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1.  Lower Hippocampal Volume Predicts Decrements in Lane Control among Drivers with Amnestic MCI 
There are few methods to discern driving risks in patients with early dementia and Mild Cognitive Impairment (MCI). We aimed to determine whether structural 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.
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.
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 MCI patients (B = −1.63, SE = .74, Wald = 4.85, P = .028), but not in controls (B = 0.13, SE = .415, Wald = 0.10, P = .752). The odds ratio (OR) and 95% confidence interval (CI) 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.
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 AD and whether these could be early markers of clinically meaningful driving risk.
PMCID: PMC4114386  PMID: 24212246
MCI (mild cognitive impairment); Volumetric MRI; Driving performance
2.  MRI Volume of the Angular Gyri Predicts Financial Skill Deficits in Patients with Amnestic Mild Cognitive Impairment 
Persons with amnestic mild cognitive impairment (MCI) have demonstrated subtle impairments in IADLs including financial abilities, although the underlying brain changes related to these IADL impairments is poorly understood. The purpose of this investigation was to better understand how brain atrophy in MCI as measured by MRI volumetrics could impact IADLs such as financial abilities.
Controlled, matched sample, cross-sectional analysis regressing MRI volumetrics with financial performance measures.
University medical and research center.
Thirty-eight MCI patients and 28 older adult controls.
MRI volumetric measurement of the hippocampi, angular gyri, precunei, and medial frontal lobes. Participants also completed neuropsychological tests and the Financial Capacity Instrument (FCI).
We performed correlations between FCI scores and MRI volumes in the MCI group. Patients with MCI performed significantly below controls on the FCI and had significantly smaller hippocampi. Among MCI patients, performance on the FCI was moderately correlated with angular gyri and precunei volumes. Regression models demonstrated that angular gyri volumes were predictive of FCI scores. Tests of mediation showed that the relationship of angular gyri volume with FCI score was partially mediated by measures of arithmetic and possibly attention.
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 impact everyday financial skills. The findings have implications for diagnosis and clinical care of patients with MCI and AD.
PMCID: PMC3711192  PMID: 20374402
magnetic resonance imaging; mild cognitive impairment; financial capacity; angular gyrus; hippocampus; precuneus
3.  MRI Volume of the Medial Frontal Cortex Predicts Financial Capacity in Patients with Mild Alzheimer’s Disease 
Brain imaging and behavior  2013;7(3):10.1007/s11682-013-9226-3.
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.
PMCID: PMC3716854  PMID: 23504597
Alzheimer’s disease; financial capacity; magnetic resonance imaging; frontal cortex; precuneus; angular gyrus
4.  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 = 0.46, p < 0.05). The relationship of NAA/Cr with decision-making suggests a role for posterior cortical neuronal functioning in performance of complex IADLs in MCI.
PMCID: PMC3133695  PMID: 20373179
magnetic resonance spectroscopy; mild cognitive impairment; decision making; posterior cingulate gyrus; hippocampus
5.  An examination of Bayesian statistical approaches to modeling change in cognitive decline in an Alzheimer’s disease population 
The mini mental state examination (MMSE) is a common tool for measuring cognitive decline in Alzhiemer’s Disease (AD) subjects. Subjects are usually observed for a specified period of time or until death to determine the trajectory of the decline which for the most part appears to be linear. However, it may be noted that the decline may not be modeled by a single linear model over a specified period of time. There may be a point called a change point where the rate or gradient of the decline may change depending on the length of time of observation. A Bayesian approach is used to model the trajectory and determine an appropriate posterior estimate of the change point as well as the predicted model of decline before and after the change point. Estimates of the appropriate parameters as well as their posterior credible regions or regions of interest are established. Coherent prior to posterior analysis using mainly non informative priors for the parameters of interest is provided. This approach is applied to an existing AD database.
PMCID: PMC2791328  PMID: 20161460
Alzheimer’s Disease; Bayesian; Change Point; Mini Mental State; Trajectory
6.  Contributions of volumetrics of the hippocampus and thalamus to verbal memory in temporal lobe epilepsy patients 
Brain and cognition  2008;69(1):65-72.
Recent theories have posited that the hippocampus and thalamus serve distinct, yet related, roles in episodic memory. Whereas the hippocampus has been implicated in long-term memory encoding and storage, the thalamus, as a whole, has been implicated in the selection of items for subsequent encoding and the use of retrieval strategies. However, dissociating the memory impairment that occurs following thalamic injury as distinguished from that following hippocampal injury has proven difficult. This study examined relationships between MRI volumetric measures of the hippocampus and thalamus and their contributions to prose and rote verbal memory functioning in 18 patients with intractable temporal lobe epilepsy (TLE). Results revealed that bilateral hippocampal and thalamic volume independently predicted delayed prose verbal memory functioning. However, bilateral hippocampal, but not thalamic, volume predicted delayed rote verbal memory functioning. Follow-up analyses indicated that bilateral thalamic volume independently predicted immediate prose, but not immediate rote, verbal recall, whereas bilateral hippocampal volume was not associated with any of these immediate memory measures. These findings underscore the cognitive significance of thalamic atrophy in chronic TLE, demonstrating that hippocampal and thalamic volume make quantitatively, and perhaps qualitatively, distinct contributions to episodic memory functioning in TLE patients. They are also consistent with theories proposing that the hippocampus supports long-term memory encoding and storage, whereas the thalamus is implicated in the executive aspects of episodic memory.
PMCID: PMC2796537  PMID: 18599175
Hippocampus; Thalamus; Verbal memory; MRI volumetrics; Temporal lobe epilepsy
This study investigated financial abilities of 154 patients with mild cognitive impairment (MCI) (116 Caucasian, 38 African American) using the Financial Capacity Instrument (FCI). In a series of linear regression models, we examined the effect of race on FCI performance and identified preliminary predictor variables that mediated observed racial differences on the FCI. Prior/premorbid abilities were identified. Predictor variables examined in the models included race and other demographic factors (age, education, gender), performance on global cognitive measures (MMSE, DRS-2 Total Score), history of cardiovascular disease (hypertension, diabetes, hypercholesterolemia), and a measure of educational achievement (WRAT-3 Arithmetic). African American patients with MCI performed below Caucasian patients with MCI on six of the seven FCI domains examined and on the FCI total score. WRAT-3 Arithmetic emerged as a partial mediator of group differences on the FCI, accounting for 54% of variance. In contrast, performance on global cognitive measures and history of cardiovascular disease only accounted for 14% and 2%, respectively, of the variance. Racial disparities in financial capacity appear to exist among patients with amnestic MCI. Basic academic math skills related to educational opportunity and quality of education account for a substantial proportion of the group difference in financial performance.
PMCID: PMC2992589  PMID: 20625268
Mild Cognitive Impairment; financial capacity; IADL; disability; ethnicity; African American
8.  Cerebrospinal Fluid Profiles Predict Prospective Course and Outcome Among Persons with Amnestic Mild Cognitive Impairment 
Archives of neurology  2011;68(1):113-119.
To examine the effect of specific “CSF profiles” on the rate of cognitive decline, disease progression, and risk of conversion to Alzheimer's disease (AD) dementia in patients with amnestic mild cognitive impairment (MCI).
Total tau (t-tau), tau phosphorylated at threonine 181 (p-tau181), and β-amyloid 1-42 peptide (Aβ42) were immunoassayed in CSF samples obtained from MCI patients enrolled in the Alzheimer's Disease Neuroimaging Initiative. Patients were then stratified by “CSF profiles”: (1) normal t-tau and Aβ42 levels (i.e., normal–t-tauAβ42), (2) normal t-tau but abnormal Aβ42 (i.e., abnormal–Aβ42), (3) abnormal t-tau but normal Aβ42 (i.e., abnormal–t-tau), and (4) abnormal t-tau and Aβ42 (i.e., abnormal–t-tauAβ42).
Fifty-eight sites in the US and Canada.
One hundred ninety-five MCI patients.
Main Outcome Measures
A composite cognitive measure, the CDR-Sum of Boxes, and conversion to AD.
MCI patients with a CSF profile of abnormal–Aβ42 or abnormal–t-tauAβ42 experienced a faster rate of decline on the composite cognitive measure and the CDR-Sum of Boxes compared to those with normal–t-tauAβ42. They also had a greater risk of converting to AD relative to the normal–t-tauAβ42 group. In contrast, those with a CSF profile of abnormal–t-tau did not differ from the normal–t-tauAβ42 group on any outcome. These findings were generally replicated when the sample was reclassified by patterns of p-tau181 and Aβ42 abnormalities.
β-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 levels of Aβ42 may be prime targets for drug treatment and clinical trials in MCI.
PMCID: PMC3058271  PMID: 21220682
CSF; MCI; cognitive decline; disease progression; conversion to AD
Self and informant reports of functional abilities are weighted heavily in diagnostic decision making regarding mild cognitive impairment (MCI). However, it is unclear whether patients with MCI are fully aware and provide reliable estimates of their functional status. In this study, we used three different approaches to examine accuracy of self report of financial abilities among patients with MCI.
Cross-sectional, case-comparison group study.
University medical center.
Seventy-four patients with MCI and their informants, and 73 cognitively healthy older adults and their informants.
We compared MCI patients’ report of their financial abilities to their performance on an objective measure of financial capacity. We also compared informant reports of patients’ abilities to patients’ objective test performance, and informant reports to patients’ self report.
We found that the discrepancy between self report and objective performance was higher among MCI patients compared to the cognitively healthy older adults on the financial domains of Checkbook Management, Bank Statement Management, and Bill Payment, and on overall financial capacity. We also found that MCI patients with poorer global cognition overestimated their financial abilities whereas those with higher depressive symptoms underestimated their financial abilities. Overall, MCI patients were better at estimating their financial abilities than their informants.
Patients with MCI are not fully aware of deficits in their financial abilities. Both cognitive impairment and depression impact MCI patients’ self-reported functioning. In addition, MCI informants misestimate patients’ financial abilities. This raises concerns about the widespread use of informant report as the gold standard against which to evaluate patient self-report of functioning.
PMCID: PMC3189703  PMID: 18669943
financial capacity; awareness; anosognosia; report-based measures; objective testing; MCI; AD
Archives of neurology  2010;67(6):688-696.
To investigate the effect of CSF abnormalities on rate of decline in everyday function in normal aging, MCI, and mild AD.
T-tau, p-tau181, and Aβ42 were immunoassayed in CSF obtained from participants in the AD Neuroimaging Initiative. Random effects regressions were used to examine the relationship between CSF abnormalities, cognitive impairment (assessed with the ADAS-Cog), and functional decline (assessed with Pfeffer’s FAQ); and to determine whether the impact of CSF abnormality on functional decline is mediated by cognitive impairment.
Fifty-eight sites in the US and Canada.
One hundred fourteen cognitively-intact adults, 195 MCI patients, and 100 mild AD patients.
Decline in Pfeffer’s FAQ.
All CSF analytes were associated with functional decline in MCI and all but t-tau/Aβ42 were associated with functional decline in controls. No CSF analyte was associated with functional decline in AD. Among controls, p-tau181 was the most sensitive to functional decline whereas in MCI it was Aβ42. CSF biomarkers were uniformly more sensitive to functional decline than the ADAS-Cog among controls and variably so in MCI, whereas the ADAS-Cog was unequivocally more sensitive than CSF biomarkers in AD. The impact of CSF abnormalities on functional decline in MCI was partially mediated by their impact on cognitive status. Across all diagnostic groups, persons with both tau and Aβ42 abnormalities exhibited the steepest rate of functional decline.
CSF abnormalities are associated with functional decline, and thus with future development of AD in controls and MCI patients. However, they do not predict further functional degradation in AD. Persons with comorbid tau and Aβ42 abnormalities are at greatest risk of functional loss.
PMCID: PMC2888499  PMID: 20558388
CSF; FAQ; ADAS-Cog; activities of daily living; functional decline; MCI; AD
11.  Clinical Interview Assessment of Financial Capacity in Older Adults with Mild Cognitive Impairment and Alzheimer’s Disease 
To investigate financial capacity in patients with mild cognitive impairment (MCI) and Alzheimer’s disease (AD) using a clinician interview approach.
Tertiary care medical center.
Healthy older adults (N=75), patients with amnestic MCI (N=58), mild AD (N=97), and moderate AD (N=31).
The investigators and five study physicians developed a conceptually based, semi-structured clinical interview for evaluating seven core financial domains and overall financial capacity (Semi-Structured Clinical Interview for Financial Capacity; SCIFC). For each participant, a physician made capacity judgments (capable, marginally capable, or incapable) for each financial domain and for overall capacity.
Study physicians made a total of over 11,000 capacity judgments across the study sample (N=261). Very good inter-rater agreement was obtained for the SCIFC judgments. Increasing proportions of marginal and incapable judgment ratings were associated with increasing disease severity across the four study groups. For overall financial capacity, 95 percent of physician judgments for older controls were rated as capable, as compared to only 82% for patients with MCI, 26% for patients with mild AD, and 4% for patients with moderate AD.
Financial capacity in cognitively impaired older adults can be reliably evaluated by physicians using a relatively brief, semi-structured clinical interview. Financial capacity shows mild impairment in MCI, emerging global impairment in mild AD, and advanced global impairment in moderate AD. MCI patients and their families should proactively engage in financial and legal planning given these patients’ risk of developing AD and accelerated loss of financial abilities.
PMCID: PMC2714907  PMID: 19453308
financial capacity; competency; clinical assessment; mild cognitive impairment; Alzheimer’s disease
12.  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.
PMCID: PMC2765349  PMID: 19587066
Parkinson's disease with dementia; Alzheimer's disease; Executive function; List learning; Neuropsychologic tests; Comparative studies
13.  Neurocognitive predictors of financial capacity across the dementia spectrum: Normal aging, mild cognitive impairment, and Alzheimer’s disease 
Financial capacity is a complex instrumental activity of daily living critical to independent functioning of older adults and sensitive to impairment in patients with amnestic mild cognitive impairment (MCI) and Alzheimer’s disease (AD). However, little is known about the neurocognitive basis of financial impairment in dementia. We developed cognitive models of financial capacity in cognitively healthy older adults (n = 85) and patients with MCI (n = 113) and mild AD (n = 43). All participants were administered the Financial Capacity Instrument (FCI) and a neuropsychological test battery. Univariate correlation and multiple regression procedures were used to develop cognitive models of overall FCI performance across groups. The control model (R2 = .38) comprised (in order of entry) written arithmetic skills, delayed story recall, and simple visuomotor sequencing. The MCI model (R2 = .69) comprised written arithmetic skills, visuomotor sequencing and set alternation, and race. The AD model (R2 = .65) comprised written arithmetic skills, simple visuomotor sequencing, and immediate story recall. Written arithmetic skills (WRAT-3 Arithmetic) was the primary predictor across models, accounting for 27% (control model), 46% (AD model), and 55% (MCI model) of variance. Executive function and verbal memory were secondary model predictors. The results offer insight into the cognitive basis of financial capacity across the dementia spectrum of cognitive aging, MCI, and AD.
PMCID: PMC2838718  PMID: 19203439
Financial capacity; IADLs; Cognitive predictors; Cognitive aging; MCI; AD
14.  Brain metabolism differs in Alzheimer disease and Parkinson disease dementia 
Few comparative studies exist of metabolic brain changes among neurodegenerative illnesses. We compared brain metabolic abnormalities in Alzheimer’s disease (AD) and in Parkinson’s disease with dementia (PDD) as measured by proton magnetic resonance spectroscopy (MRS).
Twelve patients with idiopathic PDD, 22 patients with probable mild AD, and 61 healthy older controls underwent posterior cingulate MRS.
Patients with AD showed reduced N-acetylaspartate (NAA)/creatine (Cr) (p <0.05) and increased choline (Cho)/Cr (p <0.05) and myo-Inositol (mI)/Cr (p <0.01) compared to controls. Patients with PDD showed reduced NAA/Cr (p <0.05) and glutamate (Glu)/Cr (p <0.01) compared to controls. There was reduced Glu/Cr in PDD compared to AD (p <0.01).
Patients with AD and patients with PDD showed distinct brain metabolic MRS profiles. Findings suggest that comparison of brain MRS profiles across dementias provides useful direction for future study.
PMCID: PMC2600665  PMID: 19012867
Parkinson Disease; Alzheimer Disease; MR Spectroscopy; N-acetylaspartate; Gyrus Cinguli
15.  Medical Decision-Making Capacity in Cognitively Impaired Parkinson's Disease Patients Without Dementia 
Little is currently known about the higher order functional skills of patients with Parkinson disease and cognitive impairment. Medical decision-making capacity (MDC) was assessed in patients with Parkinson's disease (PD) with cognitive impairment and dementia. Participants were 16 patients with PD and cognitive impairment without dementia (PD-CIND), 16 patients with PD dementia (PDD), and 22 healthy older adults. All participants were administered the Capacity to Consent to Treatment Instrument (CCTI), a standardized capacity instrument assessing MDC under five different consent standards. Parametric and non-parametric statistical analyses were utilized to examine capacity performance on the consent standards. In addition, capacity outcomes (capable, marginally capable, or incapable outcomes) on the standards were identified for the two patient groups. Relative to controls, PD-CIND patients demonstrated significant impairment on the understanding treatment consent standard, clinically the most stringent CCTI standard. Relative to controls and PD-CIND patients, patients with PDD patients were impaired on the three clinical standards of understanding, reasoning, and appreciation. The findings suggest that impairment in decisional capacity is already present in cognitively impaired PD patients without dementia, and increases as these patients develop dementia. Clinicians and researchers should carefully assess decisional capacity in all PD patients with cognitive impairment.
PMCID: PMC2579319  PMID: 18759361
consent capacity; medical decision-making; cognitive impairment without dementia; functional change; Parkinson's disease
16.  Awareness of Functional Difficulties in Mild Cognitive Impairment: A Multi-Domain Assessment Approach 
Self-report of functional abilities is accorded significant weight in the clinical discrimination of mild cognitive impairment (MCI) from dementia. However, it is unclear whether patients with MCI are fully aware of and provide reliable estimates of their functional status. Prior studies that examined accuracy of self-report of functional abilities in MCI have presented mixed findings. Common limitations of these studies include the use of informant report as the yardstick for ascertaining accuracy of patient self-report, and the failure to account for potential heterogeneity in awareness across functional domains.
Controlled, matched-samples, cross-sectional analysis.
University medical and research centers.
57 persons with amnestic MCI and 68 normal controls.
The study examined accuracy of self-report in MCI across five functional domains by comparing patients’ report of functioning to their performance on laboratory-based measures of function.
The discrepancy between self-report and objective performance was significantly higher in MCI patients compared to cognitively-normal peers only on financial abilities. Patients with MCI overestimated their abilities on this functional domain. MCI patients also tended to overestimate their driving abilities, though this was not statistically significant.
These findings provide evidence that awareness of functional difficulties is not a unitary construct; rather, it varies across functional domains. They also suggest that self-report of functional abilities in MCI may be, on the whole, as accurate as among cognitively-intact older adults. Even so, the self-objective discrepancies noted for both study groups suggest that supplementing self-report information with objective functional assessment might improve the detection of MCI.
PMCID: PMC2738847  PMID: 19467146
MCI; functional abilities; awareness; heterogeneity

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