To determine the rate of progression of mild cognitive impairment (MCI) to dementia with Lewy bodies (DLB).
We followed 337 patients with MCI in the Mayo Alzheimer's Disease Research Center (range 2–12 years). Competing risks survival models were used to examine the rates of progression to clinically probable DLB and Alzheimer disease (AD). A subset of patients underwent neuropathologic examination.
In this clinical cohort, 116 remained as MCI, while 49 progressed to probable DLB, 162 progressed to clinically probable AD, and 10 progressed to other dementias. Among nonamnestic MCI, progression rate to probable DLB was 20 events per 100 person-years and to probable AD was 1.6 per 100 person-years. Among amnestic MCI, progression rate to probable AD was 17 events per 100 person-years, and to DLB was 1.5 events per 100 person-years. In 88% of those who developed probable DLB, the baseline MCI diagnosis included attention and/or visuospatial deficits. Those who developed probable DLB were more likely to have baseline daytime sleepiness and subtle parkinsonism. In 99% of the clinically probable AD group, the baseline MCI diagnosis included memory impairment. Neuropathologic confirmation was obtained in 24 of 30 of those with clinically probable AD, and in 14 of 18 of those with clinically probable DLB.
In a clinical sample, patients with nonamnestic MCI were more likely to develop DLB, and those with amnestic MCI were more likely to develop probable AD.
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.
dementia with Lewy bodies; acetylcholinesterase inhibitors; MRI; PiB; PET; amyloid
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.
BNT; RCI; Aging; Dementia; Serial; Assessment
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.
Community-dwelling adults participating in the Mayo Clinic Alzheimer’s Disease Patient Registry (ADPR) and Alzheimer’s Disease Research Center (ADRC).
Three thousand two hundred fifty-four adults (2819 Caucasian, 435 African American) aged 60 and older.
MMSE at study entry.
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.
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.
MMSE; African American; ethnicity; dementia; cognition
Differential item functioning (DIF) occurs when a test item has different statistical properties in subgroups, controlling for the underlying ability measured by the test. DIF assessment is necessary when evaluating measurement bias in tests used across different language groups. However, other factors such as educational attainment can differ across language groups, and DIF due to these other factors may also exist. How to conduct DIF analyses in the presence of multiple, correlated factors remains largely unexplored. This study assessed DIF related to Spanish versus English language in a 44-item object naming test. Data come from a community-based sample of 1,755 Spanish- and English-speaking older adults. We compared simultaneous accounting, a new strategy for handling differences in educational attainment across language groups, with existing methods. Compared to other methods, simultaneously accounting for language- and education-related DIF yielded salient differences in some object naming scores, particularly for Spanish speakers with at least 9 years of education. Accounting for factors that vary across language groups can be important when assessing language DIF. The use of simultaneous accounting will be relevant to other cross-cultural studies in cognition and in other fields, including health-related quality of life.
cognitive testing; item response theory; logistic regression; test bias; translation
The Boston Naming Test is one of the most widely used neuropsychological instruments; yet, there has been limited use of modern psychometric methods to investigate its properties at the item level. The current study used Item response theory to examine each item's difficulty and discrimination properties, as well as the test's measurement precision across the range of naming ability. Participants included 300 consecutive referrals to the outpatient neuropsychology service at Mayo Clinic in Florida. Results showed that successive items do not necessarily reflect a monotonic increase in psychometric difficulty, some items are inadequate to distinguish individuals at various levels of naming ability, multiple items provide redundant psychometric information, and measurement precision is greatest for persons within a low-average range of ability. These findings may be used to develop short forms, improve reliability in future test versions by replacing psychometrically poor items, and analyze profiles of intra-individual variability.
Boston Naming Test; Item response theory; Item difficulty; Item discriminability
KIBRA SNP rs17070145 was identified in a GWAS of memory performance, with some but not all follow-up studies confirming association of its T allele with enhanced memory. This allele was associated with reduced Alzheimer's disease (AD) risk in one study, which also found overexpression of KIBRA in memory-related brain regions of ADs. We genotyped rs17070145 and 14 additional SNPs in 2571 LOADs vs. 2842 controls, including African-Americans. We found significantly reduced risk for rs17070145 T allele in the older African-American subjects (p=0.007) and a suggestive effect in the older Caucasian series. Meta-analysis of this allele in >8000 subjects from our and published series showed a suggestive protective effect (p=0.07). Analysis of episodic memory in control subjects did not identify associations with rs17070145, though other SNPs showed significant associations in one series. KIBRA showed evidence of overexpression in the AD temporal cortex (p=0.06) but not cerebellum. These results suggest a modest role for KIBRA as a cognition and AD risk gene, and also highlight the multifactorial complexity of its genetic associations.
Alzheimer's disease; Association studies in genetics; Case control studies
Numerous kindreds with familial frontotemporal dementia and/or amyotrophic lateral sclerosis have been linked to chromosome 9, and an expansion of the GGGGCC hexanucleotide repeat in the non-coding region of chromosome 9 open reading frame 72 has recently been identified as the pathogenic mechanism. We describe the key characteristics in the probands and their affected relatives who have been evaluated at Mayo Clinic Rochester or Mayo Clinic Florida in whom the hexanucleotide repeat expansion were found. Forty-three probands and 10 of their affected relatives with DNA available (total 53 subjects) were shown to carry the hexanucleotide repeat expansion. Thirty-six (84%) of the 43 probands had a familial disorder, whereas seven (16%) appeared to be sporadic. Among examined subjects from the 43 families (n = 63), the age of onset ranged from 33 to 72 years (median 52 years) and survival ranged from 1 to 17 years, with the age of onset <40 years in six (10%) and >60 in 19 (30%). Clinical diagnoses among examined subjects included behavioural variant frontotemporal dementia with or without parkinsonism (n = 30), amyotrophic lateral sclerosis (n = 18), frontotemporal dementia/amyotrophic lateral sclerosis with or without parkinsonism (n = 12), and other various syndromes (n = 3). Parkinsonism was present in 35% of examined subjects, all of whom had behavioural variant frontotemporal dementia or frontotemporal dementia/amyotrophic lateral sclerosis as the dominant clinical phenotype. No subject with a diagnosis of primary progressive aphasia was identified with this mutation. Incomplete penetrance was suggested in two kindreds, and the youngest generation had significantly earlier age of onset (>10 years) compared with the next oldest generation in 11 kindreds. Neuropsychological testing showed a profile of slowed processing speed, complex attention/executive dysfunction, and impairment in rapid word retrieval. Neuroimaging studies showed bilateral frontal abnormalities most consistently, with more variable degrees of parietal with or without temporal changes; no case had strikingly focal or asymmetric findings. Neuropathological examination of 14 patients revealed a range of transactive response DNA binding protein molecular weight 43 pathology (10 type A and four type B), as well as ubiquitin-positive cerebellar granular neuron inclusions in all but one case. Motor neuron degeneration was detected in nine patients, including five patients without ante-mortem signs of motor neuron disease. While variability exists, most cases with this mutation have a characteristic spectrum of demographic, clinical, neuropsychological, neuroimaging and especially neuropathological findings.
frontotemporal dementia; amyotrophic lateral sclerosis; motor neuron disease; TDP-43; neurogenetics; chromosome 9
The Dementia Rating Scale (DRS) is a widely used measure of global cognition, with age- and education-corrected norms derived from a cross-sectional sample of adults participating in Mayo's Older Americans Normative Studies (MOANS). In recent years, however, studies have indicated that cross-sectional normative samples of older adults represent an admixture of individuals who are indeed cognitively normal (i.e., disease-free) and individuals with incipient neurodegenerative disease. Theoretically, the “contamination” of cross-sectional normative samples with cases of preclinical dementia can lead to underestimation of the test mean and overestimation of the variance, thus reducing the clinical utility of the norms. Robust norming, in which dementia cases are removed from the normative cohort through longitudinal follow-up, is an alternative approach to norm development. The current study presents a reappraisal of the original MOANS DRS norms, provides robust and expanded norms based on a sample of 894 adults age 55 and over, and critically evaluates the benefits of robust norming.
Dementia Rating Scale; DRS; Alzheimer's disease; Robust; Norms
The Geriatric Depression Scale (GDS) is one of the most widely used self-rated mood questionnaires for older adults. It is highly correlated with clinical diagnoses of depression and has demonstrated validity across different patient populations. However, the reliability of the GDS among African American older adults remains to be firmly established. In a baseline sample of 401 African American adults age 51 and over, the GDS-15 item short form demonstrates good internal consistency (KR20=.71). Stability over a 15-month interval in a retest sample of 51 adults is deemed adequate (r=.68). These findings support the use of the GDS-15 item short form as a reliable mood questionnaire among African American older adults.
Geriatric depression scale; GDS; Depression; African American; Reliability
The measurement of cognitive abilities across diverse cultural, racial, and ethnic groups has a contentious history, with broad political, legal, economic, and ethical repercussions. Advances in psychometric methods and converging scientific ideas about genetic variation afford new tools and theoretical contexts to move beyond the reflective analysis of between-group test score discrepancies. Neuropsychology is poised to benefit from these advances to cultivate a richer understanding of the factors that underlie cognitive test score disparities. To this end, the present article considers several topics relevant to the measurement of cognitive abilities across groups from diverse ancestral origins, including fairness and bias, equivalence, diagnostic validity, item response theory, and differential item functioning.
Cross-cultural neuropsychology; measurement; genomics; ethnicity; race; differential item functioning
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.
Boston Naming Test; Item response theory; Differential item functioning; Ethnicity; Race; Bias
Accurate neuropsychological assessment of older individuals from heterogeneous backgrounds is a major challenge. Education, ethnicity, language, and age are associated with scale level differences in test scores, but item level bias might contribute to these differences. We evaluated several strategies for dealing with item and scale level demographic influences on a measure of executive abilities defined by working memory and fluency tasks. We determined the impact of differential item functioning (DIF). We compared composite scoring strategies on the basis of their relationships with volumetric MRI measures of brain structure. Participants were 791 Hispanic, White, and African American older adults. DIF had a salient impact on test scores for 9% of the sample. MRI data were available on a subset of 153 participants. Validity in comparison with structural MRI was higher after scale level adjustment for education, ethnicity/language, and gender, but item level adjustment did not have a major impact on validity. Age adjustment at the scale level had a negative impact on relationships with MRI, most likely because age adjustment removes variance related to age-associated diseases.
composite scores; item response theory; dementia; demographic-adjusted T scores; ordinal logistic regression; test bias