Mild cognitive impairment: How can you be sure?

• hippocampal atrophy¹³
  
• reduced metabolism in the temporoparietal cortex and posterior cingulum¹⁴
  
• elevated CSF tau and the 42 amino acid form of ß-amyloid (Aß 42).¹⁵
  

Research techniques such as structural neuroimaging, positron-emission tomography, functional magnetic resonance imaging (fMRI), and cerebrospinal fluid biomarkers have not been defined for clinical use, however.

Neuropsychiatric symptoms. Individuals with MCI and neuropsychiatric symptoms may be at particular risk for progressing to dementia. Agitation or depression are more prevalent in persons with MCI than in normal elderly but less prevalent than in those with dementia (Table 3).^10,16

The cross-sectional, community-based Cardiovascular Health Study showed one or more neuropsychiatric symptom in:

• 16% of normal healthy elderly
  
• 43% of MCI patients
  
• 75% of dementia patients.¹⁶
  

Depression (20%), apathy (15%), and irritability (15%) were the neuropsychiatric symptoms reported most frequently in MCI patients, compared with apathy (36%), depression (32%), and agitation/aggression (30%) in dementia patients.

Sleep disturbances and anxiety in persons with MCI may predict progression to AD.¹⁰ A baseline high frequency of apathy in aMCI patients has been associated with progression to AD within 1 year.¹¹

Table 1

Amnestic MCI: Proposed diagnostic criteria

Subjective memory impairment, preferably corroborated by a reliable informant
Reduced performance on objective memory tests, compared with persons of similar age and educational background
Typical general cognitive function
Intact basic activities of daily living and intact or minimally impaired instrumental activities of daily living
Absence of dementia
MCI: mild cognitive impairment
Source: Reference 8

Table 2

Factors shown to predict conversion from MCI to dementia

Category	Predictors of conversion
Clinical	Cognitive: Amnestic MCI Neuropsychiatric: Depression, apathy, and possibly nighttime behaviors and anxiety
Neuropsychological tests	Clock-drawing test, Trail-Making Test B, Symbol Digit Modalities Test, Delayed 10-Word List Recall, New York University Paragraph Recall Test (Delayed), ADAS-Cog total score
Neuroimaging	MRI: Entorhinal cortex and hippocampal atrophy PET: Medial temporal region, parietotemporal association cortex, and posterior cingulate hypometabolism fMRI: Abnormal hippocampal, posterior cingulate, and medial temporal region activation on memory tasks
CSF markers	Increase: t-tau, p-tau Decrease: Aß 42
Genetic markers	ApoE e4 carriers
ADAS-Cog: Alzheimer’s Disease Assessment Scale-Cognitive subscale; ApoE e4: apolipoprotein E gene, e4 allele; CSF: cerebrospinal fluid; MCI: mild cognitive impairment; MRI: magnetic resonance imaging; fMRI: functional MRI; PET: positron-emission tomography
Source: References 7,9-15

Table 3

Neuropsychiatric symptoms: Rising prevalence mirrors cognitive deterioration in elderly patients*

Neuropsychiatric symptoms	Normal elderly	MCI	Mild AD
Depressed mood/dysphoria	+	++	+++
Nighttime behaviors/sleep	+	++	+++
Irritability	+	++	+++
Anxiety	+/-	++	+++
Apathy/indifference	+/-	++	+++
Agitation/aggression	+/-	+/++	+++
Eating/appetite disturbance	+/-	+	++
Disinhibition	+/-	+/-	++
Aberrant motor behavior	0	+	++
Delusions	0	+/-	++
Euphoria	0	+/-	+/-
Hallucinations	0	0	+
* 0 = 0%; +/- = 1% to 5%; + = 6% to 10%; ++ = 11% to 20%; +++ = 21% to 40%
MCI: mild cognitive impairment; AD: Alzheimer’s disease
Source: References 10,16

Depression and MCI

Depression and cognitive complaints overlap considerably in older adults. Depressed patients without dementia show persistent cognitive deficits even after depression remits. In some patients, new-onset geriatric depression is considered a prodrome of MCI and AD. Given that AD neuropathologic changes precede clinical symptoms by many years, depression and AD have been proposed as different clinical manifestations of AD pathology.¹⁷

Among patients with MCI, 20% meet criteria for major depression and 26% for minor depression. Symptoms often include sadness, poor concentration, inner tension, pessimistic thoughts, lassitude, and insomnia.¹⁸

Depressed MCI patients are at higher risk of developing dementia than those without depression, especially if cognitive measures do not improve after depression is treated.¹² Similarly, cognitively intact older persons who develop depression are at increased risk for MCI, particularly if they carry the ApoE e4 genotype.¹⁹

In the only study in which MCI patients’ neuropsychiatric symptoms have been treated, 39 elderly patients with depression and MCI received open-label sertraline, ≤200 mg/d, for 12 weeks. Among the 26 patients who completed the trial, 17 showed moderate improvement in depressive symptoms, attention, and executive function, and 9 showed no response.²⁰

Recommendation. In clinical practice, antidepressant treatment—usually a selective serotonin reuptake inhibitor (SSRI), with or without psychotherapy—is recommended for the MCI patient with comorbid major depression.

CASE CONTINUED: No signs of depression

Mr. R’s medical, neurologic, and substance use history is unremarkable. Family history includes AD in a paternal aunt diagnosed at age 82. Mr. R reports no history of mood, sleep, or appetite changes and no psychotic symptoms. He shows no deficits in activities of daily living (ADL), although his wife recently took over paying household bills after he forgot to make a payment.

Evidence-based workup

Functional assessment. In the differential diagnosis of MCI, give special attention to functional impairment, which points toward dementia. ADL generally are preserved in MCI, and minimal deterioration is seen in instrumental activities of daily living (IADL). A relatively easy way to assess function is to use the Alzheimer’s Disease Functional Assessment and Change Scale (ADFACS), which is based on 16 ADL and IADL items (Table 4).²¹