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

Dubois, Bruno; Feldman, Howard; Jacova, Claudia; Hampel, Harald; Molinuevo, José Luís; Blennow, Kaj; DeKosky, Steven T.; Gauthier, Serge; Selkoe, Dennis J.; Bateman, Randall J.; Cappa, Stefano F.; Crutch, Sebastian J.; Engelborghs, Sebastiaan; Frisoni, Giovanni B.; Fox, Nick C.; Galasko, Douglas; Habert, Marie‐Odile; Jicha, Gregory A.; Nordberg, Agneta; Pasquier, Florence; Rabinovici, Gil D.; Robert, Philippe; Rowe, Christopher C.; Salloway, Stephen; Sarazin, Marie; Epelbaum, Stéphane; Souza, Leonardo Cruz de; Vellas, Bruno; Visser, Pieter Jelle; Schneider, Lon S.; Stern, Yaakov; Scheltens, Philip; Cummings, Jeffrey L.

doi:10.1016/s1474-4422(14)70090-0

Cited by 2,792 publications

(2,488 citation statements)

References 213 publications

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“…To help solve this issue, it has been shown that the use of CSF biomarkers can improve the validity of clinical criteria. 38,[40][41][42] We therefore strongly recommended providing evidence of the AD pathophysiological process prior to any WES.…”

Section: Discussionmentioning

confidence: 99%

Screening of dementia genes by whole-exome sequencing in early-onset Alzheimer disease: input and lessons

Nicolas¹,

Wallon²,

Charbonnier³

et al. 2015

Eur J Hum Genet

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Causative variants in APP, PSEN1 or PSEN2 account for a majority of cases of autosomal dominant early-onset Alzheimer disease (ADEOAD, onset before 65 years). Variant detection rates in other EOAD patients, that is, with family history of lateonset AD (LOAD) (and no incidence of EOAD) and sporadic cases might be much lower. We analyzed the genomes from 264 patients using whole-exome sequencing (WES) with high depth of coverage: 90 EOAD patients with family history of LOAD and no incidence of EOAD in the family and 174 patients with sporadic AD starting between 51 and 65 years. We found three PSEN1 and one PSEN2 causative, probably or possibly causative variants in four patients (1.5%). Given the absence of PSEN1, PSEN2 and APP causative variants, we investigated whether these 260 patients might be burdened with protein-modifying variants in 20 genes that were previously shown to cause other types of dementia when mutated. For this analysis, we included an additional set of 160 patients who were previously shown to be free of causative variants in PSEN1, PSEN2 and APP: 107 ADEOAD patients and 53 sporadic EOAD patients with an age of onset before 51 years. In these 420 patients, we detected no variant that might modify the function of the 20 dementia-causing genes. We conclude that EOAD patients with family history of LOAD and no incidence of EOAD in the family or patients with sporadic AD starting between 51 and 65 years have a low variant-detection rate in AD genes.

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Section: Discussionmentioning

confidence: 99%

Screening of dementia genes by whole-exome sequencing in early-onset Alzheimer disease: input and lessons

Nicolas¹,

Wallon²,

Charbonnier³

et al. 2015

Eur J Hum Genet

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“…Participants included 68 patients with amnestic AD according to International Working Group 2 (IWG‐2) criteria14 with an AD‐indicative CSF AD biomarker profile (T‐tau/Aβ 42 >0.52)15; 19 patients with PCA, also with a CSF T‐tau/Aβ 42 >0.52, according to Tang‐Wai criteria and fulfilling the latest international criteria for diagnosis of “PCA‐AD”16, 17; and 27 controls who were spouses or friends of patients with no history or symptoms of neurodegenerative disease at the time of lumbar puncture (LP). These healthy individuals underwent a thorough neurological examination, as well as a standardized neuropsychological assessment using the Mattis Dementia Rating Scale 18, 19.…”

Section: Methodsmentioning

confidence: 99%

CSF neurogranin or tau distinguish typical and atypical Alzheimer disease

Wellington¹,

Paterson

Suárez‐González

et al. 2018

Ann Clin Transl Neurol

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ObjectiveTo assess whether high levels of cerebrospinal fluid neurogranin are found in atypical as well as typical Alzheimer's disease.MethodsImmunoassays were used to measure cerebrospinal fluid neurogranin in 114 participants including healthy controls (n = 27), biomarker‐proven amnestic Alzheimer's disease (n = 68), and the atypical visual variant of Alzheimer's (n = 19) according to international criteria. CSF total‐tau, Aβ42, and neurofilament light concentrations were investigated using commercially available assays. All affected individuals had T1‐weighted volumetric MR images available for analysis of whole and regional brain volumes. Associations between neurogranin, brain volumes, total‐tau, Aβ42, and neurofilament light were assessed.ResultsMedian cerebrospinal fluid neurogranin concentrations were higher in typical and atypical Alzheimer's compared to controls (P < 0.001 and P = 0.005). Both neurogranin and total‐tau concentrations, but not neurofilament light and Aβ42, were higher in typical Alzheimer's compared to atypical patients (P = 0.004 and P = 0.03). There were significant differences in the left hippocampus and right and left superior parietal lobules in atypical patients, which were larger (P = 0.03) and smaller (P = 0.001 and P < 0.001), respectively, compared to typical patients. We found no evidence of associations between neurogranin and brain volumes but a strong association with total‐tau (P < 0.001) and a weaker association with neurofilament light (P = 0.005).InterpretationThese results show significant differences in neurogranin and total‐tau between typical and atypical patients, which may relate to factors other than disease topography. The differential relationships between neurogranin, total‐tau and neurofilament light in the Alzheimer's variants, provide evidence for mechanistically distinct and coupled markers of neurodegeneration.

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“…The procedures for clinical assessment and patient recruitment are detailed elsewhere. 12 At baseline, six patients were diagnosed with AD dementia (that is, probable AD and a positive [ 11 C]PIB PET scan 19,20 ), and 10 with prodromal AD (that is, amnestic multi-domain mild cognitive impairment and a positive [ 11 C]PIB PET scan 20,21 During the follow-up interval, four of the patients with prodromal AD developed AD dementia.…”

Section: Study Samplementioning

confidence: 99%

Longitudinal changes of tau PET imaging in relation to hypometabolism in prodromal and Alzheimer’s disease dementia

et al. 2017

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The development of tau-specific positron emission tomography (PET) tracers allows imaging in vivo the regional load of tau pathology in Alzheimer's disease (AD) and other tauopathies. Eighteen patients with baseline investigations enroled in a 17-month follow-up study, including 16 with AD (10 had mild cognitive impairment and a positive amyloid PET scan, that is, prodromal AD, and six had AD dementia) and two with corticobasal syndrome. INTRODUCTIONThe aggregation of abnormally hyperphosphorylated tau protein into paired helical filaments is a key aspect of the pathology of Alzheimer's disease (AD). 1 Both the regional distribution of tau pathology in the brains of patients with AD and the sequential staging of its progression have been extensively described in postmortem studies. 2-5 These studies indicated, for the first time, that an early and relatively long preclinical phase of tau aggregation precedes the symptomatic stages of AD. 6,7 Despite this, the time course of tau pathology propagation, especially in relation to changes in the concomitant clinical and cognitive profiles of the individual patients, remains largely speculative because of the inherent limitations of post-mortem studies.During the past 5 years, the development of tau-specific positron emission tomography (PET) tracers 8 has provided a valuable addition to the neuroimaging arsenal. THK5317 [(S)-THK5117], a well characterised tau-specific tracer, 9-11 showed high retention in patients with AD with a regional pattern matching that of the distribution of tau pathology described by post-mortem studies. 12 Cross-sectionally, high load of tau pathology, as measured with THK5317 PET, was associated with

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

Cited by 2,792 publications

References 213 publications

Screening of dementia genes by whole-exome sequencing in early-onset Alzheimer disease: input and lessons

Screening of dementia genes by whole-exome sequencing in early-onset Alzheimer disease: input and lessons

CSF neurogranin or tau distinguish typical and atypical Alzheimer disease

Longitudinal changes of tau PET imaging in relation to hypometabolism in prodromal and Alzheimer’s disease dementia

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