Search Results (35)

Background: Apathy is a common neuropsychiatric symptom in all stages of dementia, significantly complicating patient management. This study examines the prevalence of apathy across Alzheimer’s Disease (AD), Lewy Body Dementia (LBD), Frontotemporal Dementia (FTD), and Vascular Dementia (VD) and explores its associations with cognitive functions, neuropsychiatric symptoms, and magnetic resonance imaging (MRI) findings. Methods: This retrospective, cross-sectional study included 200 patients diagnosed with AD, LBD, FTD, and VD along with 100 healthy controls (HCs). Apathy was assessed using the Apathy Evaluation Scale. Depression and anxiety in patients were evaluated using the Geriatric Depression Scale and the Geriatric Anxiety Scale, respectively. Cognitive function was measured with the Mini-Mental State Examination (MMSE) and Addenbrooke’s Cognitive Examination-Revised (ACE-R). MRI findings were evaluated using atrophy scales that are routinely utilized in dementia assessments. Results: Apathy was significantly more prevalent in dementia and MCI patients compared to HC. However, there were no significant differences in apathy prevalence among dementia subtypes. Apathy showed no significant correlation with depression, anxiety, or cognitive performance. Notably, MRI analysis revealed a strong association between apathy and orbitofrontal (OF) sulci atrophy. Conclusions: Apathy is a critical symptom in dementia, linked to OF atrophy and presenting challenges in management. These findings emphasize the importance of integrating apathy assessments in clinical practice. Larger, longitudinal studies are needed to further clarify the pathophysiology and management of apathy in dementia. Full article

Background/Objectives: Multiple system atrophy (MSA) presents a challenging diagnosis due to its clinical overlap with other neurodegenerative disorders, especially other α-synucleinopathies. The main purpose of this systematic review and meta-analysis was to assess neurofilament light chain (NfL) differences in the CSF and blood of patients with MSA versus the healthy control group (HC), patients with Parkinson’s disease (PD) and patients with Lewy body dementia (LBD). Secondarily, the diagnostic metrics of CSF and circulating NfL in MSA versus HC, PD, LBD, progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) were discussed. Methods: MEDLINE and EMBASE were thoroughly searched for relevant case-control studies. Standardized mean differences (SMDs) were calculated separately for CSF and blood NfL per comparison. Statistical heterogeneity was assessed based on the Q and I^2 statistics. Results: Twenty-five relevant studies were retrieved. Quantitative syntheses revealed elevated CSF and circulating NfL levels in individuals with MSA versus HC [SMD = 1.80 (95%CI = 1.66, 1.94) and SMD = 2.00 (95%CI = 1.36, 2.63), respectively] versus PD [SMD = 1.65 (95%CI = 1.26, 2.03) and SMD = 1.63 (95%CI = 0.84, 2.43), respectively] as well as versus LBD [SMD = 1.17, (95%CI = 0.71, 1.63) and SMD = 0.65 (95%CI = 0.30, 1.00), respectively]. Diagnostic accuracy was outstanding for CSF and blood NfL in MSA versus HC and PD, and it was moderate in MSA versus LBD. On the other hand, it was suboptimal in MSA vs. PSP and CBD. Conclusions: Both CSF and circulating NfL levels are elevated in MSA compared to HC, PD and LBD. To achieve optimal diagnostic properties, further work is required in the standardization of processes and the establishment of reference NfL intervals and/or thresholds. Full article

Alpha-synuclein (ASyn) is a protein that is known to play a critical role in Parkinson’s disease (PD) due to its propensity for misfolding and aggregation. Furthermore, this process leads to oxidative stress and the formation of free radicals that cause neuronal damage. In this study, we have utilized a biomimetic approach to design new peptides derived from marine natural resources. The peptides were designed using a peptide scrambling approach where antioxidant moieties were combined with fibrillary inhibition motifs in order to design peptides that would have a dual targeting effect on ASyn misfolding. Of the 20 designed peptides, 12 were selected for examining binding interactions through molecular docking and molecular dynamics approaches, which revealed that the peptides were binding to the pre-NAC and NAC (non-amyloid component) domain residues such as Tyr39, Asn65, Gly86, and Ala85, among others. Because ASyn filaments derived from Lewy body dementia (LBD) have a different secondary structure compared to pathogenic ASyn fibrils, both forms were tested computationally. Five of those peptides were utilized for laboratory validation based on those results. The binding interactions with fibrils were confirmed using surface plasmon resonance studies, where EQALMPWIWYWKDPNGS, PYYYWKDPNGS, and PYYYWKELAQM showed higher binding. Secondary structural analyses revealed their ability to induce conformational changes in ASyn fibrils. Additionally, PYYYWKDPNGS and PYYYWKELAQM also demonstrated antioxidant properties. This study provides insight into the binding interactions of varying forms of ASyn implicated in PD. The peptides may be further investigated for mitigating fibrillation at the cellular level and may have the potential to target ASyn. Full article

Background: Attention deficits are notable in Lewy body dementia (LBD) and in Alzheimer’s disease (AD). In this study, we combined functional magnetic resonance imaging (fMRI) and electroencephalograph (EEG) to detect neural correlates of attention dysfunctions in LBD and AD. Methods: We recruited 33 patients with LBD, 15 patients with AD and 19 elderly healthy controls. The participants performed the modified Attention Network Task (ANT) to investigate the attention dysfunctions. Results: We found that LBD had alerting attention deficits and AD showed apparent orienting attention dysfunctions, while LBD and AD maintained relatively normal executive/conflict attention. Based on source-level EEG analyses, LBD had frontal-central deficits for alerting attention while AD showed inferior frontal and precentral impairments for orienting attention. In addition, the insular and inferior frontal areas were hyper-activated in LBD and AD for executive/conflict attention. Apart from these areas, LBD showed activity in the complementary temporal-central-occipital network for the modified ANT task. Furthermore, the oscillational sources for the ANT effects indicated that the alpha and theta bands were partly impaired in dementia patients. Conclusions: In summary, using source-localised EEG, we found that attention dysfunctions in LBD and AD engaged different neural networks. Full article

Multiple system atrophy and Lewy body diseases (LBDs) such as Parkinson’s disease, dementia with Lewy bodies, and Parkinson’s disease with dementia, known as synucleinopathies, are defined neuropathologically by the accumulation and deposition of aberrant protein aggregates, primarily in neuronal cells. Seeding aggregation assays (SAA) have significant potential as biomarkers for early diagnosis, monitoring disease progression, and evaluating treatment efficacy for these diseases. Real-time quaking-induced conversion (RT-QuIC) and Protein Misfolding Cyclic Amplification (PMCA) assays represent two ultrasensitive protein amplification techniques that were initially tested for the field of prion disorders. Although the fundamental idea behind the creation of these two methods is very similar, their technical differences resulted in different levels of diagnostic accuracy for the identification of prion proteins, making the RT-QuIC assay the most trustworthy and effective instrument for the detection of suspected cases of LBDs and prion-like diseases. Full article

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. Full article

Neuropathological assessment was conducted on 1630 subjects, representing 5% of all the deceased that had been sent to the morgue of Uppsala University Hospital during a 15-year-long period. Among the 1630 subjects, 1610 were ≥41 years of age (range 41 to 102 years). Overall, hyperphosphorylated (HP) τ was observed in the brains of 98% of the 1610 subjects, and amyloid β-protein (Aβ) in the brains of 64%. The most common alteration observed was Alzheimer disease neuropathologic change (ADNC) (56%), followed by primary age-related tauopathy (PART) in 26% of the subjects. In 16% of the subjects, HPτ was limited to the locus coeruleus. In 14 subjects (<1%), no altered proteins were observed. In 3 subjects, only Aβ was observed, and in 17, HPτ was observed in a distribution other than that seen in ADNC/PART. The transactive DNA-binding protein 43 (TDP43) associated with limbic-predominant age-related TDP encephalopathy (LATE) was observed in 565 (35%) subjects and α-synuclein (αS) pathology, i.e., Lewy body disease (LBD) or multi system atrophy (MSA) was observed in the brains of 21% of the subjects. A total of 39% of subjects with ADNC, 59% of subjects with PART, and 81% of subjects with HPτ limited to the locus coeruleus lacked concomitant pathologies, i.e., LATE-NC or LBD-NC. Of the 293 (18% of the 1610 subjects) subjects with dementia, 81% exhibited a high or intermediate level of ADNC. In 84% of all individuals with dementia, various degrees of concomitant alterations were observed; i.e., MIXED-NC was a common cause of dementia. A high or intermediate level of PART was observed in 10 subjects with dementia (3%), i.e., tangle-predominant dementia. No subjects exhibited only vascular NC (VNC), but in 17 subjects, severe VNC might have contributed to cognitive decline. Age-related tau astrogliopathy (ARTAG) was observed in 37% of the 1610 subjects and in 53% of those with dementia. Full article

Parkinsonism may be a clinical manifestation of a wide range of disease entities, and still poses a great diagnostic challenge. In an attempt to provide further insight into the differential diagnosis of PD versus progressive supranuclear palsy (PSP), multiple system atrophy (MSA), corticobasal degeneration (CBD), and Lewy body dementia (LBD), several biomarkers have been investigated, yielding inconclusive results, OCT being among them. The present review aims to explore the potential diagnostic value of evaluating retinal parameters through OCT implementation among patients presenting with a Parkinsonian syndrome, with an emphasis on effective differentiation between distinct syndromes. Having reviewed all the available literature published within the last decade, neurodegeneration seems to be paralleled with degeneration and alterations of the retina that may be quantified by OCT. Specific patterns of structural changes within the retina may provide valuable information on the underlying pathology, thus highlighting the role of OCT as a diagnostic tool within this group of patients. Although still not utilized in clinical practice, OCT, if further explored and validated, may significantly enhance overall Parkinsonism care. Full article

This study aimed to elucidate the long-term progression of mild cognitive impairment (MCI) within a comprehensive longitudinal dataset, distinguish it from healthy aging, explore the influence of a dementia subtype on this progression, and identify potential contributing factors. Patients with prodromal and preclinical cases underwent regular neuropsychological assessments utilizing various tools. The study included a total of 140 participants with MCI, categorized into Alzheimer’s disease (AD) and non-AD subtypes. Our dataset revealed an overall progression rate of 92.8% from MCI to the clinical stage of dementia during the follow-up period, with an annual rate of 15.7%. Notably, all prodromal cases of Lewy body dementia/Parkinson’s disease (LBD/PDD) and frontotemporal dementia (FTD) advanced to clinical stages, whereas 7% of vascular dementia (VaD) cases and 8.4% of AD cases remained in the prodromal stage throughout follow-up. Furthermore, we observed a faster progression rate in MCI-AD cases compared to non-AD sufferers (53.9% vs. 35.5%, Entropy: 0.850). This study revealed significant cognitive changes in individuals with MCI over time. The mini-mental state examination (MMSE), global deterioration scale (GDS), and calculation tests were the most effective tests for evaluation of MCI. These findings may offer valuable insights for the development of personalized interventions and management strategies for individuals with MCI. Full article

Seven major neurodegenerative diseases and their variants share many overlapping biomarkers that are calmodulin-binding proteins: Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), frontotemporal lobar dementia (FTD), Huntington’s disease (HD), Lewy body disease (LBD), multiple sclerosis (MS), and Parkinson’s disease (PD). Calcium dysregulation is an early and persistent event in each of these diseases, with calmodulin serving as an initial and primary target of increased cytosolic calcium. Considering the central role of calcium dysregulation and its downstream impact on calcium signaling, calmodulin has gained interest as a major regulator of neurodegenerative events. Here, we show that calmodulin serves a critical role in neurodegenerative diseases via binding to and regulating an abundance of biomarkers, many of which are involved in multiple neurodegenerative diseases. Of special interest are the shared functions of calmodulin in the generation of protein biomarker aggregates in AD, HD, LBD, and PD, where calmodulin not only binds to amyloid beta, pTau, alpha-synuclein, and mutant huntingtin but also, via its regulation of transglutaminase 2, converts them into toxic protein aggregates. It is suggested that several calmodulin binding proteins could immediately serve as primary drug targets, while combinations of calmodulin binding proteins could provide simultaneous insight into the onset and progression of multiple neurodegenerative diseases. Full article

Lewy body dementia (LBD) is an often misdiagnosed and mistreated neurodegenerative disorder clinically characterized by the emergence of neuropsychiatric symptoms followed by motor impairment. LBD falls within an undefined range between Alzheimer’s disease (AD) and Parkinson’s disease (PD) due to the potential pathogenic synergistic effects of tau, beta-amyloid (Aβ), and alpha-synuclein (αsyn). A lack of reliable and relevant animal models hinders the elucidation of the molecular characteristics and phenotypic consequences of these interactions. Here, the goal was to evaluate whether the viral-mediated overexpression of αsyn in adult hTau and APP/PS1 mice or the overexpression of tau in Line 61 hThy1-αsyn mice resulted in pathology and behavior resembling LBD. The transgenes were injected intravenously via the tail vein using AAV-PHP.eB in 3-month-old hThy1-αsyn, hTau, or APP/PS1 mice that were then aged to 6-, 9-, and 12-months-old for subsequent phenotypic and histological characterization. Although we achieved the widespread expression of αsyn in hTau and tau in hThy1-αsyn mice, no αsyn pathology in hTau mice and only mild tau pathology in hThy1-αsyn mice was observed. Additionally, cognitive, motor, and limbic behavior phenotypes were not affected by overexpression of the transgenes. Furthermore, our APP/PS1 mice experienced premature deaths starting at 3 months post-injection (MPI), therefore precluding further analyses at later time points. An evaluation of the remaining 3-MPI indicated no αsyn pathology or cognitive and motor behavioral changes. Taken together, we conclude that the overexpression of αsyn in hTau and APP/PS1 mice and tau in hThy1-αsyn mice does not recapitulate the behavioral and neuropathological phenotypes observed in LBD. Full article

Alzheimer’s disease (AD) is the most prevalent dementia, but it shows similar initial symptoms to other neurocognitive diseases (Lewy body disease (LBD) and frontotemporal dementia (FTD)). Thus, the identification of reliable AD plasma biomarkers is required. The aim of this work is to evaluate the use of a few plasma biomarkers to develop an early and specific AD screening method. Plasma p-Tau181, neurofilament light (NfL), and glial fibrillary acid protein (GFAP) were determined by Single Molecule Assay (SIMOA^® Quanterix, Billerica, MA, USA) in patients with mild cognitive impairment due to AD (MCI-AD, n = 50), AD dementia (n = 10), FTD (n = 20), LBD (n = 5), and subjective cognitive impairment (SCI (n = 21)). Plasma p-Tau181 and GFAP showed the highest levels in AD dementia, and significant correlations with clinical AD characteristics; meanwhile, NfL showed the highest levels in FTD, but no significant correlations with AD. The partial least squares (PLS) diagnosis model developed between the AD and SCI groups showed good accuracy with a receiver operating characteristic (ROC) area under curve (AUC) of 0.935 (CI 95% 0.87–0.98), sensitivity of 86%, and specificity of 88%. In a first screen, NfL plasma levels could identify FTD patients among subjects with cognitive impairment. Then, the developed PLS model including p-Tau181 and GFAP levels could identify AD patients, constituting a simple, early, and specific diagnosis approach. Full article

Inflammatory mechanisms are increasingly recognized as important contributors to the pathogenesis of neurodegenerative diseases, including Lewy body dementia (LBD). Our objectives were to, firstly, review inflammation investigation methods in LBD (dementia with Lewy bodies and Parkinson’s disease dementia) and, secondly, identify alterations in inflammatory signals in LBD compared to people without neurodegenerative disease and other neurodegenerative diseases. A systematic scoping review was performed by searching major electronic databases (MEDLINE, Embase, Web of Science, and PSYCHInfo) to identify relevant human studies. Of the 2509 results screened, 80 studies were included. Thirty-six studies analyzed postmortem brain tissue, and 44 investigated living subjects with cerebrospinal fluid, blood, and/or brain imaging assessments. Largely cross-sectional data were available, although two longitudinal clinical studies investigated prodromal Lewy body disease. Investigations were focused on inflammatory immune cell activity (microglia, astrocytes, and lymphocytes) and inflammatory molecules (cytokines, etc.). Results of the included studies identified innate and adaptive immune system contributions to inflammation associated with Lewy body pathology and clinical disease features. Different signals in early and late-stage disease, with possible late immune senescence and dystrophic glial cell populations, were identified. The strength of these associations is limited by the varying methodologies, small study sizes, and cross-sectional nature of the data. Longitudinal studies investigating associations with clinical and other biomarker outcomes are needed to improve understanding of inflammatory activity over the course of LBD. This could identify markers of disease activity and support therapeutic development. Full article

Insulin resistance as a hallmark of type 2 DM (T2DM) plays a role in dementia by promoting pathological lesions or enhancing the vulnerability of the brain. Numerous studies related to insulin/insulin-like growth factor 1 (IGF-1) signaling are linked with various types of dementia. Brain insulin resistance in dementia is linked to disturbances in Aβ production and clearance, Tau hyperphosphorylation, microglial activation causing increased neuroinflammation, and the breakdown of tight junctions in the blood–brain barrier (BBB). These mechanisms have been studied primarily in Alzheimer’s disease (AD), but research on other forms of dementia like vascular dementia (VaD), Lewy body dementia (LBD), and frontotemporal dementia (FTD) has also explored overlapping mechanisms. Researchers are currently trying to repurpose anti-diabetic drugs to treat dementia, which are dominated by insulin sensitizers and insulin substrates. Although it seems promising and feasible, none of the trials have succeeded in ameliorating cognitive decline in late-onset dementia. We highlight the possibility of repositioning anti-diabetic drugs as a strategy for dementia therapy by reflecting on current and previous clinical trials. We also describe the molecular perspectives of various types of dementia through the insulin/IGF-1 signaling pathway. Full article

With increasing aging, dementia is a growing public health concern globally. Patients with dementia have multiple psychological and behavioral changes, including depression, anxiety, inappropriate behavior, paranoia, agitation, and hallucinations. The major types of dementia are Alzheimer’s disease (AD), vascular dementia (VCID), Lewy body dementia (LBD), frontotemporal dementia (FTD), and mixed dementia (MiAD). Among these, AD is the most common form of dementia in the elderly population. In the last three decades, tremendous progress has been made in understanding AD’s biology and disease progression, particularly its molecular basis, biomarker development, and drug discovery. Multiple cellular changes have been implicated in the progression of AD, including amyloid beta, phosphorylated tau, synaptic damage, mitochondrial dysfunction, deregulated microRNAs, inflammatory changes, hormonal deregulation, and others; based on these changes, therapeutic strategies have been developed, which are currently being tested in animal models and human clinical trials. The purpose of our article is to highlight recent therapeutic strategies’ developments, critically discuss current strategies’ failures, and propose new strategies to combat this devasting mental illness. Full article