The Effect of Changing the Amyloid &bgr;42 Cut-off of Cerebrospinal Fluid Biomarkers on Alzheimer Disease Diagnosis in a Memory Clinic Population in Norway

Abstract

A lzheimer disease is the most common type of dementia, and according to the amyloid cascade hypothesis, the pathophysiological changes seen in Alzheimer disease begin with the deposition of extracellular amyloid and the phosphorylation of intracellular tau proteins.1 These changes are detectible in the cerebrospinal fluid (CSF), and measurements of amyloid (Aβ42), phospho-tau (P-tau), and total tau (T-tau) are used to supplement clinical symptoms in order to diagnose Alzheimer disease at an early stage. A number of studies have shown that CSF biomarkers can be used to distinguish patients with Alzheimer disease from healthy controls.2 However, when analyzed in various clinical settings among people with a variety of clinical diagnoses causing cognitive impairment, the discriminating power of CSF biomarkers is less convincing.3 In a previous study of a heterogeneous memory clinic population, we found a much lower sensitivity (SS) of 31.9% and a specificity (SP) of 92.5% when combining amyloid β (Aβ42) with P-tau or T-tau compared with previous findings.4 In June 2017, the Norwegian laboratory analyzing our samples decided to change the Aβ42 cut-off level for a pathologic test result; this was done without changing the laboratory’s methodological routines. This decision was based on the results of studies comparing CSF Aβ42 with amyloid positron emission tomography (PET) (18F-flutemetamol-PET) that revealed positive amyloid PET at higher CSF Aβ42 levels than 550.5,6 Thus, the aim of the present study was to explore how a change in the Aβ42 cut-off influenced the diagnostic performance of CSF biomarkers in a memory clinic setting. METHODS The methods are described extensively in our previous paper.4 This was a cross-sectional study conducted at the memory clinic at Oslo University Hospital (OUH), Ullevaal, that included 205 patients referred for a diagnostic workup between January 2009 and July 2014. The only inclusion criterion was that a lumbar puncture to measure the CSF biomarkers Aβ42 and tau proteins had been done; no exclusion criteria were defined. All patients were examined according to a standardized research protocol. Clinical information was obtained from the patients, their caregivers, the referring physician, and the hospital records. The patients were examined by experienced physicians and submitted to a neuropsychological examination [including, among other diagnostic tools, the Mini-Mental State Examination (MMSE), the Consortium to Establish a Registry of Alzheimer’s Disease (CERAD) 10-item word list, the ClockDrawing Test (CDT), and the Trail-Making Tests A and B (TMT A and B)]. Physical examinations including blood and spinal fluid samples and magnetic resonance imaging (MRI) brain scans and, in some cases, single-photon emission computer tomography (SPECT), DaTscan (Ioflupane I 123 injection), or 18F-2-fluoro-2-deoxy-D-glucose PET were performed as well. Diagnoses were made in consensus by 2 experienced physicians, a neurologist and a geriatrician, independent of the results of the CSF biomarkers.