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1.  Dissociable executive functions in behavioral variant frontotemporal and Alzheimer dementias 
Neurology  2013;80(24):2180-2185.
Objective:
The objective of this study was to determine which aspects of executive functions are most affected in behavioral variant frontotemporal dementia (bvFTD) and best differentiate this syndrome from Alzheimer disease (AD).
Methods:
We compared executive functions in 22 patients diagnosed with bvFTD, 26 with AD, and 31 neurologically healthy controls using a conceptually driven and comprehensive battery of executive function tests, the NIH EXAMINER battery (http://examiner.ucsf.edu).
Results:
The bvFTD and the AD patients were similarly impaired compared with controls on tests of working memory, category fluency, and attention, but the patients with bvFTD showed significantly more severe impairments than the patients with AD on tests of letter fluency, antisaccade accuracy, social decision-making, and social behavior. Discriminant function analysis with jackknifed cross-validation classified the bvFTD and AD patient groups with 73% accuracy.
Conclusions:
Executive function assessment can support bvFTD diagnosis when measures are carefully selected to emphasize frontally specific functions.
doi:10.1212/WNL.0b013e318296e940
PMCID: PMC3721104  PMID: 23658382
2.  Mild Cognitive Impairment: A Concept and Diagnostic Entity in Need of Input from Neuropsychology 
This virtual issue consists of studies previously published in the Journal of the International Neuropsychological Society and selected on the basis of their content related to one of the most highly researched concepts in behavioral neurology and neuropsychology over the past decade: mild cognitive impairment (MCI). The reliance on cognitive screening measures, staging-based rating scales, and limited neuropsychological testing in diagnosing MCI across most research studies may miss individuals with subtle cognitive declines or mis-diagnose MCI in those who are otherwise cognitively normal on a broader neuropsychological battery of tests. The assembled articles highlight the perils of relying on these conventional criteria for MCI diagnosis and reveal how the reliability of diagnosis is improved when sound neuropsychological approaches are adopted. When these requirements are met, we illustrate with a second series of articles that neuropsychological measures associate strongly with biomarkers and often reflect pathology beyond or instead of typical AD distributions. The final set of articles reveal that people with MCI demonstrate mild but identifiable functional difficulties, and a challenge for neuropsychology is how to incorporate this information to better define MCI and distinguish it from early dementia. Neuropsychology is uniquely positioned to improve upon the state of the science in MCI research and practice by providing critically important empirical information on the specific cognitive domains affected by the predominant neurodegenerative disorders of late life as well as on the diagnostic decision-making strategies used in studies. When such efforts to more comprehensively assess neuropsychological functions are undertaken, better characterizations of spared and impaired cognitive and functional abilities result and lead to more convincing associations with other biomarkers as well as to prediction of clinical outcomes.
doi:10.1017/S1355617714000010
PMCID: PMC4039178  PMID: 24490866
Mild cognitive impairment; Alzheimer’s disease; Neuropsychology; Episodic memory; Semantic memory; Executive functions; Neuroimaging; Magnetic resonance imaging; Functional MRI; Diffusion tensor imaging; Cerebrospinal fluid; Biomarkers; Activities of daily living; Functional capacity
3.  What is the quality of life in the oldest old? 
International psychogeriatrics / IPA  2011;23(6):1003-1010.
Background
Maintaining and improving quality of life has become a major focus in geriatric medicine, but the oldest old have received limited attention in clinical investigations. We aimed to investigate the relationship between self-perceived and caregiver-perceived quality of life (QOL), cognitive functioning, and depressive symptoms in the oldest old.
Methods
This IRB-approved prospective study recruited community dwellers aged 90–99 years old. Collected data included neurological evaluation, DSM III-R criteria for dementia, Mini-Mental State Examination (MMSE), Dementia Rating Scale (DRS), Geriatric Depression Scale (GDS), Record of Independent Living (ROIL), and QOL assessment using the Linear Analogue Self Assessment (LASA).
Results
Data on 144 subjects (56 cognitively normal (normal), 13 mild cognitive impairment (MCI), 41 dementia (DEM), 34 dementia with stroke and parkinsonism (DEMSP)) over a three-year period were analyzed. Mean ages ranged from 93 to 94 years, and the majority were female with at least high school education. Overall functional ability was higher in groups without dementia (p < 0.0001). All subjects reported high overall QOL (range 6.76–8.3 out of 10), regardless of cognitive functioning. However, caregivers perceived the subjects’ overall QOL to be lower with increasing severity of cognitive impairment (p < 0.0001). Lower GDS scores correlate with higher self-perceived overall QOL (ρ = −0.38, p < 0.0001).
Conclusions
In our community sample of the oldest old, there was a fairly high level of overall QOL, whether or not cognitive impairment exists. Individuals perceive their QOL better than caregivers do, and the difference in subjects’ and caregivers’ perception is more pronounced for the groups with dementia. QOL is more strongly correlated with depressive symptoms than with dementia severity.
doi:10.1017/S1041610210002462
PMCID: PMC3924179  PMID: 21281556
geriatric; well being; cognition; depression; dementia; stroke; parkinsonism; MCI
4.  Successful Aging: Definitions and Prediction of Longevity and Conversion to Mild Cognitive Impairment 
Objectives
To examine alternative models of defining and characterizing successful aging.
Design
A retrospective cohort study
Setting
Olmsted County, MN.
Participants
560 community-dwelling non-demented adults, aged 65 years and older.
Measurements
Three models were developed. Each model examined subtests in four cognitive domains: memory, attention/executive function, language, and visual-spatial skills. A composite domain score was generated for each of the four domains. In Model 1, a global z-score was further generated from the four cognitive domains, and subjects with mean global z-score in the top 10% were classified as “successful agers” whereas those in the remaining 90% were classified as “typical agers”. In Model 2, subjects with all 4 domain scores above the 50th percentile were classified as “successful agers.” In Model 3, a primary neuropsychological variable was selected from each domain, and subjects whose score remained above minus 1 SD compared to norms for young adults were labeled successful agers. Validation tests were conducted to determine the ability of each model to predict survival and conversion to mild cognitive impairment (MCI).
Results
Model 1 showed 65% lower mortality in successful agers compared to typical agers, and also a 25% lower conversion rate to MCI.
Conclusion
Model 1 was most strongly associated with longevity and cognitive decline; as such, it can be useful in investigating various predictors of successful aging, including plasma level, APOE genotype, and neuroimaging measurements.
doi:10.1097/JGP.0b013e3181f17ec9
PMCID: PMC3918503  PMID: 21606901
successful aging; optimal aging; longevity; cognitive decline
5.  Polysomnographic Findings in Dementia With Lewy Bodies 
The neurologist  2013;19(1):1-6.
Introduction
The clinical features of dementia with Lewy bodies (DLB) during wakefulness are well known. Other than REM sleep behavior disorder (RBD), only limited data exists on other sleep disturbances and disorders in DLB. We sought to characterize the polysomnographic (PSG) findings in a series of DLB patients with sleep-related complaints.
Methods
Retrospective study of patients with DLB who underwent clinical PSG at Mayo Clinic Rochester or Mayo Clinic Jacksonville over an almost 11 year span for evaluation of dream enactment behavior, excessive nocturnal movements, sleep apnea, hypersomnolence, or insomnia. The following variables were analyzed: respiratory disturbance index (RDI) in disordered breathing events/hour, periodic limb movement arousal index (PLMAI), arousals for no apparent reason (AFNAR), total arousal index (TAI), presence of REM sleep without atonia (RSWA), and percent sleep efficiency (SE).
Results
Data on 78 patients (71M, 7F) were analyzed. The mean age was 71 ± 8 years. Seventy-five (96%) patients had histories of recurrent dream enactment during sleep with 83% showing confirmation of RSWA +/- dream enactment during PSG. Mean RDI = 11.9 ± 5.8, PLMAI = 5.9 ± 8.5, AFNARI = 10.7 ± 12.0, and TAI = 26.6 ± 17.4. SE was <80% in 72% of the sample, <70% in 49%, and <60% in 24%. In patients who did not show evidence of significant disordered breathing (23 with RDI<5), 62% of arousals were AFNARs. In those patients who had significant disordered breathing (55 with RDI ≥ 5), 36% of arousals were AFNARs. Six patients underwent evaluations with PSG plus MSLT. Two patients had mean initial sleep latencies less than five minutes, and both had RDI<5. No patient had any sleep onset rapid eye movement periods. Nineteen patients have undergone neuropathologic examination, and 18 have had limbic- or neocortical-predominant Lewy body pathology. One had progressive supranuclear palsy, but no REM sleep was recorded in prior PSG.
Conclusions
In patients with DLB and sleep-related complaints, several sleep disturbances in addition to RBD are frequently present. In this sample, about three quarters had a significant number of arousals not accounted for by a movement or breathing disturbance, and the primary sleep disorders do not appear to entirely account for the poor sleep efficiency in DLB, especially in those without a significant breathing disorder. Further studies are warranted to better understand the relationship between disturbed sleep, arousal and DLB; such characterization may provide insights into potential avenues of treatment of symptoms which could impact quality of life.
doi:10.1097/NRL.0b013e31827c6bdd
PMCID: PMC3587292  PMID: 23269098
Sleep disorders; REM sleep behavior disorder; dementia with Lewy bodies; synucleinopathy
6.  Multimodality Imaging Characteristics of Dementia with Lewy Bodies 
Neurobiology of Aging  2011;33(9):2091-2105.
Dementia with Lewy bodies (DLB) is the second most common cause of neurodegenerative dementia after Alzheimer's disease (AD). Our objective was to determine whether the 11C–Pittsburgh Compound-B (PiB) retention and regional hypometabolism on PET and regional cortical atrophy on MRI are complementary in characterizing patients with DLB and differentiating them from AD. We studied age, gender and education matched patients with a clinical diagnosis of DLB (n=21), AD (n=21), and cognitively normal subjects (n=42). Hippocampal atrophy, global cortical PiB retention and occipital lobe metabolism in combination distinguished DLB from AD better than any of the measurements alone (area under the receiver operating characteristic=0.98).Five of the DLB and AD patients who underwent autopsy were distinguished through multimodality imaging. These data demonstrate that MRI and PiB PET contribute to characterizing the distinct pathological mechanisms in patients with AD compared to DLB. Occipital and posterior parietotemporal lobe hypometabolism is a distinguishing feature of DLB and this regional hypometabolic pattern is independent of the amyloid pathology.
doi:10.1016/j.neurobiolaging.2011.09.024
PMCID: PMC3288845  PMID: 22018896
Dementia with Lewy bodies; MRI; PET; FDG; PiB; Alzheimer's disease
7.  Focal atrophy on MRI and neuropathologic classification of dementia with Lewy bodies 
Neurology  2012;79(6):553-560.
Objective:
To determine the association between the focal atrophy measures on antemortem MRI and postmortem neuropathologic classification of dementia with Lewy bodies (DLB) using the Third Report of the DLB Consortium criteria.
Methods:
We retrospectively identified 56 subjects who underwent antemortem MRI and had Lewy body (LB) pathology at autopsy. Subjects were pathologically classified as high (n = 25), intermediate (n = 22), and low likelihood DLB (n = 9) according to the Third Report of the DLB Consortium criteria. We included 2 additional pathologic comparison groups without LBs: one with low likelihood Alzheimer disease (AD) (control; n = 27) and one with high likelihood AD (n = 33). The associations between MRI-based volumetric measurements and the pathologic classification of DLB were tested with analysis of covariance by adjusting for age, sex, and MRI-to-death interval.
Results:
Antemortem hippocampal and amygdalar volumes increased from low to intermediate to high likelihood DLB (p < 0.001, trend test). Smaller hippocampal and amygdalar volumes were associated with higher Braak neurofibrillary tangle stage (p < 0.001). Antemortem dorsal mesopontine gray matter (GM) atrophy was found in those with high likelihood DLB compared with normal control subjects (p = 0.004) and those with AD (p = 0.01). Dorsal mesopontine GM volume decreased from low to intermediate to high likelihood DLB (p = 0.01, trend test).
Conclusion:
Antemortem hippocampal and amygdalar volumes increase and dorsal mesopontine GM volumes decrease in patients with low to high likelihood DLB according to the Third Report of the DLB Consortium criteria. Patients with high likelihood DLB typically have normal hippocampal volumes but have atrophy in the dorsal mesopontine GM nuclei.
doi:10.1212/WNL.0b013e31826357a5
PMCID: PMC3413765  PMID: 22843258
8.  Imaging and acetylcholinesterase inhibitor response in dementia with Lewy bodies 
Brain  2012;135(8):2470-2477.
Acetylcholinesterase inhibitors are commonly used to treat patients with dementia with Lewy bodies. Hippocampal atrophy on magnetic resonance imaging and amyloid-β load on positron emission tomography are associated with the Alzheimer’s disease-related pathology in patients with dementia with Lewy bodies. To date, few studies have investigated imaging markers that predict treatment response in patients with dementia with Lewy bodies. Our objective was to determine whether imaging markers of Alzheimer’s disease-related pathology such as hippocampal volume, brain amyloid-β load on 11C Pittsburgh compound B positron emission tomography predict treatment response to acetylcholinesterase inhibitors in patients with dementia with Lewy bodies. We performed a retrospective analysis on consecutive treatment-naive patients with dementia with Lewy bodies (n = 54) from the Mayo Clinic Alzheimer’s Disease Research Centre who subsequently received acetylcholinesterase inhibitors and underwent magnetic resonance imaging with hippocampal volumetry. Baseline and follow-up assessments were obtained with the Mattis Dementia Rating Scale. Subjects were divided into three groups (reliable improvement, stable or reliable decline) using Dementia Rating Scale reliable change indices determined previously. Associations between hippocampal volumes and treatment response were tested with analysis of covariance adjusting for baseline Dementia Rating Scale, age, gender, magnetic resonance field strength and Dementia Rating Scale interval. Seven subjects underwent 11C Pittsburgh compound B imaging within 12 weeks of magnetic resonance imaging. Global cortical 11C Pittsburgh compound B retention (scaled to cerebellar retention) was calculated in these patients. Using a conservative psychometric method of assessing treatment response, there were 12 patients with reliable decline, 29 stable cases and 13 patients with reliable improvement. The improvers had significantly larger hippocampi than those that declined (P = 0.02) and the stable (P = 0.04) group. An exploratory analysis demonstrated larger grey matter volumes in the temporal and parietal lobes in improvers compared with those who declined (P < 0.05). The two patients who had a positive 11C Pittsburgh compound B positron emission tomography scan declined and those who had a negative 11C Pittsburgh compound B positron emission tomography scan improved or were stable after treatment. Patients with dementia with Lewy bodies who do not have the imaging features of coexistent Alzheimer’s disease-related pathology are more likely to cognitively improve with acetylcholinesterase inhibitor treatment.
doi:10.1093/brain/aws173
PMCID: PMC3407425  PMID: 22810436
dementia with Lewy bodies; acetylcholinesterase inhibitors; MRI; PiB; PET; amyloid
9.  Antemortem amyloid imaging and β-amyloid pathology in a case with dementia with Lewy Bodies 
Neurobiology of Aging  2010;33(5):878-885.
The association between antemortem [11C]-Pittsburgh Compound B (PiB) retention and β-amyloid (Aβ) load, Lewy body (LB) and neurofibrillary tangle (NFT) densities were investigated in a pathologically confirmed case of dementia with LB (DLB). 76-year-old man presenting with a clinical diagnosis of DLB had undergone PiB–positron emission tomography (PET), 18F FDG-PET and MRI 18 months before death. The pathologic diagnosis was DLB neocortical-type with low-likelihood of Alzheimer's disease by NIA-Reagan criteria. Sections from regions of interest (ROI) on post-mortem examination were studied. A significant correlation was found between cortical Aβ density and PiB retention in the 17 corresponding ROIs (r=0.899; p<0.0001). Bielschowsky silver stain revealed mostly sparse neocortical neuritic plaques; whereas diffuse plaques were frequent. There was no correlation between LB density and PiB retention (r=0.13; p=0.66); nor between NFT density and PiB retention (r=−0.36; p=0.17). The ROI-based analysis of imaging and histopathological data confirms that PiB uptake on PET is a specific marker for Aβ density, but cannot differentiate neuritic from diffuse amyloid plaques in this case with DLB.
doi:10.1016/j.neurobiolaging.2010.08.007
PMCID: PMC3026854  PMID: 20961664
Dementia with Lewy bodies; amyloid imaging; PET; pathology; amyloid
10.  Reliable Change on the Boston Naming Test 
Serial assessments are commonplace in neuropsychological practice and used to document cognitive trajectory for many clinical conditions. However, true change scores may be distorted by measurement error, repeated exposure to the assessment instrument, or person variables. The present study provides reliable change indices (RCI) for the Boston Naming Test, derived from a sample of 844 cognitively normal adults aged 56 years and older. All participants were retested between 9 and 24 months after their baseline exam. Results showed that a 4-point decline during a 9–15 month retest period or a 6-point decline during a 16–24 month retest period represents reliable change. These cutoff values were further characterized as a function of a person’s age and family history of dementia. These findings may help clinicians and researchers to characterize with greater precision the temporal changes in confrontation naming ability.
doi:10.1017/S1355617711001810
PMCID: PMC3617478  PMID: 22264406
BNT; RCI; Aging; Dementia; Serial; Assessment
11.  Diagnostic Validity of Age- And Education-Corrections for the Mini-Mental State Examination (MMSE) in African American Elders 
Objectives
To investigate whether demographic (age and education) adjustments for the Mini-Mental State Examination (MMSE) attenuate mean score discrepancies between African American and Caucasian adults, and to determine whether demographically-adjusted MMSE scores improve the diagnostic classification accuracy of dementia in African American adults when compared to unadjusted MMSE scores.
Design
Cross-sectional study.
Setting
Community-dwelling adults participating in the Mayo Clinic Alzheimer’s Disease Patient Registry (ADPR) and Alzheimer’s Disease Research Center (ADRC).
Participants
Three thousand two hundred fifty-four adults (2819 Caucasian, 435 African American) aged 60 and older.
Measurements
MMSE at study entry.
Results
African American adults obtained significantly lower unadjusted MMSE scores (23.0 ± 7.4) compared to Caucasian adults (25.3 ± 5.4). This discrepancy persisted despite adjustment of MMSE scores for age and years of education using established regression weights or newly-derived weights. However, controlling for dementia severity at baseline and adjusting MMSE scores for age and quality of education attenuated this discrepancy. Among African American adults, an age- and education-adjusted MMSE cut score of 23/24 provided optimal dementia classification accuracy, but this represented only a modest improvement over an unadjusted MMSE cut score of 22/23. The posterior probability of dementia in African American adults is presented for various unadjusted MMSE cut scores and prevalence rates of dementia.
Conclusion
Age, dementia severity at study entry, and quality of educational experience are important explanatory factors to understand the existing discrepancies in MMSE performance between Caucasian and African American adults. Our findings support the use of unadjusted MMSE scores when screening African American elders for dementia, with an unadjusted MMSE cut score of 22/23 yielding optimal classification accuracy.
doi:10.1111/j.1532-5415.2011.03766.x
PMCID: PMC3288600  PMID: 22150301
MMSE; African American; ethnicity; dementia; cognition
12.  Probable REM Sleep Behavior Disorder Increases Risk for Mild Cognitive Impairment and Parkinson’s Disease: A Population-Based Study 
Annals of Neurology  2012;71(1):49-56.
Objective
REM sleep behavior disorder (RBD) is associated with neurodegenerative disease and particularly with the synucleinopathies. Convenience samples involving subjects with idiopathic RBD have suggested an increased risk of incident mild cognitive impairment (MCI), dementia (usually dementia with Lewy bodies) or Parkinson’s disease (PD). There is no data on such risk in a population-based sample.
Methods
Cognitively normal subjects aged 70–89 in a population-based study of aging who screened positive for probable RBD using the Mayo Sleep Questionnaire were followed at 15 month intervals. In a Cox Proportional Hazards Model, we measured the risk of developing MCI, dementia, PD among the exposed (pRBD+) and unexposed (pRBD−) cohorts.
Results
Forty-four subjects with pRBD+ at enrollment (median duration of pRBD features was 7.5 years), and 607 pRBD− subjects, were followed prospectively for a median of 3.8 years. Fourteen of the pRBD+ subjects developed MCI and one developed PD (15/44=34% developed MCI / PD); none developed dementia. After adjustment for age, sex, education, and medical comorbidity, pRBD+ subjects were at increased risk of MCI / PD [Hazard Ratio (HR) 2.2, 95% Confidence Interval (95%CI) 1.3 – 3.9; p=0.005]. Inclusion of subjects who withdrew from the study produced similar results, as did exclusion of subjects with medication-associated RBD. Duration of pRBD symptoms did not predict the development of MCI / PD (HR 1.05 per 10 years, 95%CI 0.84 – 1.3; p=0.68).
Interpretation
In this population-based cohort study, we observed that pRBD confers a 2.2-fold increased risk of developing MCI / PD over four years.
doi:10.1002/ana.22655
PMCID: PMC3270692  PMID: 22275251
sleep disorders; parasomnias; dementia; Alzheimer’s disease; dementia with Lewy bodies; parkinsonism; synuclein
13.  Predicting Functional Ability in Mild Cognitive Impairment with the Dementia Rating Scale-2 
BACKGROUND
We examined the utility of cognitive evaluation to predict instrumental activities of daily living (IADLs) and decisional ability in Mild Cognitive Impairment (MCI).
METHODS
Sixty-seven individuals with single domain amnestic MCI were administered the Dementia Rating Scale-2 as well as the Everyday Cognition (ECog) form to assess functional ability.
RESULTS
DRS-2 Total Scores and Initiation/Perseveration and Memory subscales were found to be predictive of IADLs, with Total Scores accounting for 19% of the variance in IADL performance on average. Additionally, DRS-2 Initiation/Perseveration and Total Score were predictive of ability to understand information, and DRS-2 Conceptualization helped predict ability to communicate with others, both key variables in decision making ability.
CONCLUSIONS
These findings suggest that performance on the DRS-2, and specific subscales related to executive function and memory, is significantly related to IADLs in individuals with MCI. These cognitive measures are also associated in decision making related abilities in MCI.
doi:10.1017/S1041610211002717
PMCID: PMC3348287  PMID: 22265236
Mild Cognitive Impairment; Cognitive Ability; Activities of Daily Living; Decision Making Ability
14.  Computerized Analysis of Speech and Language to Identify Psycholinguistic Correlates of Frontotemporal Lobar Degeneration 
Objective
To evaluate the use of a semiautomated computerized system for measuring speech and language characteristics in patients with frontotemporal lobar degeneration (FTLD).
Background
FTLD is a heterogeneous disorder comprising at least 3 variants. Computerized assessment of spontaneous verbal descriptions by patients with FTLD offers a detailed and reproducible view of the underlying cognitive deficits.
Methods
Audiorecorded speech samples of 38 patients from 3 participating medical centers were elicited using the Cookie Theft stimulus. Each patient underwent a battery of neuropsychologic tests. The audio was analyzed by the computerized system to measure 15 speech and language variables. Analysis of variance was used to identify characteristics with significant differences in means between FTLD variants. Factor analysis was used to examine the implicit relations between subsets of the variables.
Results
Semiautomated measurements of pause-to-word ratio and pronoun-to-noun ratio were able to discriminate between some of the FTLD variants. Principal component analysis of all 14 variables suggested 4 subjectively defined components (length, hesitancy, empty content, grammaticality) corresponding to the phenomenology of FTLD variants.
Conclusion
Semiautomated language and speech analysis is a promising novel approach to neuropsychologic assessment that offers a valuable contribution to the toolbox of researchers in dementia and other neurodegenerative disorders.
doi:10.1097/WNN.0b013e3181c5dde3
PMCID: PMC3365864  PMID: 20829666
spontaneous speech; language; prosody; frontotemporal lobar degeneration; automated speech analysis
15.  Validation of the Mayo Sleep Questionnaire to Screen for REM Sleep Behavior Disorder in an Aging and Dementia Cohort 
Sleep medicine  2011;12(5):445-453.
Objective
To validate a questionnaire focused on REM sleep behavior disorder (RBD) among participants in an aging and dementia cohort.
Background
RBD is a parasomnia that can develop in otherwise neurologically-normal adults as well as in those with a neurodegenerative disease. Confirmation of RBD requires polysomnography (PSG). A simple screening measure for RBD would be desirable for clinical and research purposes.
Methods
We had previously developed the Mayo Sleep Questionnaire (MSQ), a 16 item measure, to screen for the presence of RBD and other sleep disorders. We assessed the validity of the MSQ by comparing the responses of patients’ bed partners with the findings on PSG. All subjects recruited in the Mayo Alzheimer’s Disease Research Center at Mayo Clinic Rochester and Mayo Clinic Jacksonville from 1/00 to 7/08 who had also undergone a PSG were the focus of this analysis.
Results
The study sample was comprised of 176 subjects [150 male; median age 71 years (range 39–90)], with the following clinical diagnoses: normal (n=8), mild cognitive impairment (n=44), Alzheimer’s disease (n=23), dementia with Lewy bodies (n=74), as well as other dementia and/or parkinsonian syndromes (n=27). The core question on recurrent dream enactment behavior yielded a sensitivity (SN) of 98% and specificity (SP) of 74% for the diagnosis of RBD. The profile of responses on four additional subquestions on RBD and one on obstructive sleep apnea improved specificity.
Conclusions
These data suggest that among aged subjects with cognitive impairment and/or parkinsonism, the MSQ has adequate SN and SP for the diagnosis of RBD. The utility of this scale in other patient populations will require further study.
doi:10.1016/j.sleep.2010.12.009
PMCID: PMC3083495  PMID: 21349763
sleep disorders; parasomnias; dementia; Alzheimer’s disease; dementia with Lewy bodies; parkinsonism
16.  Neuropsychiatric Aspects of Primary Progressive Aphasia 
Few studies have reported neuropsychiatric symptoms (NPS) in Primary Progressive Aphasia (PPA), a neurodegenerative disorder that primarily affects the left hemisphere. Depression is associated with left-sided stroke, but it remains unclear if depression and other NPS are also associated with PPA. The authors compared the frequency of NPS in 55 cases of PPA with 110 cognitively normal persons matched for age, sex and education. Depression, apathy, agitation, anxiety, appetite change, and irritability are associated with PPA. Hallucinations, delusion and night time behavior were not associated with PPA.
doi:10.1176/appi.neuropsych.23.2.168
PMCID: PMC3204925  PMID: 21677245
17.  Predicting functional decline in behavioural variant frontotemporal dementia 
Brain  2011;134(2):432-448.
Behavioural variant frontotemporal dementia is characterized by a change in comportment. It is associated with considerable functional decline over the course of the illness albeit with sometimes dramatic variability among patients. It is unknown whether any baseline features, or combination of features, could predict rate of functional decline in behavioural variant frontotemporal dementia. The aim of this study was to investigate the effects of different baseline clinical, neuropsychological, neuropsychiatric, genetic and anatomic predictors on the rate of functional decline as measured by the Clinical Dementia Rating Sum of Boxes scale. We identified 86 subjects with behavioural variant frontotemporal dementia that had multiple serial Clinical Dementia Rating Sum of Boxes assessments (mean 4, range 2–18). Atlas-based parcellation was used to generate volumes for specific regions of interest at baseline. Volumes were utilized to classify subjects into different anatomical subtypes using the advanced statistical technique of cluster analysis and were assessed as predictor variables. Composite scores were generated for the neuropsychological domains of executive, language, memory and visuospatial function. Behaviours from the brief questionnaire form of the Neuropsychiatric Inventory were assessed. Linear mixed-effects regression modelling was used to determine which baseline features predict rate of future functional decline. Rates of functional decline differed across the anatomical subtypes of behavioural variant frontotemporal dementia, with faster rates observed in the frontal dominant and frontotemporal subtypes. In addition, subjects with poorer performance on neuropsychological tests of executive, language and visuospatial function, less disinhibition, agitation/aggression and night-time behaviours at presentation, and smaller medial, lateral and orbital frontal lobe volumes showed faster rates of decline. In many instances, the effect of the predictor variables observed across all subjects was also preserved within anatomical subtypes. Furthermore, some of the predictor variables improved our prediction of rate of functional decline after anatomical subtype was taken into account. In particular, age at onset was a highly significant predictor but only after adjusting for subtype. We also found that although some predictor variables, for example gender, Mini-Mental State Examination score, and apathy/indifference, did not affect the rate of functional decline; these variables were associated with the actual Clinical Dementia Rating Sum of Boxes score estimated for any given time-point. These findings suggest that in behavioural variant frontotemporal dementia, rate of functional decline is driven by the combination of anatomical pattern of atrophy, age at onset, and neuropsychiatric characteristics of the subject at baseline.
doi:10.1093/brain/awq348
PMCID: PMC3030765  PMID: 21252111
frontotemporal dementia; behaviour; functional decline; brain volumes; mixed effects models
18.  Mayo Older Americans Normative Studies: Factor Analysis of an Expanded Neuropsychological Battery 
The Mayo Cognitive Factor Scores were derived from a “core battery” consisting of the WAIS-R, WMS-R, and Auditory Verbal Learning Test. The present study sought to clarify the factor structure of an expanded neuropsychological battery in normal elderly controls. Confirmatory factor analysis was performed on the WAIS-III, WRAT-3 Reading, Boston Naming Test, Controlled Oral Word Association Test, Category Fluency, Rey-Osterrieth Complex Figure, Visual Form Discrimination, and Trail Making Test A & B. A base four-factor model consistent with the WAIS-III factor structure was utilized. Only one novel five factor model differentiating processing and motor speed tests improved upon this base model. Other models did not, including a factor for executive function, division of construction/visuospatial ability, or “hold”/“no hold” language abilities.
doi:10.1080/13854040801891686
PMCID: PMC2877131  PMID: 18609331
19.  A behavioral rehabilitation intervention for amnestic Mild Cognitive Impairment 
Individuals with amnestic Mild Cognitive Impairment (MCI) currently have few treatment options for combating their memory loss. The Memory Support System (MSS) is a calendar and organization system with accompanying 6-week curriculum designed for individuals with progressive memory impairment. Ability to learn the MSS and its utility were assessed in 20 participants. Participants were significantly more likely to successfully use the calendar system after training. Ninety-five percent were compliant with the MSS at training completion, and 89% continued to be compliant at follow-up. Outcome measures revealed a medium effect size for improvement in functional ability. Subjects further reported improved independence, self-confidence, and mood. This initial examination of the MSS suggests that with appropriate training, individuals with amnestic MCI can and will use a memory notebook system to help compensate for memory loss. These results are encouraging that the MSS may help with the symptoms of memory decline in MCI.
doi:10.1177/1533317508320352
PMCID: PMC2845519  PMID: 18955724
mild cognitive impairment; cognitive rehabilitation; memory loss; functional ability; behavioral interventions; memory notebook
20.  Differential Item Functioning of the Boston Naming Test in Cognitively Normal African American and Caucasian Older Adults 
Scores on the Boston Naming Test (BNT) are frequently lower for African American when compared to Caucasian adults. Although demographically-based norms can mitigate the impact of this discrepancy on the likelihood of erroneous diagnostic impressions, a growing consensus suggests that group norms do not sufficiently address or advance our understanding of the underlying psychometric and sociocultural factors that lead to between-group score discrepancies. Using item response theory and methods to detect differential item functioning (DIF), the current investigation moves beyond comparisons of the summed total score to examine whether the conditional probability of responding correctly to individual BNT items differs between African American and Caucasian adults. Participants included 670 adults age 52 and older who took part in Mayo's Older Americans and Older African Americans Normative Studies. Under a 2-parameter logistic IRT framework and after correction for the false discovery rate, 12 items where shown to demonstrate DIF. Six of these 12 items (“dominoes,” “escalator,” “muzzle,” “latch,” “tripod,” and “palette”) were also identified in additional analyses using hierarchical logistic regression models and represent the strongest evidence for race/ethnicity-based DIF. These findings afford a finer characterization of the psychometric properties of the BNT and expand our understanding of between-group performance.
doi:10.1017/S1355617709990361
PMCID: PMC2835360  PMID: 19570311
Boston Naming Test; Item response theory; Differential item functioning; Ethnicity; Race; Bias
21.  COMPARATIVE DIAGNOSTIC UTILITY OF DIFFERENT MR MODALITIES IN MILD COGNITIVE IMPAIRMENT AND ALZHEIMER’S DISEASE 
This study compares diagnostic accuracy of magnetic resonance (MR)-based hippocampal volumetry, single voxel (SV) 1H MR Spectroscopy (MRS) and MR diffusion weighted imaging (DWI) measurements in discriminating patients with amnestic mild cognitive impairment (MCI), Alzheimer’s disease (AD) and normally aging elderly. Sixty-one normally aging elderly, 24 MCI, and 22 AD patients underwent MR-based hippocampal volumetry, 1H MRS, and DWI. 1H MRS voxels were placed over both of the posterior cingulate gyri and N-acetyl aspartate (NAA) / creatine (Cr), myoinositol (MI) /Cr and NAA /MI ratios were obtained. Apparent diffusion coefficient (ADC) maps were derived from DWI and hippocampal borders were traced to measure hippocampal ADC. At 80% specificity, the most sensitive single measurement to discriminate MCI (79 %) and AD (86 %) from controls was hippocampal volumes. The most sensitive single measurement to discriminate AD from MCI was posterior cingulate gyrus NAA /Cr (67 %). At high specificity (>85 –90%) combinations of MR measures had superior diagnostic sensitivity compared to any single MR measurement for the AD vs. control and control vs. MCI comparisons. The MR measures that best discriminate more from less affected individuals along the cognitive continuum from normal to AD vary with disease severity. Selection of imaging measures used for clinical assessment or monitoring efficiency of therapeutic intervention should be tailored to the clinical stage of the disease.
PMCID: PMC2796574  PMID: 12411762
Alzheimer’s disease; mild cognitive impairment; 1H MRS; diffusion weighted imaging; hippocampal volumetry; MRI
22.  Abnormal TDP-43 immunoreactivity in AD modifies clinicopathological and radiological phenotype 
Neurology  2008;70(19 Pt 2):1850-1857.
Background
TAR DNA-binding protein 43 (TDP-43) is one of the major disease proteins in frontotemporal lobar degeneration with ubiquitin immunoreactivity. Approximately 1/4 of subjects with pathologically confirmed Alzheimer's disease (AD) have abnormal TDP-43 (abTDP-43) immunoreactivity. The aim of this study was to determine if subjects with pathologically confirmed AD and abTDP-43 immunoreactivity have distinct clinical, neuropsychological, imaging or pathological features compared to subjects with AD without abTDP-43 immunoreactivity.
Methods
Eighty-four subjects were identified that had a pathological diagnosis of AD, neuropsychometric testing, and volumetric MRI. Immunohistochemistry for TDP-43 was performed on sections of hippocampus and medial temporal lobe, and positive cases were classified into one of three types. Neuropsychometric data was collated and compared in subjects with and without abTDP-43 immunoreactivity. Voxel-based morphometry was used to assess patterns of gray matter atrophy in subjects with and without abTDP-43 immunoreactivity compared to age and gender matched controls.
Results
Twenty-nine (34%) of the 84 AD subjects had abTDP-43 immunoreactivity. Those with abTDP-43 immunoreactivity were older at onset and death, and performed worse on the Clinical Dementia Rating scale, Mini-Mental State Examination and Boston Naming Test than subjects without abTDP-43 immunoreactivity. Subjects with and without abTDP-43 immunoreactivity had medial temporal and temporoparietal gray matter loss compared to controls; however, those with abTDP-43 immunoreactivity showed greater hippocampal atrophy. Multivariate logistic regression adjusting for age at death demonstrated that hippocampal sclerosis was the only pathological predictor of abTDP-43 immunoreactivity.
Conclusions
The presence of abTDP-43 immunoreactivity is associated with a modified AD clinicopathological and radiological phenotype.
doi:10.1212/01.wnl.0000304041.09418.b1
PMCID: PMC2779031  PMID: 18401022
23.  DWI PREDICTS FUTURE PROGRESSION TO ALZHEIMER’S DISEASE IN AMNESTIC MILD COGNITIVE IMPAIRMENT 
Neurology  2005;64(5):902-904.
This study tests if measures of hippocampal water diffusivity at baseline can predict future progression to Alzheimer’s Disease (AD) in amnestic mild cognitive impairment (aMCI). Higher baseline hippocampal diffusivity was associated with a greater hazard of progression to AD in aMCI (p=0.002). MR diffusion weighted imaging (DWI) may help identify patients with aMCI who will progress to AD as well or better than structural MRI measures of hippocampal atrophy.
doi:10.1212/01.WNL.0000153076.46126.E9
PMCID: PMC2771335  PMID: 15753434
24.  The Rate of Medial Temporal Lobe Atrophy in Typical Aging and Alzheimer's Disease 
Neurology  1998;51(4):993-999.
Objectives
To determine the annualized rates of volumetric change of the hippocampus and temporal horn in cognitively normal elderly control subjects and individually matched patients with Alzheimer's disease (AD). To test the hypothesis that these rates were different .
Background
Cross-sectional studies consistently reveal cerebral atrophy in elderly non-demented subjects compared to healthy young adults, and greater atrophy in patients with AD relative to elderly controls. However, rates of atrophy are most accurately estimated by performing serial measurements in the same individuals.
Methods
Magnetic resonance imaging (MRI)-based volume measurements of the hippocampi and temporal horns were performed in 24 cognitively normal subjects ages 70–89 years who were individually matched with respect to gender and age with 24 patients with AD. Each subject underwent an MRI scanning protocol twice, separated by 12 months or more.
Results
The mean annualized rate of hippocampal volume loss among controls was −1.55% ± 1.38%/year and the temporal horns increased in volume by 6.15% ± 7.69%/year. These rates were significantly greater among AD patients: hippocampus −3.98% ± 1.92%/year, P <.001; temporal horn 14.16% ± 8.47%/year, P = .002.
Conclusion
A statistically significant yearly decline in hippocampal volume and increase in temporal horn volume was identified in elderly controls who represent typical aging individuals. These rates were approximately 2◻ times greater in patients with AD than in individually age and gender matched controls.
PMCID: PMC2768817  PMID: 9781519
25.  1H MR SPECTROSCOPY IN COMMON DEMENTIAS 
Neurology  2004;63(8):1393-1398.
Objective
To determine the 1H MR spectroscopic (MRS) findings and inter-group differences among common dementias: Alzheimer's disease (AD), vascular dementia (VaD), dementia with Lewy bodies (DLB), and frontotemporal lobar degeneration (FTLD).
Methods
We consecutively recruited 206 normal elderly, 121 patients with AD, 41 with FTLD, 20 with DLB, and 8 with VaD. We evaluated the 1H MRS metabolite ratio changes in common dementias with respect to normal, and also differences among the common dementias.
Results
N-acetylaspartate/Creatine (NAA/Cr) was lower than normal in patients with AD, FTLD, and VaD. Myo-inositol (mI)/Cr was higher than normal in patients with AD and FTLD. Choline (Cho)/Cr was higher than normal in patients with, AD, FTLD, and DLB. There were no metabolite differences between patients with AD and FTLD, nor between patients with DLB and VaD. NAA /Cr was lower in patients with AD and FTLD than DLB. MI /Cr was higher in patients with AD and FTLD than VaD. MI /Cr was also higher in patients with FTLD than DLB.
Conclusions
NAA/Cr levels are decreased in dementias that are characterized by neuron loss such as AD, FTLD, and VaD. MI/Cr levels are elevated in dementias that are pathologically characterized by gliosis such as AD and FTLD. Cho/Cr levels are elevated in dementias that are characterized by a profound cholinergic deficit such as AD and DLB.
PMCID: PMC2766798  PMID: 15505154

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