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Objective  The diagnostic accuracy of cerebrospinal fluid ( CSF ) biomarkers for Alzheimer's disease ( AD ) must be improved before widespread clinical use. This study aimed to determine whether  CSF  A β 42/A β 40 and A β 42/A β 38 ratios are better diagnostic biomarkers of  AD  during both predementia and dementia stages in comparison to  CSF  A β 42 alone.    Methods  The study comprised three different cohorts ( n  = 1182) in whom  CSF  levels of A β 42, A β 40, and A β 38 were assessed.  CSF  A β s were quantified using three different immunoassays (Euroimmun, Meso Scale Discovery, Quanterix). As reference standard, we used either amyloid ( 18 F‐flutemetamol) positron emission tomography ( PET ) imaging ( n  = 215) or clinical diagnosis ( n  = 967) of well‐characterized patients.    Results  When using three different immunoassays in cases with subjective cognitive decline and mild cognitive impairment, the  CSF  A β 42/A β 40 and A β 42/A β 38 ratios were significantly better predictors of abnormal amyloid  PET  than  CSF  A β 42. Lower A β 42, A β 42/A β 40, and A β 42/A β 38 ratios, but not A β 40 and A β 38, correlated with smaller hippocampal volumes measured by magnetic resonance imaging. However, lower A β 38, A β 40, and A β 42, but not the ratios, correlated with non‐ AD ‐specific subcortical changes, that is, larger lateral ventricles and white matter lesions. Further, the A β 42/A β 40 and A β 42/A β 38 ratios showed increased accuracy compared to A β 42 when distinguishing  AD  from dementia with Lewy bodies or Parkinson's disease dementia and subcortical vascular dementia, where all A β s (including A β 42) were decreased.    Interpretation  The  CSF  A β 42/A β 40 and A β 42/A β 38 ratios are significantly better than  CSF  A β 42 to detect brain amyloid deposition in prodromal  AD  and to differentiate  AD  dementia from non‐ AD  dementias. The ratios reflect  AD ‐type pathology better, whereas decline in  CSF  A β 42 is also associated with non‐AD subcortical pathologies. These findings strongly suggest that the ratios rather than  CSF  A β 42 should be used in the clinical work‐up of  AD .

CSF A β 42/A β 40 and A β 42/A β 38 ratios: better diagnostic markers of Alzheimer disease