ABSTRACT
Parkinson's disease (PD) and dementia with Lewy bodies (DLB) share underlying neuropathology. Despite overlapping biology, therapeutic development has been approached separately for these clinical syndromes and there remains no treatment to slow, stop or prevent progression of clinical symptoms and development disability for people living with PD or DLB. Recent advances in biomarker tools, however, have paved new paths for biologic definition and staging of PD and DLB under a shared research framework. Patient-centered research funding organizations see the opportunity for a novel biological staging system for PD and DLB to accelerate and increase success of therapeutic development for the patient communities they serve. Amid growing momentum in the field to develop biological definitions for these neurodegenerative diseases, 7 international nonprofit organizations focused on PD and DLB came together to drive multistakeholder discussion and input on a biological staging system for research. The impact of these convenings to date can be seen in changes incorporated into a proposed biological staging system and growing alignment within the field to rapidly apply new scientific knowledge and biomarker tools to inform clinical trial design. In working together, likeminded nonprofit partners who were initially catalyzed by the significant potential for a biological staging system also realized the power of a shared voice in calling the field to action and have since worked together to establish a coalition to advance precompetitive progress and reduce hurdles to developing better treatments for PD, DLB and biologically related disorders. Plain Language Summary. Disease-focused nonprofit organizations serve to speed new treatments for patients through research funding and advocacy. In the Parkinson's disease (PD) and dementia with Lewy bodies (DLB) fields, several international nonprofit organizations came together to facilitate multistakeholder input on a new biological staging system for research. Stakeholders gathered included researchers, clinicians, drug developers, regulatory agencies, additional nonprofits, and people affected by PD and DLB. This example, fueled by a shared perspective that new drug development tools will improve clinical trials and get better treatments to patients sooner, serves as a model for continued collaborations across the PD and DLB fields. A new, international coalition of nonprofit organizations has emerged to support advancement of treatments to slow, stop, and one day prevent PD, DLB and related disorders, in part, by facilitating future multistakeholder collaborations.
ABSTRACT
Cognitive impairments are a common feature of synucleinopathies such as Parkinson's Disease Dementia and Dementia with Lewy Bodies. These pathologies are characterized by accumulation of Lewy bodies and Lewy neurites as well as neuronal cell death. Alpha-synuclein is the main proteinaceous component of Lewy bodies and Lewy neurites. To model these pathologies in vivo, toxins that selectively target certain neuronal populations or different means of inducing alpha-synuclein aggregation can be used. Alpha-synuclein accumulation can be induced by genetic manipulation, viral vector overexpression or the use of preformed fibrils of alpha-synuclein. In this review, we summarize the cognitive impairments associated with different models of synucleinopathies and relevance to observations in human diseases.
ABSTRACT
Lewy body dementia (LBD), a class of disorders comprising Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB), features substantial clinical and pathological overlap with Alzheimer's disease (AD). The identification of biomarkers unique to LBD pathophysiology could meaningfully advance its diagnosis, monitoring, and treatment. Using quantitative mass spectrometry (MS), we measured over 9,000 proteins across 138 dorsolateral prefrontal cortex (DLPFC) tissues from a University of Pennsylvania autopsy collection comprising control, Parkinson's disease (PD), PDD, and DLB diagnoses. We then analyzed co-expression network protein alterations in those with LBD, validated these disease signatures in two independent LBD datasets, and compared these findings to those observed in network analyses of AD cases. The LBD network revealed numerous groups or "modules" of co-expressed proteins significantly altered in PDD and DLB, representing synaptic, metabolic, and inflammatory pathophysiology. A comparison of validated LBD signatures to those of AD identified distinct differences between the two diseases. Notably, synuclein-associated presynaptic modules were elevated in LBD but decreased in AD relative to controls. We also found that glial-associated matrisome signatures consistently elevated in AD were more variably altered in LBD, ultimately stratifying those LBD cases with low versus high burdens of concurrent beta-amyloid deposition. In conclusion, unbiased network proteomic analysis revealed diverse pathophysiological changes in the LBD frontal cortex distinct from alterations in AD. These results highlight the LBD brain network proteome as a promising source of biomarkers that could enhance clinical recognition and management.
Subject(s)
Alzheimer Disease , Lewy Body Disease , Proteomics , Humans , Lewy Body Disease/metabolism , Lewy Body Disease/pathology , Alzheimer Disease/metabolism , Alzheimer Disease/pathology , Proteomics/methods , Aged , Female , Male , Aged, 80 and over , Biomarkers/metabolism , Brain/metabolism , Brain/pathology , Prefrontal Cortex/metabolism , Parkinson Disease/metabolism , Parkinson Disease/pathologyABSTRACT
The mechanisms responsible for neuronal death causing cognitive loss in Alzheimer's disease (AD) and many other dementias are not known. Serum amyloid P component (SAP) is a constitutive plasma protein, which is cytotoxic for cerebral neurones and also promotes formation and persistence of cerebral Aß amyloid and neurofibrillary tangles. Circulating SAP, which is produced exclusively by the liver, is normally almost completely excluded from the brain. Conditions increasing brain exposure to SAP increase dementia risk, consistent with a causative role in neurodegeneration. Furthermore, neocortex content of SAP is strongly and independently associated with dementia at death. Here, seeking genomic evidence for a causal link of SAP with neurodegeneration, we meta-analysed three genome-wide association studies of 44 288 participants, then conducted cis-Mendelian randomization assessment of associations with neurodegenerative diseases. Higher genetically instrumented plasma SAP concentrations were associated with AD (odds ratio 1.07, 95% confidence interval (CI) 1.02; 1.11, p = 1.8 × 10-3), Lewy body dementia (odds ratio 1.37, 95%CI 1.19; 1.59, p = 1.5 × 10-5) and plasma tau concentration (0.06 log2(ng l-1) 95%CI 0.03; 0.08, p = 4.55 × 10-6). These genetic findings are consistent with neuropathogenicity of SAP. Depletion of SAP from the blood and the brain, by the safe, well tolerated, experimental drug miridesap may thus be neuroprotective.
Subject(s)
Genome-Wide Association Study , Neurodegenerative Diseases , Serum Amyloid P-Component , Humans , Neurodegenerative Diseases/genetics , Neurodegenerative Diseases/etiology , Neurodegenerative Diseases/metabolism , Serum Amyloid P-Component/metabolism , Serum Amyloid P-Component/genetics , Alzheimer Disease/genetics , Alzheimer Disease/metabolism , Alzheimer Disease/etiology , Polymorphism, Single Nucleotide , Genetic Predisposition to Disease , Mendelian Randomization Analysis , Biomarkers , tau Proteins/metabolism , tau Proteins/genetics , Lewy Body Disease/genetics , Lewy Body Disease/metabolism , Male , FemaleABSTRACT
Lewy body dementia (LBD) is the second most frequent neurodegenerative disorder after Alzheimer disease (AD). In this study, we compared functional decline between LBD and AD patients, considering motor dysfunction, over an 18-month follow-up period. We included all patients >70 years of age, with initial MMSE ≥ 20 and a diagnosis of possible or probable LBD or AD, who consulted at the memory centre of the Pitié-Salpêtrière hospital. Statistical analyses were performed using univariate tests and multivariate linear regression. Thirty-seven AD and 36 LBD patients were included, with a median age of 81 and a median MMSE score of 24/30. Global ADL Katz score decreased significantly for LBD people, compared to AD patients: -0.40 ± 0.75 versus 0 ± 0.24; p=0.003. Global IADL score decreased in the two populations but without a significant difference between the two groups: -1.71 ± 2.19 in LBD versus -1.32 (± 1.55); p=0.38. This study shows a significant decrease in autonomy in LBD patients over time that was faster than that in AD patients, related, in particular, to bathing, dressing and personal care.
Subject(s)
Activities of Daily Living , Alzheimer Disease , Lewy Body Disease , Humans , Lewy Body Disease/psychology , Lewy Body Disease/physiopathology , Alzheimer Disease/psychology , Male , Female , Aged , Aged, 80 and over , Disease ProgressionABSTRACT
Depressive episodes with psychotic symptoms are prevalent among the older adults, emphasizing the need to differentiate them from dementia with Lewy bodies (DLB), in which depressive and psychotic symptoms commonly coexist. In contrast, psychotic symptoms occur more frequently in depressive episodes of bipolar disorder (BD) than in major depressive disorder (MDD). Although MDD is a significant risk factor for dementia, studies exploring the relationship between BD and dementia are lacking. This report details the case of a 74-year-old female who experienced severe psychotic depression that led to suicide attempts during a long-term course of young-onset BD. Ultimately, she was diagnosed with DLB based on her neurocognitive symptoms and results of the neuroimaging examination. She had experienced multiple relapses in the past, predominantly characterized by depressive episodes in her old age. Notably, she had never undergone lithium treatment, which is known for its potential efficacy in preventing relapse and dementia. Recent systematic reviews and meta-analyses have suggested that patients with BD have a higher risk of dementia than the general population, and that lithium usage is associated with a reduced risk. Moreover, patients with BD have been suggested to have an elevated risk of developing Parkinson's disease (PD), and the pathophysiological relationship between BD and PD may be attributed to dopamine dysregulation resulting from multiple relapses. Future research is imperative to identify strategies for preventing dementia in patients with BD and to develop interventions for the comorbidities of BD and DLB.
ABSTRACT
BACKGROUND: People with different types of dementia may have distinct symptoms and experiences that affect their quality of life. This study investigated whether quality of life varied across types of dementia and over time. METHODS: The participants were 1555 people with mild-to-moderate dementia and 1327 carers from the IDEAL longitudinal cohort study, recruited from clinical services. As many as possible were followed for up to 6 years. Diagnoses included were Alzheimer's disease, vascular dementia, mixed Alzheimer's and vascular dementia, Parkinson's disease dementia, dementia with Lewy bodies, and frontotemporal dementia. Self- and informant-rated versions of the Quality of Life in Alzheimer's Disease scale were used. A joint model, incorporating a mixed effects model with random effects and a survival model to account for dropout, was used to examine whether quality of life varied by dementia type at the time of diagnosis and how trajectories changed over time. RESULTS: The strongest associations between dementia type and quality of life were seen around the time of diagnosis. For both self-ratings and informant ratings, people with Parkinson's disease dementia or dementia with Lewy bodies had lower quality of life scores. Over time there was little change in self-rated scores across all dementia types (- 0.15 points per year). Informant-rated scores declined over time (- 1.63 points per year), with the greatest decline seen in ratings by informants for people with dementia with Lewy bodies (- 2.18 points per year). CONCLUSIONS: Self-rated quality of life scores were relatively stable over time whilst informant ratings showed a steeper decline. People with Parkinson's disease dementia or dementia with Lewy bodies report particularly low levels of quality of life, indicating the importance of greater attention to the needs of these groups.
Subject(s)
Dementia , Quality of Life , Humans , Quality of Life/psychology , Male , Female , Longitudinal Studies , Aged , Dementia/psychology , Aged, 80 and over , Middle AgedABSTRACT
Dementia, a multifaceted neurological syndrome characterized by cognitive decline, poses significant challenges to daily functioning. The main causes of dementia, including Alzheimer's disease (AD), frontotemporal dementia (FTD), Lewy body dementia (LBD), and vascular dementia (VD), have different symptoms and etiologies. Genetic regulators, specifically non-coding RNAs (ncRNAs) such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), are known to play important roles in dementia pathogenesis. MiRNAs, small non-coding RNAs, regulate gene expression by binding to the 3' untranslated regions of target messenger RNAs (mRNAs), while lncRNAs and circRNAs act as molecular sponges for miRNAs, thereby regulating gene expression. The emerging concept of competing endogenous RNA (ceRNA) interactions, involving lncRNAs and circRNAs as competitors for miRNA binding, has gained attention as potential biomarkers and therapeutic targets in dementia-related disorders. This review explores the regulatory roles of ncRNAs, particularly miRNAs, and the intricate dynamics of ceRNA interactions, providing insights into dementia pathogenesis and potential therapeutic avenues.
Subject(s)
Dementia , Gene Expression Regulation , MicroRNAs , RNA, Circular , RNA, Long Noncoding , RNA, Untranslated , Humans , Dementia/genetics , Dementia/metabolism , MicroRNAs/genetics , MicroRNAs/metabolism , RNA, Circular/genetics , RNA, Circular/metabolism , RNA, Long Noncoding/genetics , RNA, Long Noncoding/metabolism , RNA, Untranslated/genetics , RNA, Untranslated/metabolism , Animals , Biomarkers , Alzheimer Disease/genetics , Alzheimer Disease/metabolismABSTRACT
OBJECTIVE: To describe the 10-year preclinical cognitive trajectories of older, non-demented individuals towards the onset of the four most prevalent types of dementia, i.e., Alzheimer's disease(AD), Lewy body(LBD), vascular(VD) and frontotemporal dementia(FTD). METHODS: Our analysis focused on data from older (≥ 60years) NACC (National Alzheimer's Coordinating Center) participants. Four distinct presymptomatic dementia groups (AD-LBD-VD-FTD) and a comparison group of cognitively unimpaired(CU) participants were formed. Comprehensive cognitive assessments involving verbal episodic memory, semantic verbal fluency, confrontation naming, mental processing speed - attention and executive function - cognitive flexibility were conducted at baseline and on an approximately yearly basis. Descriptive analyses (adjusted general linear models) were performed to determine and compare the yearly cognitive scores of each group throughout the follow-up. Exploratory analyses were conducted to estimate the rates of cognitive decline. RESULTS: There were 3343 participants who developed AD, 247 LBD, 108 FTD, 155 VD and 3398 composed the CU group. Participants with AD performed worse on episodic memory than those with VD and LBD for about 3 to 4 years prior to dementia onset (the FTD group documented an intermediate course). Presymptomatic verbal fluency and confrontation naming trajectories differentiated quite well between the FTD group and the remaining dementia entities. Participants with incident LBD and VD performed worse than those with AD on executive functions and mental processing speed-attention since about 5 years prior to the onset of dementia, and worse than those with FTD more proximally to the diagnosis of the disorder. CONCLUSIONS: Heterogeneous cognitive trajectories characterize the presymptomatic courses of the most prevalent dementia entities.
Subject(s)
Cognition , Dementia , Humans , Aged , Male , Female , Longitudinal Studies , Cognition/physiology , Dementia/epidemiology , Neuropsychological Tests , Middle Aged , Alzheimer Disease/psychology , Aged, 80 and over , Disease Progression , Databases, Factual , Frontotemporal Dementia/psychology , Frontotemporal Dementia/physiopathology , Lewy Body Disease/psychology , Lewy Body Disease/physiopathology , Dementia, Vascular/psychology , Dementia, Vascular/physiopathology , Memory, Episodic , Cognitive Dysfunction/diagnosis , Executive Function/physiologyABSTRACT
Dementia with Lewy bodies (DLB) and Alzheimer's disease (AD), the two most common neurodegenerative dementias, both exhibit altered emotional processing. However, how vocal emotional expressions alter in and differ between DLB and AD remains uninvestigated. We collected voice data during story reading from 152 older adults comprising DLB, AD, and cognitively unimpaired (CU) groups and compared their emotional prosody in terms of valence and arousal dimensions. Compared with matched AD and CU participants, DLB patients showed reduced overall emotional expressiveness, as well as lower valence (more negative) and lower arousal (calmer), the extent of which was associated with cognitive impairment and insular atrophy. Classification models using vocal features discriminated DLB from AD and CU with an AUC of 0.83 and 0.78, respectively. Our findings may aid in discriminating DLB patients from AD and CU individuals, serving as a surrogate marker for clinical and neuropathological changes in DLB. Highlights: DLB showed distinctive reduction in vocal expression of emotions.Cognitive impairment was associated with reduced vocal emotional expression in DLB.Insular atrophy was associated with reduced vocal emotional expression in DLB.Emotional expression measures successfully differentiated DLB from AD or controls.
ABSTRACT
Background: Localized pantothenic acid deficiencies have been observed in several neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease dementia (PDD), and Huntington's disease (HD), indicating downstream energetic pathway perturbations. However, no studies have yet been performed to see whether such deficiencies occur across the dementia with Lewy bodies (DLB) brain, or what the pattern of such dysregulation may be. Objective: Firstly, this study aimed to quantify pantothenic acid levels across ten regions of the brain in order to determine the localization of any pantothenic acid dysregulation in DLB. Secondly, the localization of pantothenic acid alterations was compared to that previously in AD, PDD, and HD brains. Methods: Pantothenic acid levels were determined in 20 individuals with DLB and 19 controls by ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) across ten brain regions. Case-control differences were determined by nonparametric Mann-Whitney U test, with the calculation of S-values, risk ratios, E-values, and effect sizes. The results were compared with those previously obtained in DLB, AD, and HD. Results: Pantothenic acid levels were significantly decreased in six of the ten investigated brain regions: the pons, substantia nigra, motor cortex, middle temporal gyrus, primary visual cortex, and hippocampus. This level of pantothenic acid dysregulation is most similar to that of the AD brain, in which pantothenic acid is also decreased in the motor cortex, middle temporal gyrus, primary visual cortex, and hippocampus. DLB appears to differ from other neurodegenerative diseases in being the only of the four to not show pantothenic acid dysregulation in the cerebellum. Conclusions: Pantothenic acid deficiency appears to be a shared mechanism of several neurodegenerative diseases, although differences in the localization of this dysregulation may contribute to the differing clinical pathways observed in these conditions.
Decreases in a molecule called pantothenic acid (also known as vitamin B5) have been observed in several areas of the brain in multiple dementia disease, including Alzheimer's disease, Parkinson's disease dementia, and Huntington's disease. However, it is unknown whether such changes also occur in another dementia disease, dementia with Lewy bodies, which shows many of the same symptoms and molecular changes as these conditions. As such, this study was performed in order to determine if and where changes in pantothenic acid occur throughout the dementia with Lewy bodies brain. Using a methodology called liquid chromatographymass spectrometry, which is able to measure pantothenic acid levels in a highly precise manner in brain tissues, we found that several regions of the dementia with Lewy bodies brain show decreases in pantothenic acid, including some involved in movement such as the substantia nigra and motor cortex, as well as regions associated with cognition and memory such as the hippocampuslooking most similar to the pattern of changes already seen in Alzheimer's disease. It is possible that these changes contribute to the progression of dementia with Lewy bodies; however, further studies need to be performed to determine at what point these changes happen during the disease and how they may contribute to the development of symptoms.
Subject(s)
Alzheimer Disease , Lewy Body Disease , Pantothenic Acid , Humans , Aged , Male , Lewy Body Disease/metabolism , Female , Aged, 80 and over , Alzheimer Disease/metabolism , Brain/metabolism , Case-Control Studies , Middle Aged , Tandem Mass Spectrometry , Chromatography, High Pressure LiquidABSTRACT
The question whether Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB) are expressions of the same underlying disease has been vigorously debated for decades. The recently proposed biological definitions of Lewy body disease, which do not assign any particular importance to the dopamine system over other degenerating neurotransmitter systems, has once more brought the discussion about different types of Lewy body disease to the forefront. Here, we briefly compare PDD and DLB in terms of their symptoms, imaging findings, and neuropathology, ultimately finding them to be indistinguishable. We then present a conceptual framework to demonstrate how one can view different clinical syndromes as manifestations of a shared underlying Lewy body disease. Early Parkinson's disease, isolated RBD, pure autonomic failure and other autonomic symptoms, and perhaps even psychiatric symptoms, represent diverse manifestations of the initial clinical stages of Lewy body disease. They are characterized by heterogeneous and comparatively limited neuronal dysfunction and damage. In contrast, Lewy body dementia, an encompassing term for both PDD and DLB, represents a more uniform and advanced stage of the disease. Patients in this category display extensive and severe Lewy pathology, frequently accompanied by co-existing pathologies, as well as multi-system neuronal dysfunction and degeneration. Thus, we propose that Lewy body disease should be viewed as a single encompassing disease entity. Phenotypic variance is caused by the presence of individual risk factors, disease mechanisms, and co-pathologies. Distinct subtypes of Lewy body disease can therefore be defined by subtype-specific disease mechanisms or biomarkers.
Subject(s)
Lewy Body Disease , Parkinson Disease , Humans , Lewy Body Disease/pathology , Parkinson Disease/complications , Parkinson Disease/pathology , Diagnosis, DifferentialABSTRACT
Lewy Body Dementias (LBD), including Parkinson's disease dementia and Dementia with Lewy Bodies, are characterized by widespread accumulation of intracellular alpha-Synuclein protein deposits in regions beyond the brainstem, including in the cortex. However, the impact of local pathology in the cortex is unknown. To investigate this, we employed viral overexpression of human alpha-Synuclein protein targeting the mouse prefrontal cortex (PFC). We then used in vivo 2-photon microscopy to image awake head-fixed mice via an implanted chronic cranial window to assess the early consequences of alpha-Synuclein overexpression in the weeks following overexpression. We imaged apical tufts of Layer V pyramidal neurons in the PFC of Thy1-YFP transgenic mice at 1-week intervals from 1 to 2 weeks before and 9 weeks following viral overexpression, allowing analysis of dynamic changes in dendritic spines. We found an increase in the relative dendritic spine density following local overexpression of alpha-Synuclein, beginning at 5 weeks post-injection, and persisting for the remainder of the study. We found that alpha-Synuclein overexpression led to an increased percentage and longevity of newly-persistent spines, without significant changes in the total density of newly formed or eliminated spines. A follow-up study utilizing confocal microscopy revealed that the increased spine density is found in cortical cells within the alpha-Synuclein injection site, but negative for alpha-Synuclein phosphorylation at Serine-129, highlighting the potential for effects of dose and local circuits on spine survival. These findings have important implications for the physiological role and early pathological stages of alpha-Synuclein in the cortex.
Subject(s)
Dendritic Spines , Mice, Transgenic , Prefrontal Cortex , alpha-Synuclein , Animals , Humans , Male , Mice , alpha-Synuclein/metabolism , Cell Survival/physiology , Dendritic Spines/metabolism , Mice, Inbred C57BL , Prefrontal Cortex/metabolism , Prefrontal Cortex/pathology , Pyramidal Cells/metabolism , Pyramidal Cells/pathologyABSTRACT
Background: Parkinson's disease (PD) is a condition that affects movement and is usually seen in those over the age of 50. It is caused by the death of dopaminergic neurons, particularly in the substantia nigra. PD has shifted from being perceived as an uncommon condition to a significant neurological illness, mostly due to the increasing number of elderly individuals and the impact of environmental factors. Parkinson's plus syndromes, such as progressive supranuclear palsy (PSP), multiple system atrophy (MSA), corticobasal degeneration (CBD), and vascular Parkinsonism (VaP), provide difficulties in distinguishing them clinically from PD since they have similar characteristics. Methodology: A thorough examination was performed utilizing the PubMed, Medline, Scopus, and Web of Science databases. The search utilized specific keywords like "Parkinson's disease," "Parkinson's plus syndrome," "Lewy body dementia," "Alzheimer's dementia," "progressive supranuclear palsy," and "multiple system atrophy." The selection criteria were aimed at English-language literature, with a particular focus on examining the connection between PD and associated disorders or dementias. Results and Discussion: Parkinson's plus syndromes, such as PSP, MSA, CBD, and VaP, exhibit unique clinical characteristics, imaging results, and diverse reactions to levodopa. This makes it difficult to distinguish them from PD. LBD is characterized by Lewy bodies containing α-synuclein, which leads to both motor and cognitive deficits. PD and Alzheimer's disease (AD) exhibit a complex interaction, including common pathogenic processes, genetic predispositions, and clinical characteristics of dementia. Conclusion: The interrelatedness of PD, Parkinson's plus syndromes, LBD, and AD highlights the significance of comprehending shared disease-causing processes. Aberrant protein clumping, impaired functioning of mitochondria, increased oxidative stress, and inflammation in the brain are common factors which can be addressed for specific treatments. More research is essential for understanding complicated connections and developing effective therapies for these sophisticated neurological illnesses.
ABSTRACT
Introduction: The presence of a widespread cortical synucleinopathy is the main neuropathological hallmark underlying clinical entities such as Parkinson's disease with dementia (PDD) and dementia with Lewy bodies (DLB). There currently is a pressing need for the development of non-human primate (NHPs) models of PDD and DLB to further overcome existing limitations in drug discovery. Methods: Here we took advantage of a retrogradely-spreading adeno-associated viral vector serotype 9 coding for the alpha-synuclein A53T mutated gene (AAV9-SynA53T) to induce a widespread synucleinopathy of cortical and subcortical territories innervating the putamen. Four weeks post-AAV deliveries animals were sacrificed and a comprehensive biodistribution study was conducted, comprising the quantification of neurons expressing alpha-synuclein, rostrocaudal distribution and their specific location. Results: Intraputaminal deliveries of AAV9-SynA53T lead to a disseminated synucleinopathy throughout ipsi- and contralateral cerebral cortices, together with transduced neurons located in the ipsilateral caudal intralaminar nuclei and in the substantia nigra pars compacta (leading to thalamostriatal and nigrostriatal projections, respectively). Cortical afferent systems were found to be the main contributors to putaminal afferents (superior frontal and precentral gyri in particular). Discussion: Obtained data extends current models of synucleinopathies in NHPs, providing a reproducible platform enabling the adequate implementation of end-stage preclinical screening of new drugs targeting alpha-synuclein.
ABSTRACT
BACKGROUND: Donepezil has been approved in Japan for the treatment of dementia with Lewy bodies (DLB) based on clinical trials showing its beneficial effects on cognitive impairment. This phase IV study evaluated the efficacy of donepezil by focusing on global clinical status during a 12-week double-blind phase. METHODS: Patients with probable DLB were randomly assigned to the placebo (n = 79) or 10 mg donepezil (n = 81) groups. The primary endpoint was changes in global clinical status, assessed using the Clinician's Interview-Based Impression of Change plus Caregiver Input (CIBIC-plus). We also assessed four CIBIC-plus domains (general condition, cognitive function, behaviour, and activities of daily living) and changes in cognitive impairment and behavioural and neuropsychiatric symptoms measured using the Mini-Mental State Examination (MMSE) and the Neuropsychiatric Inventory (NPI), respectively. RESULTS: Although donepezil's superiority was not shown in the global clinical status, a significant favourable effect was detected in the cognitive domain (P = 0.006). MMSE scores improved in the donepezil group after adjustments in post hoc analysis (MMSE mean difference, 1.4 (95% confidence interval (CI), 0.42-2.30), P = 0.004). Improvements in NPIs were similar between the groups (NPI-2: -0.2 (95% CI, -1.48 to 1.01), P = 0.710; NPI-10: 0.1 (95% CI, -3.28 to 3.55), P = 0.937). CONCLUSION: The results support the observation that the efficacy of 10 mg donepezil in improving cognitive function is clinically meaningful in DLB patients. The evaluation of global clinical status might be affected by mild to moderate DLB patients enrolled in this study. No new safety concerns were detected.
Subject(s)
Donepezil , Lewy Body Disease , Humans , Donepezil/therapeutic use , Lewy Body Disease/drug therapy , Male , Female , Double-Blind Method , Aged , Treatment Outcome , Aged, 80 and over , Japan , Nootropic Agents/therapeutic use , Nootropic Agents/adverse effects , Cholinesterase Inhibitors/therapeutic use , Cholinesterase Inhibitors/adverse effects , Activities of Daily Living , Piperidines/therapeutic use , Piperidines/adverse effects , Indans/therapeutic use , Indans/adverse effects , Cognition/drug effects , Neuropsychological Tests/statistics & numerical data , Mental Status and Dementia TestsABSTRACT
BACKGROUND: Mild cognitive impairment (MCI) may evolve into dementia. Early recognition of possible evolution to Alzheimer's disease (AD) and dementia with Lewy Bodies (DLB) is of importance, but actual diagnostic criteria have some limitations. In this systematic review and meta-analysis, we aimed to find the most accurate markers that can discriminate patients with DLB versus AD, in MCI stage. METHODS: We searched several databases up to 17 August 2023 including studies comparing markers that may distinguish DLB-MCI from AD-MCI. We reported data regarding sensitivity, specificity, and the area under the curves (AUCs) with their 95% confidence intervals (CIs). RESULTS: Among 2219 articles initially screened, eight case-control studies and one cohort study were included for a total of 832 outpatients with MCI. The accuracy of cerebrospinal fluid (CSF) markers was the highest among the markers considered (AUC > 0.90 for the CSF markers), with the AUC of CSF Aß42/Aß40 of 0.94. The accuracy for clinical symptom scales was very good (AUC = 0.93), as evaluated in three studies. Although limited to one study, the accuracy of FDG-PET (cingulate island sign ratio) was very good (AUC = 0.95) in discriminating DLB from AD in MCI, while the accuracy of SPECT markers and EEG frequencies was variable. CONCLUSIONS: Few studies have assessed the accuracy of biomarkers and clinical tools to distinguish DLB from AD at the MCI stage. While results are promising for CSF markers, FDG-PET and clinical symptoms scales, more studies, particularly with a prospective design, are needed to evaluate their accuracy and clinical usefulness. CLINICAL TRIAL REGISTRATION: Prospero (CRD42023422600).
Subject(s)
Alzheimer Disease , Cognitive Dysfunction , Lewy Body Disease , Humans , Alzheimer Disease/diagnosis , Cohort Studies , Fluorodeoxyglucose F18 , Lewy Body Disease/diagnosis , Cognitive Dysfunction/diagnosisABSTRACT
The prodromal stage of Lewy body dementia includes a mild cognitive impairment with visual processing and/or attention-executive deficits. A clinical presentation with progressive visual loss is indeed seldom reported and can be misleading with a posterior cortical atrophy disease. While the neurodegeneration at the occipital cortex can only partially explain the visual disturbances of Lewy body dementia, more recently a retinal dysfunction has been suggested by preliminary optical coherence tomography and autoptic findings. Herein, we present a case of a mild cognitive impairment with Lewy bodies, who presented initially with visual disturbances and signs of both retinal and cortical visual processing dysfunction. A complete neuropsychological, neurophysiological and brain imaging assessment highlighted a prominent ventral visual pathway involvement. This report provides first that the prodromal stage of Lewy body dementia can manifest as a primarily progressive visual loss, second that the involvement of visual pathway, particularly the ventral stream, can be detectable from the retinal to the cortical level.
ABSTRACT
BACKGROUND: Current evidence for the management of symptoms associated with dementia with Lewy bodies (DLB) using donepezil is limited. We conducted a meta-analysis of three randomised controlled trials of donepezil in patients with DLB to investigate the overall efficacy of donepezil on Mini-Mental State Examination (MMSE), Neuropsychiatric Inventory (NPI), and Clinician's Interview-Based Impression of Change-plus Caregiver Input (CIBIC-plus). METHODS: A meta-analysis was performed using the data of 312 patients administered placebo or 10 mg donepezil. Overall mean score differences for MMSE, NPI-2, and NPI-10 from baseline to week 12 and their 95% confidence intervals (CI) were estimated. For CIBIC-plus, which was transformed from a seven-point grade to a dichotomous outcome (improvements/no improvements), odds ratio (OR) and its 95% CI were estimated. Random-effects models were used, and heterogeneity was evaluated using the Cochrane's Q test and I2 statistic. RESULTS: Heterogeneity was suspected for NPI-2 (P < 0.05; I2 = 87.2%) and NPI-10 (P < 0.05; I2 = 67.7%) while it was not suspected for MMSE (P = 0.23; I2 = 32.4%) and CIBIC-plus (P = 0.26; I2 = 19.8%). The overall mean MMSE score difference (mean difference: 1.50; 95% CI, 0.67-2.34) and the overall odds of improving CIBIC-plus (OR: 2.20; 95% CI, 1.13-4.26) from baseline to week 12 were higher in the donepezil group than in the placebo group. CONCLUSION: Results of our meta-analysis indicated overall efficacy of donepezil on cognitive impairment and global clinical status in patients with DLB.
Subject(s)
Donepezil , Lewy Body Disease , Randomized Controlled Trials as Topic , Humans , Donepezil/therapeutic use , Lewy Body Disease/drug therapy , Aged , Treatment Outcome , Double-Blind Method , Female , Male , Cholinesterase Inhibitors/therapeutic use , Nootropic Agents/therapeutic use , Mental Status and Dementia Tests/statistics & numerical data , Neuropsychological Tests/statistics & numerical data , Indans/therapeutic use , Aged, 80 and overABSTRACT
Neurodegenerative pathologies such as Alzheimer disease neuropathologic change (ADNC), Lewy body disease (LBD), limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC), and cerebrovascular disease (CVD) frequently coexist, but little is known about the exact contribution of each pathology to cognitive decline and dementia in subjects with mixed pathologies. We explored the relative cognitive impact of concurrent common and rare neurodegenerative pathologies employing multivariate logistic regression analysis adjusted for age, gender, and level of education. We analyzed a cohort of 6,262 subjects from the National Alzheimer's Coordinating Center database, ranging from 0 to 6 comorbid neuropathologic findings per individual, where 95.7% of individuals had at least 1 neurodegenerative finding at autopsy and 75.5% had at least 2 neurodegenerative findings. We identified which neuropathologic entities correlate most frequently with one another and demonstrated that the total number of pathologies per individual was directly correlated with cognitive performance as assessed by Clinical Dementia Rating (CDR®) and Mini-Mental State Examination (MMSE). We show that ADNC, LBD, LATE-NC, CVD, hippocampal sclerosis, Pick disease, and FTLD-TDP significantly impact overall cognition as independent variables. More specifically, ADNC significantly affected all assessed cognitive domains, LBD affected attention, processing speed, and language, LATE-NC primarily affected tests related to logical memory and language, while CVD and other less common pathologies (including Pick disease, progressive supranuclear palsy, and corticobasal degeneration) had more variable neurocognitive effects. Additionally, ADNC, LBD, and higher numbers of comorbid neuropathologies were associated with the presence of at least one APOE ε4 allele, and ADNC and higher numbers of neuropathologies were inversely correlated with APOE ε2 alleles. Understanding the mechanisms by which individual and concomitant neuropathologies affect cognition and the degree to which each contributes is an imperative step in the development of biomarkers and disease-modifying therapeutics, particularly as these medical interventions become more targeted and personalized.