Authors: Ellen Clarke
This week’s ‘Ask the experts’ column with Maria Carrillo (Alzheimer’s Association), Linda Nazarko (London North West Healthcare NHS Trust, UK), Gabriel Vargas (Amgen, CA, USA) & Henrik Zetterberg (University of Gothenburg, Sweden) focuses on the often controversial topic of screening for Alzheimer’s disease. Over the past 2 days we have introduced the topic and drilled down into the pros and cons of screening. In this final installment we will discuss the current opporutnities for Alzheimer’s diagnosis and future hopes for efficacious biomarkers. You can find out more about the panelists at the bottom of this post.
What are the standard tests used to screen for Alzheimer’s?
Carrillo: The recently updated guidance document from the USPSTF found that there is now “adequate evidence that some screening tools have sufficiently high sensitivity and specificity to be clinically useful in identifying dementia.” The Alzheimer’s Association would encourage the USPSTF to be more explicit in differentiating one-time ‘screenings’ versus regular cognitive assessments done in a medical setting. The Alzheimer’s Association encourages regular cognitive assessment to take place in a medical setting with appropriately validated tools, especially as part of the Annual Wellness Assessment.
While no single cognitive test is considered the gold standard, the Alzheimer’s Association recently convened a group of experts to review the current landscape of available tools and provider practices, and develop guidelines and an algorithm for operationalizing the detection of cognitive impairment. The published recommendations suggest three assessment tools that can be used for the initial evaluation and subsequent tracking of cognitive function in older adults – the Memory Impairment Screen (MIS), General Practitioner Assessment of Cognition (GPCOG) and the Mini-Cog. If an informant is present, such as a caregiver or family member that can attest to the individual’s changes in memory, language or function over time, the guidelines recommend use of the AD8, the informant component of the GPCOG or the Short IQCODE. It is important to note that the cognitive assessments being recommended are only the first steps in diagnosing dementia and patients with assessments that indicate cognitive impairment should be referred for a full dementia evaluation to determine an accurate diagnosis.
Zetterberg: In the medical evaluation of patients with cognitive problems MRI and CSF total tau may be used to detect neurodegeneration, CSF phosphotau may be used to detect tangle pathology, CSF Ab42 and amyloid PET may be used to detect amyloid pathology and neuropsychological testing may be used to characterize the symptoms these pathologies may cause.
What are the limitations associated with the current tests that are used to screen for Alzheimer’s?
Carrillo: The available published research on cognitive impairment screening tools is lacking in quality and quantity. More information is needed around the comparative validity of brief cognitive assessment tools especially in non-white ethnic group and races, persons for whom English is a second language and low-education populations. The Alzheimer’s Association strongly recommends that further research is needed to develop better and simpler diagnostic tools and validate emerging technologies that could assist in cognitive testing such as online or electronic applications.
In addition, the currently available cognitive assessment tools cannot provide insight on the underlying disease mechanisms. Several recent studies indicate that many people have brain pathology associated with more than one type of dementia. This ‘mixed dementia’ is particularly common in older age individuals and may obscure identifying a specific disease state.
As we go earlier in the disease process, it becomes more difficult to detect subtle cognitive changes. Tests are needed that have high sensitivity and specificity in indicating or predicting subtle cognitive impairment; especially tests that can differentiate early decline due to a disease state from normal aging. Current diagnosis of Alzheimer’s depends heavily on documenting mental decline but by the time cognitive symptoms are visible, significant damage to the brain has already occurred. For this reason, there is much emphasis on finding accurate ways to detect the disease before clinical symptoms are evident. One of the most promising paths to earlier and easier detection of Alzheimer’s and other dementias is through discovery and validation of biomarkers that would indicate the presence of disease in the absence of clinical symptoms.
Zetterberg: MRI is insensitive, amyloid PET is expensive and not available everywhere, CSF requires a lumbar puncture and there are still some standardization issues in regards to preanalytical and analytical variability.
How should a cut-off be chosen to decide who is diagnosed?
Nazarko: I believe that we need to streamline diagnosis. We need to make it simple and efficient. Some people who present with advanced dementia and who could find a CT traumatizing could have a working diagnosis of dementia. This would enable the person to receive appropriate support and help. Some people who have more complex problems or early onset dementia may need a more robust investigative pathway. We need to keep the question “How will this investigation affect treatment and care?” in the forefront so that people are not subject to lengthy and distressing investigations if they will not affect clinical care, support or quality of life.
What are some of the most promising biomarkers for future screening?
Carrillo: While PET imaging of amyloid accumulation in the brain holds promise as a biological marker of AD, it is very expensive, not currently covered by insurance and suffers from limited access in many regions. Measurement of biomarkers in cerebrospinal fluid has made great strides to become one of the most globally standardized analytical methods in development.
In late 2015, the Joint Committee for Traceability in Laboratory Medicine formally accepted a mass spectrometry procedure for the measurement of beta-amyloid (Aβ42) concentrations in cerebrospinal fluid. While this is a key step toward a diagnostic method that is highly standardized and precise, it requires a non-routine lumbar puncture to obtain the cerebrospinal fluid needed. It is important to note that Aβ42 is not specific to AD; it is observed in other dementias. Also, at this time it is unknown how the changes in the levels of this protein reflect the state of cognitive impairment or dementia. More population studies are needed to determine (a) the range of the protein levels for early detection and (b) its viability as a screening tool.
An important advancement would be the development of a simple, inexpensive and noninvasive test, such as a blood test, that could be used at the point-of-care. This test could measure a biomarker, or panel of biomarkers (e.g. a combination of proteins and lipids in the blood), that would be specific for AD. While blood tests are generally inexpensive, easily obtained and have played a critical role in detecting and changing the course of other deadly diseases, there are unique challenges to using blood-based biomarkers for neurodegenerative diseases. Many of the pathological changes occurring in the brain may not be readily detected in the blood due to the blood-brain barrier. Research is underway to develop, standardize and validate blood-based biomarker tests with the necessary accuracy and reliability needed to diagnose AD.
What are the challenges associated with discovering new biomarkers and making them available in the clinic?
Zetterberg: I am very positive about the currently available biomarkers. Both amyloid PET and CSF biomarkers are used in the clinic in many countries. However, a simple blood test would be a major contribution to this field, and I am cautiously optimistic that we are moving in that direction using novel ultrasensitive measurement techniques. Another important research field would be to develop more robust biomarkers for other pathologies that often affect the brain, also in AD. These include markers of Lewy body and TDP-43 pathologies. I think the most effective way of developing such biomarkers would be to start in brain tissue, identify pathology-specific isoforms of the protein constituents and then develop specific, most likely ultrasensitive tests, for these protein isoforms and then examine CSF and blood samples in small pilot studies. Following this, large prospective multicentre studies will be needed before clinical implementation. Clinical implementation is a major undertaking from a standardization perspective; only the most promising markers should enter that route.
Vargas: Reproducibility has been a huge issue in the attempt to find peripheral biomarkers for AD. Many high profile publications have claimed success on the identification of peripheral biomarkers only to find that other labs were unable to duplicate the original finding. This is most likely due to a combination of preanalytical and analytical issues. Assays are sensitive to the specimen handling and if this is not standardized different labs may reach different results. Once discovered, the biomarkers must be validated, which means they need to be incorporated into large clinical trials to show they do what they are supposed to do. This is expensive and takes a long time.
If you missed the first two instalments of this series, don’t forget to check them out:
Maria C. Carrillo, Chief Science Officer, Medical & Scientific Relations, Alzheimer’s Association (IL, USA)
Biography: Maria Carrillo, Ph.D., is Chief Science Officer, Medical and Scientific Relations, at the Alzheimer’s Association. Dr. Carrillo has a wide range of responsibilities, including oversight of the Association’s grant-making process and communication of scientific findings within and outside of the organization. Dr. Carrillo directly manages several Alzheimer’s Association initiatives, including the Research Roundtable, the World-Wide Alzheimer’s Disease Neuroimaging Initiative, and the Global Alzheimer’s Association Interactive Network. She is coauthor of the National Institute on Aging–Alzheimer’s Association revised criteria for the diagnosis of Alzheimer’s, and the Appropriate Use Criteria for Amyloid Imaging. She is on the Advisory Committee for the World Health Organization Dementia Setting Priorities & Portfolio Analysis.
Linda Nazarko, Consultant Nurse at London North West Healthcare NHS Trust (UK)
Biography: Linda Nazarko MSc, PgDip, Pg Cert, BSc (Hons), RN, NIP, OBE, FRCN is consultant nurse at London North West Healthcare NHS Trust (UK). She works as a clinician, educator and adviser with colleagues in the inpatient units and within intermediate care and community teams. Linda has clinical responsibility for two nurse led inpatient wards in a community hospital. She leads a team of nurses and therapists and admits patients directly from home and from A&E into the step-up unit and from acute hospitals into the step-down unit. Linda is also clinical lead for the IV service and for dementia. She has for the last year led a Commissioning for Quality and Innovation (CQUIN) on improving care for people with dementia within Ealing Community Services. Linda lectures and assesses at universities and speaks at conferences in the UK and Europe. Linda has specialized in care of older people for 30 years and has qualifications in gerontology, physical assessment, diagnostic reasoning, prescribing, continence, stoma care, research and management. She is the author of several books, reviews and contributes to major UK nursing journals.
Gabriel Vargas, Executive Medical Director and Head of the General Medicine, Bone & Neuroscience Therapeutic Area in Early Development, Amgen (CA, USA)
Biography: Gabriel Vargas, MD, PhD is a board certified psychiatrist and basic scientist. Gabriel obtained his undergraduate degree from the University of California at Berkeley (CA, USA) where he majored in anthropology & genetics. He received his MD and PhD degrees from the University of California at Irvine (CA, USA) and went on to complete a basic science research track residency in Psychiatry at the University of California at San Francisco (UCSF, CA, USA).
After both a clinical and research fellowship he was appointed an assistant professor in the Psychiatry Department at UCSF where he spent 3 years leading a research group studying G-protein coupled receptor (GPCR) signaling and trafficking. He also served as the Medical Director of the UCSF prodromal schizophrenia research program. He has published in the areas of GPCR signaling and membrane trafficking with a particular expertise in approaches using basic science to understand the molecular pathophysiology of genetic diseases. After leaving academia in 2006 he spent 5 years at Roche, the last three in Basel (Switzerland), as Head of the CNS Biomarker Group where he worked on biomarkers and diagnostics for Alzheimer’s disease, autism and schizophrenia.
He joined Amgen in 2011 and leads a group of physician-scientists doing early development work on migraine, Alzheimer’s disease and schizophrenia.
Henrik Zetterberg, University of Gothenburg (Sweden)
Biography: Henrik Zetterberg, MD, PhD, is Professor of Neurochemistry at the University of Gothenburg, Sweden, and at University College London, UK, as well as the Head of the Department of Psychiatry and Neurochemistry at the Sahlgrenska Academy at the University of Gothenburg, Sweden. With a background in molecular biology and medicine, Dr. Zetterberg has spent the past 10 years focusing on the development of biomarkers for Alzheimer’s disease and other brain disorders. His research involves evaluation of biomarkers in cell and animal models, as well as in longitudinal studies of patients and healthy individuals. He has published more than 500 scientific articles and has received the Erik K. Fernström prize for young scientists, the Inga Sandeborg prize for research on Alzheimer’s disease and the Parkinson Research Foundation Award.
The opinions expressed in this interview are those of the interviewees and do not necessarily reflect those of Neurology Central or Future Science Group.