Publications by authors named "Harald Hampel"

371 Publications

Common variants in Alzheimer's disease and risk stratification by polygenic risk scores.

Nat Commun 2021 06 7;12(1):3417. Epub 2021 Jun 7.

Servei de Neurologia, Hospital Universitari i Politècnic La Fe, Valencia, Spain.

Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer's disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer's disease.
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http://dx.doi.org/10.1038/s41467-021-22491-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184987PMC
June 2021

State-of-the-art of lumbar puncture and its place in the journey of patients with Alzheimer's disease.

Alzheimers Dement 2021 May 27. Epub 2021 May 27.

Eisai Inc., Neurology Business Group, Woodcliff Lake, New Jersey, USA.

Recent advances in developing disease-modifying therapies (DMT) for Alzheimer's disease (AD), and the recognition that AD pathophysiology emerges decades before clinical symptoms, necessitate a paradigm shift of health-care systems toward biomarker-guided early detection, diagnosis, and therapeutic decision-making. Appropriate incorporation of cerebrospinal fluid biomarker analysis in clinical practice is an essential step toward system readiness for accommodating the demand of AD diagnosis and proper use of DMTs-once they become available. However, the use of lumbar puncture (LP) in individuals with suspected neurodegenerative diseases such as AD is inconsistent, and the perception of its utility and safety differs considerably among medical specialties as well as among regions and countries. This review describes the state-of-the-art evidence concerning the safety profile of LP in older adults, discusses the risk factors for LP-associated adverse events, and provides recommendations and an outlook for optimized use and global implementation of LP in individuals with suspected AD.
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http://dx.doi.org/10.1002/alz.12372DOI Listing
May 2021

Omics sciences for systems biology in Alzheimer's disease: State-of-the-art of the evidence.

Ageing Res Rev 2021 Aug 27;69:101346. Epub 2021 Apr 27.

Sorbonne University, GRC n° 21, Alzheimer Precision Medicine (APM), AP-HP, Pitié-Salpêtrière Hospital, Boulevard de l'hôpital, Paris, France; Brain & Spine Institute (ICM), INSERM U 1127, CNRS UMR 7225, Boulevard de l'hôpital, Paris, France; Institute of Memory and Alzheimer's Disease (IM2A), Department of Neurology, Pitié-Salpêtrière Hospital, AP-HP, Boulevard de l'hôpital, Paris, France. Electronic address:

Alzheimer's disease (AD) is characterized by non-linear, genetic-driven pathophysiological dynamics with high heterogeneity in biological alterations and disease spatial-temporal progression. Human in-vivo and post-mortem studies point out a failure of multi-level biological networks underlying AD pathophysiology, including proteostasis (amyloid-β and tau), synaptic homeostasis, inflammatory and immune responses, lipid and energy metabolism, oxidative stress. Therefore, a holistic, systems-level approach is needed to fully capture AD multi-faceted pathophysiology. Omics sciences - genomics, epigenomics, transcriptomics, proteomics, metabolomics, lipidomics - embedded in the systems biology (SB) theoretical and computational framework can generate explainable readouts describing the entire biological continuum of a disease. Such path in Neurology is encouraged by the promising results of omics sciences and SB approaches in Oncology, where stage-driven pathway-based therapies have been developed in line with the precision medicine paradigm. Multi-omics data integrated in SB network approaches will help detect and chart AD upstream pathomechanistic alterations and downstream molecular effects occurring in preclinical stages. Finally, integrating omics and neuroimaging data - i.e., neuroimaging-omics - will identify multi-dimensional biological signatures essential to track the clinical-biological trajectories, at the subpopulation or even individual level.
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http://dx.doi.org/10.1016/j.arr.2021.101346DOI Listing
August 2021

Measures of resting state EEG rhythms for clinical trials in Alzheimer's disease: Recommendations of an expert panel.

Alzheimers Dement 2021 Apr 15. Epub 2021 Apr 15.

School of Psychology, University of Glasgow, Glasgow, UK.

The Electrophysiology Professional Interest Area (EPIA) and Global Brain Consortium endorsed recommendations on candidate electroencephalography (EEG) measures for Alzheimer's disease (AD) clinical trials. The Panel reviewed the field literature. As most consistent findings, AD patients with mild cognitive impairment and dementia showed abnormalities in peak frequency, power, and "interrelatedness" at posterior alpha (8-12 Hz) and widespread delta (< 4 Hz) and theta (4-8 Hz) rhythms in relation to disease progression and interventions. The following consensus statements were subscribed: (1) Standardization of instructions to patients, resting state EEG (rsEEG) recording methods, and selection of artifact-free rsEEG periods are needed; (2) power density and "interrelatedness" rsEEG measures (e.g., directed transfer function, phase lag index, linear lagged connectivity, etc.) at delta, theta, and alpha frequency bands may be use for stratification of AD patients and monitoring of disease progression and intervention; and (3) international multisectoral initiatives are mandatory for regulatory purposes.
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http://dx.doi.org/10.1002/alz.12311DOI Listing
April 2021

EEG measures for clinical research in major vascular cognitive impairment: recommendations by an expert panel.

Neurobiol Aging 2021 Jul 10;103:78-97. Epub 2021 Mar 10.

Centre for Healthy Brain Ageing (CHeBA), School of Psychiatry, University of New South Wales; Neuropsychiatric Institute, The Prince of Wales Hospital, Sydney, Australia.

Vascular contribution to cognitive impairment (VCI) and dementia is related to etiologies that may affect the neurophysiological mechanisms regulating brain arousal and generating electroencephalographic (EEG) activity. A multidisciplinary expert panel reviewed the clinical literature and reached consensus about the EEG measures consistently found as abnormal in VCI patients with dementia. As compared to cognitively unimpaired individuals, those VCI patients showed (1) smaller amplitude of resting state alpha (8-12 Hz) rhythms dominant in posterior regions; (2) widespread increases in amplitude of delta (< 4 Hz) and theta (4-8 Hz) rhythms; and (3) delayed N200/P300 peak latencies in averaged event-related potentials, especially during the detection of auditory rare target stimuli requiring participants' responses in "oddball" paradigms. The expert panel formulated the following recommendations: (1) the above EEG measures are not specific for VCI and should not be used for its diagnosis; (2) they may be considered as "neural synchronization" biomarkers to enlighten the relationships between features of the VCI-related cerebrovascular lesions and abnormalities in neurophysiological brain mechanisms; and (3) they may be tested in future clinical trials as prognostic biomarkers and endpoints of interventions aimed at normalizing background brain excitability and vigilance in wakefulness.
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http://dx.doi.org/10.1016/j.neurobiolaging.2021.03.003DOI Listing
July 2021

Progress regarding the context-of-use of tau as biomarker of Alzheimer's disease and other neurodegenerative diseases.

Expert Rev Proteomics 2021 Jan 7;18(1):27-48. Epub 2021 Mar 7.

Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.

: Tau protein misfolding and accumulation in toxic species is a critical pathophysiological process of Alzheimer's disease (AD) and other neurodegenerative disorders (NDDs). Tau biomarkers, namely cerebrospinal fluid (CSF) total-tau (t-tau), 181-phosphorylated tau (p-tau), and tau-PET tracers, have been recently embedded in the diagnostic criteria for AD. Nevertheless, the role of tau as a diagnostic and prognostic biomarker for other NDDs remains controversial.: We performed a systematical PubMed-based review of the most recent advances in tau-related biomarkers for NDDs. We focused on papers published from 2015 to 2020 assessing the diagnostic or prognostic value of each biomarker.: The assessment of tau biomarkers in alternative easily accessible matrices, through the development of ultrasensitive techniques, represents the most significant perspective for AD-biomarker research. In NDDs, novel tau isoforms (e.g. p-tau217) or proteolytic fragments (e.g. N-terminal fragments) may represent candidate diagnostic and prognostic biomarkers and may help monitoring disease progression. Protein misfolding amplification assays, allowing the identification of different tau strains (e.g. 3 R- . 4 R-tau) in CSF, may constitute a breakthrough for the in vivo stratification of NDDs. Tau-PET may help tracking the spatial-temporal evolution of tau pathophysiology in AD but its application outside the AD-spectrum deserves further studies.
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http://dx.doi.org/10.1080/14789450.2021.1886929DOI Listing
January 2021

Plasma β-secretase1 concentrations correlate with basal forebrain atrophy and neurodegeneration in cognitively healthy individuals at risk for AD.

Alzheimers Dement 2021 04 1;17(4):629-640. Epub 2021 Feb 1.

Sorbonne University, GRC n° 21, Alzheimer Precision Medicine (APM), AP-HP, Pitié-Salpêtrière Hospital, Boulevard de l'hôpital, Paris, France.

Background: Increased β-secretase 1 (BACE1) protein concentration, in body fluids, is a candidate biomarker of Alzheimer's disease (AD).We reported that plasma BACE1 protein concentrations are associated with the levels of brain amyloidβ (Αβ) accumulation in cognitively healthy individuals with subjective memory complaint (SMC).

Methods: In 302 individuals from the same cohort, we investigated the cross-sectional and longitudinal association between plasma BACE1 protein concentrations and AD biomarkers of neurodegeneration (plasma t-tau and Neurofilament light chain (NfL), fluorodeoxyglucose-positron emission tomography (FDG-PET), brain volumes in the basal forebrain [BF], hippocampus, and entorhinal cortex).

Results: We report a positive longitudinal correlation of BACE1 with both NfL and t-tau, as well as a correlation between annual BACE1 changes and bi-annual reduction of BF volume. We show a positive association between BACE1 and FDG-PET signal at baseline.

Conclusions: The association between plasma BACE1 protein concentrations and BF atrophy we found in cognitively healthy individuals with SMC corroborates translational studies, suggesting a role of BACE1 in neurodegeneration.
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http://dx.doi.org/10.1002/alz.12228DOI Listing
April 2021

MiRNA-15b and miRNA-125b are associated with regional Aβ-PET and FDG-PET uptake in cognitively normal individuals with subjective memory complaints.

Transl Psychiatry 2021 Jan 27;11(1):78. Epub 2021 Jan 27.

Sorbonne University, GRC n° 21, Alzheimer Precision Medicine (APM), AP-HP, Pitié-Salpêtrière Hospital, Boulevard de l'hôpital, F-75013, Paris, France.

There is substantial experimental evidence for dysregulation of several microRNA (miRNA) expression levels in Alzheimer's disease (AD). MiRNAs modulate critical brain intracellular signaling pathways and are associated with AD core pathophysiological mechanisms. First, we conducted a real-time quantitative PCR-based pilot study to identify a set of brain-enriched miRNAs in a monocentric cohort of cognitively normal individuals with subjective memory complaints, a condition associated with increased risk of AD. Second, we investigated the impact of age, sex, and the Apolipoprotein E ε4 (APOE ε4) allele, on the identified miRNA plasma concentrations. In addition, we explored the cross-sectional and longitudinal association of the miRNAs plasma concentrations with regional brain metabolic uptake using amyloid-β (Aβ)-positron emission tomography (Aβ-PET) and F-fluorodeoxyglucose-PET (F-FDG-PET). We identified a set of six brain-enriched miRNAs-miRNA-125b, miRNA-146a, miRNA-15b, miRNA-148a, miRNA-26b, and miRNA-100. Age, sex, and APOE ε4 allele were not associated with individual miRNA abundance. MiRNA-15b concentrations were significantly lower in the Aβ-PET-positive compared to Aβ-PET-negative individuals. Furthermore, we found a positive effect of the miRNA-15b*time interaction on regional metabolic F-FDG-PET uptake in the left hippocampus. Plasma miRNA-125b concentrations, as well as the miRNA-125b*time interaction (over a 2-year follow-up), were negatively associated with regional Aβ-PET standard uptake value ratio in the right anterior cingulate cortex. At baseline, we found a significantly negative association between plasma miRNA-125b concentrations and F-FDG-PET uptake in specific brain regions. In an asymptomatic at-risk population for AD, we show significant associations between plasma concentrations of miRNA-125b and miRNA-15b with core neuroimaging biomarkers of AD pathophysiology. Our results, coupled with existing experimental evidence, suggest a potential protective anti-Aβ effect of miRNA-15b and a biological link between miRNA-125b and Aβ-independent neurotoxic pathways.
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http://dx.doi.org/10.1038/s41398-020-01184-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7840941PMC
January 2021

Aptamarker prediction of brain amyloid-β status in cognitively normal individuals at risk for Alzheimer's disease.

PLoS One 2021 4;16(1):e0243902. Epub 2021 Jan 4.

Sorbonne University, GRC n° 21, Alzheimer Precision Medicine (APM), AP-HP, Pitié-Salpêtrière Hospital, Paris, France.

The traditional approach to biomarker discovery for any pathology has been through hypothesis-based research one candidate at a time. The objective of this study was to develop an agnostic approach for the simultaneous screening of plasma for consistent molecular differences between a group of individuals exhibiting a pathology and a group of healthy individuals. To achieve this, we focused on developing a predictive tool based on plasma for the amount of brain amyloid-β deposition as observed in PET scans. The accumulation of brain amyloid-β (Aβ) plaques is a key risk factor for the development of Alzheimer's disease. A contrast was established between cognitively normal individuals above the age of 70 that differed for the amount of brain amyloid-β observed in PET scans (INSIGHT study group). Positive selection was performed against a pool of plasma from individuals with high brain amyloid and negative selection against a pool of plasma from individuals with low brain amyloid This enriched, selected library was then applied to plasma samples from 11 individuals with high levels of brain amyloid and 11 individuals with low levels of brain Aβ accumulation. Each of these individually selected libraries was then characterized by next generation sequencing, and the relative frequency of 10,000 aptamer sequences that were observed in each selection was screened for ability to explain variation in brain amyloid using sparse partial least squares discriminant analysis. From this analysis a subset of 44 aptamers was defined, and the individual aptamers were synthesized. This subset was applied to plasma samples from 70 cognitively normal individuals all above the age of 70 that differed for brain amyloid deposition. 54 individuals were used as a training set, and 15 as a test set. Three of the 15 individuals in the test set were mis-classified resulting in an overall accuracy of 80% with 86% sensitivity and 75% specificity. The aptamers included in the subset serve directly as biomarkers, thus we have named them Aptamarkers. There are two potential applications of these results: extending the predictive capacity of these aptamers across a broader range of individuals, and/or using the individual aptamers to identify targets through covariance analysis and reverse omics approaches. We are currently expanding applications of the Aptamarker platform to other diseases and target matrices.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0243902PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7781383PMC
April 2021

microRNA-Based Biomarkers in Alzheimer's Disease (AD).

Front Neurosci 2020 30;14:585432. Epub 2020 Oct 30.

LSU Neuroscience Center, Louisiana State University Health Sciences Center, New Orleans, LA, United States.

Alzheimer's disease (AD) is a multifactorial, age-related neurological disease characterized by complex pathophysiological dynamics taking place at multiple biological levels, including molecular, genetic, epigenetic, cellular and large-scale brain networks. These alterations account for multiple pathophysiological mechanisms such as brain protein accumulation, neuroinflammatory/neuro-immune processes, synaptic dysfunction, and neurodegeneration that eventually lead to cognitive and behavioral decline. Alterations in microRNA (miRNA) signaling have been implicated in the epigenetics and molecular genetics of all neurobiological processes associated with AD pathophysiology. These changes encompass altered miRNA abundance, speciation and complexity in anatomical regions of the CNS targeted by the disease, including modified miRNA expression patterns in brain tissues, the systemic circulation, the extracellular fluid (ECF) and the cerebrospinal fluid (CSF). miRNAs have been investigated as candidate biomarkers for AD diagnosis, disease prediction, prognosis and therapeutic purposes because of their involvement in multiple brain signaling pathways in both health and disease. In this review we will: (i) highlight the significantly heterogeneous nature of miRNA expression and complexity in AD tissues and biofluids; (ii) address how information may be extracted from these data to be used as a diagnostic, prognostic and/or screening tools across the entire continuum of AD, from the preclinical stage, through the prodromal, i.e., mild cognitive impairment (MCI) phase all the way to clinically overt dementia; and (iii) consider how specific miRNA expression patterns could be categorized using miRNA reporters that span AD pathophysiological initiation and disease progression.
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http://dx.doi.org/10.3389/fnins.2020.585432DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7664832PMC
October 2020

Age and sex impact plasma NFL and t-Tau trajectories in individuals with subjective memory complaints: a 3-year follow-up study.

Alzheimers Res Ther 2020 11 12;12(1):147. Epub 2020 Nov 12.

Sorbonne University, GRC n° 21, Alzheimer Precision Medicine (APM), AP-HP, Pitié-Salpêtrière Hospital, Boulevard de l'hôpital, F-75013, Paris, France.

Background: Plasma neurofilament light (NFL) and total Tau (t-Tau) proteins are candidate biomarkers for early stages of Alzheimer's disease (AD). The impact of biological factors on their plasma concentrations in individuals with subjective memory complaints (SMC) has been poorly explored. We longitudinally investigate the effect of sex, age, APOE ε4 allele, comorbidities, brain amyloid-β (Aβ) burden, and cognitive scores on plasma NFL and t-Tau concentrations in cognitively healthy individuals with SMC, a condition associated with AD development.

Methods: Three hundred sixteen and 79 individuals, respectively, have baseline and three-time point assessments (at baseline, 1-year, and 3-year follow-up) of the two biomarkers. Plasma biomarkers were measured with an ultrasensitive assay in a mono-center cohort (INSIGHT-preAD study).

Results: We show an effect of age on plasma NFL, with women having a higher increase of plasma t-Tau concentrations compared to men, over time. The APOE ε4 allele does not affect the biomarker concentrations while plasma vitamin B12 deficiency is associated with higher plasma t-Tau concentrations. Both biomarkers are correlated and increase over time. Baseline NFL is related to the rate of Aβ deposition at 2-year follow-up in the left-posterior cingulate and the inferior parietal gyri. Baseline plasma NFL and the rate of change of plasma t-Tau are inversely associated with cognitive score.

Conclusion: We find that plasma NFL and t-Tau longitudinal trajectories are affected by age and female sex, respectively, in SMC individuals. Exploring the influence of biological variables on AD biomarkers is crucial for their clinical validation in blood.
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http://dx.doi.org/10.1186/s13195-020-00704-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7663867PMC
November 2020

β-Secretase1 biological markers for Alzheimer's disease: state-of-art of validation and qualification.

Alzheimers Res Ther 2020 10 16;12(1):130. Epub 2020 Oct 16.

Sorbonne University, GRC no 21, Alzheimer Precision Medicine (APM), AP-HP, Pitié-Salpêtrière Hospital, Paris, France.

β-Secretase1 (BACE1) protein concentrations and rates of enzyme activity, analyzed in human bodily fluids, are promising candidate biological markers for guidance in clinical trials investigating BACE1 inhibitors to halt or delay the dysregulation of the amyloid-β pathway in Alzheimer's disease (AD). A robust body of evidence demonstrates an association between cerebrospinal fluid/blood BACE1 biomarkers and core pathophysiological mechanisms of AD, such as brain protein misfolding and aggregration, neurodegeneration, and synaptic dysfunction.In pharmacological trials, BACE1 candidate biomarkers may be applied to a wide set of contexts of use (CoU), including proof of mechanism, dose-finding, response and toxicity dose estimation. For clinical CoU, BACE1 biomarkers show good performance for prognosis and disease prediction.The roadmap toward validation and qualification of BACE1 biomarkers requires standardized pre-analytical and analytical protocols to reduce inter-site variance that may have contributed to inconsistent results.BACE1 biomarker-drug co-development programs, including biomarker-guided outcomes and endpoints, may support the identification of sub-populations with a higher probability to benefit from BACE1 inhibitors with a reduced risk of adverse effects, in line with the evolving precision medicine paradigm.
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http://dx.doi.org/10.1186/s13195-020-00686-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7566058PMC
October 2020

Abnormalities of resting-state EEG in patients with prodromal and overt dementia with Lewy bodies: Relation to clinical symptoms.

Clin Neurophysiol 2020 11 23;131(11):2716-2731. Epub 2020 Sep 23.

Department of Neurology, School of Medicine, Istanbul Medipol University, Istanbul, Turkey.

Objective: Here we tested if cortical sources of resting state electroencephalographic (rsEEG) rhythms may differ in sub-groups of patients with prodromal and overt dementia with Lewy bodies (DLB) as a function of relevant clinical symptoms.

Methods: We extracted clinical, demographic and rsEEG datasets in matched DLB patients (N = 60) and control Alzheimer's disease (AD, N = 60) and healthy elderly (Nold, N = 60) seniors from our international database. The eLORETA freeware was used to estimate cortical rsEEG sources.

Results: As compared to the Nold group, the DLB and AD groups generally exhibited greater spatially distributed delta source activities (DLB > AD) and lower alpha source activities posteriorly (AD > DLB). As compared to the DLB "controls", the DLB patients with (1) rapid eye movement (REM) sleep behavior disorders showed lower central alpha source activities (p < 0.005); (2) greater cognitive deficits exhibited higher parietal and central theta source activities as well as higher central, parietal, and occipital alpha source activities (p < 0.01); (3) visual hallucinations pointed to greater parietal delta source activities (p < 0.005).

Conclusions: Relevant clinical features were associated with abnormalities in spatial and frequency features of rsEEG source activities in DLB patients.

Significance: Those features may be used as neurophysiological surrogate endpoints of clinical symptoms in DLB patients in future cross-validation prospective studies.
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http://dx.doi.org/10.1016/j.clinph.2020.09.004DOI Listing
November 2020

The role of synaptic biomarkers in the spectrum of neurodegenerative diseases.

Expert Rev Proteomics 2020 Jul - Aug;17(7-8):543-559. Epub 2020 Oct 18.

Department of Clinical and Experimental Medicine, University of Pisa , Pisa, Italy.

Introduction: The quest for reliable fluid biomarkers tracking synaptic disruption is supported by the evidence of a tight association between synaptic density and cognitive performance in neurodegenerative diseases (NDD), especially Alzheimer's disease (AD).

Areas Covered: Neurogranin (Ng) is a post-synaptic protein largely expressed in neurons involved in the memory networks. Currently, Ng measured in CSF is the most promising synaptic biomarker. Several studies show Ng elevated in AD dementia with a hippocampal phenotype as well as in MCI individuals who progress to AD. Ng concentrations are also increased in Creutzfeldt Jacob Disease where widespread and massive synaptic disintegration takes place. Ng does not discriminate Parkinson's disease from atypical parkinsonisms, nor is it altered in Huntington disease. CSF synaptosomal-associated protein 25 (SNAP-25) and synaptotagmin-1 (SYT-1) are emerging candidates.

Expert Opinion: CSF Ng revealed a role as a diagnostic and prognostic biomarker in NDD. Ng increase seems to be very specific for typical AD phenotype, probably for a prevalent hippocampal involvement. Synaptic biomarkers may serve different context-of-use in AD and other NDD including prognosis, diagnosis, and tracking synaptic damage - a critical pathophysiological mechanism in NDD - thus representing reliable tools for a precision medicine-oriented approach to NDD.
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http://dx.doi.org/10.1080/14789450.2020.1831388DOI Listing
October 2020

Biomarkers for Alzheimer's Disease (AD) and the Application of Precision Medicine.

J Pers Med 2020 Sep 21;10(3). Epub 2020 Sep 21.

LSU Neuroscience Center, Louisiana State University Health Science Center, New Orleans, LA 70112, USA.

An accurate diagnosis of Alzheimer's disease (AD) currently stands as one of the most difficult and challenging in all of clinical neurology. AD is typically diagnosed using an integrated knowledge and assessment of multiple biomarkers and interrelated factors. These include the patient's age, gender and lifestyle, medical and genetic history (both clinical- and family-derived), cognitive, physical, behavioral and geriatric assessment, laboratory examination of multiple AD patient biofluids, especially within the systemic circulation (blood serum) and cerebrospinal fluid (CSF), multiple neuroimaging-modalities of the brain's limbic system and/or retina, followed up in many cases by post-mortem neuropathological examination to finally corroborate the diagnosis. More often than not, prospective AD cases are accompanied by other progressive, age-related dementing neuropathologies including, predominantly, a neurovascular and/or cardiovascular component, multiple-infarct dementia (MID), frontotemporal dementia (FTD) and/or strokes or 'mini-strokes' often integrated with other age-related neurological and non-neurological disorders including cardiovascular disease and cancer. Especially over the last 40 years, enormous research efforts have been undertaken to discover, characterize, and quantify more effectual and reliable biological markers for AD, especially during the pre-clinical or prodromal stages of AD so that pre-emptive therapeutic treatment strategies may be initiated. While a wealth of genetic, neurobiological, neurochemical, neuropathological, neuroimaging and other diagnostic information obtainable for a single AD patient can be immense: () it is currently challenging to integrate and formulate a definitive diagnosis for AD from this multifaceted and multidimensional information; and () these data are unfortunately not directly comparable with the etiopathological patterns of other AD patients even when carefully matched for age, gender, familial genetics, and drug history. Four decades of AD research have repeatedly indicated that diagnostic profiles for AD are reflective of an extremely heterogeneous neurological disorder. This commentary will illuminate the heterogeneity of biomarkers for AD, comment on emerging investigative approaches and discuss why is emerging as our best paradigm yet for the most accurate and definitive prediction, diagnosis, and prognosis of this insidious and lethal brain disorder.
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http://dx.doi.org/10.3390/jpm10030138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7565758PMC
September 2020

Association of plasma YKL-40 with brain amyloid-β levels, memory performance, and sex in subjective memory complainers.

Neurobiol Aging 2020 12 17;96:22-32. Epub 2020 Aug 17.

Sorbonne University, GRC no 21, Alzheimer Precision Medicine (APM), AP-HP, Pitié-Salpêtrière Hospital, Paris, France.

Neuroinflammation, a key early pathomechanistic alteration of Alzheimer's disease, may represent either a detrimental or a compensatory mechanism or both (according to the disease stage). YKL-40, a glycoprotein highly expressed in differentiated glial cells, is a candidate biomarker for in vivo tracking neuroinflammation in humans. We performed a longitudinal study in a monocentric cohort of cognitively healthy individuals at risk for Alzheimer's disease exploring whether age, sex, and the apolipoprotein E ε4 allele affect plasma YKL-40 concentrations. We investigated whether YKL-40 is associated with brain amyloid-β (Aβ) deposition, neuronal activity, and neurodegeneration as assessed via neuroimaging biomarkers. Finally, we investigated whether YKL-40 may predict cognitive performance. We found an age-associated increase of YKL-40 and observed that men display higher concentrations than women, indicating a potential sexual dimorphism. Moreover, YKL-40 was positively associated with memory performance and negatively associated with brain Aβ deposition (but not with metabolic signal). Consistent with translational studies, our results suggest a potentially protective effect of glia on incipient brain Aβ accumulation and neuronal homeostasis.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.07.009DOI Listing
December 2020

Different Clinical Contexts of Use of Blood Neurofilament Light Chain Protein in the Spectrum of Neurodegenerative Diseases.

Mol Neurobiol 2020 Nov 9;57(11):4667-4691. Epub 2020 Aug 9.

Unit of Neurology, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.

One of the most pressing challenges in the clinical research of neurodegenerative diseases (NDDs) is the validation and standardization of pathophysiological biomarkers for different contexts of use (CoUs), such as early detection, diagnosis, prognosis, and prediction of treatment response. Neurofilament light chain (NFL) concentration is a particularly promising candidate, an indicator of axonal degeneration, which can be analyzed in peripheral blood with advanced ultrasensitive methods. Serum/plasma NFL concentration is closely correlated with cerebrospinal fluid NFL and directly reflects neurodegeneration within the central nervous system. Here, we provide an update on the feasible CoU of blood NFL in NDDs and translate recent findings to potentially valuable clinical practice applications. As NFL is not a disease-specific biomarker, however, blood NFL is an easily accessible biomarker with promising different clinical applications for several NDDs: (1) early detection and diagnosis (i.e., amyotrophic lateral sclerosis, Creutzfeldt-Jakob disease, atypical parkinsonisms, sporadic late-onset ataxias), (2) prognosis (Huntington's disease and Parkinson's disease), and (3) prediction of time to symptom onset (presymptomatic mutation carriers in genetic Alzheimer's disease and spinocerebellar ataxia type 3).
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http://dx.doi.org/10.1007/s12035-020-02035-9DOI Listing
November 2020

Exercise benefits on Alzheimer's disease: State-of-the-science.

Ageing Res Rev 2020 09 17;62:101108. Epub 2020 Jun 17.

Faculty of Sport Sciences, Universidad Europea de Madrid, Madrid, Spain; Research Institute Hospital 12 de Octubre (i+12) and Centro de Investigación Biomédica en Red Fragilidad y Envejecimiento Saludable, Madrid, Spain. Electronic address:

Although there is no unanimity, growing evidence supports the value of regular physical exercise to prevent Alzheimer's disease as well as cognitive decline in affected patients. Together with an introductory summary on epidemiological evidence, the aim of this review is to summarize the current knowledge on the potential biological mechanisms underlying exercise benefits in this condition. Regular physical exercise has proven to be beneficial for traditional cardiovascular risk factors (e.g., reduced vascular flow, diabetes) involved in the pathogenesis of Alzheimer's disease. Exercise also promotes neurogenesis via increases in exercise-induced metabolic factors (e.g., ketone bodies, lactate) and muscle-derived myokines (cathepsin-B, irisin), which in turn stimulate the production of neurotrophins such as brain-derived neurotrophic factor. Finally, regular exercise exerts anti-inflammatory effects and improves the brain redox status, thereby ameliorating the pathophysiological hallmarks of Alzheimer's disease (e.g., amyloid-β deposition). In summary, physical exercise might provide numerous benefits through different pathways that might, in turn, help prevent risk and progression of Alzheimer's disease. More evidence is needed, however, based on human studies.
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http://dx.doi.org/10.1016/j.arr.2020.101108DOI Listing
September 2020

Future avenues for Alzheimer's disease detection and therapy: liquid biopsy, intracellular signaling modulation, systems pharmacology drug discovery.

Neuropharmacology 2021 03 11;185:108081. Epub 2020 May 11.

Sorbonne University, GRC n°21, Alzheimer Precision Medicine (APM), AP-HP, Pitié-Salpêtrière Hospital, Boulevard de L'hôpital, F-75013, Paris, France; Brain & Spine Institute (ICM), INSERM U 1127, CNRS UMR 7225, Boulevard de L'hôpital, F-75013, Paris, France; Institute of Memory and Alzheimer's Disease (IM2A), Department of Neurology, Pitié-Salpêtrière Hospital, AP-HP, Boulevard de L'hôpital, F-75013, Paris, France.

When Alzheimer's disease (AD) disease-modifying therapies will be available, global healthcare systems will be challenged by a large-scale demand for clinical and biological screening. Validation and qualification of globally accessible, minimally-invasive, and time-, cost-saving blood-based biomarkers need to be advanced. Novel pathophysiological mechanisms (and related candidate biomarkers) - including neuroinflammation pathways (TREM2 and YKL-40), axonal degeneration (neurofilament light chain protein), synaptic dysfunction (neurogranin, synaptotagmin, α-synuclein, and SNAP-25) - may be integrated into an expanding pathophysiological and biomarker matrix and, ultimately, integrated into a comprehensive blood-based liquid biopsy, aligned with the evolving ATN + classification system and the precision medicine paradigm. Liquid biopsy-based diagnostic and therapeutic algorithms are increasingly employed in Oncology disease-modifying therapies and medical practice, showing an enormous potential for AD and other brain diseases as well. For AD and other neurodegenerative diseases, newly identified aberrant molecular pathways have been identified as suitable therapeutic targets and are currently investigated by academia/industry-led R&D programs, including the nerve-growth factor pathway in basal forebrain cholinergic neurons, the sigma1 receptor, and the GTPases of the Rho family. Evidence for a clinical long-term effect on cognitive function and brain health span of cholinergic compounds, drug candidates for repositioning programs, and non-pharmacological multidomain interventions (nutrition, cognitive training, and physical activity) is developing as well. Ultimately, novel pharmacological paradigms, such as quantitative systems pharmacology-based integrative/explorative approaches, are gaining momentum to optimize drug discovery and accomplish effective pathway-based strategies for precision medicine. This article is part of the special issue on 'The Quest for Disease-Modifying Therapies for Neurodegenerative Disorders'.
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http://dx.doi.org/10.1016/j.neuropharm.2020.108081DOI Listing
March 2021

A precision medicine framework using artificial intelligence for the identification and confirmation of genomic biomarkers of response to an Alzheimer's disease therapy: Analysis of the blarcamesine (ANAVEX2-73) Phase 2a clinical study.

Alzheimers Dement (N Y) 2020 19;6(1):e12013. Epub 2020 Apr 19.

Ariana Pharmaceuticals Paris France.

Introduction: The search for drugs to treat Alzheimer's disease (AD) has failed to yield effective therapies. Here we report the first genome-wide search for biomarkers associated with therapeutic response in AD. Blarcamesine (ANAVEX2-73), a selective sigma-1 receptor (SIGMAR1) agonist, was studied in a 57-week Phase 2a trial (NCT02244541). The study was extended for a further 208 weeks (NCT02756858) after meeting its primary safety endpoint.

Methods: Safety, clinical features, pharmacokinetic, and efficacy, measured by changes in the Mini-Mental State Examination (MMSE) and the Alzheimer's Disease Cooperative Study-Activities of Daily Living scale (ADCS-ADL), were recorded. Whole exome and transcriptome sequences were obtained for 21 patients. The relationship between all available patient data and efficacy outcome measures was analyzed with unsupervised formal concept analysis (FCA), integrated in the Knowledge Extraction and Management (KEM) environment.

Results: Biomarkers with a significant impact on clinical outcomes were identified at week 57: mean plasma concentration of blarcamesine (slope MMSE: < .041), genomic variants SIGMAR1 p.Gln2Pro (ΔMMSE: < .039; ΔADCS-ADL: < .063) and COMT p.Leu146fs (ΔMMSE: < .039; ΔADCS-ADL: < .063), and baseline MMSE score (slope MMSE: < .015). Their combined impact on drug response was confirmed at week 148 with linear mixed effect models.

Discussion: Confirmatory Phase 2b/3 clinical studies of these patient selection markers are ongoing. This FCA/KEM analysis is a template for the identification of patient selection markers in early therapeutic development for neurologic disorders.
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http://dx.doi.org/10.1002/trc2.12013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7167374PMC
April 2020

A Path Toward Precision Medicine for Neuroinflammatory Mechanisms in Alzheimer's Disease.

Front Immunol 2020 31;11:456. Epub 2020 Mar 31.

Sorbonne University, GRC no. 21, Alzheimer Precision Medicine (APM), AP-HP, Pitié-Salpêtrière Hospital, Boulevard de l'hôpital, Paris, France.

Neuroinflammation commences decades before Alzheimer's disease (AD) clinical onset and represents one of the earliest pathomechanistic alterations throughout the AD continuum. Large-scale genome-wide association studies point out several genetic variants-, and -potentially linked to neuroinflammation. Most of these genes are involved in proinflammatory intracellular signaling, cytokines/interleukins/cell turnover, synaptic activity, lipid metabolism, and vesicle trafficking. Proteomic studies indicate that a plethora of interconnected aberrant molecular pathways, set off and perpetuated by TNF-α, TGF-β, IL-1β, and the receptor protein TREM2, are involved in neuroinflammation. Microglia and astrocytes are key cellular drivers and regulators of neuroinflammation. Under physiological conditions, they are important for neurotransmission and synaptic homeostasis. In AD, there is a turning point throughout its pathophysiological evolution where glial cells sustain an overexpressed inflammatory response that synergizes with amyloid-β and tau accumulation, and drives synaptotoxicity and neurodegeneration in a self-reinforcing manner. Despite a strong therapeutic rationale, previous clinical trials investigating compounds with anti-inflammatory properties, including non-steroidal anti-inflammatory drugs (NSAIDs), did not achieve primary efficacy endpoints. It is conceivable that study design issues, including the lack of diagnostic accuracy and biomarkers for target population identification and proof of mechanism, may partially explain the negative outcomes. However, a recent meta-analysis indicates a potential biological effect of NSAIDs. In this regard, candidate fluid biomarkers of neuroinflammation are under analytical/clinical validation, i.e., TREM2, IL-1β, MCP-1, IL-6, TNF-α receptor complexes, TGF-β, and YKL-40. PET radio-ligands are investigated to accomplish and longitudinal regional exploration of neuroinflammation. Biomarkers tracking different molecular pathways (body fluid matrixes) along with brain neuroinflammatory endophenotypes (neuroimaging markers), can untangle temporal-spatial dynamics between neuroinflammation and other AD pathophysiological mechanisms. Robust biomarker-drug codevelopment pipelines are expected to enrich large-scale clinical trials testing new-generation compounds active, directly or indirectly, on neuroinflammatory targets and displaying putative disease-modifying effects: novel NSAIDs, AL002 (anti-TREM2 antibody), anti-Aβ protofibrils (BAN2401), and AL003 (anti-CD33 antibody). As a next step, taking advantage of breakthrough and multimodal techniques coupled with a systems biology approach is the path to pursue for developing individualized therapeutic strategies targeting neuroinflammation under the framework of precision medicine.
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http://dx.doi.org/10.3389/fimmu.2020.00456DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7137904PMC
March 2021

In vivo staging of regional amyloid deposition predicts functional conversion in the preclinical and prodromal phases of Alzheimer's disease.

Neurobiol Aging 2020 09 17;93:98-108. Epub 2020 Mar 17.

German Center for Neurodegenerative Diseases (DZNE), Rostock, Germany; Unidad de Trastornos del Movimiento, Servicio de Neurología y Neurofisiología Clínica, Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain.

We tested the usefulness of a regional amyloid staging based on amyloid sensitive positron emission tomography to predict conversion to cognitive impairment and dementia in preclinical and prodromal Alzheimer's disease (AD). We analyzed 884 cases, including normal controls, and people with subjective cognitive decline or mild cognitive impairment (MCI), from the Alzheimer's Disease Neuroimaging Initiative with a maximum follow-up of 6 years and 318 cases with subjective memory complaints with a maximum follow-up time of three years from the INveStIGation of AlzHeimer's PredicTors cohort (INSIGHT-preAD study). Cox regression showed a significant association of regional amyloid stages with time to conversion from a cognitively normal to an MCI, and from an MCI to a dementia status. The most advanced amyloid stages identified very-high-risk groups of conversion. All results were robustly replicated across the independent samples. These findings indicate the usefulness of regional amyloid staging for identifying preclinical and prodromal AD cases at very high risk of conversion for future amyloid targeted trials.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.03.011DOI Listing
September 2020

Abnormal cortical neural synchronization mechanisms in quiet wakefulness are related to motor deficits, cognitive symptoms, and visual hallucinations in Parkinson's disease patients: an electroencephalographic study.

Neurobiol Aging 2020 07 12;91:88-111. Epub 2020 Mar 12.

Department of Biophysics, International School of Medicine, Istanbul Medipol University, Istanbul, Turkey.

Compared with Alzheimer's disease (AD), Parkinson's disease (PD) shows peculiar clinical manifestations related to vigilance (i.e., executive cognitive deficits and visual hallucinations) that may be reflected in resting-state electroencephalographic rhythms. To test this hypothesis, clinical and resting-state electroencephalographic rhythms in age-, sex-, and education-matched PD patients (N = 136) and Alzheimer's disease patients (AD, N = 85), and healthy older participants (Nold, N = 65), were available from an international archive. Electroencephalographic sources were estimated by eLORETA software. The results are as follows: (1) compared to the Nold participants, the AD and PD patients showed higher widespread delta source activities (PD > AD) and lower posterior alpha source activities (AD > PD); (2) the PD patients with the most pronounced motor deficits exhibited very low alpha source activities in widespread cortical regions; (3) the PD patients with the strongest cognitive deficits showed higher alpha source activities in widespread cortical regions; and (4) compared to the PD patients without visual hallucinations, those with visual hallucinations were characterized by higher posterior alpha sources activities. These results suggest that in PD patients resting in quiet wakefulness, abnormalities in cortical neural synchronization at alpha frequencies are differently related to cognitive, motor, and visual hallucinations. Interestingly, parallel PD neuropathological processes may have opposite effects on cortical neural synchronization mechanisms generating cortical alpha rhythms in quiet wakefulness.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.02.029DOI Listing
July 2020

The β-Secretase BACE1 in Alzheimer's Disease.

Biol Psychiatry 2021 04 13;89(8):745-756. Epub 2020 Feb 13.

Neurology Business Group, Eisai Inc., Woodcliff Lake, New Jersey; Sorbonne University, GRC No. 21, Alzheimer Precision Medicine, Pitié-Salpêtrière Hospital, Paris, France; Institute of Memory and Alzheimer's Disease, Department of Neurology, Pitié-Salpêtrière Hospital, Paris, France; Brain & Spine Institute, INSERM U 1127, CNRS UMR 7225, Paris, France. Electronic address:

BACE1 (beta-site amyloid precursor protein cleaving enzyme 1) was initially cloned and characterized in 1999. It is required for the generation of all monomeric forms of amyloid-β (Aβ), including Aβ, which aggregates into bioactive conformational species and likely initiates toxicity in Alzheimer's disease (AD). BACE1 concentrations and rates of activity are increased in AD brains and body fluids, thereby supporting the hypothesis that BACE1 plays a critical role in AD pathophysiology. Therefore, BACE1 is a prime drug target for slowing down Aβ production in early AD. Besides the amyloidogenic pathway, BACE1 has other substrates that may be important for synaptic plasticity and synaptic homeostasis. Indeed, germline and adult conditional BACE1 knockout mice display complex neurological phenotypes. Despite BACE1 inhibitor clinical trials conducted so far being discontinued for futility or safety reasons, BACE1 remains a well-validated therapeutic target for AD. A safe and efficacious compound with high substrate selectivity as well as a more accurate dose regimen, patient population, and disease stage may yet be found. Further research should focus on the role of Aβ and BACE1 in physiological processes and key pathophysiological mechanisms of AD. The functions of BACE1 and the homologue BACE2, as well as the biology of Aβ in neurons and glia, deserve further investigation. Cellular and molecular studies of BACE1 and BACE2 knockout mice coupled with biomarker-based human research will help elucidate the biological functions of these important enzymes and identify their substrates and downstream effects. Such studies will have critical implications for BACE1 inhibition as a therapeutic approach for AD.
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http://dx.doi.org/10.1016/j.biopsych.2020.02.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7533042PMC
April 2021

Accuracy of MRI Classification Algorithms in a Tertiary Memory Center Clinical Routine Cohort.

J Alzheimers Dis 2020 ;74(4):1157-1166

Sorbonne Universités, UPMC Univ Paris 06, Inserm, CNRS, ICM, Paris, France.

Background: Automated volumetry software (AVS) has recently become widely available to neuroradiologists. MRI volumetry with AVS may support the diagnosis of dementias by identifying regional atrophy. Moreover, automatic classifiers using machine learning techniques have recently emerged as promising approaches to assist diagnosis. However, the performance of both AVS and automatic classifiers have been evaluated mostly in the artificial setting of research datasets.

Objective: Our aim was to evaluate the performance of two AVS and an automatic classifier in the clinical routine condition of a memory clinic.

Methods: We studied 239 patients with cognitive troubles from a single memory center cohort. Using clinical routine T1-weighted MRI, we evaluated the classification performance of: 1) univariate volumetry using two AVS (volBrain and Neuroreader™); 2) Support Vector Machine (SVM) automatic classifier, using either the AVS volumes (SVM-AVS), or whole gray matter (SVM-WGM); 3) reading by two neuroradiologists. The performance measure was the balanced diagnostic accuracy. The reference standard was consensus diagnosis by three neurologists using clinical, biological (cerebrospinal fluid) and imaging data and following international criteria.

Results: Univariate AVS volumetry provided only moderate accuracies (46% to 71% with hippocampal volume). The accuracy improved when using SVM-AVS classifier (52% to 85%), becoming close to that of SVM-WGM (52 to 90%). Visual classification by neuroradiologists ranged between SVM-AVS and SVM-WGM.

Conclusion: In the routine practice of a memory clinic, the use of volumetric measures provided by AVS yields only moderate accuracy. Automatic classifiers can improve accuracy and could be a useful tool to assist diagnosis.
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http://dx.doi.org/10.3233/JAD-190594DOI Listing
May 2021

Resting-state posterior alpha rhythms are abnormal in subjective memory complaint seniors with preclinical Alzheimer's neuropathology and high education level: the INSIGHT-preAD study.

Neurobiol Aging 2020 06 1;90:43-59. Epub 2020 Feb 1.

GRC n° 21, Alzheimer Precision Medicine (APM), AP-HP, Pitié-Salpêtrière Hospital, Sorbonne University, Paris, France.

Cognitive reserve is present in Alzheimer's disease (AD) seniors with high education attainment making them clinically resilient to extended brain neuropathology and neurodegeneration. Here, we tested whether subjective memory complaint (SMC) seniors with AD neuropathology and high education attainment of the prospective INSIGHT-preAD cohort (Paris) may present abnormal eyes-closed resting state posterior electroencephalographic rhythms around individual alpha frequency peak, typically altered in AD patients. The SMC participants negative to amyloid PET AD markers (SMCneg) with high (over low-moderate) education level showed higher posterior alpha 2 power density (possibly "neuroprotective"). Furthermore, amyloid PET-positive SMC (SMCpos) participants with high (over low-moderate) education level showed higher temporal alpha 3 power density (possibly "neuroprotective") and lower posterior alpha 2 power density (possibly "compensatory"). This effect may reflect cognitive reserve as no differences in brain gray-white matter, and cognitive functions were observed between these SMCpos/SMCneg subgroups. Preclinical Alzheimer's neuropathology may interact with education attainment and neurophysiological mechanisms generating cortical alpha rhythms around individual alpha frequency peak (i.e., alpha 2 and 3) in quiet wakefulness.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.01.012DOI Listing
June 2020

Successful aging: insights from proteome analyses of healthy centenarians.

Aging (Albany NY) 2020 02 25;12(4):3502-3515. Epub 2020 Feb 25.

i+HeALTH, European University Miguel de Cervantes, Valladolid, Spain.

Healthy aging depends on a complex gene-environment network that is ultimately reflected in the expression of different proteins. We aimed to perform a comparative analysis of the plasma proteome of healthy centenarians (n=9, 5 women, age range 100-103 years) with a notably preserved ambulatory capacity (as a paradigm of 'successful' aging), and control individuals who died from a major age-related disease before the expected life expectancy (n=9, 5 women, age range: 67-81 years), and while having impaired ambulatory capacity (as a paradigm of 'unsuccessful' aging). We found that the expression of 49 proteins and 86 pathways differed between the two groups. Overall, healthy centenarians presented with distinct expression of proteins/pathways that reflect a healthy immune function, including a lower pro-inflammatory status (less 'inflammaging' and autoimmunity) and a preserved humoral immune response (increased B cell-mediated immune response). Compared with controls, healthy centenarians also presented with a higher expression of proteins involved in angiogenesis and related to enhanced intercellular junctions, as well as a lower expression of proteins involved in cardiovascular abnormalities. The identification of these proteins/pathways might provide new insights into the biological mechanisms underlying the paradigm of healthy aging.
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http://dx.doi.org/10.18632/aging.102826DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7066932PMC
February 2020

Association of brain network dynamics with plasma biomarkers in subjective memory complainers.

Neurobiol Aging 2020 04 23;88:83-90. Epub 2019 Dec 23.

Eisai Inc, Neurology Business Group, Woodcliff Lake, NJ, USA.

Using a single integrated analysis, we examined the relationship between brain networks and molecular pathways in a cohort of elderly individuals at risk for Alzheimer's disease. In 205 subjective memory complainers (124 females, mean age: 75.7 ± 3.4), individual functional connectome was computed for a total of 3081 functional connections (set A) and 6 core plasma biomarkers of Alzheimer's disease (set B) were assessed. Partial least squares correlation analysis identified one dimension of population covariation between the 2 sets (p < 0.006), which we named bioneural mode. Five core plasma biomarkers and 190 functional connections presented bootstrap ratios greater than the critical value |1.96|. T-tau protein showed a trend toward significance (bootstrap resampling = 1.64). The salience, the language, the visuospatial, and the default mode networks were the strongest significant networks. We detected a strong association between network dynamics and core pathophysiological blood biomarkers. Innovative composite biomarkers, such as the bioneural mode, are promising to provide outcomes and better inform drug development and clinical practice for neurodegenerative diseases.
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http://dx.doi.org/10.1016/j.neurobiolaging.2019.12.017DOI Listing
April 2020

The path to biomarker-based diagnostic criteria for the spectrum of neurodegenerative diseases.

Expert Rev Mol Diagn 2020 04 27;20(4):421-441. Epub 2020 Feb 27.

Sorbonne University, GRC n° 21, Alzheimer Precision Medicine (APM), AP-HP, Pitié-Salpêtrière Hospital, Boulevard de l'hôpital, Paris, France.

: The examination still represents the reference standard for detecting the pathological nature of chronic neurodegenerative diseases (NDD). This approach displays intrinsic conceptual limitations since NDD represent a dynamic of partially overlapping phenotypes, shared pathomechanistic alterations that often give rise to mixed pathologies.: We scrutinized the international clinical diagnostic criteria of NDD and the literature to provide a roadmap toward a biomarker-based classification of the NDD . A few pathophysiological biomarkers have been established for NDD. These are time-consuming, invasive, and not suitable for preclinical detection. Candidate screening biomarkers are gaining momentum. Blood neurofilament light-chain represents a robust first-line tool to detect neurodegeneration and serum progranulin helps detect genetic frontotemporal dementia. Ultrasensitive assays and retinal scans may identify Aβ pathology early, in blood and the eye, respectively. Ultrasound also represents a minimally invasive option to investigate the . Protein misfolding amplification assays may accurately detect α-synuclein in biofluids.: Data-driven strategies using quantitative rather than categorical variables may be more reliable for quantification of contributions from pathophysiological mechanisms and their spatial-temporal evolution. A systems biology approach is suitable to untangle the dynamics triggering loss of proteostasis, driving neurodegeneration and clinical evolution.
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http://dx.doi.org/10.1080/14737159.2020.1731306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7445079PMC
April 2020

Plasma tau correlates with basal forebrain atrophy rates in people at risk for Alzheimer disease.

Neurology 2020 01 4;94(1):e30-e41. Epub 2019 Dec 4.

From Alzheimer Precision Medicine (APM) (E.C., S.L., A.V., B.D., H.H.), AP-HP, Pitié-Salpêtrière Hospital, Sorbonne University; Brain & Spine Institute (ICM) (E.C., S.L., M.H., A.V., M.C.P., B.D.), INSERM U 1127, CNRS UMR 7225; Institute of Memory and Alzheimer's Disease (IM2A) (E.C., S.L., M.H., A.V., B.D.), Department of Neurology, Pitié-Salpêtrière Hospital, AP-HP; Qynapse (E.C.); Centre of Excellence of Neurodegenerative Disease (CoEN) (M.H.), ICM, CIC Neurosciences, APHP Department of Neurology, Hôpital Pitié-Salpêtrière, Paris, France; German Center for Neurodegenerative Diseases (DZNE)-Rostock/Greifswald (M.J.G., S.T.); Department of Psychosomatic Medicine (M.J.G., S.T.), University of Rostock, Germany; Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry (H.Z.), the Sahlgrenska Academy at the University of Gothenburg; Clinical Neurochemistry Laboratory (H.Z.), Sahlgrenska University Hospital, Mölndal, Sweden; Department of Neurodegenerative Disease (H.Z., K.B.), UCL Institute of Neurology, Queen Square; UK Dementia Research Institute at UCL (H.Z., K.B.), London, UK; Laboratoire d'Imagerie Biomédicale (M.-O.H.), Sorbonne Université, CNRS, INSERM; Centre pour l'Acquisition et le Traitement des Images (cati-neuroimaging.com) (M.-O.H.); and Département de Médecine Nucléaire (M.-O.H.), AP-HP, Hôpital Pitié-Salpêtrière, Paris, France.

Objective: To investigate whether baseline concentrations of plasma total tau (t-tau) and neurofilament light (NfL) chain proteins are associated with annual percent change (APC) of the basal forebrain cholinergic system (BFCS) in cognitively intact older adults at risk for Alzheimer disease (AD).

Methods: This was a large-scale study of 276 cognitively intact older adults from the monocentric INSIGHT-preAD (Investigation of Alzheimer's Predictors in Subjective Memory Complainers) cohort. Participants underwent baseline assessment of plasma t-tau and NfL concentrations as well as baseline and 24-month follow-up MRI scans. Linear models with and without influential observations (calculated using the Cook distance) were carried out to investigate the effect of plasma NfL and t-tau concentrations, and their interaction effect with β-amyloid status and genotype, on the APC of the whole BFCS and its anterior (Ch1/2) and posterior (Ch4) subdivisions separately.

Results: Higher plasma t-tau concentrations at baseline were associated with higher BFCS rate of atrophy (model without influencers: n = 251, F value = 4.6815; value = 0.031). Subregional analyses showed similar results for both the APC of the Ch1/2 (model without influencers: n = 256, F value = 3.9535, corrected = 0.047) and Ch4 BFCS sectors (model without influencers: n = 253, F value = 4.9090, corrected = 0.047). Baseline NfL, β-amyloid load, and carrier status did not affect APC of the BFCS.

Conclusion: Increased concentrations of baseline plasma t-tau may predict in vivo structural BFCS atrophy progression in older adults at risk for AD, independently of β-amyloid status and genotype.
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http://dx.doi.org/10.1212/WNL.0000000000008696DOI Listing
January 2020