LRP10 and α-synuclein transmission in Lewy body diseases.

Autosomal dominant variants in LRP10 have been identified in patients with Lewy body diseases (LBDs), including Parkinson's disease (PD), Parkinson's disease-dementia (PDD), and dementia with Lewy bodies (DLB). Nevertheless, there is little mechanistic insight into the role of LRP10 in disease pathogenesis. In the brains of control individuals, LRP10 is typically expressed in non-neuronal cells like astrocytes and neurovasculature, but in idiopathic and genetic cases of PD, PDD, and DLB, it is also present in α-synuclein-positive neuronal Lewy bodies. These observations raise the questions of what leads to the accumulation of LRP10 in Lewy bodies and whether a possible interaction between LRP10 and α-synuclein plays a role in disease pathogenesis. Here, we demonstrate that wild-type LRP10 is secreted via extracellular vesicles (EVs) and can be internalised via clathrin-dependent endocytosis. Additionally, we show that LRP10 secretion is highly sensitive to autophagy inhibition, which induces the formation of atypical LRP10 vesicular structures in neurons in human-induced pluripotent stem cells (iPSC)-derived brain organoids. Furthermore, we show that LRP10 overexpression leads to a strong induction of monomeric α-synuclein secretion, together with time-dependent, stress-sensitive changes in intracellular α-synuclein levels. Interestingly, patient-derived astrocytes carrying the c.1424 + 5G > A LRP10 variant secrete aberrant high-molecular-weight species of LRP10 in EV-free media fractions. Finally, we show that this truncated patient-derived LRP10 protein species (LRP10splice) binds to wild-type LRP10, reduces LRP10 wild-type levels, and antagonises the effect of LRP10 on α-synuclein levels and distribution. Together, this work provides initial evidence for a possible functional role of LRP10 in LBDs by modulating intra- and extracellular α-synuclein levels, and pathogenic mechanisms linked to the disease-associated c.1424 + 5G > A LRP10 variant, pointing towards potentially important disease mechanisms in LBDs.

Different α-synuclein prion strains cause dementia with Lewy bodies and multiple system atrophy.

The α-synuclein protein can adopt several different conformations that cause neurodegeneration. Different α-synuclein conformers cause at least three distinct α-synucleinopathies: multiple system atrophy (MSA), dementia with Lewy bodies (DLB), and Parkinson's disease (PD). In earlier studies, we transmitted MSA to transgenic (Tg) mice and cultured HEK cells both expressing mutant α-synuclein (A53T) but not to cells expressing α-synuclein (E46K). Now, we report that DLB is caused by a strain of α-synuclein prions that is distinct from MSA. Using cultured HEK cells expressing mutant α-synuclein (E46K), we found that DLB prions could be transmitted to these HEK cells. Our results argue that a third strain of α-synuclein prions likely causes PD, but further studies are needed to identify cells and/or Tg mice that express a mutant α-synuclein protein that is permissive for PD prion replication. Our findings suggest that other α-synuclein mutants should give further insights into α-synuclein prion replication, strain formation, and disease pathogenesis, all of which are likely required to discover effective drugs for the treatment of PD as well as the other α-synucleinopathies.

Characterization of reduced astrocyte creatine kinase levels in Alzheimer's disease.

The creatine-phosphocreatine cycle serves as a crucial temporary energy buffering system in the brain, regulated by brain creatine kinase (CKB), in maintaining Adenosine triphosphate (ATP) levels. Alzheimer's disease (AD) has been linked to increased CKB oxidation and loss of its regulatory function, although specific pathological processes and affected cell types remain unclear. In our study, cerebral cortex samples from individuals with AD, dementia with Lewy bodies (DLB), and age-matched controls were analyzed using antibody-based methods to quantify CKB levels and assess alterations associated with disease processes. Two independently validated antibodies exclusively labeled astrocytes in the human cerebral cortex. Combining immunofluorescence (IF) and mass spectrometry (MS), we explored CKB availability in AD and DLB cases. IF and Western blot analysis demonstrated a loss of CKB immunoreactivity correlated with increased plaque load, severity of tau pathology, and Lewy body pathology. However, transcriptomics data and targeted MS demonstrated unaltered total CKB levels, suggesting posttranslational modifications (PTMs) affecting antibody binding. This aligns with altered efficiency at proteolytic cleavage sites indicated in the targeted MS experiment. These findings highlight that the proper function of astrocytes, understudied in the brain compared with neurons, is highly affected by PTMs. Reduction in ATP levels within astrocytes can disrupt ATP-dependent processes, such as the glutamate-glutamine cycle. As CKB and the creatine-phosphocreatine cycle are important in securing constant ATP availability, PTMs in CKB, and astrocyte dysfunction may disturb homeostasis, driving excitotoxicity in the AD brain. CKB and its activity could be promising biomarkers for monitoring early-stage energy deficits in AD.

Altered structural and functional connectivity in Posterior Cortical Atrophy and Dementia with Lewy bodies.

Posterior cortical atrophy (PCA) and dementia with Lewy bodies (DLB) show distinct atrophy and overlapping hypometabolism profiles, but it is unknown how disruptions in structural and functional connectivity compare between these disorders and whether breakdowns in connectivity relate to either atrophy or hypometabolism. Thirty amyloid-positive PCA patients, 24 amyloid-negative DLB patients and 30 amyloid-negative cognitively unimpaired (CU) healthy individuals were recruited at Mayo Clinic, Rochester, MN, and underwent a 3T head MRI, including structural MRI, resting state functional MRI (rsfMRI) and diffusion tensor imaging (DTI) sequences, as well as [18F] fluorodeoxyglucose (FDG) PET. We assessed functional connectivity within and between 12 brain networks using rsfMRI and the CONN functional connectivity toolbox and calculated regional DTI metrics using the Johns Hopkins atlas. Multivariate linear-regression models corrected for multiple comparisons and adjusted for age and sex compared DTI metrics and within-network and between-network functional connectivity across groups. Regional gray-matter volumes and FDG-PET standard uptake value ratios (SUVRs) were calculated and analyzed at the voxel-level using SPM12. We used univariate linear-regression models to investigate the relationship between connectivity measures, gray-matter volume, and FDG-PET SUVR. On DTI, PCA showed degeneration in occipito-parietal white matter, posterior thalamic radiations, splenium of the corpus collosum and sagittal stratum compared to DLB and CU, with greater degeneration in the temporal white matter and the fornix compared to CU. We observed no white-matter degeneration in DLB compared to CU. On rsfMRI, reduced within-network connectivity was present in dorsal and ventral default mode networks (DMN) and the dorsal-attention network in PCA compared to DLB and CU, with reduced within-network connectivity in the visual and sensorimotor networks compared to CU. DLB showed reduced connectivity in the cerebellar network compared to CU. Between-network analysis showed increased connectivity in both cerebellar-to-sensorimotor and cerebellar-to-dorsal attention network connectivity in PCA and DLB. PCA showed reduced anterior DMN-to-cerebellar and dorsal attention-to-sensorimotor connectivity, while DLB showed reduced posterior DMN-to-sensorimotor connectivity compared to CU. PCA showed reduced dorsal DMN-to-visual connectivity compared to DLB. The multimodal analysis revealed weak associations between functional connectivity and volume in PCA, and between functional connectivity and metabolism in DLB. These findings suggest that PCA and DLB have unique connectivity alterations, with PCA showing more widespread disruptions in both structural and functional connectivity; yet some overlap was observed with both disorders showing increased connectivity from the cerebellum.

Excitatory synaptic structural abnormalities produced by templated aggregation of α-syn in the basolateral amygdala.

Parkinson's disease (PD) and Dementia with Lewy bodies (DLB) are characterized by neuronal α-synuclein (α-syn) inclusions termed Lewy Pathology, which are abundant in the amygdala. The basolateral amygdala (BLA), in particular, receives projections from the thalamus and cortex. These projections play a role in cognition and emotional processing, behaviors which are impaired in α-synucleinopathies. To understand if and how pathologic α-syn impacts the BLA requires animal models of α-syn aggregation. Injection of α-syn pre-formed fibrils (PFFs) into the striatum induces robust α-syn aggregation in excitatory neurons in the BLA that corresponds with reduced contextual fear conditioning. At early time points after aggregate formation, cortico-amygdala excitatory transmission is abolished. The goal of this project was to determine if α-syn inclusions in the BLA induce synaptic degeneration and/or morphological changes. In this study, we used C57BL/6 J mice injected bilaterally with PFFs in the dorsal striatum to induce α-syn aggregate formation in the BLA. A method was developed using immunofluorescence and three-dimensional reconstruction to analyze excitatory cortico-amygdala and thalamo-amygdala presynaptic terminals closely juxtaposed to postsynaptic densities. The abundance and morphology of synapses were analyzed at 6- or 12-weeks post-injection of PFFs. α-Syn aggregate formation in the BLA did not cause a significant loss of synapses, but cortico-amygdala and thalamo-amygdala presynaptic terminals and postsynaptic densities with aggregates of α-syn show increased volumes, similar to previous findings in human DLB cortex, and in non-human primate models of PD. Transmission electron microscopy showed that asymmetric synapses in mice with PFF-induced α-syn aggregates have reduced synaptic vesicle intervesicular distances, similar to a recent study showing phospho-serine-129 α-syn increases synaptic vesicle clustering. Thus, pathologic α-syn causes major alterations to synaptic architecture in the BLA, potentially contributing to behavioral impairment and amygdala dysfunction observed in synucleinopathies.

Immunotherapy with an antibody against CD1d modulates neuroinflammation in an α-synuclein transgenic model of Lewy body like disease.

The neuroinflammatory process in synucleinopathies of the aging population such as Parkinson's disease (PD) and dementia with Lewy bodies (DLB) involves microglial activation as well as infiltration of the CNS by T cells and natural killer T cells (NKTs). To evaluate the potential of targeting NKT cells to modulate neuroinflammation, we treated α-syn transgenic (tg) mice (e.g.: Thy1 promoter line 61) with an antibody against CD1d, which is a glycoprotein expressed in antigen presenting cells (APCs). CD1d-presented lipid antigens activate NKT cells through the interaction with T cell receptor in NKTs, resulting in the production of cytokines. Thus, we hypothesized that blocking the APC-NKT interaction with an anti-CD1d antibody might reduce neuroinflammation and neurodegeneration in models of DLB/PD. Treatment with the anti-CD1d antibody did not have effects on CD3 (T cells), slightly decreased CD4 and increased CD8 lymphocytes in the mice. Moreover, double labeling studies showed that compared to control (IgG) treated α-syn tg mice, treatment with anti-CD1d decreased numbers of CD3/interferon γ (IFN γ)-positive cells, consistent with NKTs. Further double labeling studies showed that CD1d-positive cells co-localized with the astrocytes marker GFAP and that anti-CD1d antibody reduced this effect. While in control α-syn tg mice CD3 positive cells were near astrocytes, this was modified by the treatment with the CD1d antibody. By qPCR, levels of IFN γ, CCL4, and interleukin-6 were increased in the IgG treated α-syn tg mice. Treatment with CD1d antibody blunted this cytokine response that was associated with reduced astrocytosis and microgliosis in the CNS of the α-syn tg mice treated with CD1d antibody. Flow cytometric analysis of immune cells in α-syn tg mice revealed that CD1d-tet + T cells were also increased in the spleen of α-syn tg mice, which treatment with the CD1d antibody reduced. Reduced neuroinflammation in the anti-CD1d-treated α-syn tg mice was associated with amelioration of neurodegenerative pathology. These results suggest that reducing infiltration of NKT cells with an antibody against CD1d might be a potential therapeutical approach for DLB/PD.

Diagnostic value of CSF chromogranin A to discriminate between Alzheimer's disease and dementia with Lewy bodies.

BACKGROUND: Chromogranin A (CgA) seems to be involved in the pathophysiology of different neurodegenerative pathologies such as Alzheimer's disease (AD) and dementia with Lewy Bodies (DLB). CgA is present in the aggregates of amyloid plaques and in Lewy bodies but CgA also has a function in neuroinflammatory processes via microglia. Our objective was to determine if there is a difference in the CgA concentration in the cerebrospinal fluid (CSF) of AD and DLB patients and whether the CgA concentration can discriminate between the two diseases. METHODS: Using the previously described AlphaLewyMA cohort, we included 117 patients with a CSF CgA assay: 15 control subjects (CS group), 64 DLB patients, 17 AD patients and 21 patients with both AD and probable DLB criteria (AD/DLB group). CgA concentration was assessed using the MSD platform. RESULTS: CSF CgA was increased in the AD and AD/DLB groups compared with the DLB group (p = 0.0006 between AD and DLB, p = 0.0013 between AD/DLB and DLB). No significant difference in CgA concentration was found between DLB and CS. ROC curve analysis showed an area under the curve of 0.791 between AD and DLB. CgA concentrations were correlated with t-Tau and P-Tau regardless of the pathology (for Tau: p = 0.022 for AD; p < 0.0001 for DLB; p = 0.004 for AD/DLB; for P-Tau: p = 0.032 for AD; p < 0.0001 for DLB; p = 0.0009 for AD/DLB). Aß42 was positively correlated with CgA in the DLB group but not in the AD and AD/DLB groups (for DLB: p < 0.0001; for AD: p = 0.57; for AD/DLB: p = 0.58). CONCLUSIONS: CSF CgA concentrations are increased in AD but not in DLB and correlate with P-Tau and Tau whatever the disease. These results suggest a link between tauopathy/neurodegeneration and CgA.

Identification of retinal oligomeric, citrullinated, and other tau isoforms in early and advanced AD and relations to disease status.

This study investigates various pathological tau isoforms in the retina of individuals with early and advanced Alzheimer's disease (AD), exploring their connection with disease status. Retinal cross-sections from predefined superior-temporal and inferior-temporal subregions and corresponding brains from neuropathologically confirmed AD patients with a clinical diagnosis of either mild cognitive impairment (MCI) or dementia (n = 45) were compared with retinas from age- and sex-matched individuals with normal cognition (n = 30) and non-AD dementia (n = 4). Retinal tau isoforms, including tau tangles, paired helical filament of tau (PHF-tau), oligomeric-tau (Oligo-tau), hyperphosphorylated-tau (p-tau), and citrullinated-tau (Cit-tau), were stereologically analyzed by immunohistochemistry and Nanostring GeoMx digital spatial profiling, and correlated with clinical and neuropathological outcomes. Our data indicated significant increases in various AD-related pretangle tau isoforms, especially p-tau (AT8, 2.9-fold, pS396-tau, 2.6-fold), Cit-tau at arginine residue 209 (CitR209-tau; 4.1-fold), and Oligo-tau (T22+, 9.2-fold), as well as pretangle and mature tau tangle forms like MC-1-positive (1.8-fold) and PHF-tau (2.3-fold), in AD compared to control retinas. MCI retinas also exhibited substantial increases in Oligo-tau (5.2-fold), CitR209-tau (3.5-fold), and pS396-tau (2.2-fold). Nanostring GeoMx analysis confirmed elevated retinal p-tau at epitopes: Ser214 (2.3-fold), Ser396 (2.6-fold), Ser404 (2.4-fold), and Thr231 (1.8-fold), particularly in MCI patients. Strong associations were found between retinal tau isoforms versus brain pathology and cognitive status: a) retinal Oligo-tau vs. Braak stage, neurofibrillary tangles (NFTs), and CDR cognitive scores (ρ = 0.63-0.71), b) retinal PHF-tau vs. neuropil threads (NTs) and ABC scores (ρ = 0.69-0.71), and c) retinal pS396-tau vs. NTs, NFTs, and ABC scores (ρ = 0.67-0.74). Notably, retinal Oligo-tau strongly correlated with retinal Aß42 and arterial Aß40 forms (r = 0.76-0.86). Overall, this study identifies and quantifies diverse retinal tau isoforms in MCI and AD patients, underscoring their link to brain pathology and cognition. These findings advocate for further exploration of retinal tauopathy biomarkers to facilitate AD detection and monitoring via noninvasive retinal imaging.

Metabolic network alterations as a supportive biomarker in dementia with Lewy bodies with preserved dopamine transmission.

PURPOSE: Metabolic network analysis of FDG-PET utilizes an index of inter-regional correlation of resting state glucose metabolism and has been proven to provide complementary information regarding the disease process in parkinsonian syndromes. The goals of this study were (i) to evaluate pattern similarities of glucose metabolism and network connectivity in dementia with Lewy bodies (DLB) subjects with subthreshold dopaminergic loss compared to advanced disease stages and to (ii) investigate metabolic network alterations of FDG-PET for discrimination of patients with early DLB from other neurodegenerative disorders (Alzheimer's disease, Parkinson's disease, multiple system atrophy) at individual patient level via principal component analysis (PCA). METHODS: FDG-PETs of subjects with probable or possible DLB (n = 22) without significant dopamine deficiency (z-score < 2 in putamen binding loss on DaT-SPECT compared to healthy controls (HC)) were scaled by global-mean, prior to volume-of-interest-based analyses of relative glucose metabolism. Single region metabolic changes and network connectivity changes were compared against HC (n = 23) and against DLB subjects with significant dopamine deficiency (n = 86). PCA was applied to test discrimination of patients with DLB from disease controls (n = 101) at individual patient level. RESULTS: Similar patterns of hypo- (parietal- and occipital cortex) and hypermetabolism (basal ganglia, limbic system, motor cortices) were observed in DLB patients with and without significant dopamine deficiency when compared to HC. Metabolic connectivity alterations correlated between DLB patients with and without significant dopamine deficiency (R2 = 0.597, p < 0.01). A PCA trained by DLB patients with dopamine deficiency and HC discriminated DLB patients without significant dopaminergic loss from other neurodegenerative parkinsonian disorders at individual patient level (area-under-the-curve (AUC): 0.912). CONCLUSION: Disease-specific patterns of altered glucose metabolism and altered metabolic networks are present in DLB subjects without significant dopaminergic loss. Metabolic network alterations in FDG-PET can act as a supporting biomarker in the subgroup of DLB patients without significant dopaminergic loss at symptoms onset.

Stochastic Optical Reconstruction Microscopy Imaging of Multiple System Atrophy Inclusions Suggests Stepwise α-Synuclein Aggregation.

BACKGROUND: The architecture and composition of glial (GCI) and neuronal (NCI) α-synuclein inclusions observed in multiple system atrophy (MSA) remain to be precisely defined to better understand the disease. METHODS: Here, we used stochastic optical reconstruction microscopy (STORM) to characterize the nanoscale organization of glial (GCI) and neuronal (NCI) α-synuclein inclusions in cryopreserved brain sections from MSA patients. RESULTS: STORM revealed a dense cross-linked internal structure of α-synuclein in all GCI and NCI. The internal architecture of hyperphosphorylated α-synuclein (p-αSyn) inclusions was similar in glial and neuronal cells, suggesting a common aggregation mechanism. A similar sequence of p-αSyn stepwise intracellular aggregation was defined in oligodendrocytes and neurons, starting from the perinuclear area and growing inside the cells. Consistent with this hypothesis, we found a higher mitochondrial density in GCI and NCI compared to oligodendrocytes and neurons from unaffected donors (P < 0.01), suggesting an active recruitment of the organelles during the aggregation process. CONCLUSIONS: These first STORM images of GCI and NCI suggest stepwise α-synuclein aggregation in MSA. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Abnormal Cerebrovascular Activity, Perfusion, and Glymphatic Clearance in Lewy Body Diseases.

Cerebrovascular activity is not only crucial to optimal cerebral perfusion, but also plays an important role in the glymphatic clearance of interstitial waste, including α-synuclein. This highlights a need to evaluate how cerebrovascular activity is altered in Lewy body diseases. This review begins by discussing how vascular risk factors and cardiovascular autonomic dysfunction may serve as upstream or direct influences on cerebrovascular activity. We then discuss how patients with Lewy body disease exhibit reduced and delayed cerebrovascular activity, hypoperfusion, and reductions in measures used to capture cerebrospinal fluid flow, suggestive of a reduced capacity for glymphatic clearance. Given the lack of an existing framework, we propose a model by which these processes may foster α-synuclein aggregation and neuroinflammation. Importantly, this review highlights several avenues for future research that may lead to treatments early in the disease course, prior to neurodegeneration. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Longitudinal Free-Water Changes in Dementia with Lewy Bodies.

BACKGROUND: Diffusion-weighted magnetic resonance imaging (dMRI) examines tissue microstructure integrity in vivo. Prior dementia with Lewy bodies (DLB) diffusion tensor imaging studies yielded mixed results. OBJECTIVE: We employed free-water (FW) imaging to assess DLB progression and correlate with clinical decline in DLB. METHODS: Baseline and follow-up MRIs were obtained at 12 and/or 24 months for 27 individuals with DLB or mild cognitive impairment with Lewy bodies (MCI-LB). FW was analyzed using the Mayo Clinic Adult Lifespan Template. Primary outcomes were FW differences between baseline and 12 or 24 months. To compare FW change longitudinally, we included 20 cognitively unimpaired individuals from the Alzheimer's Disease Neuroimaging Initiative. RESULTS: We followed 23 participants to 12 months and 16 participants to 24 months. Both groups had worsening in Montreal Cognitive Assessment (MoCA) and Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) scores. We found significant FW increases at both time points compared to baseline in the insula, amygdala, posterior cingulum, parahippocampal, entorhinal, supramarginal, fusiform, retrosplenial, and Rolandic operculum regions. At 24 months, we found more widespread microstructural changes in regions implicated in visuospatial processing, motor, and cholinergic functions. Between-group analyses (DLB vs. controls) confirmed significant FW changes over 24 months in most of these regions. FW changes were associated with longitudinal worsening of MDS-UPDRS and MoCA scores. CONCLUSIONS: FW increased in gray and white matter regions in DLB, likely due to neurodegenerative pathology associated with disease progression. FW change was associated with clinical decline. The findings support dMRI as a promising tool to track disease progression in DLB. © 2024 International Parkinson and Movement Disorder Society.

Conjugal Synucleinopathies: A Clinicopathologic Study.

BACKGROUND: While preclinical studies have shown that alpha-synuclein can spread through cell-to-cell transmission whether it can be transmitted between humans is unknown. OBJECTIVES: The aim was to assess the presence of a synucleinopathy in autopsied conjugal couples. METHODS: Neuropathological findings in conjugal couples were categorized as Parkinson's disease (PD), dementia with Lewy bodies (DLB), Alzheimer's disease with Lewy bodies (ADLB), incidental Lewy body disease (ILBD), or no Lewy bodies. RESULTS: Ninety conjugal couples were included; the mean age of death was 88.3 years; 32 couples had no Lewy bodies; 42 couples had 1 spouse with a synucleinopathy: 10 PD, 3 DLB, 13 ADLB, and 16 ILBD; 16 couples had both spouses with a synucleinopathy: in 4 couples both spouses had PD, 1 couple had PD and DLB, 4 couples had PD and ADLB, 2 couples had PD and ILBD, 1 couple had DLB and ADLB, in 3 couples both had ADLB, and 1 couple had ADLB and ILBD. No couples had both spouses with ILBD. CONCLUSIONS: This large series of 90 autopsied conjugal couples found 16 conjugal couples with synucleinopathies, suggesting transmission of synucleinopathy between spouses is unlikely. © 2024 International Parkinson and Movement Disorder Society.

Differences in Cognitive Trajectories of Dementia: Comparison of Alzheimer's Disease Dementia and Dementia with Lewy Bodies in a Korean Patient Cohort.

INTRODUCTION: Prediction of the dementia progression is important for patient management. We aimed to investigate the cognitive trajectories of Alzheimer's disease dementia (ADD) and dementia with Lewy bodies (DLB) according to the initial structural change measured by comprehensive visual rating scales (CVRS). METHODS: We retrospectively included the patients who initially visited the Dementia Clinic of Chonnam National University Hospital between 2010 and 2012. All patients underwent dementia workup including neuropsychological battery (Seoul Neuropsychological Screening Battery, SNSB). We recruited the participant who underwent SNSB annually for 3 years successively. A total of 136 patients of ADD and 63 patients of DLB were included for analysis. We analyzed the decline pattern of the cognitive profile according to the initial brain structural changes. RESULTS: The general cognitive trajectories between ADD and DLB patients were not different. However, DLB patients showed more rapid decline of cognitive function in language and related function, visual memory function, and frontal executive function. The scores were lower in participants with DLB with the lesser atrophy group in attention, visuospatial function, and frontal executive function. In analysis of the cognitive trajectories, the visual memory domain declined rapidly in the DLB with lesser atrophy group compared with the ADD with lesser atrophy group. CONCLUSION: We founded that the differences in the visual cognitive profile in ADD and DLB patients in serial follow-up of neuropsychological tests. It is prominent in the mild structural change group of ADD and DLB.

Influence of Behavioral and Psychological Symptoms on Caregiver Burden for Different Types of Dementia: Clinical Experience in Lima, Peru.

INTRODUCTION: People caring for patients with dementia are prone to suffering from burden. Behavioral and psychological symptoms of dementia (BPSD) may have an impact on caregiver burden. In Latin American countries, there is a lack of research on caregiver burden. We aimed to determine which BPSD have the greatest impact on caregiver burden among Peruvian patients with dementia and to compare the effects of BPSD on caregiver burden across different types of dementia. METHODS: A cross-sectional study was conducted on 231 patients living with Alzheimer's dementia (AD), behavioral variant frontotemporal dementia (bvFTD), dementia with Lewy bodies (DLB), and vascular dementia (VD) and their caregivers who attended a Peruvian memory clinic. BPSD were assessed with the Neuropsychiatric Inventory (NPI). Caregiver burden was assessed with the Zarit Burden Inventory. We used analysis of variance to compare the AD, bvFTD, DLB, and VD groups. Correlations between Zarit Burden Inventory and NPI subscale scores were assessed with Spearman's correlation. RESULTS: DLB caregivers had significantly higher levels of burden than the other patient groups (p < 0.05) and higher total NPI scores than caregivers for other patient groups (p < 0.05). bvFTD caregivers had significantly higher total NPI scores than AD and VD caregivers (p < 0.05). Hallucinations, aberrant motor behavior, and apathy were the symptoms most significantly correlated with caregiver burden in those caring for DLB, bvFTD, and AD patients, respectively. CONCLUSION: Neuropsychiatric symptoms are higher in DLB caregivers. Hallucinations, aberrant motor behavior, and apathy are the main symptoms correlated with burden.

Ecological validity of cognitive fluctuations in dementia with Lewy bodies.

OBJECTIVES: Cognitive fluctuations are a core clinical feature of dementia with Lewy bodies (DLB), but their contribution to the everyday functioning difficulties evident DLB are not well understood. The current study evaluated whether intraindividual variability across a battery of neurocognitive tests (intraindividual variability-dispersion) and daily cognitive fluctuations as measured by informant report are associated with worse daily functioning in DLB. METHODS: The study sample included 97 participants with consensus-defined DLB from the National Alzheimer's Coordinating Center (NACC). Intraindividual variability-dispersion was measured using the coefficient of variation, which divides the standard deviation of an individual's performance scores across 12 normed neurocognitive indices from the NACC neuropsychological battery by that individual's performance mean. Informants reported on daily cognitive fluctuations using the Mayo Fluctuations Scale (MFS) and on daily functioning using the functional activities questionnaire (FAQ). RESULTS: Logistic regression identified a large univariate association of intraindividual variability-dispersion and presence of daily cognitive fluctuations on the MFS (Odds Ratio = 73.27, 95% Confidence Interval = 1.38, 3,895.05). Multiple linear regression demonstrated that higher intraindividual variability-dispersion and presence of daily cognitive fluctuations as assessed by the MFS were significantly and independently related to worse daily functioning (FAQ scores). CONCLUSIONS: Among those with DLB, informant-rated daily cognitive fluctuations and cognitive fluctuations measured in the clinic (as indexed by intraindividual variability-dispersion across a battery of tests) were independently associated with poorer everyday functioning. These data demonstrate ecological validity in measures of cognitive fluctuations in DLB.

Quantitative EEG in the Differential Diagnosis of Dementia Subtypes.

OBJECTIVE: Most neurodegenerative dementias present with substantial overlap in clinical features. Therefore, differential diagnosis is often a challenging task necessitating costly and sometimes invasive diagnostic procedures. A promising, non-invasive and cost-effective method is the widely available electroencephalography (EEG). METHODS: Twenty-three subjects with Alzheimer's disease (AD), 28 subjects with dementia with Lewy bodies (DLB), 15 subjects with frontotemporal dementias (FTDs), and 22 healthy controls (HC) were enrolled. Nineteen channel computerized EEG recordings were acquired. Mean relative powers were calculated using the standard frequency bands. Theta/alpha ratio (TAR), theta/beta ratio (TBR), a spectral index of (alpha + beta)/(theta + delta) and an alpha reactivity index (alpha in eyes-open condition/alpha in eyes-closed condition) were also calculated. Receiver operating characteristic (ROC) analyses were performed to assess diagnostic accuracy. RESULTS: For the comparison of EEG measures across groups, we performed a multivariate ANOVA followed by univariate ANOVAs controlling for the effects of age, with post hoc tests. Theta power and TBR were increased in DLB compared to other groups. Alpha power was decreased in DLB compared to HC and FTD; and in AD compared to FTD. Beta power was decreased in DLB compared to AD and HC. Furthermore, regional analyses demonstrated a unique pattern of theta power increase in DLB; affecting frontal, central, parietal, occipital, and temporal regions. In AD, theta power increased compared to HC in parietal, occipital, and right temporal regions. TAR was increased in DLB compared to other groups; and in AD compared to HC. Finally, alpha reactivity index was higher in DLB compared to HC and FTD. In AD, EEG slowing was associated with cognitive impairment, while in DLB, this was associated with higher DLB characteristics. In the ROC analyses to distinguish DLB from FTD and AD, measures of EEG slowing yielded high area under curve values, with good specificities. Also, decreased alpha reactivity could distinguish DLB from FTD with good specificity. EEG slowing in DLB showed a diffuse pattern compared to AD, where a posterior and temporal slowing predominated. CONCLUSION: We showed that EEG slowing was satisfactory in distinguishing DLB patients from AD and FTD patients. Notably, this slowing was a characteristic finding in DLB patients, even at early stages, while it paralleled disease progression in AD. Furthermore, EEG slowing in DLB showed a diffuse pattern compared to AD, where a posterior and temporal slowing predominated. These findings align with the previous evidence of the diencephalic dysfunction in DLB.

Visual dysfunction in dementia with Lewy bodies.

PURPOSE OF REVIEW: To review the literature on visual dysfunction in dementia with Lewy bodies (DLB), including its mechanisms and clinical implications. RECENT FINDINGS: Recent studies have explored novel aspects of visual dysfunction in DLB, including visual texture agnosia, mental rotation of 3-dimensional drawn objects, and reading fragmented letters. Recent studies have shown parietal and occipital hypoperfusion correlating with impaired visuoconstruction performance. While visual dysfunction in clinically manifest DLB is well recognized, recent work has focused on prodromal or mild cognitive impairment (MCI) due to Lewy body pathology with mixed results. Advances in retinal imaging have recently led to the identification of abnormalities such as parafoveal thinning in DLB. Patients with DLB experience impairment in color perception, form and object identification, space and motion perception, visuoconstruction tasks, and illusions in association with visual cortex and network dysfunction. These symptoms are associated with visual hallucinations, driving impairment, falls, and other negative outcomes.

Orexin and Sleep Disturbances in Alpha-Synucleinopathies: a Systematic Review.

PURPOSE OF REVIEW: Sleep disturbances are amongst most frequent non-motor symptoms of Parkinson's Disease (PD), and they are similarly frequently reported in other alpha-syncleinopathies, such as Dementia with Lewy Bodies (DLB) and Multiple System Atrophy (MSA). More recently, the orexin system has been implicated in control of arousal based on salient environmental set points, and its dysregulation in sleep issues in alpha-synucleinopathies suggested by the findings from the translational animal models. However, its role in the patients with alpha-synucleinopathies remains unclear. We thus set to systematically review, and to critically assess, contemporary evidence on the association of the orexinergic system and sleep disturbances in alpha-synucleinopathies. In this systematic review, studies investigating orexin and sleep in alpha-synucleinopathies (Rapid Eye Movement (REM) Behaviour Disorder (RBD), Parkinson's Disease (PD), Dementia with Lewy Bodies (DLB), Multiple System Atrophy (MSA)) were identified using electronic database searches of PubMed, Web of Science and PsychINFO using MeSH terms, keywords, and title words such as "Alpha-synucleinopathies" AND "Orexin" AND "Sleep Disturbances". RECENT FINDINGS: 17 studies were included in this systemic review, of which 2 studies on RBD, 10 on PD, 4 on DLB, and 1 on MSA patients. Taken together, RBD and PD studies suggest a potential adaptive increase in orexin levels in early stages of the neurodegenerative process, with reduced levels more often reported for later, more advanced stages of illness. To date, no differences in orexin levels were demonstrated between MSA patients and healthy controls. There is a dearth of studies on the role of orexin levels in alpha-synucleinopathies. Moreover, significant methodologic limitations in the current body of work, including use of non-standardised research protocols and lack of prospective, multi-centre studies, disallow for any finite conclusion in regards to underlying pathomechanisms. Nonetheless, a picture of a complex, multifaceted relationship between the dysregulation of the orexinergic pathway and sleep disturbances in alpha-synucleinopathies is emerging. Hence, future studies disentangling orexinergic pathomechanisms of alpha-syncleinopathies are urgently needed to obtain a more comprehensive account of the role of orexinergic pathway in alpha-synucleinopathies. Pharmacological manipulations of orexins may have multiple therapeutic applications in treatment strategies, disease diagnosis, and might be effective for treating both motor and non-motor symptoms.

Mitochondrial function-associated genes underlie cortical atrophy in prodromal synucleinopathies.

Isolated rapid eye movement sleep behaviour disorder (iRBD) is a sleep disorder characterized by the loss of rapid eye movement sleep muscle atonia and the appearance of abnormal movements and vocalizations during rapid eye movement sleep. It is a strong marker of incipient synucleinopathy such as dementia with Lewy bodies and Parkinson's disease. Patients with iRBD already show brain changes that are reminiscent of manifest synucleinopathies including brain atrophy. However, the mechanisms underlying the development of this atrophy remain poorly understood. In this study, we performed cutting-edge imaging transcriptomics and comprehensive spatial mapping analyses in a multicentric cohort of 171 polysomnography-confirmed iRBD patients [67.7 ± 6.6 (49-87) years; 83% men] and 238 healthy controls [66.6 ± 7.9 (41-88) years; 77% men] with T1-weighted MRI to investigate the gene expression and connectivity patterns associated with changes in cortical thickness and surface area in iRBD. Partial least squares regression was performed to identify the gene expression patterns underlying cortical changes in iRBD. Gene set enrichment analysis and virtual histology were then done to assess the biological processes, cellular components, human disease gene terms, and cell types enriched in these gene expression patterns. We then used structural and functional neighbourhood analyses to assess whether the atrophy patterns in iRBD were constrained by the brain's structural and functional connectome. Moreover, we used comprehensive spatial mapping analyses to assess the specific neurotransmitter systems, functional networks, cytoarchitectonic classes, and cognitive brain systems associated with cortical changes in iRBD. All comparisons were tested against null models that preserved spatial autocorrelation between brain regions and compared to Alzheimer's disease to assess the specificity of findings to synucleinopathies. We found that genes involved in mitochondrial function and macroautophagy were the strongest contributors to the cortical thinning occurring in iRBD. Moreover, we demonstrated that cortical thinning was constrained by the brain's structural and functional connectome and that it mapped onto specific networks involved in motor and planning functions. In contrast with cortical thickness, changes in cortical surface area were related to distinct genes, namely genes involved in the inflammatory response, and to different spatial mapping patterns. The gene expression and connectivity patterns associated with iRBD were all distinct from those observed in Alzheimer's disease. In summary, this study demonstrates that the development of brain atrophy in synucleinopathies is constrained by specific genes and networks.