CSF neurogranin or tau distinguish typical and atypical Alzheimer disease

Abstract

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.

The diagnostic performance of neurofilament light chain in CSF and blood for Alzheimer's disease, frontotemporal dementia, and amyotrophic lateral sclerosis: A systematic review and meta‐analysis

“…In the remaining 11 studies, with 2404 AD cases and 1647 disease mimic controls, CSF NfL concentration was not statistically distinguishable between AD cases and disease mimic controls (average ratio 0.87, 95% CI 0.70–1.08, P = 0.175; Fig. 2C) [16,23,27,28,33,35,40,43,45,46].…”

“…Thus, the currently available evidence does not support the ability of NfL to differentiate AD from disease mimics. In the studies examined, disease mimics for AD included vascular dementia, Lewy body dementia, Parkinson's disease dementia, idiopathic normal pressure hydrocephalus, and posterior cortical atrophy (Supplementary Material B) [16,23,27,28,33,35,40,43,45,46].…”

ATN status in amnestic and non-amnestic Alzheimer’s disease and frontotemporal lobar degeneration

“…Recent diagnostic strategies, such as the ATN framework, have emphasized biomarkers over traditional clinical evaluations to improve antemortem predictions of AD pathology, as well as stratification from other pathologies such as FTLD. Even with the improved accuracy of antemortem predictions of AD pathology, subtle differences in CSF levels across AD variants might lead to a small number of diagnostic errors (Teng et al, 2014;Paterson et al, 2015;Wellington et al, 2018;Pillai et al, 2019). To better characterize the full spectrum of CSF profiles in AD continuum disease and evaluate diagnostic accuracy of CSF biomarkers, we compared the accuracy of CSF-based ATN classifications in AD patients with amnestic and nonamnestic clinical phenotypes, and in FTLD.…”

“…One possible source of diagnostic error is that broadly-applied cutoffs for AD pathology may better capture amnestic than non-amnestic variants of AD due to differences in CSF levels (Teng et al, 2014;Paterson et al, 2015;Wellington et al, 2018;Pillai et al, 2019). The majority of patients with AD pathology clinically present with amnestic AD, the most common form of dementia, characterized by profound loss of episodic memory (Dubois et al, 2007).…”

MRI and flortaucipir relationships in Alzheimer's phenotypes are heterogeneous

“…That is, those with Ty‐AD and prominent episodic memory loss show greater damage to allocortical (e.g., hippocampus) and mesocortical (e.g., entorhinal cortex (ERC)) structures compared with neocortex while those with Aty‐AD and prominent nonmemory impairment show greater damage to neocortical structures compared with allocortical and mesocortical structures 9 . Further supporting this classification are the many differences that have been identified between Typical and atypical AD 9–13 …”