By Richard S. Isaacson, MD
Associate Professor of Neurology (Education), Weill Cornell Medical College
Dr. Isaacson reports he is a retained consultant and on the speakers bureau for Novartis, and is a retained consultant for and receives grant/research support from Accera.
Aß 42, measured in cerebrospinal fluid, may help determine whether patients have normal or increased cortical Aß deposition. Additionally, abnormal PET 18F-flutemetamol retention levels correlate with disease stage in patients with mild cognitive symptoms.
Palmqvist S, et al. Accuracy of brain amyloid detection in clinical practice using cerebrospinal fluid ß-Amyloid 42: A cross-validation study against amyloid positron emission tomography. JAMA Neurology 2014;71:1282-1289. doi:10.1001/jamaneurol.2014.1358.
The future of Alzheimer’s disease (AD) treatment will rely on disease-modifying therapy that is begun as early as possible in the development of the disease. The most recent AD diagnostic criteria were reported in 2011, and most accurately reflect our current understanding of AD (National Institutes of Aging/Alzheimer’s Association criteria). These new standards describe a spectrum of AD that starts many years, decades in fact, before the first symptoms occur. This new model breaks down AD into three different stages. It is important to note that before AD becomes manifest in the brain, patients may be classified in the prodromal stage, meaning the disease has not started and no symptoms have begun. Stage 1 refers to AD starting in the brain without symptoms ("preclinical" AD). Stage 2 refers to mild memory loss, but the person can still perform all of their usual daily activities (mild cognitive impairment due to AD). Stage 3 refers to dementia due to AD. For the most optimal effect, future drug treatments will need to be initiated at a preclinical or prodromal stage to offer the most clinically relevant neuroprotection.
Therefore, establishing diagnostic tools that identify AD pathology at an early stage is of paramount importance. A new cross-sectional study by Palmqvist and colleagues has found that in routine clinical practice (at three memory clinics in Sweden), Aß42 that was measured in cerebrospinal fluid (CSF) may help determine whether patients have normal or increased cortical Aß deposition. Additionally, amyloid positron emission tomography (PET) imaging with 18F-flutemetamolabnormal highly correlated retention levels with disease stage in patients with mild cognitive symptoms. The study population included patients with mild cognitive symptoms (n = 118 Stage 2 of AD, with validation cohort n = 38) from the Swedish BioFINDER (Biomarkers For Identifying Neurodegenerative Disorders Early and Reliably) study (visit www.biofinder.se for additional information). Results demonstrated very high agreement between Aß classification with CSF Aß42 and 18F-flutemetamol PET, with 92% of cases identically classified using an Aß42 cutoff of ≤ 647 pg/mL. In addition, CSF Aß42 accurately predicted abnormal cortical Aß deposition in all cortical regions.
Commentary
This is the first evidence helping to determine whether levels of CSF Aß42 can be used with validity and reliability to detect abnormal brain Aß deposition when analyzed consecutively over a few years within the context of routine clinical practice. While such CSF studies tend to be ordered more frequently in subspecialty memory clinics when diagnostic accuracy is in doubt, the vast majority of neurologists have not incorporated this testing into their diagnostic armamentarium. Proof-of-concept studies such as this are necessary prior to more widespread adoption of using CSF biomarkers as part of the diagnosis of Stage 2 and 3 AD. Considering known issues of variability of CSF biomarker levels, accuracy of CSF Aß42 measurements in clinical practice was quite good. High reliability and validity of CSF Aß42 levels for predicting cortical Aß deposition was also used when using 18F-flutemetamol PET as a more appropriate "gold standard." While controversial, of the currently available methods, amyloid PET is believed to be the most suitable surrogate in vivo marker for amyloid load due to the high correlation with histopathology.
At this time, from a practical clinical perspective, alteration in clinical practice by measuring CSF Aß42 to aid in diagnosis and help stratify patients cannot yet clearly be recommended. However, these data continue to expand upon recent progress in the diagnosis of AD at the earliest clinical stages, as well as prodromal AD, and will help to select patients for a future drug most optimally suited for AD prevention.
