Stéphane Epelbaum

Advancing research diagnostic criteria for Alzheimer's disease: the IWG-2 criteria

In the past 8 years, both the International Working Group (IWG) and the US National Institute on Aging-Alzheimers Association have contributed criteria for the diagnosis of Alzheimers disease (AD) that better define clinical phenotypes and integrate biomarkers into the diagnostic process, covering the full staging of the disease. This Position Paper considers the strengths and limitations of the IWG research diagnostic criteria and proposes advances to improve the diagnostic framework. On the basis of these refinements, the diagnosis of AD can be simplified, requiring the presence of an appropriate clinical AD phenotype (typical or atypical) and a pathophysiological biomarker consistent with the presence of Alzheimers pathology. We propose that downstream topographical biomarkers of the disease, such as volumetric MRI and fluorodeoxyglucose PET, might better serve in the measurement and monitoring of the course of disease. This paper also elaborates on the specific diagnostic criteria for atypical forms of AD, for mixed AD, and for the preclinical states of AD.

Preclinical Alzheimer's disease: Definition, natural history, and diagnostic criteria

During the past decade, a conceptual shift occurred in the field of Alzheimers disease (AD) considering the disease as a continuum. Thanks to evolving biomarker research and substantial discoveries, it is now possible to identify the disease even at the preclinical stage before the occurrence of the first clinical symptoms. This preclinical stage of AD has become a major research focus as the field postulates that early intervention may offer the best chance of therapeutic success. To date, very little evidence is established on this “silent” stage of the disease. A clarification is needed about the definitions and lexicon, the limits, the natural history, the markers of progression, and the ethical consequence of detecting the disease at this asymptomatic stage. This article is aimed at addressing all the different issues by providing for each of them an updated review of the literature and evidence, with practical recommendations.

Detection of volume loss in hippocampal layers in Alzheimer's disease using 7 T MRI: A feasibility study

In Alzheimers disease (AD), the hippocampus is an early site of tau pathology and neurodegeneration. Histological studies have shown that lesions are not uniformly distributed within the hippocampus. Moreover, alterations of different hippocampal layers may reflect distinct pathological processes. 7 T MRI dramatically improves the visualization of hippocampal subregions and layers. In this study, we aimed to assess whether 7 T MRI can detect volumetric changes in hippocampal layers in vivo in patients with AD. We studied four AD patients and seven control subjects. MR images were acquired using a whole-body 7 T scanner with an eight channel transmit–receive coil. Hippocampal subregions were manually segmented from coronal T2*-weighted gradient echo images with 0.3 × 0.3 × 1.2 mm3 resolution using a protocol that distinguishes between layers richer or poorer in neuronal bodies. Five subregions were segmented in the region of the hippocampal body: alveus, strata radiatum, lacunosum and moleculare (SRLM) of the cornu Ammonis (CA), hilum, stratum pyramidale of CA and stratum pyramidale of the subiculum. We found strong bilateral reductions in the SRLM of the cornu Ammonis and in the stratum pyramidale of the subiculum (p < 0.05), with average cross-sectional area reductions ranging from −29% to −49%. These results show that it is possible to detect volume loss in distinct hippocampal layers using segmentation of 7 T MRI. 7 T MRI-based segmentation is a promising tool for AD research.

APP, PSEN1, and PSEN2 mutations in early-onset Alzheimer disease: A genetic screening study of familial and sporadic cases

Background Amyloid protein precursor (APP), presenilin-1 (PSEN1), and presenilin-2 (PSEN2) mutations cause autosomal dominant forms of early-onset Alzheimer disease (AD-EOAD). Although these genes were identified in the 1990s, variant classification remains a challenge, highlighting the need to colligate mutations from large series. Methods and findings We report here a novel update (2012–2016) of the genetic screening of the large AD-EOAD series ascertained across 28 French hospitals from 1993 onwards, bringing the total number of families with identified mutations to n = 170. Families were included when at least two first-degree relatives suffered from early-onset Alzheimer disease (EOAD) with an age of onset (AOO) ≤65 y in two generations. Furthermore, we also screened 129 sporadic cases of Alzheimer disease with an AOO below age 51 (44% males, mean AOO = 45 ± 2 y). APP, PSEN1, or PSEN2 mutations were identified in 53 novel AD-EOAD families. Of the 129 sporadic cases screened, 17 carried a PSEN1 mutation and 1 carried an APP duplication (13%). Parental DNA was available for 10 sporadic mutation carriers, allowing us to show that the mutation had occurred de novo in each case. Thirteen mutations (12 in PSEN1 and 1 in PSEN2) identified either in familial or in sporadic cases were previously unreported. Of the 53 mutation carriers with available cerebrospinal fluid (CSF) biomarkers, 46 (87%) had all three CSF biomarkers—total tau protein (Tau), phospho-tau protein (P-Tau), and amyloid β (Aβ)42—in abnormal ranges. No mutation carrier had the three biomarkers in normal ranges. One limitation of this study is the absence of functional assessment of the possibly and probably pathogenic variants, which should help their classification. Conclusions Our findings suggest that a nonnegligible fraction of PSEN1 mutations occurs de novo, which is of high importance for genetic counseling, as PSEN1 mutational screening is currently performed in familial cases only. Among the 90 distinct mutations found in the whole sample of families and isolated cases, definite pathogenicity is currently established for only 77%, emphasizing the need to pursue the effort to classify variants.

17q21.31 duplication causes prominent tau-related dementia with increased MAPT expression

To assess the role of rare copy number variations in Alzheimers disease (AD), we conducted a case–control study using whole-exome sequencing data from 522 early-onset cases and 584 controls. The most recurrent rearrangement was a 17q21.31 microduplication, overlapping the CRHR1, MAPT, STH and KANSL1 genes that was found in four cases, including one de novo rearrangement, and was absent in controls. The increased MAPT gene dosage led to a 1.6–1.9-fold expression of the MAPT messenger RNA. Clinical signs, neuroimaging and cerebrospinal fluid biomarker profiles were consistent with an AD diagnosis in MAPT duplication carriers. However, amyloid positon emission tomography (PET) imaging, performed in three patients, was negative. Analysis of an additional case with neuropathological examination confirmed that the MAPT duplication causes a complex tauopathy, including prominent neurofibrillary tangle pathology in the medial temporal lobe without amyloid-β deposits. 17q21.31 duplication is the genetic basis of a novel entity marked by prominent tauopathy, leading to early-onset dementia with an AD clinical phenotype. This entity could account for a proportion of probable AD cases with negative amyloid PET imaging recently identified in large clinical series.

Cognitive and neuroimaging features and brain β-amyloidosis in individuals at risk of Alzheimer's disease (INSIGHT-preAD): a longitudinal observational study

BACKGROUND Improved understanding is needed of risk factors and markers of disease progression in preclinical Alzheimers disease. We assessed associations between brain β-amyloidosis and various cognitive and neuroimaging parameters with progression of cognitive decline in individuals with preclinical Alzheimers disease. METHODS The INSIGHT-preAD is an ongoing single-centre observational study at the Salpêtrière Hospital, Paris, France. Eligible participants were age 70-85 years with subjective memory complaints but unimpaired cognition and memory (Mini-Mental State Examination [MMSE] score ≥27, Clinical Dementia Rating score 0, and Free and Cued Selective Reminding Test [FCSRT] total recall score ≥41). We stratified participants by brain amyloid β deposition on 18F-florbetapir PET (positive or negative) at baseline. All patients underwent baseline assessments of demographic, cognitive, and psychobehavioural, characteristics, APOE ε4 allele carrier status, brain structure and function on MRI, brain glucose-metabolism on 18F-fluorodeoxyglucose (18F-FDG) PET, and event-related potentials on electroencephalograms (EEGs). Actigraphy and CSF investigations were optional. Participants were followed up with clinical, cognitive, and psychobehavioural assessments every 6 months, neuropsychological assessments, EEG, and actigraphy every 12 months, and MRI, and 18F-FDG and 18F-florbetapir PET every 24 months. We assessed associations of amyloid β deposition status with test outcomes at baseline and 24 months, and with clinical status at 30 months. Progression to prodromal Alzheimers disease was defined as an amnestic syndrome of the hippocampal type. FINDINGS From May 25, 2013, to Jan 20, 2015, we enrolled 318 participants with a mean age of 76·0 years (SD 3·5). The mean baseline MMSE score was 28·67 (SD 0·96), and the mean level of education was high (score >6 [SD 2] on a scale of 1-8, where 1=infant school and 8=higher education). 88 (28%) of 318 participants showed amyloid β deposition and the remainder did not. The amyloid β subgroups did not differ for any psychobehavioural, cognitive, actigraphy, and structural and functional neuroimaging results after adjustment for age, sex, and level of education More participants positive for amyloid β deposition had the APOE ε4 allele (33 [38%] vs 29 [13%], p<0·0001). Amyloid β1-42 concentration in CSF significantly correlated with mean 18F-florbetapir uptake at baseline (r=-0·62, p<0·0001) and the ratio of amyloid β1-42 to amyloid β1-40 (r=-0·61, p<0·0001), and identified amyloid β deposition status with high accuracy (mean area under the curve values 0·89, 95% CI 0·80-0·98 and 0·84, 0·72-0·96, respectively). No difference was seen in MMSE (28·3 [SD 2·0] vs 28·9 [1·2], p=0·16) and Clinical Dementia Rating scores (0·06 [0·2] vs 0·05 [0·3]; p=0·79) at 30 months (n=274) between participants positive or negative for amyloid β. Four participants (all positive for amyloid β deposition at baseline) progressed to prodromal Alzheimers disease. They were older than other participants positive for amyloid β deposition at baseline (mean 80·2 years [SD 4·1] vs 76·8 years [SD 3·4]) and had greater 18F-florbetapir uptake at baseline (mean standard uptake value ratio 1·46 [SD 0·16] vs 1·02 [SD 0·20]), and more were carriers of the APOE ε4 allele (three [75%] of four vs 33 [39%] of 83). They also had mild executive dysfunction at baseline (mean FCSRT free recall score 21·25 [SD 2·75] vs 29·08 [5·44] and Frontal Assessment Battery total score 13·25 [1·50] vs 16·05 [1·68]). INTERPRETATION Brain β-amyloidosis alone did not predict progression to prodromal Alzheimers disease within 30 months. Longer follow-up is needed to establish whether this finding remains consistent. FUNDING Institut Hospitalo-Universitaire and Institut du Cerveau et de la Moelle Epinière (IHU-A-ICM), Ministry of Research, Fondation Plan Alzheimer, Pfizer, and Avid.

Diagnostic accuracy of CSF neurofilament light chain protein in the biomarker-guided classification system for Alzheimer's disease

&NA; We assessed the diagnostic accuracy of cerebrospinal fluid (CSF) neurofilament light chain (NFL) protein in the classification of patients with Alzheimers disease (AD) and cognitively healthy control individuals (HCs) and patients with frontotemporal dementia (FTD) as comparisons. Particularly, we tested the performance of CSF NFL concentration in differentiating patient groups stratified by fluid biomarker profiles, independently of the severity of cognitive impairment (mild cognitive impairment (MCI) and AD dementia individuals), using a biomarker‐guided descriptive classification system for AD. CSF NFL concentrations were examined in a multicenter cross‐sectional study of 108 participants stratified in AD pathophysiology‐negative (both CSF tau and the 42‐amino acid‐long amyloid‐beta (A&bgr;) peptide (A&bgr;1‐42)) (n = 15), tau pathology‐positive only (n = 15), A&bgr; pathology‐positive only (n = 13), AD pathophysiology‐positive (n = 33), FTD (n = 9) patients, and HCs (n = 23), according to the biomarker‐based classification system. The performance of CSF NFL in discriminating AD pathophysiology‐positive patients from HCs is fair, whereas the ability in differentiating tau‐positive patients from HCs is poor. The classificatory performance in distinguishing AD pathophysiology‐positive patients from FTD is unsatisfactory. HighlightsThe diagnostic accuracy of NFL protein in cerebrospinal fluid is examined.A biomarker‐based descriptive stratification model for AD is used.NFL protein discriminates AD pathophysiology from HCs with fair diagnostic accuracy.The ability of NFL protein in differentiating tau‐positive patients from HCs is poor.The ability of NFL in distinguishing AD pathophysiology from FTD is unsatisfactory.

Prediction of Alzheimer’s Disease Dementia: Data from the GuidAge Prevention Trial

In therapeutic trials, it is crucial to identify Alzheimers disease (AD) at its prodromal stage. We assessed the accuracy of the free and cued selective reminding test (FCSRT) compared to other cognitive tests to predict AD dementia in subjects with subjective cognitive decline or mild cognitive impairment. Subjects from the placebo group of the GuidAge trial over 70 years old and without clinical signs of dementia at baseline who completed the 5-year follow-up free of dementia (n = 840) or developed AD dementia (n = 73) were included in our study. Among all the tests, the sum of the 3 free recall of the FCSRT (FCSRT-FR) and the sum of free and cued recall (FCSRT-TR) yielded the best results to predict AD dementia occurrence (all p values <0.05 for comparison of FCSRT-FR ROC and MMSE, CDRsb, and CVF ROCs). FCSRT-FR had an area under the ROC curve of 0.799 (95% CI 0.738-0.85) and the optimal cut-off was 20 (se 68.06% , sp 81.43% , PPV 23.90% , NPV 96,75%). Concerning FCSRT-TR, the AUC was 0.776 and the optimal cut-off was 42 (se 62.5% , sp 82.26% , PPV 23.20% and NPV 96.24%). This study sets the framework for implementing the FCSRT in clinical and therapeutic trials for efficient subject selection.

In Vivo Imaging Biomarkers in Mouse Models of Alzheimer's Disease: Are We Lost in Translation or Breaking Through?

Identification of biomarkers of Alzheimers Disease (AD) is a critical priority to efficiently diagnose the patients, to stage the progression of neurodegeneration in living subjects, and to assess the effects of disease-modifier treatments. This paper addresses the development and usefulness of preclinical neuroimaging biomarkers of AD. It is today possible to image in vivo the brain of small rodents at high resolution and to detect the occurrence of macroscopic/microscopic lesions in these species, as well as of functional alterations reminiscent of AD pathology. We will outline three different types of imaging biomarkers that can be used in AD mouse models: biomarkers with clear translational potential, biomarkers that can serve as in vivo readouts (in particular in the context of drug discovery) exclusively for preclinical research, and finally biomarkers that constitute new tools for fundamental research on AD physiopathogeny.

Mechanical stress models of Alzheimer's disease pathology

Extracellular accumulation of amyloid‐β protein and intracellular accumulation of tau in brain tissues have been described in animal models of Alzheimers disease (AD) and mechanical stress‐based diseases of different mechanisms, such as traumatic brain injury (TBI), arterial hypertension (HTN), and normal pressure hydrocephalus (NPH).