A Multifactor Approach to Mild Cognitive Impairment

Taha Qarni, BHSc; Arash Salardini, MD


Semin Neurol. 2019;39(2):179-187. 

In This Article

Different Ways of Classifying Mild Cognitive Impairment

Neuropsychological Classification

The most common pathology underlying the progression of MCI to dementia is AD. The most common presentation of Alzheimer's pathology is episodic memory deficits. Therefore, it is often convenient to divide MCI into amnestic and nonamnestic MCI. The former is unsurprisingly two times more common than the nonamnestic type.[29] Another consideration in the classification of MCI is whether only a singular cognitive domain or multiple domains are affected. These are termed single-domain and multidomain, respectively. Multidomain MCIs suggest a more aggressive course of disease compared with single domain.

A more sophisticated approach will supply additional information about the deficits. For example, such an approach may specify whether MCI follows a cortical or subcortical pattern, whether it may be an early presentation of a well-known neuropsychological syndrome such as Balint's syndrome or logopenia, or it may simply list the domains that are affected.

Biomarker Classification

Presently, AD is best understood in terms of the clinical significance of biomarkers among all neurodegenerative diseases.[1,19] The current AD biomarker system is the "ATN" system, which stands for amyloid, tau, and neurodegeneration. This system is a binary system where someone is, for example, either amyloid positive or negative. Amyloid status may be gauged by either a positive amyloid positron emission tomography (PET) scan or low amyloid 42 level in the cerebrospinal fluid (CSF). Abeta42 is normalized in reference to other species of amyloid such as Abeta40, or total tau. Tau imaging has progressed in the recent years, but presently CSF is the only way to measure tau levels in the clinic. Phosphorylated tau is the species of tau which is of interest in this context and is measured directly in CSF assays. There are several ways in which neurodegeneration may be measured; for example, total tau may be a measure of neurodegeneration, magnetic resonance imaging (MRI) evidence of atrophy (especially in the medial parts of the temporal lobe) may indicate neurodegeneration, and focal changes in glucose metabolism as measured by fluorodeoxyglucose-PET can also represent neurodegeneration.

In 2018, the National Institute of Aging and Alzheimer's Association released a research framework for biomarkers which include MCI. The framework uses the following logic:[30]

a. MCI without amyloid is not likely to be due to Alzheimer's pathology. Some of the nomenclatures used are as follows:

  1. If all biomarkers are negative, then the recommended term is "normal Alzheimer's biomarkers."

  2. If one or both other biomarkers are positive, then the recommended term is "non-Alzheimer's pathologic change."

b. MCI with amyloid is likely to progress to Alzheimer's dementia in time. The following language is used for this group of patients:

  1. If amyloid is the only positive biomarker, then this is called "Alzheimer's pathologic change."

  2. If amyloid and tau are both positive, then the term "AD" may be used.

  3. If amyloid and neurodegeneration are both positive but tau is negative, then the recommended designation is "Alzheimer's and concomitant suspected non-Alzheimer pathologic change."

A future, more sophisticated system, will use values for A, T, and N as continuous variables rather than dichotomously categorical (positive vs. negative) as they are reported currently. Also, it is highly likely that the alternative methods of measuring each biomarker may not be equivalent. For example, amyloid PET may represent a different physiological aspect of amyloid pathology compared with the CSF measurement of amyloid β levels. Finally, there is a recent realization that, especially with increasing age, different dementing pathologies coexist and act synergistically; perhaps a future classification will also include synuclein, different forms of tau, and/or vascular pathology.

Pathological Classification

MCI may also be classified according to the type of dementia it will convert to in time. This is most commonly AD, as previously mentioned. For example, a patient may be said to have MCI due to Alzheimer's pathology. The concept of MCI is most useful in relation to AD, but there has been some effort to expand the scope of MCI to better suit other forms of dementias. In particular, there has been some effort to include Parkinson's disease dementia (PDD) and VCI.

a. AD-MCI: AD-MCI is the prototypic MCI which often presents as the amnestic form of MCI. Since the diagnostic certainty in AD-MCI varies from one individual to another, AD-MCI may be further subclassified by diagnostic certainty based on the patient's biomarker status.[1] This has now been superseded by the National Institute on Aging-AA framework.

b. PDD-MCI: The prevalence of MCI in Parkinson's disease is approximately 20 to 50% depending on the definitions or instruments used to make the diagnosis. The risk of PDD-MCI is higher in the akinetic-rigid form of PD, and increases with age, worsening motor symptoms, and lower educational attainment.[31,32] MoCA testing may be used in screening for this condition. However, much less is known about this entity than its AD counterpart. PDD-MCI is surprisingly heterogeneous in severity, progression, and cognitive domains involved.[33] The CamPaIGN study examined the heterogeneity of PDD and found two phenotypes: one was a subcortical type which affected mostly the fronto-subcortical circuitry and affected frontal-executive functions.[34] This phenotype was associated with dopamine depletion and was affected by the catechol-O-methyltransferase genotype. The second phenotype affects the posterior cortical functions, especially language and visuospatial function, and is associated with ApoE4 positivity. The former type interacts with VCI. The later interacts with AD.[35,36] The present definitions for PDD-MCI as promulgated by the Movement Disorders Society, for example, appear to rely on the following basic concepts:[37]

  1. Presence of PD.

  2. Presence of cognitive difficulties either discovered on neuropsychological testing or screening testing. However, the cut-offs to be used and the differential effects on the different cognitive domains are not included in the criteria.

c. VCI: VCI is a term that is used broadly for vascular pathology causing cognitive deficits, but which more specifically refers to MCI caused by vascular pathology. It is the latter usage that we adopt. VCI comes in two flavors, which may be thought of as large vessel involvement (i.e., strokes) versus small vessel involvement.[38] The two may often coexist.

Strokes that affect cognition either affect large parts of the cortex (poststroke or multi-infarct dementia) or target important central nodes in brain networks (strategic infarct dementia). For both of these, the cognitive problems have a temporal relationship to individual stroke episodes, and the type of cognitive deficits is consistent with the localization of the stroke. The consequences of these are well understood in classical neurology. In fact, much of our understanding of localization of cognition in the brain comes from studies of stroke patients and their neuropsychological deficits.[39]

VCI due to small vessel disease is more difficult to diagnose. For one thing, it causes subcortical cognitive dysfunction. Subcortical functions deteriorate in a much more graded manner than cortical functions. For example, people with small vessel VCI will have difficulty with producing words starting with a particular letter. However, this slowing happens in a graded manner depending on the degree of damage. Second, there are no reliable biomarkers for VCI. The lesions associated with VCI include (but are not limited to): enlarged perivascular spaces, lacunar infarcts, microhemorrhages/superficial siderosis, white matter hyperintensities, and diffusion restriction on diffusion-weighted imaging (DWI) MRI. None of these—in isolation or in combination—predict cognitive outcomes well.[40] The best we may be able to do is instead to take the imaging markers not as biomarkers for the severity of VCI, but as indicators of the presence of vascular disease. If the cognitive deficits are then consistent with VCI and other explanations are ruled out, then the likely culprit is VCI. The typical symptoms belong to all subcortical dementias and include reduced speed of mentation, problems with complex attention and multitasking, problems with retrieval of information, problems with initiation, gait apraxia, urinary urgency, and affective problems (either apathy or depression).[41]