales. Moreover, MSE significantly correlated with functional connectivity, and DMN-MSE correlated positively with the MMSE in Alzheimer’s disease. Most interestingly, the right hippocampal MSE was positively associated with semantic memory performance. Thus, our results suggested that cognitive decline in Alzheimer’s disease is reflected by decreased signal complexity in DMN nodes, which might further lead to disrupted DMN functional connectivity. Additionally, altered entropy in Alzheimer’s disease found in the majority of the scales indicated a disturbance of both local information processing and information transfer between distal areas. Conclusively, a loss of nodal signal complexity potentially impairs synchronization across nodes and thus preempts functional connectivity changes. MSE presents a putative functional marker for cognitive decline that might be more sensitive than functional connectivity alone

Relationship between progression of brain white matter changes and late-life depression: 3-year results from the LADIS study

Background: Brain white matter changes (WMC) and depressive symptoms are linked, but the directionality of this association remains unclear. Aims: To investigate the relationship between baseline and incident depression and progression of white matter changes. Method: In a longitudinal multicentre pan-European study (Leukoaraiosis and Disability in the elderly, LADIS), participants aged over 64 underwent baseline magnetic resonance imaging (MRI) and clinical assessments. Repeat scans were obtained at 3 years. Depressive outcomes were assessed in terms of depressive episodes and the Geriatric Depression Scale (GDS). Progression of WMC was measured using the modified Rotterdam Progression scale. Results: Progression of WMC was significantly associated with incident depression during year 3 of the study (P = 0.002) and remained significant after controlling for transition to disability, baseline WMC and baseline history of depression. There was no significant association between progression of WMC and GDS score, and no significant relationship between progression of WMC and history of depression at baseline. Conclusions: Our results support the vascular depression hypothesis and implicate WMC as causal in the pathogenesis of late-life depression.Full Tex