Diagnosis and Treatment of Mild Cognitive Impairment

Introduction

Mild cognitive impairment (MCI) is an emerging term for an intermediate stage between cognitive changes of normal aging and dementia in elderly people. While normal aging is a gradual decline in cognition, MCI refers to cognitive impairment beyond that expected for age and education, but does not meet criteria for dementia.¹ As the population ages and longevity increases, physicians will increasingly see patients experiencing memory loss, so learning an approach to states such as MCI is now warranted. Primary care physicians should be aware that dementia is preceded by a recognizable phase of MCI. They should be familiar with the concept of MCI and other similarly used terms, including cognitive impairment, not dementia (CIND). Physicians should closely monitor patients with MCI because of their increased risk of developing dementia.

Definition

The diagnostic term mild cognitive impairment refers to early, nondisabling cognitive disorders that do not meet the criteria for dementia. Although many researchers proposed a variety of criteria, the Mayo criteria are the ones most applied in the literature^2,3:

• Self-reported memory complaint, preferably corroborated by an informant
• Objective memory impairment • Preserved general cognitive function
• Intact activities of daily living (ADL) with minimal impairment in instrumental functions
• Not meeting criteria for dementia

Making the distinction between normal impairments of aging and impairments that do not represent dementia requires considerable clinical judgment that may differ among assessors.⁴ Challenges remain for lack of a uniform quantitative or systematic definition of functional impairment. The Clinical Dementia Rating (CDR) scale5 has been used in research studies and has proven to be a valuable instrument for the definition of functional impairment; however, for practical clinical application, it is too time-consuming.

Subclassifications

MCI is now recognized as heterogeneous with three accepted subclasses: (1) amnestic MCI; (2) multiple-domain MCI; (3) and single nonmemory domain MCI.⁶ Each MCI subtype can then be classified according to the presumed etiology: degenerative; vascular; psychiatric; or traumatic.

Amnestic MCI refers to the monosymptomatic amnestic form and is often used for those individuals presumed to have a MCI of degenerative etiology. Memory impairments are generally represented by defects that are 1.5 standard deviations (SD) or more below age- and education-corrected norms. Amnestic MCI is the subtype most specifically correlated with Alzheimer’s disease (AD) and is used to define a “predementia” state amenable to therapeutic interventions. The efficacy of such interventions is defined by the rate of conversion from MCI to dementia.⁴

Multiple-domain MCI refers to patients with impairment in multiple domains of cognitive and behavioral functioning with and without memory impairment. The multiple domains are only slightly impaired, no more than 0.5 SD below age- and education-matched normal subjects. Patients may manifest subtle problems with ADL but do not meet the criteria for a formal diagnosis of dementia. Patients with multiple-domain MCI may progress to AD or vascular dementia (VaD), or revert to a baseline functioning over time.⁷

Single nonmemory domain MCI refers to the monosymptomatic impairment other than memory loss. Examples include anomia (word-finding difficulties), impairment in executive functioning, visual-spatial deficits, or apraxia (impaired ability to carry out motor activities despite intact motor function).⁶ Patients with this type of MCI may progress to frontotemporal dementia (FTD), primary progressive aphasia (PPA), or dementia with Lewy bodies (DLB).

Epidemiology

Approximately 12% of those over age 70 years have MCI, as suggested by one Mayo Clinic study, and are three to four times more likely to develop AD. In recent years, severe cognitive impairment in the form of dementia declined in the elderly U.S. population. From 1982-1999 there were 310,000 fewer cases of dementia, with the decline being more marked in men than in women. Possible explanations include improved medical therapies, better education among the elderly, and a decline of VaD from overall decline in strokes.⁸

Findings from epidemiological studies vary, primarily from use of different diagnostic criteria, measuring instruments, and definitions. Nevertheless, among individuals over age 75, the incidence of MCI from prospective community-based studies was 5% annually⁹ and 13.7 per 1000.¹⁰

The prevalence of MCI ranges from 4.6% to 28.3% in elderly U.S. cohorts. Further, there is a higher prevalence of MCI in older and less-educated participants; and such findings were similar to those in European cohorts.¹¹ Gender and race are inconsistently associated with MCI in various studies; one study concluded that men and women have different risk profiles for MCI. For men, the risk factors seem linked much more to physical health (diabetes, stroke, higher body mass index), and stroke was the most significant risk factor, increasing the chances of progression of MCI to dementia. Women were more likely to have poor subjective health, and depression impacted them more than men. Based on these results, interventions should focus principally on risk of stroke in men, and depressive symptomatology and use of anticholinergic medications in women.¹²

Risk Factors

Risk factors for MCI are listed in Table I and include head trauma and hypertension.

Head Trauma
In a study of professional football players, cerebral concussions were found to be related to the development of MCI in later life. Retired professional players with three or more concussions during their years in the National Football League were five times more likely to develop MCI than those without concussions.¹³

Age and Fewer Years of Education
Odds of developing MCI are increased in those over age 75 years, primarily in individuals with low educational levels.¹⁴ Age affects all transitions, from cognitively normal to various forms of MCI, as well as transition from MCI to dementia or death.¹⁵

Change in Apolipoprotein E Epsilon 4 Gene
In a recent study by Tyas et al,¹⁴ the presence of an apolipoprotein E (APOE) gene e4 allele in women increased the odds of developing MCI more than fourfold by age 95.

Hypertension
Association between hypertension and the risk of dementia, including AD, varies with age. At younger ages (age 65-74 yr), high systolic and borderline-high diastolic pressures were associated with greater risk of all-cause dementia. At very advanced ages, an inverse association between blood pressure and dementia risk was noted. The combination of hypertension-induced arteriolar narrowing and later-sustained hypoperfusion promotes the expression of dementia. Midlife hypertension has been found to be associated with pathological hallmarks of AD, cortical and hippocampal neuritic plaques, neurofibrillary tangles, and hippocampal atrophy.¹⁶

Obesity
Obesity at midlife is associated with risk of dementia and AD. When hypertension and hyperlipidemia are added, the risk increases in an additive fashion.⁸

Diabetes
Diabetes is a risk factor for cognitive impairment and VaD but does not predispose patients to AD.⁸

Low Levels of Physical, Social, and Mental Activity
Cortical atrophy is more likely to occur if the brain is not used in a challenging way on a regular basis. A Swedish study of AD in twins demonstrated that the greater the complexity of work, particularly with people, the lower the risk of AD.¹⁷

History of Depression
Rapp et al¹⁸ reported that a lifetime history of depression is associated with increased plaques and tangles in the brain hippocampus, and is a marker of AD and cognitive decline.

Conversion to Dementia

Individuals with MCI have a 3.1 times higher risk of developing AD than the group with no cognitive impairment. Longitudinal studies of patients with MCI showed a conversion rate to dementia of 10-15% per year.¹⁹ Half of the patients with MCI will meet the criteria for dementia, particularly AD, after five years. The interval between a diagnosis of MCI and conversion to dementia may be as long as eight years, but after ten years, most will have a dementia syndrome.⁶

Approximately 20% of the patients with MCI never develop any type of dementia, remaining stable or reverting to baseline. One study in France showed that changing the risk factors for stroke in men and treating depression in women may have had a contribution in those with MCI who returned to normal.¹² Histopathologic findings at autopsy were consistent with AD in approximately 80% of patients diagnosed initially with MCI; other findings at autopsy were consistent with VaD, FTD, normal aging, or less common disease.⁶ Amnestic MCI has been linked to AD, while nonamnestic MCI may progress to other types, such as FTD, PPA, or DLB.

Parkinsonian gait and bradykinesia are predictors of conversion from MCI to AD, as these individuals have significantly inferior levels of motor performance. However, gender and education level are not predictors of conversion. An equivocal predictor is socioeconomic status. With every year of age increase after 50 years, MCI is slightly more likely to convert to AD.

Neuropsychological testing may be helpful in defining individuals at risk for dementia. More severely affected patients are at greater risk, and specific test measures, as well as instrumental ADL, have been found to have high predictive value for dementia. Follow-up testing provides helpful information, in that a decline in cognitive measures is a necessary but not sufficient predictor of dementia (good negative predictive value [90%] but poor positive predictive value [30%]).²⁰

Farlow et al²¹ found that patients with MCI carrying the APOE e4 allele had a greater degree of cognitive impairment and hippocampal atrophy on magnetic resonance imaging (MRI) as compared with noncarriers, and APOE e4 was found to be a strong predictor for conversion from MCI to AD.¹⁹

Neuroimaging longitudinal studies indicate that hippocampal atrophy on baseline volumetric MRI and widespread neocortical atrophy may be the best predictors of progression from MCI to AD. Most studies show that the hippocampus has higher annual rates of atrophy in participants with MCI that will soon progress to AD (pMCI) than in participants who show functional stability over time to follow-up (sMCI). Estimates of annualized hippocampal atrophy in pMCI are approximately 3.7% versus 2.5-2.8% in sMCI.²²

Similarly, diffusion-weighted imaging (DWI) studies indicated that apparent diffusion coefficient (ADC), which reflects neuronal loss of the hippocampus and corpus callosum, is greater in individuals with MCI who soon progress to AD.²²

Pathology

Studies have been done to determine the neuropathologic features of patients who died while their clinical classification was MCI. One study examined the extent of intermediate levels of AD pathology, cerebral infarcts, and DLB in a total of 180 Catholic clergy who died at a mean age of 76 years. Of these, 37 subjects had MCI, 83 had dementia, and 60 had no cognitive impairment. The majority of the MCI group (49.2%) had an intermediate level of AD pathology as compared with the other groups. Cerebral infarctions were present in 35.2%, and 15.6% had DLB.²³

Similarly, the neuropathologic features of amnestic MCI in another study were examined.²⁴ The study consisted of 15 patients, and their brains demonstrated intermediate levels of neurofibrillary changes that were between normal aging brain tissue and very early AD. These pathologic changes all involved the medial temporal lobe structures.

In another research trial, the neuropathologic outcome was examined in individuals with known MCI that had progressed to dementia. The most consistent neuropathologic finding was AD at a high frequency. Other findings also included VaD and DLB. Notably, amnestic versus multi-domain MCI did not predict those who developed AD versus other dementias.²⁵

Symptoms

Normal aging is associated with minor forgetfulness such as misplacing car keys, losing the car in the parking garage, or inability to remember the name of a former co-worker when met unexpectedly at the grocery store. Red flags should go up when individuals start forgetting things that they should typically remember, such as doctor appointments, weekly games, and important occasions, with a pattern developing.

Patients with MCI complain primarily of impaired memory, in contrast to unawareness of deficits commonly present in patients with AD, and they often are troubled by their symptoms. Over time, when they convert to AD there is a preponderance of informant over self-reported symptoms of increasing difficulty concentrating, completing tasks, and making decisions.

MCI involves memory loss and/or loss of cognitive functioning. The type of cognitive loss varies with the individual, as some may lose language skills first, while others may decline in executive functioning or learning abilities.

MCI is very difficult to diagnose in the primary care setting because of the subtlety of its symptoms and the hurried nature of most patient encounters with physicians.⁸ Behavioral symptoms are common in patients with MCI, with 32-75% experiencing them. The most common symptoms are depression, apathy, anxiety, and irritability. Patients with MCI with behavioral features are more prone to develop AD than are patients without these features.²⁶ Depression alone can produce symptoms and signs of cognitive impairment, particularly in elderly patients; this is a phenomenon called “depressive pseudodementia.”

In 2002, Lyketsos et al²⁷ published a study about prevalence of neuropsychiatric symptoms in patients with MCI using the Neuropsychiatric Inventory (NPI). Authors concluded that 43% exhibited symptoms in the month prior to evaluation, and 11% reported agitation and aggression.

Differential Diagnosis

The differential diagnosis for MCI is listed in Table II and includes psychiatric disease (depression) and adverse effects of medications (analgesics, anticholinergics, psychotropics, sedative-hypnotics).

Evaluation

Evaluation of patients with cognitive problems should focus first on ruling out treatable conditions, then on establishing the severity of impairments and a baseline for follow-up.

Initial interview with patient, spouse, or family member should focus on the history of cognitive and behavioral changes, the history of use of drugs that impair cognition, and past medical history of cerebrovascular accident (CVA), head trauma, alcohol abuse, Parkinson’s disease, and depression. Depression in the elderly often presents as “masked depression,” where they present with somatic complaints and are less likely to openly admit to feeling sad. This should be followed by a complete physical examination, with attention to the neurologic examination.

Laboratory testing recommended by the American Academy of Neurology (AAN) is screening for vitamin B₁₂ deficiency and hypothyroidism. Routine laboratory studies such as a complete blood count, electrolytes, glucose, and renal and liver function tests may be ordered. Red blood cell folate should be ordered in patients with ethanol dependence. Screening for neurosyphilis, rapid plasma reagin (RPR), is recommended if there is a high clinical suspicion (Table III).

Neuroimaging studies, such as brain computed tomography (CT) or MRI, are critical in excluding neurodegenerative conditions that can mimic MCI. These include brain neoplasm, subdural hematoma, and normal-pressure hydrocephalus. MRI is preferred and offers better tissue characterization; however, CT is often easier and more rapid to obtain. Results of several volumetric MRI studies corroborate the finding of statistically significant medial temporal lobe (MTL) volume differences between controls and those with MCI. The most common finding is that of attenuated hippocampal volume in MCI. DWI studies indicate that people with MCI show greater ADC values than controls in the hippocampus and corpus callosum.²²

The Quality Standards Subcommittee of the AAN provides practice parameters and guidelines for MCI. Neuropsychological testing (NST) and screening cognitive evaluations are recommended in patients with suspected cognitive impairment.³ NST provides a measure of cognitive impairment, detects depression as a causative factor, and should always be used in connection with clinical judgment. Neuropsychological batteries usually involve extensive evaluation of multiple cognitive domains (attention, orientation, executive function, verbal memory, spatial memory, language, calculations, mental flexibility, and conceptualization) and are considered useful instruments when administered to those at higher risk of memory impairment. NST that emphasizes memory function is most useful. Accepted criteria for diagnosis of MCI using NST is a 1.5 SD threshold value for tests of memory impairment.²⁸ In amnestic MCI, other cognitive domains may be impaired, usually within 0.5 SD. In multiple-domain MCI, several cognitive domains may be impaired in the 0.5 to 1.0 SD range. Once the patient meets the criteria for MCI, follow-up and yearly testing is recommended and helpful, in that evidence of decline can predict progression of MCI.

Other rating scales have been used to define MCI, including the CDR scale and the Mini-Mental State Examination (MMSE)—the most widely used cognitive test. A score of 24 out of 30 on the MMSE and a score of 0.5 on the CDR scale have been used to define MCI. A meta-analysis of 34 dementia and five MCI studies showed that MMSE had a sensitivity of 79.8% and a specificity of 81.3%, and concluded that since MMSE offers modest accuracy (with best value for ruling out a diagnosis of dementia in the community and primary care), it should be used in combination with other methods.²⁹ While time-consuming to administer (requires 60-90 min and a trained healthcare professional), the CDR scale has established validity in following disease progression over time.³⁰

Brief cognitive assessments may be considered as tests for screening for cognitive impairment and should have good performance in populations with various cultural, linguistic, and educational backgrounds. In a retrospective study, the Mini-Cog exam was compared with the MMSE (at a cut point of 25); the Mini-Cog had similar sensitivity (76% vs 79%) and specificity (89% vs 88%) for dementia.³¹ The Clock Drawing Test (asking the patient to draw the face of a clock with a specific time) is a quick examination that appears to correlate well with the MMSE, but it is not a sensitive test for identifying very mild dementia. An informant-based questionnaire of cognitive decline may also provide relevant information regarding the diagnosis and prognosis of MCI.

Prevention

Prevention of cognitive impairment involves diet and exercise, but there is little agreement on the best types of diet and forms of exercise. There are no medications at present that prevent the mild form of cognitive impairment.

A 2004 study published in the Journal of the American Medical Association concluded that a Mediterranean diet combined with not smoking, moderate (1 drink/day) alcohol consumption, and at least 30 minutes of exercise daily reduced mortality rates.³²

Evidence supports that cognitive decline can be delayed or prevented in all age groups by physical and mental exercise.⁸ The simplest form of exercise for the elderly to engage in is walking. A study of elderly men in Hawaii found that walking—especially the ability to walk quickly—is related to a reduced risk of dementia.³³ Cardiovascular fitness can be achieved through a variety of exercises such as brisk walking, bicycling, swimming, housework, or gardening.

Verghese et al³⁴ reported that risk of dementia is reduced among elderly persons who engaged in leisure activities such as reading, playing board games, playing musical instruments, and dancing. These activities also increased happiness and quality of life among older persons in the community.

Treatment

While there is no approved Food and Drug Administration (FDA) treatment for MCI, research has targeted several areas of focus.

Acetylcholinesterase Inhibitors
Two randomized controlled trials (RCTs) address the effect of donepezil on MCI. In the first study, the Alzheimer’s Disease Cooperative Study (ADCS) Group evaluated vitamin E and donepezil for treatment of patients with amnestic MCI in a double-blind study in 769 participants. Analysis of the treatment effects at six-month intervals showed a decreased probability of progression to AD in the donepezil group during the first 12 months of the study as compared with placebo, but this change did not persist to three years. Donepezil therapy showed potential benefit in delaying risk of progression to AD in the first year of treatment, but this benefit was not seen at three years. In conclusion, donepezil did not improve memory for patients with MCI.³⁵

The second study was a 24-week RCT in 270 patients with amnestic MCI. The study examined the effects of donepezil as compared with placebo on cognitive function, and found no significant treatment effects for MCI. The treatment group had a higher rate of adverse events including diarrhea, nausea, vomiting, leg cramps, and abnormal dreams, which increased the discontinuation rate in the donepezil group.³⁶

Based on these study results, acetylcholinesterase inhibitors are not routinely recommended for patients with MCI. However, for a patient with troublesome memory difficulties, a trial of donepezil may be necessary for symptomatic benefit. Patients and families should be informed of the potential risk.

Vascular Risk Factor Modificatio
Patients with MCI have a higher prevalence of atherosclerosis risk factors and are likely to have cerebrovascular and AD pathology. Studies examining aggressive treatment of the disease processes associated with diabetes, hyperlipidemia, and homocysteinemia have been conducted. Observations suggest that atherosclerosis risk factors should be aggressively treated in patients with MCI.

Elderly persons with hypertension, if treated appropriately, will have a greater absolute decrease in stroke and a greater reduction in dementia. In the Perindopril Protection Against Recurrent Stroke Study (PROGRESS), perindopril plus indapamide reduced stroke-related dementia by 34% and cognitive decline by 45%.³⁷ In the Rotterdam Study, antihypertensive drugs decreased VaD by 70%.³⁸

Randomized, controlled clinical trials of cholesterol lowering have not shown a reduction in the incidence of cognitive decline or dementia in patients taking statins.

A randomized trial comparing two oral antidiabetic agents in 156 older patients with diabetes found that higher postprandial plasma glucose excursions (less tight diabetes control) were associated with greater declines in cognitive performance measures over one year of follow-up.³⁹

A randomized, controlled clinical trial in 185 patients age over 65 years with cardiovascular disease showed that after one year, treatment with vitamin B₁₂, vitamin B₆, and folate lowered homocysteine levels but was not associated with improved cognition.³⁸

Disease-modifying Treatment
First evidence from a RCT shows that tau aggregation inhibitor (TAI) monotherapy with methylthioninium chloride (MTC; rember™) is a disease-modifying treatment for mild and moderate AD. TAI monotherapy may also have preventive application at preclinical stages of AD, but more studies are needed.⁴¹

Selective Serotonin Reuptake Inhibitors
Depression alone can produce symptoms and signs of cognitive impairment, and the diagnosis of depression in patients with impaired cognition is complicated. A therapeutic trial with an antidepressant medication such as citalopram or sertraline may be necessary because of possible additional benefits for neuropsychiatric symptoms, but more research is needed to support the benefit.

N-methyl-D-aspartate Receptor Antagonist
Memantine appears to be neuroprotective, effective in patients with moderate-to-severe AD, with some efficacy in patients with VaD, and was approved by the FDA for use in patients with moderate-to-severe AD. A systematic review of unpublished studies reported a very small but statistically significant effect of memantine on cognition in mild-to-moderate AD, but more studies are needed to support this benefit, and studies are also needed in patients with MCI.

Clinical Recommendations

Clinical recommendations are summarized in Table IV.

Conclusion

MCI is an emerging term for an intermediate stage between cognitive changes of normal aging and dementia in elderly people. Primary care physicians should be aware that dementia is preceded by a recognizable phase of mild cognitive impairment. They should be familiar with the concept of MCI and other similar terms used, including CIND. Patients with MCI should be closely monitored because of their increased risk of developing dementia, and should be evaluated for treatable causes of dementia. Patients with MCI and clinical or radiological evidence of cerebrovascular pathology should be screened and treated for vascular risk factors, especially hypertension. Treating MCI with acetylcholinesterase inhibitors is not routinely recommended, but a trial of donepezil may be needed for symptomatic benefit. Recreational activities, cognitive stimulation, and physical activity as part of a healthy lifestyle in elderly persons and patients with MCI should be promoted.

The authors report no relevant financial relationships.

Dr. Ghetu is a staff geriatrician and faculty member, Dr. Bordelon is Director of Geriatrics, and Dr. Langan is Program Director, St. Luke’s Family Medicine Residency, Bethlehem, PA.

References

1. Petersen RC, Smith GE, Waring SC, et al. Mild cognitive impairment: Clinical characterization and outcome. Arch Neurol 1999;56:303-308.

2. Winblad B, Palmer K, Kivipelto M, et al. Mild cognitive impairment-beyond controversies, towards a consensus: Report of the International Working Group on Mild Cognitive Impairment. J Intern Med 2004;256:240-246.

3. Petersen RC, Stevens JC, Ganguli M, et al. Practice parameter: Early detection of dementia: Mild cognitive impairment (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2001;56:1133-1142.

4. Grundman M, Petersen RC, Ferris SH, et al; Alzheimer’s Disease Cooperative Study. Mild cognitive impairment can be distinguished from Alzheimer disease and normal aging for clinical trials. Arch Neurol 2004:61(1):59-66.

5. Morris JC. The Clinical Dementia Rating (CDR): Current version and scoring rules. Neurology 1993;43:2412-2414.

6. Caselli RJ, Beach TG, Yaari R, Reiman EM. Alzheimer’s disease a century later. J Clin Psychiatry 2006;67:1784-1800.

7. Petersen RC. Conceptual overview. In: Petersen RC, ed. Mild Cognitive Impairment: Aging to Alzheimer’s Disease. New York, NY: Oxford University Press; 2003:1-11.

8. Larson JS, Winn M. Reducing Medicare costs: The risk, prevention, and treatment of cognitive impairment. Clinical Geriatrics 2007;15(7):18-25.

9. Kryscio RJ, Schmitt FA, Salazar JC, et al. Risk factors for transitions from normal to mild cognitive impairment and dementia. Neurology 2006;66(6):828-832.

10. Das SK, Bose P, Biswas A, et al. An epidemiologic study of mild cognitive impairment in Kolkata, India. Neurology 2007;68(23):2019-2026.

11. Ravaglia G, Forti P, Montesi F, et al. Mild cognitive impairment: Epidemiology and dementia risk in elderly Italian population. J Am Geriatr Soc 2008;56:51-58. Published Online: November 20, 2007.

12. Artero S, Ancelin ML, Portet F, et al. Risk profiles for mild cognitive impairment and progression to dementia are gender specific. J Neurol Neurosurg Psychiatry 2008;79(9):979-984. Published Online: May 1, 2008.

13. Guskiewicz KM, Marshall SW, Bailes J, et al. Association between recurrent concussion and late-life cognitive impairment in retired professional football players. Neurosurgery 2005;57:719-726.

14. Tyas SL, Salazar JC, Snowdon DA, et al. Transitions to mild cognitive impairments, dementia, and death: Findings from the Nun Study. Am J Epidemiol 2007;165(11):1231-1238. Published Online: April 12, 2007.

15. Kryscio RJ, Schmitt FA, Salazar JC, et al. Risk factors for transitions from normal to mild cognitive impairment and dementia. Neurology 2006;66(6):828-832.

16. Li G, Rhew IC, Shofer JB, et al. Age-varying association between blood pressure and risk of dementia in those aged 65 and older: A community-based prospective cohort study. J Am Geriatr Soc 2007;55:1161-1167.

17. Andel R. Crowe M, Pedersen NL, et al. Complexity of work and risk of Alzheimer’s disease: A population-based study of Swedish twins. J Gerontol B Psychol Sci Soc Sci 2005;60:P251-P258.

18. Rapp MA, Schnaider-Beeri M, Grossman HT, et al. Increased hippocampal plaques and tangles in patients with Alzheimer disease with a lifetime history of major depression. Arch Gen Psychiatry 2006;63:161-167.

19. Busse A, Bischkopf J, Riedel-Heller SG, Angermeyer RC. Subclassifications for mild cognitive impairment: Prevalence and predictive validity. Psychol Med 2003;33:1029-1038.

20. Sacuiu S, Sjögren M, Johansson B, et al. Prodromal cognitive signs of dementia in 85-year-olds using four sources of information. Neurology 2005;65:1894-1900.

21. Farlow MR, He Y, Tekin S, et al. Impact of APOE in mild cognitive impairment. Neurology 2004;63:1898-1901.

22. Ries ML, Carlsson CM, Rowley HA, et al. Magnetic resonance imaging characterization of brain structure and function in mild cognitive impairment: A review. J Am Geriatr Soc 2008;56:920-934. Published Online: April 9, 2008.

23. Bennett DA, Schneider JA, Bienias J, et al. Mild cognitive impairment is related to Alzheimer disease pathology and cerebral infarctions. Neurology 2005;64:834-841.

24. Petersen RC, Parisi JE, Dickson DW, et al. Neuropathologic features of amnestic mild cognitive impairment. Arch Neurol 2006;63:665-672.

25. Jicha GA, Parisi JE, Dickson DW, et al. Neuropathologic outcome of mild cognitive impairment following progression to clinical dementia. Arch Neurol 2006;63(5):674-681.

26. Apostolova LG, Cummings JL. Neuropsychiatric manifestations in mild cognitive impairment: A systematic review of literature. Dement Geriatr Cogn Disord 2008;25(2):115-126. Published Online: December 14, 2007.

27. Lyketsos CG, Lopez O, Jones B, et al. Prevalence of neuropsychiatric symptoms in dementia and mild cognitive impairment: Results from the Cardiovascular Health Study. JAMA 2002;288(12):1475-1483.

28. Ganguli M, Dodge HH, Shen C, DeKosky ST. Mild cognitive impairment, amnestic type: An epidemiologic study. Neurology 2004;63:115-121.

29. Mitchell AJ. A meta-analysis of the accuracy of the mini-mental state examination in the detection of dementia and mild cognitive impairment. J Psychiatr Res 2009;43(4):411-431. Published Online: June 24, 2008.

30. Schafer KA, Tractenberg RE, Sano M, et al; Alzheimer’s Disease Cooperative Study. Reliability of monitoring the clinical dementia rating in multicenter clinical trials. Alzheimer Dis Assoc Disord 2004;18(4):219-222.

31. Borson S, Scanlan JM, Chen P, Ganguili M. The Mini-Cog as a screen for dementia: Validation in a population-based sample. J Am Geriatr Soc 2003;51(10):1451-1454.

32. Knoops KT, deGroot LC, Kromhout D, et al. Mediterranean diet, lifestyle factors, and 10-year mortality in elderly European men and women: The HALE project. JAMA 2004;292:1433-1439.

33. Abbott RD, White LR, Ross GW, et al. Walking and dementia in physically capable elderly men. JAMA 2004;292:1447-1453.

34. Verghese J, Lipton RB, Katz MJ, et al. Leisure activities and the risk of dementia in the elderly. N Engl J Med 2003;348:2508-2516.

35. Petersen RC, Thomas RG, Grundman M, et al; Alzheimer’s Disease Cooperative Study Group. Vitamin E and donepezil for the treatment of mild cognitive impairment. 2005:352:2379-2388. Published Online: April 13, 2005.

36. Salloway S, Ferris S, Kluger A, et al; Donepezil 401 Study Group. Efficacy of donepezil in mild cognitive impairment: A randomized placebo-controlled trial. Neurology 2004;63:651-657.

37. PROGRESS Collaborative Group. Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6,105 individuals with previous stroke or transient ischaemic attack [published corrections appear in Lancet 2001;358(9292):1556; Lancet 2002;359(9323):2120]. Lancet 2001;358(9287):1033-1041.

38. in’t Veld BA, Ruitenberg A, Hofman A, et al. Antihypertensive drugs and incidence of dementia: The Rotterdam Study. Neurobiol Aging 2001;22:407-412.

39. Abbatecola AM, Rizzo MR, Barbieri M, et al. Postprandial plasma glucose excursions and cognitive functioning in aged type 2 diabetics. Neurology 2006;67(2):235-240.

40. Stott DJ, MacIntosh G, Lowe GD, et al. Randomized controlled trial of homocysteine-lowering vitamin treatment in elderly patients with vascular disease. Am J Clin Nutr 2005;82(6):1320-1326.

41. Wischik CM, Bentham P, Wischik DJ, et al. Tau aggregation inhibitor (TAI) therapy with remberTM arrests disease progression in mild and moderate Alzheimer’s disease over 50 weeks. Alzheimer’s and Dementia 2008:4(suppl 1):T167.