Mild Cognitive Impairment

Prevalence

Identification of patients with mild cognitive impairment (MCI) is important because patients with MCI are at risk of developing AD. In a study of the demographics of MCI, R. Petersen and colleagues[1] presented information that showed that the most common form of MCI involved memory (amnestic MCI [aMCI]) with the second most common involving attention (nonamnestic MCI [na-MCI]). Among 1704 individuals from age 70 to 89 years, the median age was 79 and the median number of years of education was 13.7. After diagnostic evaluation of the 1704 individuals, 1419 were cognitively normal whereas 285 had MCI (aMCI 210, na-amnestic MCI 75). The prevalence of MCI was 16% in this population sample (74% amnestic subtype). The prevalence of MCI increased with increasing age. In the 70- to 74-year-old age group 9.8% had MCI, whereas in the 85-89 age group 25% had MCI. MCI prevalence was inversely related to years of education. For patients with 9 or fewer years of education, MCI prevalence was 26.9%, whereas for patients with more than 16 years of education, MCI prevalence was 11.7%. MCI patients were mostly impaired in the memory domain, with attention being the second most commonly affected domain. Men represented 18.3% of the sample, with women being 13.3% of the sample.

Vascular Risk Factors for MCI and AD

Vascular risk factors in MCI subtypes were presented in a platform presentation by R. Roberts and colleagues.[2] There were 2300 subjects from Olmsted County in Minnesota (age, 70-89 years). The sampling scheme was separated into 4 cells: men aged 70-79 years and 80-89 years and women aged 70-79 years and 80-89 years. There were 550 men and 550 women included in the 70-79 age group and 600 men and 600 women included in the 80- to 89-year-old age group. Each patient had an interview with a nurse specialist with neuropsychological testing for memory, language, visuospatial abilities, and executive functions for the cognitive domains. A history of associated diabetes, hypertension, and cardiovascular disease (CAD) was evaluated. Using a cross-sectional, case-control analysis, 10.8% of subjects had aMCI; 3.9 % had na-MCI; 10.9% had dementia; and 74.4% of subjects were normal. In stratified analyses by MCI subtypes compared with normals, there was a significant association between na-MCI and diabetes, hypertension, and CAD. There was no significant association between aMCI and diabetes, hypertension, or CAD. This cross-sectional analysis suggested that aMCI is primarily a neurodegenerative disease, whereas na-MCI is associated with vascular risk factors.

An autopsy study investigating the contribution of vascular pathology to the clinical expression of AD from the Einstein Aging Study (EAS) was presented by D. Strozyk and colleagues.[3] Clinical AD was diagnosed with NINCDS-ADRDA (National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer's Disease and Related Disorders Association) criteria. Postmortem assessments included Braak staging (0 to VI) and vascular scoring, which was based on the presence or absence of 7 lesions: strokes, lacunes, microinfarctions, leukoencephalopathy, cerebral amyloid angiopathy, cribriform changes, or hippocampal sclerosis. Logistic regression was adjusted for age at death, sex, clinicopathologic interval (mean, 20 months), and neurocortical Lewy bodies. Braak AD pathology was divided into minimal (Braak 0-II) and significant pathology (Braak greater than II) to study possible threshold effects of vascular lesions. In total, 150 patients were analyzed, with 65% of them women with a mean age of 83 years. There was a significant interaction between Braak stage and vascular score. The results showed that 76.3% had vascular lesions. With a minimal Braak stage (0-II) the vascular score was associated with both AD and cognitive impairment. In severe Braak stages (III-VI) the vascular score was not associated with either AD or cognitive impairment. The conclusion of these results was that antemortem cognitive status and vascular lesions were associated. Vascular lesions have a threshold effect in contributing to the clinical expression of AD and cognitive impairment in patients with mild AD pathology but not in patients with significant AD pathology.

Imaging and Cognition

Functional magnetic resonance imaging (fMRI) tasks can be used to test selective attention, as measured by the distinctness of information representation in brain networks. By using fMRI markers that can reflect changes in the distinctness of representations in the visual association cortex (VAC), 37 healthy human subjects performed fMRI tasks that involved viewing and selecting 1 or 2 image categories (faces or scenes).[4] In these 37 patients, selective attention to a stimulus category resulted in high selectivity for that category within regions of the VAC. Ignoring the same category resulted in a decrement in selectivity in the same region. fMRI markers measured both the spatial overlap and category selectivity in the VAC. The effects of a cholinesterase inhibitor were also examined in the double-blind, placebo-controlled, crossover study. Donepezil enhanced the effect of the distinctness of information represented at the level of the VAC. Thus, fMRI may be helpful to measure attentional control dysfunction and treatment interventions.

D. Karow and colleagues,[5] from the Alzheimer's Disease Neuroimaging Initiative (ADNI), reported on results from positron emission tomographic (PET) imaging using anatomically defined regions of interest. PET imaging is known to be useful in showing hypometabolism in the temporoparietal regions. Using region-of-interest procedures, PET activity was reduced in patients with AD and MCI in the left hippocampus and entorhinal cortex. Reduction of PET activity in patients with AD was also present in the left amygdale and inferior temporal, fusiform, inferior parietal, and parahippocampal gyri.

AD Cerebrospinal Fluid Diagnostic Indicators

Cerebrospinal fluid (CSF) tau levels are known to be elevated in AD compared with normals. With regard to a differential diagnosis between AD and frontotemporal dementia (FTD), data presented by H. Bian and colleagues[6] showed that CSF tau was significantly more elevated in AD compared with FTD. In an autopsy series of 19 AD patients and 14 FTD patients, CSF tau was approximately twice the level in AD patients' CSF (523 ± 292 pg/mL) compared with tau in FTD patients' CSF (272 ± 157 pg/mL). Neuropsychological testing showed deficits in verbal fluency in FTD patients, whereas AD patients showed a greater impairment in free recall memory, recognition memory, and visual construction.

CSF tau and beta-amyloid levels were compared in 7 neurodegenerative diseases: AD, Parkinson's disease (PD), progressive supranuclear palsy (PSP), multiple system atrophy (MSA), diffuse Lewy body disease (DLBD), frontotemporal dementia (FTD), and spinocerebellar ataxia (SCA).[7] Higher tau protein levels were found in AD compared with PD, SCA, and control group (CG) patients. Higher tau-protein/beta-amyloid levels were found in AD patients compared with SCA, PD, and CG subjects. Lower beta-amyloid levels were found in AD patients vs PD and CG patients. The tau/beta-amyloid ratio had the strongest correlation to AD vs PD and CG patients (P = .001).

Preclinical Studies

Nasal administration of Protollin (ID Biomedical Corporation of Quebec, St. Laurent, Quebec, Canada), a proteasome-based adjuvant, in amyloid precursor protein (APP)-Tg mice was shown to activate microglia and reduce A-beta plaques when given chronically to young mice as prevention.[8] Age- and sex-matched APP-Tg littermates received weekly nasal Protollin beginning at age 5 months for a duration of 8 months. A reduction in amyloid fibril of 80% was found in Protollin-treated mice vs controls on pathologic examination. There was a reduction of both soluble and insoluble A-beta, an elevation of total serum A-beta, and a reduction of astrocytosis. Although microglia activation occurs in APP mice in response to A-beta deposition, it is not sufficient to clear A-beta. The ability of Protollin alone to activate microglia to phagocytized beta amyloid suggests a possible antibody-independent approach to treat AD.

In a study to evaluate the effect of statins to reduce neurofibrillary tangles (NFT), transgenic mice for NFT were used in aged normocholesterolemic mice (standard diet-fed) and young hypercholesterolemic mice (western diet-fed).[9] The aged mice were given simvastatin (blood-brain barrier [BBB]-permeable) or placebo for 1 month, and the young mice were given atorvastatin (BBB-impermeable) or placebo for 5 months. The results showed that simvastatin reduced the NFT burden by 25% to 31% with a 26% decrease in microglia. Atorvastatin-treated mice showed a reduction of NFT burden by 53% to 59% and a decrease in microglia of 20%. These results are believed to show that statins significantly reduced NFT burden regardless of BBB permeability and regardless of cholesterol-lowing properties. The statin treatments appear to decrease microglia activation related to an anti-inflammatory property and not due to a cholesterol-lowering effect.

AD Treatment and Modification

Dimebon (Medivation, Inc., San Francisco, California) is a putative neuroprotectant that may inhibit neuronal death. The mechanism of action may be alteration of mitochondrial-mediated apoptosis. In a double-blind, placebo-controlled study performed in Russia, 183 patients with mild-to-moderate AD were given Dimebon 20 mg 3 times daily or placebo for 6 months.[10] The results showed efficacy of Dimebon over placebo in Alzheimer's Disease Assessment Scale (ADAS-Cog) (4.0-point improvement; P = .0001), Clinicians' Interview-Based Impression of Change (CIBIC)-plus (0.6-point improvement; P =0.001), Mini-Mental State Examination (MMSE) (2.2-point improvement; P = .001), Neuropsychiatric Inventory (NPI) (3.6-point improvement; P = .006), and activities of daily living (ADLs) (3.4-point improvement; P = .0016). In a subanalysis, both mild AD patients (MMSE 18-24) and moderate AD patients (MMSE 10-17) showed improvement, but the moderate AD patients showed more improvement than the mild AD patients. The most common side effect was dry mouth (13.5%). There were fewer serious adverse events in the Dimebon group than in the placebo group (2.2% vs 7.4%). Gastrointestinal side effects were fewer than 3%. In this study, Dimebon appeared to improve cognition, behavior, and function over a 6-month period.

Insulin and insulin signaling may be involved in the pathopsychology of AD. A study of early AD patients and controls measured total glucose and area under the curve by linear regression models to assess the relationship of insulin and glucose measures with whole-brain volume, cognition, and dementia severity.[11] The results showed that increased serum insulin levels may be protective in nondiabetic, early AD patients. Reduced serum insulin was associated with more severe AD-related brain atrophy, cognitive dysfunction, and dementia, which suggests that reduced insulin signaling may play a role in the progression of AD.

Diet is believed to play a role in AD development and progression. In an evaluation of the Mediterranean diet (MeDi) and longevity in AD,[12] 195 community-based patients with AD in New York, NY, were prospectively followed every 1.5 years. Eighty-seven patients (45%) died in a period of 4.5 years of follow-up. Those individuals who adhered to a MeDi (high intake of vegetables, legumes, fruits, cereals, and fish; low intake of saturated fatty acids, dairy products, meat, and poultry with a mild-to-moderate amount of alcohol) had a lower mortality independent of other risk factors compared with those who did not adhere to the MeDi diet. Cox models were adjusted for age, sex, ethnicity, education, ApoE genotype, caloric intake, smoking, and body mass index. MeDi may not only favorably affect risk for AD, but also the disease course.

Summary

In summary, progress is being made in understanding the pathophysiology of AD. Many treatment models with Tg mice have shown a promising reduction of disease burden with several treatment types. To date, no disease-modifying drug has been shown to be safe and effective in human trials, although that day may not be far away. Dietary factors, such as the MeDi, regular exercise, and intellectual involvement, seem to favorably modify the disease course and may help to prevent or delay AD. While we wait for new drug therapies, lifestyle and personal habits will be very important, and these factors will remain important considerations in the future.