Mild Cognitive Impairment and Changes in Everyday Function Over Time: The Importance of Evaluating Both Speed and Accuracy.

OBJECTIVES: Research estimates that a significant percentage of individuals with mild cognitive impairment (MCI) experience functional difficulties. In addition to reduced accuracy on measures of everyday function, cross-sectional research has demonstrated that speed of performing instrumental activities of daily living (IADLs) is slowed in individuals with MCI. The present study investigated whether baseline and longitudinal changes in speed and accuracy of IADL performance differed between persons with MCI and cognitively normal peers. DESIGN: Linear mixed models were used to estimate the group differences in longitudinal performance on measures of IADLs. SETTING: Assessments were conducted at university and medical research centers. PARTICIPANTS: The sample consisted of 80 participants with MCI and 80 control participants who were enrolled in the Alzheimer's Disease Research Center's Measuring Independent Living in the Elderly Study. MEASUREMENTS: Instrumental activities of daily living speed and accuracy were directly assessed using selected domains of the Financial Capacity Instrument, the Timed IADL assessment, and driving-related assessments (Useful Field of View, Road Sign Test). RESULTS: Individuals with MCI performed worse on speed and accuracy measures of IADLs in comparison to cognitively normal peers and demonstrated significantly steeper rates of decline over three years in either speed or accuracy in all domains assessed. CONCLUSION: Both speed and accuracy of performance on measures of IADL are valuable indices for early detection of functional change in MCI. The performance pattern may reflect a trade-off between speed and accuracy that can guide clinical recommendations for maintaining patient independence.

Difficulty, effort and cardiovascular response to a working memory challenge: Older adults with and without mild cognitive impairment.

We presented cognitively healthy older adults and patients with mild cognitive impairment (MCI) three versions of a modified Sternberg memory task designed to range in difficulty from low to high. Among cognitively healthy older adults, blood pressure responses assessed during the work periods rose with difficulty. By contrast, among MCI patients, blood pressure responses assessed during the work periods were low irrespective of difficulty. Findings are discussed primarily in relation to a conceptual analysis concerned with ability determinants of effort (task engagement) and associated cardiovascular responses. They also are discussed in the context of other recent cardiovascular studies involving older adults and with regard to the potential for exaggerated cardiovascular responses to accelerate cognitive decline in advanced age.

Lower hippocampal volume predicts decrements in lane control among drivers with amnestic mild cognitive impairment.

OBJECTIVES: There are few methods to discern driving risks in patients with early dementia and mild cognitive impairment (MCI). We aimed to determine whether structural magnetic resonance imaging (MRI) of the hippocampus-a biomarker of probable Alzheimer pathology and a measure of disease severity in those affected--is linked to objective ratings of on-road driving performance in older adults with and without amnestic MCI. METHODS: In all, 49 consensus-diagnosed participants from an Alzheimer's Disease Research Center (15 diagnosed with amnestic MCI and 34 demographically similar controls) underwent structural MRI and on-road driving assessments. RESULTS: Mild atrophy of the left hippocampus was associated with less-than-optimal ratings in lane control but not with other discrete driving skills. Decrements in left hippocampal volume conferred higher risk for less-than-optimal lane control ratings in the patients with MCI (B = -1.63, standard error [SE] = .74, Wald = 4.85, P = .028), but not in controls (B = 0.13, SE = .415, Wald = 0.10, P = .752). The odds ratio and 95% confidence interval for below-optimal lane control in the MCI group was 4.41 (1.18-16.36), which was attenuated to 3.46 (0.88-13.60) after accounting for the contribution of left hippocampal volume. CONCLUSION: These findings suggest that there may be a link between hippocampal atrophy and difficulties with lane control in persons with amnestic MCI. Further study appears warranted to better discern patterns of brain atrophy in MCI and Alzheimer disease and whether these could be early markers of clinically meaningful driving risk.

MRI volume of the medial frontal cortex predicts financial capacity in patients with mild Alzheimer's disease.

Persons with mild Alzheimer's disease (AD) have significant deficits in financial abilities. This study examined the relationship between brain structure volumes, cognition, and financial capacity in patients with mild AD. Sixteen mild AD patients and 16 older adult comparisons completed the Financial Capacity Instrument (FCI), a psychometric measure of financial abilities, and also underwent magnetic resonance imaging (MRI) to obtain volumes of the bilateral hippocampi, angular gyri, precunei, and medial and dorsolateral frontal cortices. Mild AD patients performed significantly below comparisons on the FCI and had significantly smaller hippocampi. Among mild AD patients, FCI performance was moderately correlated with frontal (medial and dorsolateral frontal cortex) and posterior (angular gyri and precunei) cortical volumes. Stepwise regression demonstrated that medial frontal cortex volume predicted FCI score. The relationship between medial frontal cortex volume and overall FCI score was partially mediated by two measures of simple attention (DRS Attention, DRS Construction). The findings suggest that medial frontal cortex atrophy and associated declines in simple attention play an increasingly important role in declining financial skills in patients with mild AD.

Cerebrospinal fluid profiles and prospective course and outcome in patients with amnestic mild cognitive impairment.

OBJECTIVES: To examine the effect of specific cerebrospinal fluid (CSF) profiles on the rate of cognitive decline, disease progression, and risk of conversion to Alzheimer disease (AD) dementia in patients with amnestic mild cognitive impairment (MCI). DESIGN: Total tau (T-tau), tau phosphorylated at threonine 181, and ß-amyloid 1-42 peptide (Aß42) were immunoassayed in CSF samples obtained from patients with MCI enrolled in the Alzheimer's Disease Neuroimaging Initiative. Patients were then stratified by CSF profiles: (1) normal T-tau and normal Aß42 (ie, normal-T-tauAß42), (2) normal T-tau but abnormal Aß42 (ie, abnormal-Aß42), (3) abnormal T-tau but normal Aß42 (ie, abnormal-T-tau), and (4) abnormal T-tau and abnormal Aß42 (ie, abnormal-T-tauAß42). SETTING: Fifty-eight sites in the United States and Canada. PARTICIPANTS: One hundred ninety-five patients with MCI. MAIN OUTCOME MEASURES: A composite cognitive measure, the Clinical Dementia Rating Scale-sum of boxes subscale, and conversion to AD dementia. RESULTS: Patients with MCI with a CSF profile of abnormal-Aß42 or abnormal-T-tauAß42 experienced a faster rate of decline on the composite cognitive measure and the Clinical Dementia Rating Scale-sum of boxes subscale compared with those with normal-T-tauAß42. They also had a greater risk of converting to AD dementia relative to the normal-T-tauAß42 group. In contrast, those with a CSF profile of abnormal-T-tau did not differ from the normal-T-tauAß42 group on any outcome. These findings were generally replicated when the sample was reclassified by patterns of tau phosphorylated at threonine 181 and Aß42 abnormalities. CONCLUSIONS: ß-Amyloid abnormalities but not tau alterations are associated with cognitive deterioration, disease progression, and increased risk of conversion to AD dementia in patients with MCI. Patients with abnormal Aß42 may be prime candidates for drug treatment and clinical trials in MCI.

Cerebrospinal fluid abnormalities and rate of decline in everyday function across the dementia spectrum: normal aging, mild cognitive impairment, and Alzheimer disease.

OBJECTIVE: To investigate the effect of cerebrospinal fluid (CSF) abnormalities on the rate of decline in everyday function in normal aging, mild cognitive impairment (MCI), and mild Alzheimer disease (AD). DESIGN: Immunoassays of total tau (t-tau), tau phosphorylated at threonine 181 (p-tau(181)), and beta-amyloid 1-42 (Abeta(42)) concentrations were performed in CSF obtained from participants in the Alzheimer's Disease Neuroimaging Initiative. Random effects regressions were used to examine the relationship among CSF abnormalities, cognitive impairment (assessed with the Alzheimer Disease Assessment Scale-cognitive subscale [ADAS-Cog]), and functional decline (assessed with the Pfeffer Functional Activities Questionnaire) and to determine whether the impact of CSF abnormalities on functional decline is mediated by cognitive impairment. SETTING: Fifty-eight sites in the United States and Canada. PARTICIPANTS: One hundred fourteen cognitively intact adults, 195 patients with MCI, and 100 patients with mild AD. Main Outcome Measure Decline in the Pfeffer Functional Activities Questionnaire score. RESULTS: Abnormalities in all CSF analytes were associated with functional decline in MCI, and all but the t-tau:Abeta(42) ratio were associated with functional decline in controls. No abnormal CSF analyte was associated with functional decline in AD. Among controls, p-tau(181) concentration was the most sensitive to functional decline, whereas in MCI it was Abeta(42) concentration. Cerebrospinal fluid biomarkers were uniformly more sensitive to functional decline than the ADAS-Cog score among controls and variably so in MCI, whereas the ADAS-Cog score was unequivocally more sensitive than CSF biomarkers in AD. The impact of CSF abnormalities on functional decline in MCI was partially mediated by their effect on cognitive status. Across all diagnostic groups, persons with both tau and Abeta(42) abnormalities exhibited the steepest rate of functional decline. CONCLUSIONS: Abnormalities in CSF are associated with functional decline and thus with future development of AD in controls and patients with MCI. However, they do not predict further functional degradation in patients with AD. Persons with comorbid tau and Abeta(42) abnormalities are at greatest risk of functional loss.

Brain metabolic correlates of decision making in amnestic mild cognitive impairment.

Persons with amnestic mild cognitive impairment (MCI) have subtle impairments in medical decision-making capacity (MDC). We examined the relationship between proton magnetic resonance spectroscopy (MRS) and MDC in MCI. Twenty-nine MCI patients and 42 controls underwent MRS to obtain ratios of N-acetylaspartate (NAA)/Creatine (Cr), Choline (Cho)/Cr, and myo-Inositol (mI)/Cr of the posterior cingulate. They also completed the Capacity to Consent to Treatment Instrument (CCTI), a vignette-based instrument measuring decisional standards of expressing choice, appreciating consequences of choice, providing rational reasons for choice, and understanding treatment choices. Patients showed abnormal MRS ratios of mI/Cr and Cho/Cr compared to controls, and impairments on the CCTI understanding and reasoning Standards. Performance on the reasoning standard of the CCTI was correlated with NAA/Cr (r = .46, p < .05). The relationship of NAA/Cr with decision-making suggests a role for posterior cortical neuronal functioning in performance of complex IADLs in MCI.

Magnetic resonance imaging volume of the angular gyri predicts financial skill deficits in people with amnestic mild cognitive impairment.

OBJECTIVES: To better understand how brain atrophy in amnestic mild cognitive impairment (MCI) as measured using magnetic resonance imaging (MRI) volumetrics could affect instrumental activities of daily living (IADLs) such as financial abilities. DESIGN: Controlled, matched-sample, cross-sectional analysis regressing MRI volumetrics with financial performance measures. SETTING: University medical and research center. PARTICIPANTS: Thirty-eight people with MCI and 28 older adult controls. MEASUREMENTS: MRI volumetric measurement of the hippocampi, angular gyri, precunei, and medial frontal lobes. Participants also completed neuropsychological tests and the Financial Capacity Instrument (FCI). RESULTS: Correlations were performed between FCI scores and MRI volumes in the group with MCI. People with MCI performed significantly below controls on the FCI and had significantly smaller hippocampi. Among people with MCI, performance on the FCI was moderately correlated with angular gyri and precunei volumes. Regression models demonstrated that angular gyrus volumes were predictive of FCI scores. Tests of mediation showed that measures of arithmetic and possibly attention partially mediated the relationship between angular gyrus volume and FCI score. CONCLUSION: Impaired financial abilities in amnestic MCI correspond with volume of the angular gyri as mediated by arithmetic knowledge. The findings suggest that early neuropathology within the lateral parietal region in MCI leads to a breakdown of cognitive abilities that affect everyday financial skills. The findings have implications for diagnosis and clinical care of people with MCI and AD.

The contribution of executive control on verbal-learning impairment in patients with Parkinson's disease with dementia and Alzheimer's disease.

Deficits in learning, memory, and executive functions are common cognitive sequelae of Parkinson's disease with dementia (PDD) and Alzheimer's disease (AD); however, the pattern of deficits within these populations is distinct. Hierarchical regression was used to investigate the contribution of two measures with executive function properties (Verbal Fluency and CLOX) on list-learning performance (CVLT-II total words learned) in a sample of 25 PDD patients and 25 matched AD patients. Executive measures were predictive of list learning in the PDD group after the contribution of overall cognition and contextual verbal learning was accounted for, whereas in the AD group the addition of executive measures did not add to prediction of variance in CVLT-II learning. These findings suggest that deficits in executive functions play a vital role in learning impairments in patients with PDD; however, for AD patients, learning difficulties appear relatively independent of executive dysfunction.

Proton magnetic resonance spectroscopy in dementias and mild cognitive impairment.

With the anticipated increase in dementias due to the aging demographic of industrialized nations, biomarkers for neurodegenerative diseases are increasingly important as new therapies are being developed for clinical trials. Proton MR spectroscopy ((1)H MRS) appears poised to be a viable means of tracking brain metabolic changes due to neurodegenerative diseases and potentially as a biomarker for treatment effects in clinical therapeutic trials. This review highlights the body of literature investigating brain metabolic abnormalities in Alzheimer's disease, amnestic mild cognitive impairment, frontotemporal dementia, vascular dementia, Lewy body dementia, and Parkinson's disease dementia. In particular, the review addresses the viability of (1)H MRS to discriminate among dementias, to measure disease progression, and to measure the effects of pharmacological treatments. While findings to date are encouraging, more study is needed in longitudinal patterns of brain metabolic changes, correspondence with changes in clinical markers of disease progression, and sensitivity of (1)H MRS measures to treatment effects. Such developments will hopefully benefit the search for effective treatments of dementias in the twenty-first century.