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The definition of the mild cognitive impairment (MCI) stage in Alzheimer's disease (AD) was originally developed by the National Institute on Aging (NIA) and the Alzheimer’s Association (AA) in 2011. Since then, the concept has been extensively used worldwide, both in clinical and research settings.2-4
To establish MCI due to AD diagnosis the following is recommended:4-6
Patient History and Differential Diagnosis7,8
It is important to identify comorbid medical conditions and reversible or transient causes of MCI.
Documentation of Complete Patient Medical History
Including current symptoms described by the patient or the informant (partner, family member, or care partner), past medical conditions, medication, and family history to be able to identify risk factors.
- Causes of Transient MCI
- E.g., sleep apnea, drug use, adverse drug reactions as seen for example with anticholinergic, antipsychotics or sedative drugs, or trauma after anesthesia (post-operative).
Laboratory Tests
Including (but not limited to) to complete blood cell count, blood glucose, thyroid-stimulating hormone, estrogen, serum B12 and folate, serum electrolytes, liver function and renal function tests and urinalysis.
- Causes of Transient MCI
- E.g., urinary tract infection, vitamin B12 and/or folate deficiency, hormonal abnormalities (thyroid, estrogen), or metabolic disorders (dehydration, renal, hepatic).
Physical Exam and Neuroimaging
Including (but not limited to) routine tests to check overall health, neurological exam, structural MRI, or CT.
- MCI Differential Diagnosis
- E.g., depression, ischemic brain disease, multiple-infarct stroke, infection, tumor pathology, vascular dementia or other neurodegenerative disorders.
Assessment of Clinical Criteria for MCI
MCI identifies a spectrum of symptoms that includes impairment in both memory and non-memory cognitive domains. When assessing MCI from a clinical perspective, it is important to quantify the severity of the symptoms as well as objectively assessing the nature of the cognitive complaint.11
The following four criteria are used to clinically define MCI:4,11
1. Subjective Cognitive Complaint
The patient, the informant (relative) and/or the clinician observe subtle intraindividual (vs. previous individual state) problems with memory, cognitive function or mild behavioral changes. The term used for such early signs is subjective cognitive decline (SCD) which is detected via so called "informant-based assessments”.12,13 These types of complaints or subtle problems are the trigger for using cognitive assessment tools.5
- Examples of Subjective Assessment Tools
- AD8 The AD8 is the Eight-item Interview to Differentiate Ageing and Dementia with better utility in mildly impaired individuals.14 QDRS The Quick Dementia Rating System was validated to identify and stage individuals in clinical practice covering prominent symptoms of MCI including cognitive, behavioral, and functional domains.15 M@T The Memory Alteration Test discriminates between subjective memory complaints, MCI and AD.16 SCD-Q The Subjective Cognitive Decline Questionnaire may be able to predict amyloid PET outcome.18,19
2. Objective Evidence of Impairment in 1 or More Cognitive Domains
As opposed to informant-based assessments, the objective confirmation of cognitive impairment relies on interindividual age norms and consists of "performance-based assessments" which are administered by the HCP to detect cognitive changes.
Due to the heterogeneous clinical presentation of MCI it is important to do a multidomain cognitive assessment. The main cognitive domains taken into account for early detection of MCI are memory, executive function, attention, language, and visuospatial function.3 Existing screening instruments are insufficient to make a diagnosis but are important to isolate domains of impairment and to advise the physician on further assessments.20
- Examples of Objective Assessment Tools
- MMSE and MoCA The Mini-Mental Status Examination and the Montreal Cognitive Assessment are two popular short multiple domain screening tools used across Europe for assessment of cognitive impairment. MoCA is recommended for differentiating more subtle changes of MCI.21-24 MIS The Memory Impairment Screen is a broadly used screening tool focusing on the amnestic domain, as episodic memory is one of the first affected domains in MCI and has been associated with a higher risk of progressing to AD dementia.11,25,26
An optimal screening approach is to combine performance, informant, and self-reports to improve diagnostic accuracy. Such a combined assessment is less affected by education, age, and gender than objective performance assessment alone.27-29
- Example of a Combined Assessment Tool
- GPCOG The General Practitioner assessment of Cognition (GPCOG) is an optimal screening tool combining subjective and objective evidence of cognitive decline.30
3. Essentially Normal Functional Activities
Cognitive decline doesn't interfere with a patient’s ability to carry out independently basic activities of daily living (ADL), like for example bathing.31 Instrumental activities of daily living (IADL) are either intact or minimally affected.11 IADL measures how someone can take care of themselves and their home and includes more complex planning and thinking.32
4. Absence of Dementia
Individuals who are still independent in their ADL will be classified as "not demented".
Assessment of the Underlying AD Pathology
Confirmation of amyloid beta (Aβ) pathology is a critical component of MCI due to AD diagnosis and assists in ruling out cognitive decline due to other neurological conditions.6
There are two methods for confirming Aβ accumulation in the brain:37
Evidence of Amyloid Beta (Aβ) Accumulation
- Cerebrospinal fluid (CSF) testing: Decreased CSF levels of Aβ due to reduced clearance from the brain measured via immunoassay (CSF Aβ42 or CSF Aβ42/Aβ40 ratio).
- Neuroimaging: Accumulated brain Aβ measured via positron emission tomography (amyloid PET).
CSF Aβ42 levels and CSF Aβ42 ratios (Aβ42/Aβ40, p-tau/Aβ42, t-tau/Aβ42) show strong concordance with amyloid PET results, making both methods reasonable for clinical diagnostics.37,38
Other Biomarkers of AD Pathology
The accumulation of Aβ is believed to promote the abnormal phosphorylation of tau protein, which leads to the formation of neurofibrillary tangles within neurons causing neuronal injury and synaptic dysfunction.36
For this reason, measuring biomarkers of downstream neurodegenerative processes, such as phosphorylated tau (p-tau) or total tau (t-tau) will strengthen diagnosis and help predict clinical decline and the risk of conversion from MCI to dementia stages. For pure amnestic AD phenotype measuring tau pathology is also recommended as in this case amyloid positivity alone is not specific for AD.6
Aggregated and phosphorylated tau is a marker for the neurofibrillary tangle pathology in the brain while t-tau reflects the intensity of neuronal and axonal degeneration in general.6,36
Evidence of Neurofibrillary Tangle Formation (p-Tau)
- Cerebrospinal fluid (CSF) testing: Increased levels of CSF p-tau.
- Neuroimaging: Accumulated tau measured via positron emission tomography (tau PET).
Evidence of Neurodegeneration
- Cerebrospinal fluid (CSF) testing: Increased levels of CSF t-tau.
- Neuroimaging: Brain hypometabolism measured via positron emission tomography (FDG PET).
- Neuroimaging: Hippocampal atrophy measured via structural magnetic resonance imaging (anatomic MRI).
A Selection of Validated Short Screening Tools for Detection of MCI Used in Clinical Setting to Assess Cognitive, Functional, and Behavioural Decline
Objective Performance Assessment
MMSE (~10 min)22
MoCA (~10 min)23
MIS (only aMCI, ~5 min)25
Combined Assessment (Objective & Subjective)
GPCOG (~4 min)30
Subjective Self- or Informant Reports
SCD-Q (3-5 min)18
M@T (only aMCI, 5 min)17
Subjective Self- or Informant Reports
ADL (~10 min)31
IADL (~10 min)32
Subjective Self-or Informant Reports
AD8 (2-3 min)35
QDRS (3-5 min)15
Subjective Self- or Informant Reports
NPI-Q (~5 min)39,40
MBI-C (~5-7 min)33
GDS (~5-10 min)34
Screening tools with increased sensitivity in mildly impaired individuals.
There is no gold standard to specify which neuropsychological test battery to use, but it is important that all the main cognitive areas are examined. Typically, memory, executive function, attention, language and visuospatial function are taken into account for early detection of MCI.3
Additionally, MBI (Mild Behavioural Impairment) symptoms are considered early indicators of cognitive decline and may indicate the emergence of impactful neuropsychiatric symptoms (NPS) at age 50 and above. The MBI-Checklist (MBI-C) is a measure specifically developed to assess mild behavioral impairment.33 As depression is a root cause of cognitive decline, early detection of depression is important. There are several brief scales available, as for example the Neuropsychiatric Inventory Questionnaire (NPI-Q)39,40, or the Geriatric Depression Scale (GDS). 27,34
Major AD biomarkers become abnormal in a temporally ordered manner through the Alzheimer’s Disease Continuum.1
Timely diagnosis of Alzheimer's disease at the MCI stage can potentially shorten the patient journey and enable optimal medical management. By improving quality of care, the risk of disease progression and conversion to AD dementia stages may be reduced. These benefits emphasize the important role of physicians in discussing brain health with patients and monitoring for early signs and symptoms of AD.9,10
WHATS NEXT
Benefits of Early Alzheimer’s Disease Diagnosis
A timely and accurate diagnosis of MCI due to AD can help patients preserve their independence for as long as possible.
References
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