Mild Cognitive Impairment

Victor W. Henderson, MD, MS Departments of Health Research & Policy (Epidemiology) and of Neurology & Neurological Sciences Stanford University Director, Stanford Alzheimer’s Disease Research Center

Mild cognitive impairment (MCI) is a present when cognitive decline interferes with conceptually important way station between independent function in usual, everyday normal cognitive aging and dementia. activities, such as managing a household and paying the bills. Cognitive aging and dementia Mild Cognitive Impairment Cognitive aging represents typical changes in mental abilities that occur as people grow MCI describes cognitive decline beyond what older. Dementia, in contrast, represents more can be explained by age alone, but the decline drastic cognitive impairment. Dementia is the has not affected function to an important result of pathological change (change caused extent. Through the years, various terms and by disease) in the brains of some people as definitions have been used for cognitive they age. decline short of dementia. Cognitive aging has positive and negative Criteria for MCI were developed at the Mayo effects on mental abilities. With time and Clinic to describe people with memory loss experience, we gain new knowledge and but no dementia (Petersen et al., 1991). The skills. We become wiser. However, for most goal was to identify people who seemed likely adults cognitive aging also brings slower to develop Alzheimer’s disease. The original mental processing, reduced mental flexibility, criteria were (1) a memory complaint, (2) increased susceptibility to distraction, and abnormal memory for age, (3) normal more difficulty learning new things. As an cognition apart from memory, (4) normal example, the amount of detail recalled from a activities of daily living, and (5) no dementia. short story or the number of words recalled Neuropsychology tests were used to help from a long list of words drops with age. This determine normal general cognition and decline begins as early as age 20. Cognitive abnormal memory. aging by itself does not lead to dementia. Five years later, an international working Dementia is a general condition with many group expanded the concept of MCI to include causes and two key features. Alzheimer’s deficits in mental domains other than memory disease is the most common cause of (Winblad et al., 2004). It was thought that dementia. The first key feature is cognitive MCI should still represent cognitive decline decline that is not related to a temporary short of dementia, but decline might be seen in medical condition like medication toxicity. ways other than memory (Table 1). The second is an adverse impact on function or independence. Dementia is said to be

Stanford ADRC | Page 1 | Supported by the NIH (AG046366) V W Henderson / Mild Cognitive Impairment

Table 1. General criteria for MCI The word “amnestic” was used to describe the two varieties that involved memory and “non- • Cognitive complaint amnestic” for the two varieties that did not. • Cognition not normal for age, but there is no Amnestic MCI is about twice as common as dementia non-amnestic MCI. • Cognitive decline by self-report or informant report and impairment on objective cognitive The four forms of MCI are conceived to tasks, or evidence of decline over time on represent the very early symptoms of a variety objective cognitive tasks, or both of dementing disorders, not just Alzheimer’s • Essentially normal functional activities disease. These other disorders include (after Winblad et al., 2004) vascular dementia (caused by stroke and other processes affecting blood vessels and brain The proposal, which specified four varieties of circulation), dementia with Lewy bodies or MCI, was widely adopted and is used today Parkinson's disease dementia, and (Figure 1). In this scheme, memory can be frontotemporal dementia. In general, diseases impaired by itself or memory can be impaired that cause dementia are now well known. In a together with a deficit in one or more other person with dementia, these diseases can be cognitive areas. If memory is normal, an area identified by a pathologist who examines the of cognitive function other than memory can brain at the time of death. be impaired in isolation, or several areas of cognition can be impaired at the same time.

Figure 1. Subtypes of Mild cognitive impairment (MCI)

Meets general criteria for MCI (must be YES) Is memory impaired?

YES NO Only memory? More than one cognitive domain?

YES: Amnestic MCI, single domain YES: Non-amnestic MCI, multidomain NO: Amnestic MCI, multidomain NO: Non-amnestic MCI, single domain (after Winblad, 2004)

When viewed in this way, dementia, MCI, and Table 2. Key characteristics of cognitive aging, cognitive aging do not lie on a continuum MCI and dementia (Table 2). Both dementia and MCI result Symptoms Symptoms due from specific, identifiable pathological Cognitive impair to dementia changes in the brain like, for example, the category independence? pathology? neuritic plaques and neurofibrillary tangles of Cognitive aging No No Alzheimer’s disease. Cognitive aging reflects MCI No Yes Dementia Yes Yes other age-related changes that do not, by themselves, lead to dementia. (after Henderson, 2014)

Stanford ADRC | Page 2 | Supported by the NIH (AG046366) V W Henderson / Mild Cognitive Impairment

MCI due to Alzheimer’s disease support for Alzheimer change. Amyloid can be imaged by an amyloid-PET scan (PET Alzheimer’s disease is the most common stands for positron emission tomography). It cause of dementia. Some researchers now is important to keep in mind that brain refer to Alzheimer’s disease in people without amyloid is a risk factor for Alzheimer’s dementia, although in clinical practice disease, but not everyone with this biomarker Alzheimer’s disease is understood to mean the will go on to develop dementia. presence of dementia. Tau protein biomarkers are usually abnormal A work group established by the National only after amyloid has begun to accumulate in Institute on Aging and the Alzheimer’s the brain. Tau and phospho-tau levels are Association suggests that “MCI due to increased in the spinal fluid. (Phospho-tau is a Alzheimer’s disease” can be diagnosed in the modified form of tau protein, which is more presence of MCI when the medical history, specific — but not completely specific — for physical examination, and laboratory tests fail Alzheimer's disease). Tau-PET imaging may to identify an alternative diagnosis other than show increased amounts of tau in the brain. Alzheimer’s disease (Albert et al., 2011). Like amyloid, phospho-tau accumulates in the Biomarkers of MCI due to Alzheimer’s brain in Alzheimer’s disease, and it is the disease main component of the neurofibrillary tangles. The work group suggested that a diagnosis of Other biomarkers assesses nerve cell injury MCI due to Alzheimer’s disease can be made inferred by brain shrinkage or by reduced with more assurance when spinal fluid tests or brain metabolism. Computed tomography brain imaging tests provide additional (CT) or magnetic resonance imaging (MRI) evidence for Alzheimer changes in the brain scans might show that the volume of the (Albert et al., 2011). These tests are hippocampus or the entire brain is smaller sometimes referred to as biomarkers, a than expected. (The hippocampus and nearby laboratory measurement associated with the brain areas are involved in memory formation, presence of a disease. Several broad and early microscopic changes of Alzheimer’s categories of biomarkers are used to infer disease affect this part of the brain.) Alzheimer pathology in the brain. These are The brain can also be imaged with an FDG- based on amyloid, tau, and nerve cell damage, PET scan, which provides a measure of and they are determined from cerebrospinal metabolism in brain regions commonly fluid measurements and from brain imaging affected by Alzheimer pathology. FDG-PET studies (Albert et al., 2011; Jack et al., 2016). is based on the amount of blood sugar used by Amyloid is an abnormal protein that the brain. (FDG stands for aggregates and accumulates in brains of fluorodeoxyglucose, a sugar-like molecule people with Alzheimer’s disease. It is found that can be labeled with a radioactive tracer.) in the core of the neuritic plaques. A low Tau and structural imaging (CT and MRI level of amyloid in the spinal fluid (the spinal scans) biomarkers can be difficult to interpret fluid surrounds the brain) or a high level of in isolation, because other brain conditions amyloid on a brain scan provides biomarker damage neurons, not just Alzheimer’s disease.

Stanford ADRC | Page 3 | Supported by the NIH (AG046366) V W Henderson / Mild Cognitive Impairment

Assessment and treatment physician should consider the possibility of depression and look for evidence of anxiety. The evaluation of MCI is similar to the evaluation of dementia but is in some ways Laboratory tests depend on the individual more difficult. There is sometimes no clear circumstances but usually include a screening distinction between cognitive problems due to blood test for kidney, liver, and related MCI and problems due to cognitive aging on metabolic functions; a blood test for thyroid its own. function; and a blood test to determine the Physician evaluation level of vitamin B12. Brain imaging is performed if there is concern for an In most instances, a diagnosis of MCI should underlying brain disorder. Brain imaging with be made or confirmed by a geriatrician, a CT (computed tomography) scan or MRI neurologist, or geriatric psychiatrist. A (magnetic resonance imaging) scan is used to neurologist is best qualified to recognize and evaluate brain structures and to help exclude diagnose early signs of neurological stroke, tumor, and other less common conditions that might cause MCI. neurological causes of cognitive impairment. The physician's assessment includes a careful None of these tests can prove the presence of medical, neurological, and psychiatric history; early Alzheimer's disease. a family history to see whether close family Specialized biomarker testing (spinal fluid members have a similar or related disorder; a tests or PET scan imaging) is usually not general physical examination; and a needed, but it is useful for research can be neurological examination. It is important for considered when the added information may the physician to review prescription and over- change treatment plans. the-counter medications. Many older adults take multiple drugs. A number of these impair Clinical implications mental function. MCI is a worrisome diagnosis, and people The physician should consider the possibility with MCI are at higher risk of dementia than of underlying depression, sleep disorders like someone without MCI. obstructive sleep apnea, excess alcohol Virtually everyone with dementia went consumption, and the presence of stressors through a stage of MCI. However, not that could affect mental abilities. These everyone with MCI goes on to develop stressors might include work or financial dementia. In a community setting, roughly problems, adjusting to retirement, marital 6% to 10% of older people with MCI develop problems, aging parents, difficult teenage and dementia each year. Some people with MCI adult children, and many more. are later reclassified as normal.

The physician’s evaluation includes tests of At one time it was thought that amnestic memory and other cognitive abilities. These forms of MCI would likely lead to can be supplemented when needed by more Alzheimer’s disease, whereas forms of MCI detailed testing by a neuropsychologist. The without memory impairment would more likely lead to dementia due to vascular disease

Stanford ADRC | Page 4 | Supported by the NIH (AG046366) V W Henderson / Mild Cognitive Impairment or some other disorder. However, Alzheimer and board games, and reading. There is no changes may underlie most cases of MCI evidence that one form of mental stimulation regardless of whether MCI is amnestic or non- — such as a set of computerized tasks — is amnestic. Conversely, some patients with better than another. amnestic MCI will turn out to have other dementia pathologies. References Treatment Albert, M.A., DeKosky, S.T., Dickson, D., et al. (2011) The diagnosis of mild cognitive impairment due to The treatment of MCI depends on the Alzheimer’s disease. Alzheimers Dement. 7, 270- underlying cause. There are specific 279. treatments for disorders like depression, Henderson, V.W. (2014) Three midlife strategies to prevent cognitive impairment due to Alzheimer’s obstructive sleep apnea, and thyroid disease. disease. Climacteric 17 (suppl. 2), 38-46. Medication regimens can often be simplified Henderson, V.W. and Kerchner, G.A. (2014) or changed in ways less likely to affect Alzheimer's disease. Reference Module in cognition. Factors that increase the risk of Biomedical Sciences. Elsevier. doi: 10.1016/B978- 0-12-801238-3.00017-9. stroke — like hypertension, diabetes, and high blood cholesterol — can be treated, and there Jack, C.R. Jr., Bennett, D. A., Blennow, K., et al. (2016) A/T/N: an unbiased descriptive classification are programs for cigarette smoking cessation. scheme for Alzheimer disease biomarkers. Neurology, 87, 539-547. There are no known effective drugs for MCI Petersen, R.C., Smith, G.E., Waring, S.C., et al. (1999) when the underlying cause is early changes of Mild cognitive impairment: clinical characterization Alzheimer’s disease or another and outcome. Arch. Neurol. 56, 303-308. neurodegenerative brain disorder. Drugs Winblad, B. Palmerm K. Kivipelto, M., et al. (2004) approved for treatment of dementia in Mild cognitive impairment. Beyond controversies, towards a consensus: report of the International Alzheimer’s disease have not been shown to Working Group on Mild Cognitive Impairment. J. lower the risk of future dementia, and there is Intern. Med. 256, 240-246. usually no improvement in cognitive symptoms. Resources Many physicians recommend regular physical Alzheimer’s Association exercise, mental stimulation, social www.alz.org engagement, and good nutrition for people National Institute on Aging, Alzheimer's with MCI. There is circumstantial evidence, Disease Centers but no proof, that these might help maintain https://www.nia.nih.gov/research/dn/alzheime cognitive abilities. If health permits, one rs-disease-centers target goal for aerobic exercise is brisk National Institute on Aging, Alzheimer's walking, about 150 minutes each week, disease information resources divided into periods of about 30 minutes each, www.nihttps://www.nia.nih.gov/health/alzhei five days a week. mers National Institute on Aging, Alzheimer's Mental activity is potentially important. disease fact sheet People obtain mental stimulation through www.nia.nih.gov/alzheimers/publication/alzhe social interactions inside and outside the imers-disease-fact-sheet home, hobbies, computer tasks, card games

Stanford ADRC | Page 5 | Supported by the NIH (AG046366) V W Henderson / Mild Cognitive Impairment

Stanford Alzheimer’s Disease Research Center adrc.stanford.edu Stanford Center for Memory Disorders https://stanfordhealthcare.org/medical- clinics/memory-disorders-center.html Stanford Health Care Aging Adult Services https://stanfordhealthcare.org/medical- clinics/aging-adult-services.html

© 2017 by Victor W. Henderson; all rights reserved. The author gives readers permission to download single copies for nonexclusive, noncommercial use.

Stanford ADRC | Page 6 | Supported by the NIH (AG046366)