An Alzheimer's Disease-Derived Biomarker Signature Identifies Parkinson's Disease Patients with Dementia.
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ABSTRACT:
SUBMITTER: Berlyand Y
PROVIDER: S-EPMC4727929 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:A definitive diagnosis of Alzheimer's disease (AD), even in the presence of co-morbid neuropathology (occurring in > 50% of AD cases), is a significant unmet medical need that has obstructed the discovery of effective AD therapeutics. An AD-biomarker, the Morphometric Imaging (MI) assay on cultured skin fibroblasts, was used in a double-blind, allcomers (ages 55-90) trial of 3 patient cohorts: AD dementia patients, N = 25, all autopsy confirmed, non-AD dementia patients, N = 21-all autopsy or genetically confirmed; and non-demented control (AHC) patients N = 27. Fibroblasts cells isolated from 3-mm skin punch biopsies were cultured on a 3-D Matrigel matrix with movement dynamics quantified by image analysis. From counts of all aggregates (N) in a pre-defined field image and measures of the average area (A) of aggregates per image, the number-to-area ratios in a natural logarithmic form Ln(A/N) were determined for all patient samples. AD cell lines formed fewer large aggregates (cells clustered together) than non-AD or AHC cell lines. The cut-off value of Ln(A/N) = 6.98 was determined from the biomarker values of non-demented apparently healthy control (AHC) cases. Unequivocal validation by autopsy, genetics, and/or dementia criteria was possible for all 73 patient samples. The samples were collected from multiple centers-four US centers and one center in Japan. The study found no effect of center-to-center variation in fibroblast isolation, cell growth, or cell aggregation values (Ln(A/N)). The autopsy-confirmed MI Biomarker distinguished AD from non-AD dementia (non-ADD) patients and correctly diagnosed AD even in the presence of other co-morbid pathologies at autopsy (True Positive = 25, False Negative = 0, False Positive = 0, True Negative = 21, and Accuracy = 100%. Sensitivity and specificity were calculated as 100% (95% CI = 84 to 100.00%). From these findings, the MI assay appears to detect AD with great accuracy-even with abundant co-morbidity.
| S-EPMC9626495 | biostudies-literature
Project description:BackgroundParkinson'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.MethodologyA 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 discussionParkinson'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.ConclusionThe 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.
| S-EPMC10982460 | biostudies-literature
Project description:This study aim to determine changes of serum butyrylcholinesterase (BChE) activity in PD patients and related dementia.Consecutive PD patients and healthy controls were included and clinical data were collected. Fast serum BChE activity was determined and compared between healthy controls and PD patients. Independent risk factors were performed for BChE activity, PD, and related dementia. The relationship between BChE activity and disease severity was also evaluated. Receiver operating characteristic (ROC) curves were obtained to explore serum BChE activity in distinguishing PD patients and related dementia.Serum BChE activity mainly independently correlated with gender, albumin, triglyceride, body mass index, and PD. Serum BChE activity decreased in PD patients compared with healthy controls. Based on the ROC curve, the optimal cut-off point was 6864.08 IU/L for distinguishing PD patients, and the sensitivity and specificity values were 61.8% and 72.1%. It inversely correlated with Unified Parkinson's Disease Rating Scale score. BChE activity decreased in PD-related dementia compared with those without dementia. The sensitivity and specificity values were 70.6% and 76.3%, respectively, with an optimal cut-off point of 6550.00 IU/L.Serum BChE activity can be regarded as a biomarker for PD and related dementia.
| S-EPMC5559914 | biostudies-other
Project description:Metabolic brain biomarkers have been incorporated in various diagnostic guidelines of neurodegenerative diseases, recently. To improve their diagnostic accuracy a biologically and clinically homogeneous sample is needed for their identification. Alzheimer's disease-related pattern (ADRP) has been identified previously in cohorts of clinically diagnosed patients with dementia due to Alzheimer's disease (AD), meaning that its diagnostic accuracy might have been reduced due to common clinical misdiagnosis. In our study, we aimed to identify ADRP in a cohort of AD patients with CSF confirmed diagnosis, validate it in large out-of-sample cohorts and explore its relationship with patients' clinical status. For identification we analyzed 2-[18F]FDG PET brain scans of 20 AD patients and 20 normal controls (NCs). For validation, 2-[18F]FDG PET scans from 261 individuals with AD, behavioral variant of frontotemporal dementia, mild cognitive impairment and NC were analyzed. We identified an ADRP that is characterized by relatively reduced metabolic activity in temporoparietal cortices, posterior cingulate and precuneus which co-varied with relatively increased metabolic activity in the cerebellum. ADRP expression significantly differentiated AD from NC (AUC = 0.95) and other dementia types (AUC = 0.76-0.85) and its expression correlated with clinical measures of global cognition and neuropsychological indices in all cohorts.
| S-EPMC9273623 | biostudies-literature
Project description:BackgroundThe search for biomarkers in Parkinson's disease (PD) is crucial to identify the disease early and monitor the effectiveness of neuroprotective therapies. We aim to assess whether a gene signature could be detected in blood from early/mild PD patients that could support the diagnosis of early PD, focusing on genes found particularly altered in the substantia nigra of sporadic PD.ResultsThe transcriptional expression of seven selected genes was examined in blood samples from 62 early stage PD patients and 64 healthy age-matched controls. Stepwise multivariate logistic regression analysis identified five genes as optimal predictors of PD: p19 S-phase kinase-associated protein 1A (odds ratio [OR] 0.73; 95% confidence interval [CI] 0.60-0.90), huntingtin interacting protein-2 (OR 1.32; CI 1.08-1.61), aldehyde dehydrogenase family 1 subfamily A1 (OR 0.86; 95% CI 0.75-0.99), 19?S proteasomal protein PSMC4 (OR 0.73; 95% CI 0.60-0.89) and heat shock 70-kDa protein 8 (OR 1.39; 95% CI 1.14-1.70). At a 0.5 cut-off the gene panel yielded a sensitivity and specificity in detecting PD of 90.3 and 89.1 respectively and the area under the receiving operating curve (ROC AUC) was 0.96. The performance of the five-gene classifier on the de novo PD individuals alone composing the early PD cohort (n?=?38), resulted in a similar ROC with an AUC of 0.95, indicating the stability of the model and also, that patient medication had no significant effect on the predictive probability (PP) of the classifier for PD risk. The predictive ability of the model was validated in an independent cohort of 30 patients at advanced stage of PD, classifying correctly all cases as PD (100% sensitivity). Notably, the nominal average value of the PP for PD (0.95 (SD?=?0.09)) in this cohort was higher than that of the early PD group (0.83 (SD?=?0.22)), suggesting a potential for the model to assess disease severity. Lastly, the gene panel fully discriminated between PD and Alzheimer's disease (n?=?29).ConclusionsThe findings provide evidence on the ability of a five-gene panel to diagnose early/mild PD, with a possible diagnostic value for detection of asymptomatic PD before overt expression of the disorder.
| S-EPMC3424147 | biostudies-literature
Project description:As the differential diagnosis of dementias based on established clinical criteria is often difficult, biomarkers for applicable diagnostic testing are currently under intensive investigation. Amyloid plaques deposited in the brain of patients suffering from Alzheimer's disease, dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) mainly consist of carboxy-terminally elongated forms of amyloid-beta (Abeta) peptides, such as Abeta1-42. Absolute Abeta1-42 levels in CSF have shown diagnostic value for the diagnosis of Alzheimer's disease, but the discrimination among Alzheimer's disease, DLB and PDD was poor. A recently established quantitative urea-based Abeta-sodium-dodecylsulphate-polyacrylamide-gel-electrophoresis with Western immunoblot (Abeta-SDS-PAGE/immunoblot) revealed a highly conserved Abeta peptide pattern of the carboxy-terminally truncated Abeta peptides 1-37, 1-38, 1-39 in addition to 1-40 and 1-42 in human CSF. We used the Abeta-SDS-PAGE/immunoblot to investigate the CSF of 23 patients with Alzheimer's disease, 21 with DLB, 21 with PDD and 23 non-demented disease controls (NDC) for disease-specific alterations of the Abeta peptide patterns in its absolute and relative quantities. The diagnostic groups were matched for age and severity of dementia. The present study is the first attempt to evaluate the meaning of Abeta peptide patterns in CSF for differential diagnosis of the three neurodegenerative diseases--Alzheimer's disease, DLB and PDD. The Abeta peptide patterns displayed disease-specific variations and the ratio of the differentially altered Abeta1-42 to the Abeta1-37 levels subsequently discriminated all diagnostic groups from each other at a highly significant level, except DLB from PDD. Additionally, a novel peptide with Abeta-like immunoreactivity was observed constantly in the CSF of all 88 investigated patients. The pronounced percentage increase of this peptide in DLB allowed a highly significant discrimination from PDD. Using a cut-off point of 0.954%, this marker yielded a diagnostic sensitivity and specificity of 81 and 71%, respectively. From several lines of indication, we consider this peptide to represent an oxidized alpha-helical form of Abeta1-40 (Abeta1-40*). The increased abundance of Abeta1-40* probably reflects a disease-specific alteration of the Abeta1-40 metabolism in DLB. We conclude that Abeta peptide patterns reflect disease-specific pathophysiological pathways of different dementia syndromes as distinct neurochemical phenotypes. Although Abeta peptide patterns failed to fulfil the requirements for a sole biomarker, their combined evaluation with other biomarkers is promising in neurochemical dementia diagnosis. It is noteworthy that DLB and PDD exhibit distinct clinical temporal courses, despite their similar neuropathological appearance. Their distinct molecular phenotypes support the view of different pathophysiological pathways for each of these neurodegenerative diseases.
| S-EPMC5403412 | biostudies-literature
Project description:Dementia with Lewy bodies (DLB) and Alzheimer's disease (AD) require differential management despite presenting with symptomatic overlap. Currently, there is a need of inexpensive DLB biomarkers which can be fulfilled by electroencephalography (EEG). In this regard, an established electrophysiological difference in DLB is a decrease of dominant frequency (DF)-the frequency with the highest signal power between 4 and 15?Hz. Here, we investigated network connectivity in EEG signals acquired from DLB patients, and whether these networks were able to differentiate DLB from healthy controls (HCs) and associated dementias. We analysed EEG recordings from old adults: HCs, AD, DLB and Parkinson's disease dementia (PDD) patients. Brain networks were assessed with the minimum spanning tree (MST) within six EEG bands: delta, theta, high-theta, alpha, beta and DF. Patients showed lower alpha band connectivity and lower DF than HCs. DLB and PDD showed a randomised MST compared with HCs and AD in high-theta and alpha but not in DF. The MST randomisation in DLB and PDD reflects decreased brain efficiency as well as impaired neural synchronisation. However, the lack of network topology differences at the DF between all dementia groups and HCs may indicate a compensatory response of the brain to the neuropathology.
| S-EPMC5854590 | biostudies-literature
Project description:BackgroundDementia is a prevalent non-motor manifestation among individuals with advanced Parkinson's disease (PD). Glial fibrillary acidic protein (GFAP) is an inflammatory marker derived from astrocytes. Research has demonstrated the potential of plasma GFAP to forecast the progression to dementia in PD patients with mild cognitive impairment (PD-MCI). However, the predictive role of cerebrospinal fluid (CSF) GFAP on future cognitive transformation and alterations in Alzheimer's disease (AD)-associated CSF biomarkers in newly diagnosed PD patients has not been investigated.Methods210 de novo PD patients from the Parkinson's Progression Markers Initiative were recruited. Cognitive progression in PD participants was evaluated using Cox regression. Cross-sectional and longitudinal associations between baseline CSF GFAP and cognitive function and AD-related CSF biomarkers were evaluated using multiple linear regression and generalized linear mixed model.ResultsAt baseline, the mean age of PD participants was 60.85 ± 9.78 years, including 142 patients with normal cognition (PD-NC) and 68 PD-MCI patients. The average follow-up time was 6.42 ± 1.69 years. A positive correlation was observed between baseline CSF GFAP and age (β = 0.918, p < 0.001). There was no statistically significant difference in baseline CSF GFAP levels between PD-NC and PD-MCI groups. Higher baseline CSF GFAP predicted greater global cognitive decline over time in early PD patients (Montreal Cognitive Assessment, β = - 0.013, p = 0.014). Furthermore, Cox regression showed that high baseline CSF GFAP levels were associated with a high risk of developing dementia over an 8-year period in the PD-NC group (adjusted HR = 3.070, 95% CI 1.119-8.418, p = 0.029). In addition, the baseline CSF GFAP was positively correlated with the longitudinal changes of not only CSF α-synuclein (β = 0.313, p < 0.001), but also CSF biomarkers associated with AD, namely, amyloid-β 42 (β = 0.147, p = 0.034), total tau (β = 0.337, p < 0.001) and phosphorylated tau (β = 0.408, p < 0.001).ConclusionsCSF GFAP may be a valuable prognostic tool that can predict the severity and progression of cognitive deterioration, accompanied with longitudinal changes in AD-associated pathological markers in early PD.
| S-EPMC10357612 | biostudies-literature
Project description:Dementia is one of the most disabling nonmotor symptoms of Parkinson's disease (PD). However, the risk factors contributing to its development remain unclear. To investigate genetic variants associated with dementia in PD, we performed microarray genotyping based on a customized platform utilizing variants identified in previous genetic studies. Microarray genotyping was performed in 313 PD patients with dementia, 321 PD patients without dementia, and 635 healthy controls. The primary analysis was performed using a multiple logistic regression model adjusted for age and sex. SNCA single nucleotide polymorphism (SNP) rs11931074 was determined to be most significantly associated with PD (odds ratio = 0.66, 95% confidence interval = 0.56-0.78, p = 7.75 × 10-7). In the analysis performed for patients with PD only, MUL1 SNP rs3738128 (odds ratio = 2.52, 95% confidence interval = 1.68-3.79, p = 8.75 × 10-6) was found to be most significantly associated with dementia in PD. SNPs in ZHX2 and ERP29 were also associated with dementia in PD. This microarray genomic study identified new loci of MUL1 associated with dementia in PD, suggesting an essential role of mitochondrial dysfunction in the development of dementia in patients with PD.
| S-EPMC8701809 | biostudies-literature
Project description:(1) Background: Systemic infection is associated with increased neuroinflammation and accelerated cognitive decline in AD patients. Activated neutrophils produce neutrophil-derived microvesicles (NMV), which are internalised by human brain microvascular endothelial cells and increase their permeability in vitro, suggesting that NMV play a role in blood-brain barrier (BBB) integrity during infection. The current study investigated whether microRNA content of NMV from AD patients is significantly different compared to healthy controls and could impact cerebrovascular integrity. (2) Methods: Neutrophils isolated from peripheral blood samples of five AD and five healthy control donors without systemic infection were stimulated to produce NMV. MicroRNAs isolated from NMV were analysed by RNA-Seq, and online bioinformatic tools were used to identify significantly differentially expressed microRNAs in the NMV. Target and pathway analyses were performed to predict the impact of the candidate microRNAs on vascular integrity. (3) Results: There was no significant difference in either the number of neutrophils (p = 0.309) or the number of NMV (p = 0.3434) isolated from AD donors compared to control. However, 158 microRNAs were significantly dysregulated in AD NMV compared to controls, some of which were associated with BBB dysfunction, including miR-210, miR-20b-5p and miR-126-5p. Pathway analysis revealed numerous significantly affected pathways involved in regulating vascular integrity, including the TGFβ and PDGFB pathways, as well as Hippo, IL-2 and DNA damage signalling. (4) Conclusions: NMV from AD patients contain miRNAs that may alter the integrity of the BBB and represent a novel neutrophil-mediated mechanism for BBB dysfunction in AD and the accelerated cognitive decline seen as a result of a systemic infection.
| S-EPMC9180128 | biostudies-literature