scholarly journals AT(N) MODEL AND ITS ASSOCIATION WITH NEUROPSYCHOLOGICAL MARKERS

2021 ◽  
Author(s):  
Luciano Mariano ◽  
Larissa Salvador ◽  
Patrícia Peles ◽  
Clarisse Friedlaender ◽  
Viviane Carvalho ◽  
...  
Keyword(s):  
Neuropsychological Tests ◽  
Memory Deficits ◽  
Csf Biomarkers ◽  
Phosphorylated Tau ◽  
Classification Methods ◽  
Cognitive Markers ◽  
Total Tau ◽  
Neuropsychological Profile ◽  
N Classification ◽  
Cluster 2

Background: The National Institute on Aging and Alzheimer’s Association (NIA-AA) proposed the AT(N) model to diagnose Alzheimer’s disease (AD) considering some biomarkers: amyloid beta (A), phosphorylated tau (T), and neurodegeneration (N). Still, AT(N) correlation with cognitive markers is not yet covered. Objective: To investigate the neuropsychological profile of patients with CSF biomarkers according to AT(N) classification. Methods: Sixty-five patients with thorough neuropsychological data and results of CSF biomarkers were included in the study. We performed a cluster analysis using biomarkers results. The validity was checked by neuropsychological tests scores. Results: We found three clusters: Cluster 1 (n=24), classified as non-AD; Clusters 2 (n=9) and 3 (n=32), classified as AD. Cluster 2 had a higher burden of phosphorylated tau and total tau. All groups were similar regarding sociodemographics and functionality. AD groups had worse memory deficits than the non-AD cluster, but Cluster 2 was more affected than Cluster 3. No other cognitive difference was found, except in the Cubes subtest (Cluster 3>Cluster 2).Conclusion: Memory was the sole domain able to discriminate AD from non-AD, probably due to Cluster 1 heterogeneity. Further studies are warranted to explore this hypothesis. A smaller cluster with AD shows variability in the biomarker profile, which is relevant given its worse cognitive scores.

scholarly journals Standardization of Assay Procedures for Analysis of the CSF Biomarkers Amyloidβ(1-42), Tau, and Phosphorylated Tau in Alzheimer's Disease: Report of an International Workshop

2010 ◽  
Vol 2010 ◽  
pp. 1-6 ◽  
Author(s):  
Charlotte E. Teunissen ◽  
Niek A. Verwey ◽  
Maartje I. Kester ◽  
Kees van Uffelen ◽  
Marinus A. Blankenstein
Keyword(s):  
Alzheimer’S Disease ◽  
Amino Acid ◽  
International Workshop ◽  
Csf Biomarkers ◽  
Phosphorylated Tau ◽  
Total Tau ◽  
Sources Of Error ◽  
Assay Performance ◽  
Potential Sources ◽  
Analytical Procedures

Large variation in assay performance and outcomes of CSF Aβ1-42, total Tau (Tau), and phosphorylated Tau (pTau) (at amino acid 181) levels is observed between laboratories. The aim of this study was to assess the differences in assay procedures between several experienced international laboratories, as potential sources of error. 14 groups performed the Aβ42, Tau, and pTau assays according to the guidelines of the manufacturer. Differences in analytical procedures between the laboratories were monitored. At least 23 items in assay procedures were identified that varied between the laboratories, including procedures for washing, pipetting, incubation, finishing, and sample handing. In general, the inter- and intra-assay variation between the groups was generally below 10% for all three assays. We concluded that 17 international centers that use the same assays for Aβ42, Tau and pTau on a regular basis do not uniformly adhere to the procedures recommended by the manufacturer. For harmonization of intercenter results of these biomarkers standardization of protocols is highly needed.

scholarly journals On the design of early-phase Alzheimer’s disease clinical trials with cerebrospinal fluid tau outcomes

2021 ◽  
pp. 174077452110344
Author(s):  
Michelle M Nuño ◽  
Joshua D Grill ◽  
Daniel L Gillen ◽  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Cerebrospinal Fluid ◽  
Phosphorylated Tau ◽  
Inclusion Criteria ◽  
Eligibility Criteria ◽  
Total Tau ◽  
Prodromal Alzheimer’S Disease ◽  
Study Power

Background/Aims: The focus of Alzheimer’s disease studies has shifted to earlier disease stages, including mild cognitive impairment. Biomarker inclusion criteria are often incorporated into mild cognitive impairment clinical trials to identify individuals with “prodromal Alzheimer’s disease” to ensure appropriate drug targets and enrich for participants likely to develop Alzheimer’s disease dementia. The use of these eligibility criteria may affect study power. Methods: We investigated outcome variability and study power in the setting of proof-of-concept prodromal Alzheimer’s disease trials that incorporate cerebrospinal fluid levels of total tau (t-tau) and phosphorylated (p-tau) as primary outcomes and how differing biomarker inclusion criteria affect power. We used data from the Alzheimer’s Disease Neuroimaging Initiative to model trial scenarios and to estimate the variance and within-subject correlation of total and phosphorylated tau. These estimates were then used to investigate the differences in study power for trials considering these two surrogate outcomes. Results: Patient characteristics were similar for all eligibility criteria. The lowest outcome variance and highest within-subject correlation were obtained when phosphorylated tau was used as an eligibility criterion, compared to amyloid beta or total tau, regardless of whether total tau or phosphorylated tau were used as primary outcomes. Power increased when eligibility criteria were broadened to allow for enrollment of subjects with either low amyloid beta or high phosphorylated tau. Conclusion: Specific biomarker inclusion criteria may impact statistical power in trials using total tau or phosphorylated tau as the primary outcome. In concert with other important considerations such as treatment target and population of clinical interest, these results may have implications to the integrity and efficiency of prodromal Alzheimer’s disease trial designs.

scholarly journals Functional genomic analyses uncover APOE-mediated regulation of brain and cerebrospinal fluid beta-amyloid levels in Parkinson disease

2020 ◽  
Vol 8 (1) ◽  
Author(s):  
Laura Ibanez ◽  
Jorge A. Bahena ◽  
Chengran Yang ◽  
Umber Dube ◽  
Fabiana H. G. Farias ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Amyloid Beta ◽  
Alpha Synuclein ◽  
Phosphorylated Tau ◽  
Polygenic Risk ◽  
Total Tau ◽  
Genomic Architecture ◽  
Genome Wide ◽  
Csf Biomarker

AbstractAlpha-synuclein is the main protein component of Lewy bodies, the pathological hallmark of Parkinson’s disease. However, genetic modifiers of cerebrospinal fluid (CSF) alpha-synuclein levels remain unknown. The use of CSF levels of amyloid beta1–42, total tau, and phosphorylated tau181 as quantitative traits in genetic studies have provided novel insights into Alzheimer’s disease pathophysiology. A systematic study of the genomic architecture of CSF biomarkers in Parkinson’s disease has not yet been conducted. Here, genome-wide association studies of CSF biomarker levels in a cohort of individuals with Parkinson’s disease and controls (N = 1960) were performed. PD cases exhibited significantly lower CSF biomarker levels compared to controls. A SNP, proxy for APOE ε4, was associated with CSF amyloid beta1–42 levels (effect = − 0.5, p = 9.2 × 10−19). No genome-wide loci associated with CSF alpha-synuclein, total tau, or phosphorylated tau181 levels were identified in PD cohorts. Polygenic risk score constructed using the latest Parkinson’s disease risk meta-analysis were associated with Parkinson’s disease status (p = 0.035) and the genomic architecture of CSF amyloid beta1–42 (R2 = 2.29%; p = 2.5 × 10−11). Individuals with higher polygenic risk scores for PD risk presented with lower CSF amyloid beta1–42 levels (p = 7.3 × 10−04). Two-sample Mendelian Randomization revealed that CSF amyloid beta1–42 plays a role in Parkinson’s disease (p = 1.4 × 10−05) and age at onset (p = 7.6 × 10−06), an effect mainly mediated by variants in the APOE locus. In a subset of PD samples, the APOE ε4 allele was associated with significantly lower levels of CSF amyloid beta1–42 (p = 3.8 × 10−06), higher mean cortical binding potentials (p = 5.8 × 10−08), and higher Braak amyloid beta score (p = 4.4 × 10−04). Together these results from high-throughput and hypothesis-free approaches converge on a genetic link between Parkinson’s disease, CSF amyloid beta1–42, and APOE.

scholarly journals Cerebrospinal Fluid Biomarkers for Kii Amyotrophic Lateral Sclerosis/Parkinsonism-Dementia Complex

2013 ◽  
Vol 2013 ◽  
pp. 1-4
Author(s):  
Yui Nakayama ◽  
Satoru Morimoto ◽  
Misao Yoneda ◽  
Shigeki Kuzuhara ◽  
Yasumasa Kokubo
Keyword(s):  
Alzheimer’S Disease ◽  
Parkinson’S Disease ◽  
Alzheimer's Disease ◽  
Parkinson's Disease ◽  
Amyotrophic Lateral Sclerosis ◽  
Cerebrospinal Fluid ◽  
Enzyme Linked Immunosorbent Assay ◽  
Phosphorylated Tau ◽  
Total Tau ◽  
Lateral Sclerosis

Objective. Amyotrophic lateral sclerosis/parkinsonism-dementia complex is classified as one of the tauopathies. Methods. The total tau, phosphorylated tau, and amyloid β42 levels were assayed in cerebrospinal fluid from patients with Kii amyotrophic lateral sclerosis/parkinsonism-dementia complex (), Alzheimer’s disease (), Parkinson’s disease (), amyotrophic lateral sclerosis (), and controls () using specific enzyme-linked immunosorbent assay methods. Results. Total tau and phosphorylated tau did not increase and amyloid β42 was relatively reduced in Kii amyotrophic lateral sclerosis/parkinsonism-dementia complex. Relatively reduced amyloid β42 might discriminate Kii amyotrophic lateral sclerosis/parkinsonism-dementia complex from amyotrophic lateral sclerosis and Parkinson’s disease, and the ratios of phosphorylated-tau to amyloid β42 could discriminate Kii amyotrophic lateral sclerosis/parkinsonism-dementia complex from Alzheimer’s disease. Conclusions. Cerebrospinal fluid analysis may be useful to differentiate amyotrophic lateral sclerosis/parkinsonism-dementia complex from Alzheimer’s disease, amyotrophic lateral sclerosis, and Parkinson’s disease.

scholarly journals Neuropsychological profile of a male psychiatric patient with a Morgagni-Stewart-Morel syndrome

2014 ◽  
Vol 27 (1) ◽  
pp. 60-64 ◽  
Author(s):  
Aksel Hansen ◽  
Liliana Engelhardt ◽  
Wolfgang Pleschutznig ◽  
Gerhard Dammann ◽  
Stephanie Vietze
Keyword(s):  
Case Report ◽  
Psychiatric Patient ◽  
Neuropsychological Tests ◽  
Psychiatric Symptoms ◽  
Case Reports ◽  
Neuropsychiatric Symptoms ◽  
Pain Syndrome ◽  
Admission Diagnosis ◽  
Neuropsychological Profile ◽  
Definition Of

In 1765 Giovanni Morgagni described a syndrome consisting of hyperostosis frontalis interna (HFI), obesity and hirsutism. In 1928 Stewart and in 1930 Morel added neuropsychiatric symptoms, e.g. depression and dementia, which led to the definition of the Morgagni-Stewart-Morel Syndrome (MSM). Although mostly women were characterized in literature no gender specifity is demanded. This case report presents the rare case of a 66 year old male psychiatric patient with Morgagni-Stewart-Morel Syndrome. The patient complained of loss of concentration and difficulties with activities of daily living. Admission diagnosis was an opioid misuse on the basis of a chronic pain syndrome. In this case report we are describing clinical features, the patient history and technical (MRI) and neuropsychological tests. Although severe psychiatric symptoms and neuropsychological deficits are commonly seen in these patients, our patient showed only mild symptoms. This case reports shows the possibility of a male patient with MSM. If MSM is a separate entity or just an epiphenomena of hormone dysregulation should be investigated in further studies.

scholarly journals Prevalence of preclinical Alzheimer disease

Neurology ◽  
2018 ◽  
Vol 90 (19) ◽  
pp. e1682-e1691 ◽  
Author(s):  
Silke Kern ◽  
Henrik Zetterberg ◽  
Jürgen Kern ◽  
Anna Zettergren ◽  
Margda Waern ◽  
...  
Keyword(s):  
At Risk ◽  
Alzheimer Disease ◽  
Population Sample ◽  
Population Based ◽  
Classification Systems ◽  
Phosphorylated Tau ◽  
Tau Pathology ◽  
Clinical Dementia Rating ◽  
Total Tau ◽  
Preclinical Ad

ObjectiveTo determine the prevalence of preclinical Alzheimer disease (AD) according to current classification systems by examining CSF from a representative general population sample of 70-year-olds from Gothenburg, Sweden.MethodThe sample was derived from the population-based H70 Gothenburg Birth Cohort Studies in Gothenburg, Sweden. The participants (n = 322, age 70 years) underwent comprehensive neuropsychiatric, cognitive, and somatic examinations. CSF levels of β-amyloid (Aβ)42, Aβ40, total tau, and phosphorylated tau were measured. Preclinical AD was classified according to criteria of the A/T/N system, Dubois 2016, National Institute on Aging–Alzheimer's Association (NIA-AA) criteria, and International Working Group-2 (IWG-2) criteria. Individuals with Clinical Dementia Rating score >0 were excluded, leaving 259 cognitively unimpaired individuals.ResultsThe prevalence of amyloid pathology was 22.8%, of total tau pathology was 33.2%, and of phosphorylated tau pathology was 6.9%. With the A/T/N system, the prevalence of A+/T−/N− was 13.1%, A+/T−/N+ was 7.3%, A+/T+/N+ was 2.3%, A−/T−/N+ was 18.9%, and A−/T+/N+ was 4.6%. When the Dubois criteria were applied, the prevalence of asymptomatic at risk for AD was 36.7% and of preclinical AD was 9.7%. With the NIA-AA criteria, the prevalence of stage 1 was 13.1% and stage 2 was 9.7%. With the IWG-2 criteria, the prevalence of asymptomatic at risk for AD was 9.7%. TheAPOEε4 allele was associated with several of the categories. Men more often had total tau pathology, A+/T−/N+, preclinical AD according to Dubois 2016, asymptomatic at risk for AD according to the IWG-2 criteria, and NIA-AA stage 2.ConclusionThe prevalence of pathologic AD markers was very common (46%) in a representative population sample of 70-year-olds. The clinical implications of these findings need to be scrutinized further in longitudinal studies.

scholarly journals Value of Neuropsychological Tests to Identify Patients with Depressive Symptoms on the Alzheimer’s Disease Continuum

2020 ◽  
Vol 78 (2) ◽  
pp. 819-826
Author(s):  
Felix Menne ◽  
Carola Gertrud Schipke ◽  
Arne Klostermann ◽  
Manuel Fuentes-Casañ ◽  
Silka Dawn Freiesleben ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Depressive Symptoms ◽  
Neuropsychological Tests ◽  
Neuropsychological Test ◽  
Memory Task ◽  
Geriatric Depression Scale ◽  
Depression Scale ◽  
Area Under The Curve ◽  
Csf Biomarkers

Background: Depressive symptoms often co-occur with Alzheimer’s disease (AD) and can impact neuropsychological test results. In early stages of AD, disentangling cognitive impairments due to depression from those due to neurodegeneration often poses a challenge. Objective: We aimed to identify neuropsychological tests able to detect AD-typical pathology while taking into account varying degrees of depressive symptoms. Methods: A battery of neuropsychological tests (CERAD-NP) and the Geriatric Depression Scale (GDS) were assessed, and cerebrospinal fluid (CSF) biomarkers were obtained. After stratifying patients into CSF positive or negative and into low, moderate, or high GDS score groups, sensitivity and specificity and area under the curve (AUC) were calculated for each subtest. Results: 497 participants were included in the analyses. In patients with low GDS scores (≤10), the highest AUC (0.72) was achieved by Mini-Mental State Examination, followed by Constructional Praxis Recall and Wordlist Total Recall (AUC = 0.714, both). In patients with moderate (11–20) and high (≥21) GDS scores, Trail Making Test-B (TMT-B) revealed the highest AUCs with 0.77 and 0.82, respectively. Conclusion: Neuropsychological tests showing AD-typical pathology in participants with low GDS scores are in-line with previous results. In patients with higher GDS scores, TMT-B showed the best discrimination. This indicates the need to focus on executive function rather than on memory task results in depressed patients to explore a risk for AD.

Neurogranin as a Novel Biomarker in Alzheimer’s Disease

2020 ◽  
Author(s):  
Luisa Agnello ◽  
Caterina Maria Gambino ◽  
Bruna Lo Sasso ◽  
Giulia Bivona ◽  
Salvatore Milano ◽  
...  
Keyword(s):  
Operating Characteristic ◽  
Neurological Diseases ◽  
Area Under The Curve ◽  
Curve Analysis ◽  
Phosphorylated Tau ◽  
Roc Curve Analysis ◽  
Total Tau ◽  
Novel Biomarkers ◽  
Good Diagnostic Accuracy

Abstract Background In this study, we investigated the possible role of 2 novel biomarkers of synaptic damage, namely, neurogranin and α-synuclein, in Alzheimer disease (AD). Methods The study was performed in a cohort consisting of patients with AD and those without AD, including individuals with other neurological diseases. Cerebrospinal fluid (CSF) neurogranin and α-synuclein levels were measured by sensitive enzyme-linked immunosorbent assays (ELISAs). Results We found significantly increased levels of CSF neurogranin and α-synuclein in patients with AD than those without AD. Neurogranin was correlated with total tau (tTau) and phosphorylated tau (pTau), as well as with cognitive decline, in patients with AD. Receiver operating characteristic (ROC) curve analysis showed good diagnostic accuracy of neurogranin for AD at a cutoff point of 306 pg per mL with an area under the curve (AUC) of 0.872 and sensitivity and specificity of 84.2% and 78%, respectively. Conclusions Our findings support the use of CSF neurogranin as a biomarker of synapsis damage in patients with AD.

scholarly journals Do cerebrospinal fluid transfer methods affect measured amyloid β42, total tau, and phosphorylated tau in clinical practice?

2015 ◽  
Vol 1 (3) ◽  
pp. 380-384 ◽  
Author(s):  
Ross W. Paterson ◽  
Jamie Toombs ◽  
Miles D. Chapman ◽  
Jennifer M. Nicholas ◽  
Amanda J. Heslegrave ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Clinical Practice ◽  
Phosphorylated Tau ◽  
Total Tau ◽  
Fluid Transfer

scholarly journals Explosive-driven double-blast exposure: molecular, histopathological, and behavioral consequences

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Erin K. Murphy ◽  
Diego Iacono ◽  
Hongna Pan ◽  
Jamie B. Grimes ◽  
Steven Parks ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Protein Level ◽  
Tau Phosphorylation ◽  
Behavioral Changes ◽  
Phosphorylated Tau ◽  
Total Tau ◽  
Blast Exposure ◽  
Psychiatric Sequelae ◽  
Relevant Finding

Abstract Traumatic brain injury generated by blast may induce long-term neurological and psychiatric sequelae. We aimed to identify molecular, histopathological, and behavioral changes in rats 2 weeks after explosive-driven double-blast exposure. Rats received two 30-psi (~ 207-kPa) blasts 24 h apart or were handled identically without blast. All rats were behaviorally assessed over 2 weeks. At Day 15, rats were euthanized, and brains removed. Brains were dissected into frontal cortex, hippocampus, cerebellum, and brainstem. Western blotting was performed to measure levels of total-Tau, phosphorylated-Tau (pTau), amyloid precursor protein (APP), GFAP, Iba1, αII-spectrin, and spectrin breakdown products (SBDP). Kinases and phosphatases, correlated with tau phosphorylation were also measured. Immunohistochemistry for pTau, APP, GFAP, and Iba1 was performed. pTau protein level was greater in the hippocampus, cerebellum, and brainstem and APP protein level was greater in cerebellum of blast vs control rats (p < 0.05). GFAP, Iba1, αII-spectrin, and SBDP remained unchanged. No immunohistochemical or neurobehavioral changes were observed. The dissociation between increased pTau and APP in different regions in the absence of neurobehavioral changes 2 weeks after double blast exposure is a relevant finding, consistent with human data showing that battlefield blasts might be associated with molecular changes before signs of neurological and psychiatric disorders manifest.

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