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Authors: Hampel, Harald

Article Type: Review Article

Abstract: Amyloid-β (Aβ) deposition in the brain is one of the key pathological features of Alzheimer's disease (AD). Neither traditional clinical-pathological studies nor modern in vivo biomarker investigations of brain amyloid load, however, could reveal a convincing relationship between brain Aβ load and cognitive deficits and decline in patients with AD. Evidence suggests that pathophysiological Aβ dysregulation and accumulation are very early events that precede the onset of cognitive impairment reaching a plateau at the clinical stage of the beginning dementia syndrome. Therefore, research efforts have focused on the role of Aβ in asymptomatic older adults: the results of combined amyloid-PET …and neuropsychological studies show a modest but significant correlation between brain fibrillar amyloid load and various subtle cognitive deficits, most notably in challenging episodic associative memory tasks. In order to elucidate the pathophysiological link between cognition and Aβ, a number of combined functional neuroimaging studies have been performed, resulting in early and complex functional alterations in cognitively relevant neural networks such as the default mode network and the largely overlapping episodic memory networks. Multimodal studies using amyloid-tracing imaging methods and neurodegeneration biomarkers strongly suggest that neural network discoordination is specifically related to Aβ-mediated functional and potentially reversible disruption of synaptic plasticity rather than a direct consequence to neurodegenerative pathological processes. These pathophysiological processes and mechanisms may dynamically and non-linearly evolve through fully reversible adaptive compensatory stages and through reactive decompensatory stages into fully irreversible neurodegenerative stages of AD. Show more

Keywords: Alzheimer's disease, amyloid-β, amyloid cascade hypothesis, asymptomatic, biomarkers, connectivity, CSF, default mode network, dementia, detection, diagnosis, dimers, DMN, fMRI, mild cognitive impairment, molecular mechanisms, neurophysiology, network paradigm, neural networks, oligomers, pathophysiology, preclinical, prodromal

DOI: 10.3233/JAD-2012-129003

Citation: Journal of Alzheimer's Disease, vol. 33, no. s1, pp. S79-S86, 2013

Authors: Lista, Simone | O’Bryant, Sid E. | Blennow, Kaj | Dubois, Bruno | Hugon, Jacques | Zetterberg, Henrik | Hampel, Harald

Article Type: Research Article

Abstract: Most forms of Alzheimer’s disease (AD) are sporadic (sAD) or inherited in a non-Mendelian fashion, and less than 1% of cases are autosomal-dominant. Forms of sAD do not exhibit familial aggregation and are characterized by complex genetic and environmental interactions. Recently, the expansion of genomic methodologies, in association with substantially larger combined cohorts, has resulted in various genome-wide association studies that have identified several novel genetic associations of AD. Currently, the most effective methods for establishing the diagnosis of AD are defined by multi-modal pathways, starting with clinical and neuropsychological assessment, cerebrospinal fluid (CSF) analysis, and brain-imaging procedures, all of …which have significant cost- and access-to-care barriers. Consequently, research efforts have focused on the development and validation of non-invasive and generalizable blood-based biomarkers. Among the modalities conceptualized by the systems biology paradigm and utilized in the “exploratory biomarker discovery arena”, proteome analysis has received the most attention. However, metabolomics, lipidomics, transcriptomics, and epigenomics have recently become key modalities in the search for AD biomarkers. Interestingly, biomarker changes for familial AD (fAD), in many but not all cases, seem similar to those for sAD. The integration of neurogenetics with systems biology/physiology-based strategies and high-throughput technologies for molecular profiling is expected to help identify the causes, mechanisms, and biomarkers associated with the various forms of AD. Moreover, in order to hypothesize the dynamic trajectories of biomarkers through disease stages and elucidate the mechanisms of biomarker alterations, updated and more sophisticated theoretical models have been proposed for both sAD and fAD. Show more

Keywords: Alzheimer’s disease, blood-based biomarkers, cerebrospinal fluid biomarkers, familial Alzheimer’s disease, metabolomics/lipidomics, neuroimaging markers, proteomics, sporadic Alzheimer’s disease, systems biology, temporal ordering of biomarkers

DOI: 10.3233/JAD-143006

Citation: Journal of Alzheimer's Disease, vol. 47, no. 2, pp. 291-317, 2015

Authors: Matsunaga, Shinji | Kishi, Taro | Annas, Peter | Basun, Hans | Hampel, Harald | Iwata, Nakao

Article Type: Research Article

Abstract: Background: This is the first meta-analysis of randomized placebo-controlled trials testing lithium as a treatment for patients with Alzheimer’s disease (AD) and individuals with mild cognitive impairment (MCI). Methods: The primary outcome measure was efficacy on cognitive performance as measured through the Alzheimer’s Disease Assessment Scale cognitive subscale or the Mini-Mental State Examination. Other outcome measures were drug discontinuation rate, individual side effects, and biological markers (phosphorylated tau 181, total tau, and amyloid-β42 ) in cerebrospinal fluid (CSF). Results: Three clinical trials including 232 participants that met the study’s inclusion criteria were identified. Lithium significantly decreased cognitive decline as compared …to placebo (standardized mean difference = –0.41, 95% confidence interval = –0.81 to –0.02, p  = 0.04, I 2  = 47% , 3 studies, n  = 199). There were no significant differences in the rate of attrition, discontinuation due to all causes or adverse events, or CSF biomarkers between treatment groups. Conclusions: The results indicate that lithium treatment may have beneficial effects on cognitive performance in subjects with MCI and AD dementia. Show more

Keywords: Alzheimer’s disease, lithium, meta-analysis, mild cognitive impairment, systematic review

DOI: 10.3233/JAD-150437

Citation: Journal of Alzheimer's Disease, vol. 48, no. 2, pp. 403-410, 2015

Authors: Taverna, Mara | Straub, Tobias | Hampel, Harald | Rujescu, Dan | Lichtenthaler, Stefan F.

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is the most common neurodegenerative disorder. Frequently used diagnostic biomarkers are amyloid-β42 (Aβ42 ), tau, and phospho-tau, which are measured in cerebrospinal fluid (CSF), and allow a reasonable, but not full, separation of AD patients and controls. Besides Aβ42 , additional proteolytic cleavage products of the amyloid-β protein precursor (AβPP) have been investigated as potential biomarkers. This includes the α-secretase cleaved soluble AβPP ectodomain (sAβPPα). However, some studies found a reduction of sAβPPα, whereas other studies reported an increase of sAβPPα in the CSF of AD patients. The divergent findings may result from the detection of sAβPPα …with antibodies, such as 6E10, which do not exclusively detect sAβPPα, but also the alternative β-secretase cleavage product sAβPPβ'. Here, we used the sAβPPα-specific antibody 14D6 and developed an ELISA-like sandwich immunoassay. The assay specifically detected sAβPPα in cell culture supernatants, in human CSF and even in serum, which is more readily accessible than CSF. The assay was used to analyze sAβPPα levels in CSF and serum of AD patients and controls. The assay detected a mild, but significant increase in sAβPPα in the CSF of AD patients compared to non-demented controls, while a mild reduction was observed in serum. The 14D6 assay in CSF allowed a better separation of AD patients from controls compared to the 6E10 antibody. Taken together, the new assay is widely applicable for specific sAβPPα measurement in culture media, CSF, and serum. Show more

Keywords: α-Secretase, Alzheimer's disease, amyloid-β protein precursor, biomarker, sandwich immunoassay

DOI: 10.3233/JAD-130509

Citation: Journal of Alzheimer's Disease, vol. 37, no. 4, pp. 667-678, 2013

Authors: Friese, Uwe | Meindl, Thomas | Herpertz, Sabine C. | Reiser, Maximilian F. | Hampel, >Harald | Teipel, Stefan J.

Article Type: Research Article

Abstract: We report evidence that multivariate analyses of deformation-based morphometry and diffusion tensor imaging (DTI) data can be used to discriminate between healthy participants and patients with Alzheimer's disease (AD) with comparable diagnostic accuracy. In contrast to other studies on MRI-based biomarkers which usually only focus on a single modality, we derived deformation maps from high-dimensional normalization of T1-weighted images, as well as mean diffusivity maps and fractional anisotropy maps from DTI of the same group of 21 patients with AD and 20 healthy controls. Using an automated multivariate analysis of the entire brain volume, widespread decreased white matter integrity and …atrophy effects were found in cortical and subcortical regions of AD patients. Mean diffusivity maps and deformation maps were equally effective in discriminating between AD patients and controls (AUC =0.88 vs. AUC=0.85) while fractional anisotropy maps performed slightly inferior. Combining the maps from different modalities in a logistic regression model resulted in a classification accuracy of AUC=0.86 after leave-one-out cross-validation. It remains to be shown if this automated multivariate analysis of DTI-measures can improve early diagnosis of AD in predementia stages. Show more

Keywords: Alzheimer's disease, biomarker, deformation-based morphometry, diagnostic utility, diffusion tensor imaging, MRI

DOI: 10.3233/JAD-2010-1386

Citation: Journal of Alzheimer's Disease, vol. 20, no. 2, pp. 477-490, 2010

Authors: Sun, Qiying | Hampel, Harald | Blennow, Kaj | Lista, Simone | Levey, Allan | Tang, Beisha | Li, Rena | Shen, Yong

Article Type: Research Article

Abstract: Evidence suggests that the tumor necrosis factor receptor (TNFR)-signaling pathway contributes to the pathogenesis of Alzheimer's disease (AD). TNF-α converting enzyme (TACE/ADAM-17) can cleave both pro-TNF-α and TNF receptors. Recently, we have shown that TACE activity in the cerebrospinal fluid (CSF) of subjects with mild cognitive impairment (MCI) and AD patients is significantly higher than that of cognitively healthy controls (HC). To date, it is not clear whether TACE activity could be detected in the human plasma and whether TACE activity in MCI and AD patients is different from that in HC. We analyzed TACE expression and activity in a …large clinical sample of 64 patients with AD, 88 subjects with MCI, and 50 age-matched HC recruited from two distinct academic centers. Plasma TACE protein levels did not differ significantly in the three study groups (AD, MCI, and HC). However, plasma TACE activity in subjects with MCI and AD patients was significantly higher than that in HC. Moreover, in MCI and AD groups, we found a significant correlation between plasma TACE activity and CSF t-tau and Aβ42 levels and CSF Aβ42 /tau ratios. In AD patients, the levels of plasma TACE activity correlated significantly and negatively with cognition. These findings further support the role of the TNF-α receptor complex in AD-related neuroinflammation and propose TACE plasma activity as a promising hypothesis-driven biomarker candidate for detection, diagnosis, and prognosis of prodromal and clinical AD. Show more

Keywords: Alzheimer's disease, biomarker, mild cognitive impairment, plasma, tumor necrosis factor converting enzyme

DOI: 10.3233/JAD-140177

Citation: Journal of Alzheimer's Disease, vol. 41, no. 3, pp. 877-886, 2014

Authors: Hampel, Harald | Vergallo, Andrea | Perry, George | Lista, Simone | Alzheimer Precision Medicine Initiative (APMI)

Collaborators: AGUILAR, Lisi Flores | BABILONI, Claudio | BALDACCI, Filippo | BENDA, Norbert | BLACK, Keith L. | BOKDE, Arun L.W. | BONUCCELLI, Ubaldo | BROICH, Karl | CACCIOLA, Francesco | CASTRILLO†, Juan | CAVEDO, Enrica | CERAVOLO, Roberto | CHIESA, Patrizia A. | CORVOL, Jean-Christophe | CUELLO, Augusto Claudio | CUMMINGS, Jeffrey L. | DEPYPERE, Herman | DUBOIS, Bruno | DUGGENTO, Andrea | ESCOTT-PRICE, Valentina | FEDEROFF, Howard | FERRETTI, Maria Teresa | FIANDACA, Massimo | FRANK, Richard A. | GARACI, Francesco | GEERTS, Hugo | GIORGI, Filippo S. | GRAZIANI, Manuela | HABERKAMP, Marion | HABERT, Marie-Odile | HAMPEL, Harald | HERHOLZ, Karl | KARRAN, Eric | KIM, Seung H. | KORONYO, Yosef | KORONYO-HAMAOUI, Maya | LANGEVIN, Todd | LEHÉRICY, Stéphane | LISTA, Simone | LORENCEAU, Jean | MANGO, Dalila | MAPSTONE, Mark | NERI, Christian | NISTICÓ, Robert | O’BRYANT, Sid E. | PERRY, George | RITCHIE, Craig | ROSSI, Simone | SAIDI, Amira | SANTARNECCHI, Emiliano | SCHNEIDER, Lon S. | SPORNS, Olaf | TOSCHI, Nicola | VERDOONER, Steven R. | VERGALLO, Andrea | VILLAIN, Nicolas | WELIKOVITCH, Lindsay A. | WOODCOCK, Janet | YOUNESI, Erfan

Article Type: Review Article

Abstract: Precision medicine (PM) is an evolving scientific renaissance movement implementing key breakthrough technological and scientific advances to overcome the limitations of traditional symptom- and sign-based phenotypic diagnoses and clinical “one-size-fits-all, magic bullet drug development” in these largely heterogeneous target populations. It is a conceptual shift from ineffective treatments for biologically heterogeneous “population averages” to individually-tailored biomarker-guided targeted therapies. PM is defining which therapeutic approach will be the most effective for a specific individual, at a determined disease stage, across multiple medical research fields, including neuroscience, neurology and psychiatry. The launch of the Alzheimer Precision Medicine Initiative (APMI) and its associated …cohort program in 2016—facilitated by the academic core coordinating center run by the Sorbonne University Clinical Research Group in Alzheimer Precision Medicine (Sorbonne University GRC n°21 APM)”—is geared at transforming healthcare, conventional clinical diagnostics, and drug development research in Alzheimer’s disease. Ever since the commencement of the APMI, the international interdisciplinary research network has introduced groundbreaking translational neuroscience programs on the basis of agnostic exploratory genomics, systems biology, and systems neurophysiology applying innovative “big data science”, including breakthrough artificial intelligence-based algorithms. Here, we present the scientific breakthrough advances and the pillars of the theoretical and conceptual development leading to the APMI. Show more

Keywords: Alzheimer’s disease, APMI, All of Us Research Program, artificial intelligence, big data, biomarker-guided therapies, precision medicine, systems biology, systems neurophysiology, translational research programs.

DOI: 10.3233/JAD-181121

Citation: Journal of Alzheimer's Disease, vol. 68, no. 1, pp. 1-24, 2019

Authors: Suppa, Per | Hampel, Harald | Spies, Lothar | Fiebach, Jochen B. | Dubois, Bruno | Buchert, Ralph | and Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Hippocampus volumetry based on magnetic resonance imaging (MRI) has not yet been translated into everyday clinical diagnostic patient care, at least in part due to limited availability of appropriate software tools. In the present study, we evaluate a fully-automated and computationally efficient processing pipeline for atlas based hippocampal volumetry using freely available Statistical Parametric Mapping (SPM) software in 198 amnestic mild cognitive impairment (MCI) subjects from the Alzheimer’s Disease Neuroimaging Initiative (ADNI1). Subjects were grouped into MCI stable and MCI to probable Alzheimer’s disease (AD) converters according to follow-up diagnoses at 12, 24, and 36 months. Hippocampal grey matter volume …(HGMV) was obtained from baseline T1-weighted MRI and then corrected for total intracranial volume and age. Average processing time per subject was less than 4 minutes on a standard PC. The area under the receiver operator characteristic curve of the corrected HGMV for identification of MCI to probable AD converters within 12, 24, and 36 months was 0.78, 0.72, and 0.71, respectively. Thus, hippocampal volume computed with the fully-automated processing pipeline provides similar power for prediction of MCI to probable AD conversion as computationally more expensive methods. The whole processing pipeline has been made freely available as an SPM8 toolbox. It is easily set up and integrated into everyday clinical patient care. Show more

Keywords: ADNI, Alzheimer’s disease, atlas-based segmentation, fully automated, hippocampus volumetry, magnetic resonance imaging, mild cognitive impairment, prediction

DOI: 10.3233/JAD-142280

Citation: Journal of Alzheimer's Disease, vol. 46, no. 1, pp. 199-209, 2015

Authors: Santos, Alexander Navarrete | Ewers, Michael | Minthon, Lennart | Simm, Andreas | Silber, Rolf-Edgar | Blennow, Kaj | Prvulovic, David | Hansson, Oskar | Hampel, Harald

Article Type: Research Article

Abstract: Oligomers of the amyloid-β peptide (Aβ) are thought to be the most toxic form of Aβ and are linked to the development of Alzheimer's disease (AD). Here, we used a flow cytometric approach for the detection and assessment of oligomers in cerebrospinal fluid (CSF) from AD patients and other neurological disorders. 30 CSF samples from patients suffering from AD (n = 14), non-demented controls (n = 12), and other neurological disorders (dementia with Lewy bodies, n = 2; vascular dementia, n = 1; primary progressive aphasia, n = 1) were analyzed for the presence of Aβ-oligomers by flow cytometry. The …CSF levels of total tau (t-tau), phosphorylated tau (p-tau), and amyloid-β (Aβ)42 were determined using ELISA. CSF Aβ-oligomer levels in AD patients were elevated in comparison to the non-AD group (p = 0.073). The ratio Aβ-oligomers/Aβ42 was significantly elevated in AD subjects compared to non-AD subjects (p = 0.001). Most important, there was a negative correlation between the amount of Aβ-oligomers and the Mini-Mental Status Exam score (r = −0.65; p = 0.013) in AD patients. The detection of Aβ-oligomers using flow cytometry analysis seems to be useful in assessing the stage of AD. This is a novel and important finding as none of the currently used CSF biomarkers are clearly associated with dementia severity. Show more

Keywords: Alzheimer's disease, amyloid-β, biomarkers, cognitive decline, flow cytometry, oligomers

DOI: 10.3233/JAD-2012-111361

Citation: Journal of Alzheimer's Disease, vol. 29, no. 1, pp. 171-176, 2012

Authors: Levy Nogueira, Marcel | Samri, Dalila | Epelbaum, Stéphane | Lista, Simone | Suppa, Per | Spies, Lothar | Hampel, Harald | Dubois, Bruno | Teichmann, Marc

Article Type: Research Article

Abstract: The International Working Group recently provided revised criteria of Alzheimer’s disease (AD) proposing that the diagnosis of typical amnesic AD should be established by a clinical-biological signature, defined by the phenotype of an “amnesic syndrome of the hippocampal type” (ASHT) combined with positive in vivo evidence of AD pathophysiology in the cerebrospinal fluid (CSF) or on amyloid PET imaging. The application and clinical value of this refined diagnostic algorithm, initially intended for research purposes, is explored in three memory clinic cases presenting with different cognitive profiles including an ASHT, hippocampal atrophy, and CSF AD-biomarker data. The case reports highlight that …the isolated occurrence of one of the two proposed AD criteria, ASHT or positive pathophysiological markers, does not provide a reliable diagnosis of typical AD. It is proposed that the twofold diagnostic IWG algorithm can be applied and operationalized in memory clinic settings to improve the diagnostic accuracy of typical amnesic AD in clinical practice. Show more

Keywords: Alzheimer’s disease, amnesic syndrome, biomarkers, cerebrospinal fluid, diagnosis, magnetic resonance imaging

DOI: 10.3233/JAD-170574

Citation: Journal of Alzheimer's Disease, vol. 60, no. 2, pp. 577-583, 2017