At the American Academy of Neurology (AAN) 58th Annual Meeting, many scientific presentations provided new information to advance our understanding of Alzheimer's disease (AD) and its treatment.
Patients with mild cognitive impairment (MCI) are at risk of developing AD. Patients who have amnestic mild cognitive impairment (aMCI) are at the highest risk of developing AD compared with patients who have MCI with cognitive deficits other than in memory.
Neuropsychological testing designed to identify subtypes of MCI was correlated with imaging in a series of MCI patients in data presented from a study conducted at the Mayo Clinic in Rochester, Minnesota.[1] In this study, 164 patients with MCI were evaluated. Voxel-based morphometry was used to measure regional gray matter atrophy in each subset of MCI patients as defined by prior neuropsychological testing. A predominate memory deficit was identified in 121 MCI patients, language deficits in 15, attention deficits in 13, and visuospatial deficits in 15. Subjects with predominant memory impairment type MCI (aMCI) had regional gray matter loss in the bilateral mesial and inferior temporal lobes, and to a lesser extent in the posterior temporal and parietal areas compared with the controls. MCI patients with primarily language impairments had the greatest gray matter loss in the bilateral mesial and inferior temporal lobes. MCI patients with impairments in language had gray matter loss in the bilateral basal forebrain and hypothalamus. The pattern of bilateral mesial-basal temporal lobe atrophy in aMCI patients had the same imaging pattern as patients with early AD. These imaging data support the concept that aMCI is prodromal AD.
The risk of developing MCI or AD in relation to baseline brain atrophy or subclinical cerebrovascular disease (CVD) in patients with normal cognitive function was discussed in a study by Rosano and colleagues.[2] A group of 198 cognitively normal patients (mean, 72.5 years; 61% women, 81% white) who had neuropsychological testing underwent total brain volume MRI scanning at baseline and at the end of study from 1997 to 1999 and again from 2001 to 2003. The volume of medial temporal lobe structures (amygdala, parahippocampus, hippocampus, and entorhinal cortex) and of the striatum (putamen and caudate), and the presence of T2 hyperintensities and identifiable brain infarctions (greater than 3 mm) were evaluated. Results from the study showed that the greatest risk for conversion from cognitively normal to AD was for those subjects with at least 1 brain infarction or with severe atrophy of the left amygdala, left entorhinal cortex, or right putamen. Those with severe medial temporal atrophy and 1 or more infarction had more than a 10 times greater risk of converting to AD compared with those without infarctions. Normal subjects with severe left hippocampal atrophy were at greatest risk for conversion to MCI during the observation period.
In a longitudinal analysis from the Mayo Clinic Study of Aging, Geda and colleagues[3] showed that patients with MCI were more likely to have neuropsychiatric symptoms than cognitively normal controls. In total, 104 elderly individuals from 70 to 89 years of age with MCI and 312 cognitively normal controls from the same age range were evaluated with neuropsychiatric data obtained with the Neuropsychiatric Inventory (NPI). Apathy was observed in 24% of MCI patients vs 6.1% of controls (P = .0001), depression in 26% of MCI patients vs 11.5% of controls (P = .0004), anxiety in 11.5% of MCI patients vs 3.9% of controls (P = .004), and irritability in 18.3% of MCI patients vs 8.7% of controls (P = .007). Results from this study showed that apathy may be the most distinguishing feature of MCI compared with normal cognitive aging. Although depression is a common symptom in the elderly, the clinician should be vigilant to recognize the features of apathy separately from the features of depression so that symptoms are not overlooked that may indicate early cognitive decline, which should be addressed with a separate evaluation and treatment approach.
Behavioral data for 520 AD patients who were followed for up to 14 years were presented by Scarmeas and colleagues.[4] Outcomes measures assessed were cognition (with the Mini-Mental State Examination [MMSE]), function (with the Blessed Dementia Rating Scale [BDRS]), time to institutionalization, and time to death. The presence of wandering, verbal outbursts, physical threats, agitation, and sundowning were measured on a 0-5 scale. The results showed that each additional behavioral symptom was associated with an increased risk for cognitive and functional decline with institutionalization but not with death. Agitation had the greatest association with global decline of all the behaviors, whereas wandering had the greatest association with institutionalization.
Marshall and colleagues[5] presented data for 22 autopsy-verified AD patients who had early- and late-onset-type AD without other concomitant disease. Choline acetyltransferase (ChAT) activity from the orbitofrontal cortex, superior temporal cortex, and the occipital cortex was calculated. Six patients had early-onset AD (onset before 65 years) and 16 had late-onset AD (onset after age 65). The mean age of onset of all patients was 71 years and the mean age of death was 80.6. Regional and mean ChAT activity correlated with age of onset of AD. There were no differences between the groups in education, last MMSE, or the duration of dementia. Mean cortical ChAT activity results showed that activity of ChAT was significantly lower in the early-onset AD group than in the late-onset AD group, thereby indicating a greater cholinergic deficit in the younger onset group. Mean ChAT for the early-onset group was 35.1 nmol ACh/mg protein/hour vs 59.0 for the late-onset group (P = .042). The fact that the cholinergic deficit was greater in the early-onset AD group, yet the degree of dementia was the same in the early- and late-onset groups suggests that a greater cholinergic deficit is better tolerated in younger patients probably because other factors are compensating. Patients with later onset AD experienced a greater cognitive decline with a smaller cholinergic deficit, thereby indicating their decreased resilience to the loss of cholinergic function.
Mungas and colleagues[6] reported results from a study designed to evaluate the comorbidities of AD and CVD, two conditions that commonly occur together. Autopsy data for patients who had 2 or more neuropsychological assessments were examined for independent effects of AD and CVD on memory and executive function. Forty-four patients were evaluated. At study entry, 17 patients were diagnosed as cognitively normal; 9 patients were diagnosed with MCI; and 18 patients were diagnosed with dementia. Dependent variables were psychometrically matched measures of memory (MEM) and executive function (EXEC). Independent variables were the Braak staging of neurofibrillary tangle pathology (BRAAK) and a standardized rating of cerebrovascular brain injury (CVD-Path). The results of the study showed that there was a strong relationship between MEM and BRAAK, and that EXEC was independently and equally affected by BRAAK and CVD-Path. Therefore, these data indicate that MEM was related only to AD neuropathology but that EXEC was complexly related to both AD and CVD neuropathology.
The influence of the severity of cerebral white matter lesions (WML) was assessed in a 4-year observational study of the development of dementia on the basis of Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria in 225 patients from the Perindopril Protection Against Recurrent Stroke (PROGRESS) study in France.[7] To be included in the study, patients were required to have a history of stroke or transient ischemic attack. At baseline, 44 patients (19.6%) had severe WML. WML were positively correlated to age and elevated blood pressure. Over the 4-year observation period, 16 patients (7.1%) developed dementia. The incidence of dementia ranged from 2.1% in patients without WML at baseline to 20.5% in patients with severe WML at baseline (P = .004). Most of the dementia patients (15 or 16) did not have another stroke during this period, thereby indicating that the presence of severe WML is strongly associated with an increased risk of developing dementia even without another clinical event. The number of patients who may have significant concomitant AD may be learned at neuropathologic evaluation.
Two papers presented information showing a high incidence of medication use that could increase cognitive impairment in patients at risk of developing AD, or that would interfere with the action of cholinesterase inhibitors (ChEI). Barton and colleagues[8] presented data from 100 patients who were consecutively evaluated at the San Francisco VA Medical Center Memory Disorder Clinic, San Francisco, California, showing that 22% of cognitively impaired patients with a mean MMSE of 22.9, were taking 1 or more inappropriate medications that could potentially affect their cognition. The most frequently used, inappropriate medications were benzodiazepines, oxybutynin, fluoxetine, amitriptyline, and diphenhydramine. Twenty-eight patients had been prescribed a ChEI. Four of these patients (14%) were also taking a medication with anticholinergic properties that would interfere with the action of the ChEI.
In another study, 5139 patients over the age of 65 with cognitive impairment (862 with MCI and 4277 with dementia) from the Alzheimer's Disease Research Centers of California (ARCCs) were assessed for the use of inappropriate medications.[9] Inappropriate medications were defined according to the 2003 Beers criteria, focusing on drugs with central nervous system side effects. The results showed that 901 (18%) were taking at least 1 potentially inappropriate medication. The most frequent classes of drugs represented were sedative-hypnotics (7%), tricyclic antidepressants (5%), and anticholinergics (4%). In a multivariate analysis, independent risk factors for the use of potentially inappropriate drugs were female gender, with more than 6 medications, and a history of alcohol abuse.
The data presented in the scientific sessions on "Aging and Dementia" at the 58th Annual Meeting of the AAN included much useful information to assist clinicians. One lesson that was learned is that patients with AD and even clinically silent CVD can have up to a 10-fold accelerated course of their dementia. In addition, patients with AD but with significant executive dysfunction are likely to have clinically relevant cerebrovascular neuropathology. Results showed that imaging can be useful to predict which patients with MCI have prodromal AD and those who are more likely to have a more aggressive course, and that neuropsychological testing can be similarly useful to determine prognosis. Lastly, the importance of clinician vigilance about the use of concomitant medications that may be worsening a cognitive disorder or interfering with the action of a ChEI, including over-the-counter drugs, was discussed.
As time progresses, treatments for AD are likely to improve, and at least some preventive or early interventions may be shown to slow the course of the neurodegenerative progression of AD. Some of the information presented at this year's AAN meeting may help confirm the early diagnosis of MCI or prodromal AD and allow treatment to begin earlier in order to ameliorate this tragic personal illness and major healthcare problem.