The diagnosis of dementia due to Alzheimer's disease: Recommendations from the National Institute on Aging‐Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease

ObjectiveFrontotemporal lobar degeneration (FTLD) is the second most prevalent dementia in young patients and is characterized by the presence of two main protein aggregates in the brain, tau (FTLD‐Tau) or TDP43 (FTLD‐TDP), which likely require distinct pharmacological therapy. However, specific diagnosis of FTLD and its subtypes remains challenging due to largely overlapping clinical phenotypes. Here, we aimed to assess the clinical performance of novel cerebrospinal fluid (CSF) biomarkers for discrimination of FTLD and its pathological subtypes.Methods YKL40, FABP4, MFG‐E8, and the activities of catalase and specific lysosomal enzymes were analyzed in patients with FTLD‐TDP (n = 30), FTLD‐Tau (n = 20), AD (n = 30), DLB (n = 29), and nondemented controls (n = 29) obtained from two different centers. Models were validated in an independent CSF cohort (n = 188).Results YKL40 and catalase activity were increased in FTLD‐TDP cases compared to controls. YKL40 levels were also higher in FTLD‐TDP compared to FTLD‐Tau. We identified biomarker models able to discriminate FTLD from nondemented controls (MFG‐E8, tTau, and Aβ 42; 78% sensitivity and 83% specificity) and non‐FTLD dementia (YKL40, pTau, p/tTau ratio, and age; 90% sensitivity, 78% specificity), which were validated in an independent cohort. In addition, we identified a biomarker model differentiating FTLD‐TDP from FTLD‐Tau (YKL40, MFGE‐8, βHexA together with βHexA/tHex and p/tTau ratios and age) with 80% sensitivity and 82% specificity.InterpretationThis study identifies CSF protein signatures distinguishing FTLD and the two main pathological subtypes with optimal accuracy (specificity/sensitivity > 80%). Validation of these models may allow appropriate selection of cases for clinical trials targeting the accumulation of Tau or TDP43, thereby increasing their efficiency and facilitating the development of successful therapies.

Section: Methodsmentioning

confidence: 99%

Novel CSF biomarkers to discriminate FTLD and its pathological subtypes

Campo

Galimberti

Elias

et al. 2018

“…The baseline characteristics of participants are presented in Table 1. Clinical diagnoses of dementia, Alzheimer dementia (AD), and mild cognitive impairment (MCI) were based on the NIA‐AA clinical criteria 20, 21. A total of 200 medical and paramedical staff examined participants between 6:30 to 13:00 over 10 days at Iwaki culture center.…”

Section: Methodsmentioning

confidence: 99%

Aging and APOE‐ε4 are determinative factors of plasma Aβ42 levels

Nakamura

Kawarabayashi

Seino

et al. 2018

ObjectiveThe aim of this study was to confirm determinative factors for plasma Aβ and its association with cognitive function.MethodsFasting plasma Aβ40 and Aβ42 levels were measured by ELISA in 1019 participants in the Iwaki Health Promotion Project. The relationships between plasma Aβ and health‐related items, including physical characteristics, cognitive function tests, blood chemistry, and APOE‐ε4 genotype were analyzed.ResultsThe plasma levels of Aβ40 and Aβ42, and Aβ40/42 ratio were found to significantly increase with aging. The age‐dependent increase in Aβ42 level was significantly suppressed by APOE‐ε4. Renal function was an associated factor for the plasma Aβ40 level. The plasma Aβ42 level and Aβ40/42 ratio correlated with cognitive function.InterpretationAge and APOE‐ε4 are major determinative factors of plasma levels of Aβ42 and the Aβ40/42 ratio. These factors are critical adjustment factors for the usage of plasma Aβ as a biomarker of central nervous system amyloidosis.

“…Participants ( N = 10; Mean Age = 67.2 years, SD Age = 7.3; Mean MMSE = 22 SD MMSE = 4) were clinically diagnosed with typical AD in the interdisciplinary center for memory disorders of the University Hospital Cologne and the Department of Psychiatry, University Hospital Bonn using the recommended diagnostic guidelines,6 and supported by the diagnostic PET imaging results evaluated by the experts from the Department of Nuclear Medicine (J. H., T. v. E., A. D.). All participants underwent a trimodal PET imaging protocol at the University Hospital Cologne, including [ 11 C]PiB PET, [ 18 F]AV‐1451, [ 18 F]FDG‐PET in the course of their clinical work‐up for dementia.…”

Section: Methodsmentioning

confidence: 99%

Impact of tau and amyloid burden on glucose metabolism in Alzheimer's disease

Bischof

Jessen

Fließbach

et al. 2016

In a multimodal PET imaging approach, we determined the differential contribution of neurofibrillary tangles (measured with [18F]AV‐1451) and beta‐amyloid burden (measured with [11C]PiB) on degree of neurodegeneration (i.e., glucose metabolism measured with [18F]FDG‐PET) in patients with Alzheimer's disease. Across brain regions, we observed an interactive effect of beta‐amyloid burden and tau deposition on glucose metabolism which was most pronounced in the parietal lobe. Elevated beta‐amyloid burden was associated with a stronger influence of tau accumulation on glucose metabolism. Our data provide the first in vivo insights into the differential contribution of Aβ and tau to neurodegeneration in Alzheimer's disease.