Cerebrospinal Fluid Biomarkers Of Neurodegeneration Synaptic Dysfunction And Axonal Injury Relate To Atrophy In Structural Brain Regions Specific To Alzheimer’s Disease
Department of Neurology, Vanderbilt Memory & Alzheimer’s Center, Vanderbilt University Medical Center, Nashville, Tennessee
Elizabeth E. Moore and Katherine A. Gifford contributed equally.
Department of Neurology, Vanderbilt Memory & Alzheimer’s Center, Vanderbilt University Medical Center, Nashville, Tennessee
Elizabeth E. Moore and Katherine A. Gifford contributed equally.
Department of Neurology, Vanderbilt Memory & Alzheimer’s Center, Vanderbilt University Medical Center, Nashville, Tennessee
Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
Department of Radiology & Radiological Sciences, Vanderbilt University Medical Center, Nashville, Tennessee
Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee
Department of Electrical Engineering and Computer Science, Vanderbilt University, Nashville, Tennessee
Kaj Blennow
Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden
Clinical Neurochemistry Lab, Sahlgrenska University Hospital, Mölndal, Sweden
Henrik Zetterberg
Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden
Clinical Neurochemistry Lab, Sahlgrenska University Hospital, Mölndal, Sweden
UK Dementia Research Institute at UCL, London, UK
Correspondence
Kaj Blennow
Laboratory Screening Tests Combined With Advanced Bloodborne Biomarkers
Like structural imaging, screening for deficiencies in B12 and thyroid stimulating hormone are low-cost, high-yield tests for identifying reversible causes of dementia . However, they are insufficient for detecting AD, because they are only used to exclude other conditions.
To move from a diagnosis of exclusion to a diagnosis of inclusion, one must consider including apolipoprotein E genotyping. Also controversial, the rationale for doing so is as follows. The lifetime risk for developing AD for a patient who is homozygotic for the APOE 4 is 91%, and the lifetime risk for a patient who is heterozygotic for APOE 4 is 47% . APOE 4 carrier status is highly predictive of AD an APOE 4 carrier who is symptomatic has a 9497% chance of having AD . In one study, the clinical diagnosis of AD improved from 55% to 84% when APOE 4 carrier status was added to the model . In addition, 50% of MCI subjects who are APOE 4 carriers progress to AD dementia in 3 years compared to 20% of non-APOE 4 carriers . MCI subjects who are APOE 4 carriers convert to AD > 99% of the time . APOE 4 carriers are 26 times more likely to progress in cognitive decline. In addition, the presence of the APOE 4 allele predicts AD pathology on PET imaging .
Goal : Prevent And Effectively Treat Alzheimer’s Disease And Related Dementias By 2025
Research continues to expand our understanding of the causes of, treatments for, and prevention of AD/ADRD. This goal seeks to develop effective prevention and treatment modalities by 2025. Ongoing research and clinical inquiry can inform our ability to delay onset of AD/ADRD, minimize its symptoms, and delay its progression. Under this goal, HHS will prioritize and accelerate the pace of scientific research and ensure that as evidence-based solutions are identified, they are quickly translated, put into practice, and brought to scale so that individuals with AD/ADRD can benefit from increases in scientific knowledge. HHS will identify interim milestones and set ambitious deadlines for achieving these milestones in order to meet this goal.
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To Explore The Predictive Power Of Visuomotor Network Dysfunctions In Mild Cognitive Impairment And Alzheimers Disease
- 1Vestibular and Ocular Motor Research Group, Department of Neuroscience, Erasmus MC, Rotterdam, Netherlands
- 2Section of Geriatric Medicine, Department of Internal Medicine, Erasmus MC, Rotterdam, Netherlands
- 3Center for Economic Research, Tilburg University, Tilburg, Netherlands
- 4Department of Technology and Operations Management, Rotterdam School of Management, Erasmus University, Rotterdam, Netherlands
- 5Royal Dutch Visio, Huizen, Netherlands
Background: Research into Alzheimers disease has shifted toward the identification of minimally invasive and less time-consuming modalities to define preclinical stages of Alzheimers disease.
Method: Here, we propose visuomotor network dysfunctions as a potential biomarker in AD and its prodromal stage, mild cognitive impairment with underlying the Alzheimers disease pathology. The functionality of this network was tested in terms of timing, accuracy, and speed with goal-directed eye-hand tasks. The predictive power was determined by comparing the classification performance of a zero-rule algorithm , a decision tree, a support vector machine, and a neural network using functional parameters to classify controls without cognitive disorders, mild cognitive impaired patients, and Alzheimers disease patients.
Comparison with Existing Method: The classification performance found in the present study is comparable to that of the existing CSF and MRI biomarkers.
Strategy 2a: Build A Workforce With The Skills To Provide High
The workforce that cares for people with AD/ADRD includes health care and LTSS providers such as: primary care physicians specialists such as neurologists, geriatricians, and psychiatrists registered nurses and advanced practice nurses community health workers social workers psychologists pharmacists dentists allied health professionals and direct care workers, home health aides, and certified nursing assistants, who provide care across the care continuum. These providers need accurate information about furnishing care to a person with AD/ADRD including the benefits of early diagnosis, how to address the physical, cognitive, emotional, and behavioral symptoms of the disease, and how to assist caregivers as they cope with the physical and emotional aspects of their caregiving responsibilities. Enhanced specialist training is also needed to prepare these practitioners for the unique challenges faced by people with AD/ADRD. In addition, work is needed to expand the capacity of the primary care community to serve people with AD/ADRD. Dementia-specific capabilities within the direct care workforce need to be expanded and enhanced. The actions below will facilitate specific training for care professionals in order to strengthen a workforce that provides high-quality care to people living with AD/ADRD.
Action 2.A.1: Educate health care providers
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Icipants And Clinical Phenotyping
The prospective study fulfills the international standards for studies of diagnostic test accuracy in dementia .
For the present study, 61 disease control subjects and 39 AD cases were acquired from a prospective study designed and initiated by the gerontopsychiatric unit of the department of psychiatry and psychotherapy at the LVR Clinics, University of Duisburg-Essen, between 2009 and 2013 . The study was approved by the ethical board of the University of Duisburg-Essen and the research use of the samples and data was in accord with the terms of the informed consents. Sample acquisition and dementia diagnostics were made according to the criteria of the National Institute for Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association and included the 2011 recommendations from the National Institute on Aging. The clinical diagnosis of DC was performed according to the International Classification of Diseases . Patients were investigated by psychometric testing and CSF-guided neurochemical dementia diagnostics. A detailed description of the clinical cohort can be found in the study by Nabers et al. .
Strategy 1a: Identify Research Priorities And Milestones
Research agencies undertake research planning processes on an ongoing basis, but a special effort is needed to identify the priorities and milestones to achieve Goal 1. The actions below will identify the priorities, establish milestones, and ensure that appropriate stakeholders are involved in the planning process aimed at minimizing AD/ADRD as a health burden by 2025. During the course of this work, NIH and partner agencies will develop research priorities and a plan for implementing each phase of research in a coordinated manner.
Action 1.A.1: Regularly convene an Alzheimer’s disease research summit to update priorities
In the spring of 2018, the NIH Alzheimer’s Disease Research Summit 2018: Path to Treatment and Prevention expanded on the research agenda set in place at the first two of such summits held in 2012 and 2015. The 2018 gathering brought hundreds of experts in AD and other chronic diseases together to identify critical knowledge gaps and set priorities across the AD/ADRD research community for the kinds of new resources, infrastructure, and multi-stakeholder partnerships needed to fully realize emerging research opportunities. NIH is committed to regularly updating its research priorities and planning is underway for an AD research summit in the spring of 2021.
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Action 1.A.2: Solicit diverse community input on Alzheimer’s disease research priorities
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Specificity To Alzheimers Disease
Upregulation of clusterin and abnormal staining of lesions for apoE is not limited to AD. Brain levels of clusterin seem to be elevated in many conditions involving injury or chronic inflammation of the brain. Elevated levels of the mRNA for clusterin are seen in the hippocampus in Pick’s disease as well as in AD.4 Abnormal staining for clusterin has been seen in dystrophic neurites and some NFTs in the Parkinson‘s dementia complex of Guam . It has also been seen in humans in ischemic Purkinje cells which showed the shrunken and pyknotic appearance characteristic of irreversible damage.45 Intense staining for clusterin has been seen in hypertrophic astrocytes in cases of multiple sclerosis, stroke and AIDS encephalitis. In these cases, however, the distribution of clusterin did not appear to correlate with that of the MAC,46 a correlation which does appear to occur in AD.9
Apolpoprotein E staining has been found associated with the amyloid in various types of human cerebral or systemic amyloidosis,53,54 including the kuru plaques in CreutzfeldtJakob disease,39 and with the mainly extracellular NFTs and occasional diffuse Ap deposit in the Parkinson’s dementia complex of Guam.30,55 As in AD, not all of the tau-positive tangles were also stained for apoE.55 A comparison of staining for Ap and apoE in AD and the Parkinson’s dementia complex is shown in Figure 7.2.
Another Lifestyle Change To Prevent Dementia: Exercise
While regular exercise is a proven way to lower the risk for a host of health problems, from headaches and depression to heart disease and high blood pressure, it can also be one of the most important things you can do to potentially avoid dementia, including Alzheimers.
In fact, according to the Alzheimers Association, of all the lifestyle changes that have been researched, regular exercise appears to be one of the top things you can do to reduce your risk of dementia.
Several studies have shown aerobic exercise that boosts your heart rate in middle-aged and older adults improves thinking and memory and may stave off dementia. Moreover, 11 prospective studies concluded regular exercise can significantly reduce the rate of developing dementia by 30 percent. And, when it comes to Alzheimers disease specifically, the risk was reduced by a hope-inspiring 45 percent.
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Sensitivity And Specificity Of Neuropsychological Tests For Mild Cognitive Impairment Vascular Cognitive Impairment And Alzheimer’s Disease
Published online by Cambridge University Press: 31 July 2003
- C. A. DE JAGER
- Affiliation:Department of Pharmacology, University of Oxford and Oxford Project to Investigate Memory and Ageing , Oxford
- E. HOGERVORST
- Affiliation:Department of Pharmacology, University of Oxford and Oxford Project to Investigate Memory and Ageing , Oxford
- M. COMBRINCK
- Affiliation:Department of Pharmacology, University of Oxford and Oxford Project to Investigate Memory and Ageing , Oxford
- M. M. BUDGE
- Affiliation:
Strategy 3b: Enable Family Caregivers To Continue To Provide Care While Maintaining Their Own Health And Well
Even though unpaid caregivers usually prefer to provide care to their loved ones in their home or other community settings, sometimes the round-the-clock care needs of the person with AD/ADRD may necessitate nursing home placement. While they are providing care, supports for families and caregivers can help lessen feelings of depression and stress and help delay or avert institutional care. The actions below will further support informal caregivers by identifying their support needs developing and disseminating interventions giving caregivers information they need, particularly in crisis situations and assisting caregivers in maintaining their health and well-being.
Action 3.B.1: Develop and disseminate evidence-based interventions for people with Alzheimer’s disease and related dementias and their caregivers
NIA is supporting an ongoing project involving AHRQ and NASEM to conduct a systematic review of evidence of care interventions for persons with disabilities and their caregivers and to take stock of the current state of knowledge and inform decision making about which care interventions for PWD and caregivers are ready for dissemination and implementation on a broad scale . The NASEM committee held a workshop in April 2020. AHRQ released its final systematic review report in August 2020. A NASEM report that informs decision making about which care interventions are supported by sufficient evidence to be widely disseminated and implemented is forthcoming.
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Strategy 3e: Assess And Address The Housing Needs Of People With Alzheimer’s Disease And Related Dementias
Stable housing is essential to helping people with AD/ADRD remain in the community, particularly as they experience an increasing need for services and supports as the disease progresses. Housing is a crucial platform for delivering the necessary health and supportive services. Recognizing these links, HHS and the U.S. Department of Housing and Urban Development are working together to improve health outcomes and housing stability through supportive services for vulnerable populations including people with AD/ADRD. Through the actions below, HHS will assess the availability of services in the settings where people with AD/ADRD live. This information will form the basis of future actions to further link housing with services for people with AD/ADRD.
Action 3.E.1: Evaluate the Support And Services at Home program
ASPE and HUD completed an evaluation of the Support And Services at Home program for the first years of the program . The SASH program in Vermont is an approach to providing support services and care coordination to older adults and individuals with disabilities, using affordable housing properties as a platform for service delivery. Under contract from HHS and HUD, RTI International conducted a mixed-methods evaluation of the SASH program.
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Action 3.E.2: Assess utilization of home health benefits
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Strategy 4a: Educate The Public About Alzheimer’s Disease And Related Dementias
Greater public awareness of AD/ADRD can encourage families to seek assessment, reduce isolation and misunderstanding felt by caregivers, and help link people in need to accurate information, resources and services.
Action 4.A.1: Enhance public outreach about Alzheimer’s disease and related dementias
Through its grant and resource center programs, ACL continues to build awareness of AD/ADRD. All ACL grantees include awareness and outreach in their programs. Numerous grantee programs include dementia-friendly community activities in their projects, partnering with established AD/ADRD stakeholders, as well as training volunteer educators of community organizations including, but not limited to, faith-based organizations, business leaders and grass roots volunteer organizations like Rotary clubs.
ACL’s NADRC website is an established hub for resources to support community outreach and education efforts. The website offers a broad range of resources to support the development and implementation of community-based AD/ADRD education programs.
For its part, CDC’s Alzheimer’s Disease and Health Aging Program publishes web features, a series of podcasts, weekly newsletters , and social media to increase awareness and engagement by the public and its stakeholders about AD/ADRD. Web features for 2019-2020 include:
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Action 4.A.2: Facilitate translation of data and surveillance to inform the public
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Goals As Building Blocks For Transformation
Achieving the vision of eliminating the burden of AD/ADRD starts with concrete goals. Below are the five that form the foundation of the National Plan:
Could Alzheimers Be A Metabolic Disease Impacted By Diet
Some scientists are questioning why the treatments targeted at breaking down the buildup of amyloid plaques in the brains of people with Alzheimers havent worked. A team of Brigham Young University researchers suggests the explanation could well be that amyloid plaque is a result, not the cause, of AD.
They are looking at the disease with an alternative theory which calls into question whether amyloid plaques produce Alzheimers. Instead, they think the disease could be a result of metabolic dysfunction in the brain, and theyve found clues suggesting that how the body responds to insulin plays a role in AD.
Insulin is the hormone produced by the pancreas, which regulates blood sugar levels and helps glucose enter the body’s cells, where it can be used for energy or stored for future use. Type 1 diabetes is an autoimmune disease in which the pancreas produces no, or almost no, insulin.
But type 2 diabetes, the most common type of diabetes, is different. It is usually related to lifestyle factors and is marked by insulin resistance, which means the cells of the body cannot respond normally to insulin and take up glucose. Instead, glucose rises in the blood.
And it now appears insulin resistance impacts the brain and may play an important role in the development of AD.
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Strategy 1c: Accelerate Efforts To Identify Early And Presymptomatic Stages Of Alzheimer’s Disease And Related Dementias
Significant advances in the use of imaging and biomarkers in brain, blood, and spinal fluid have made it possible to detect the onset of AD/ADRD and track its progression, with the hope that it will be possible to monitor the effect of treatment in people with the disease. Without these advances, these neurodegenerative processes could only be evaluated in non-living tissues. Accelerated research will improve and expand the application of biomarkers in research and practice. These advances have shown that the brain changes that lead to AD/ADRD begin up to 10 years before symptoms. Identifying imaging and other biomarkers in presymptomatic people will facilitate earlier diagnoses in clinical settings, as well as aid in the development of more efficient interventions to slow or delay progression.
Action 1.C.1: Identify imaging and biomarkers to monitor disease progression
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In addition to these large initiatives, NIA and NINDS have released FOAs in the past year that call for research to further the development of imaging and biomarker research.
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