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1.  Loss of Calbindin-D28K is Associated with the Full Range of Tangle Pathology within Basal Forebrain Cholinergic Neurons in Alzheimer's Disease 
Neurobiology of aging  2015;36(12):3163-3170.
Basal forebrain cholinergic neurons (BFCN) are selectively vulnerable in Alzheimer's disease (AD). We have shown that the majority of BFCN in the human brain contain the calcium binding protein calbindin-D28K (CB), a large proportion lose their CB in the course of normal aging, and the BFCN which degenerate in AD lack CB. Here we investigated the relationship between CB in the BFCN and the process of tangle formation in AD using antibodies to Tau epitopes that appear early, intermediate or late in the process of tangle formation. Very small percentages (0-3.7%) of CB-positive BFCN contained pre-tangles/tangles and very small percentages (0-5%) of the total BFCN pre-tangles/tangles were in CB-immunoreactive neurons. The number of CB-positive BFCN which contained Tau immunoreactivity was highest for the early epitope and lower for intermediate epitopes. A late appearing epitope was absent from CB-positive BFCN. Age-related loss of CB appears to coincide with tangle formation in the BFCN and is associated with the full range of Tau pathology, including late appearing epitopes.
PMCID: PMC4641850  PMID: 26417681
Alzheimer's disease; Calbindin-D28k; Basal Forebrain Cholinergic Neurons; Selective Neuronal Vulnerability; Tangles; Tau epitope
2.  What do pauses in narrative production reveal about the nature of word retrieval deficits in PPA? 
Neuropsychologia  2015;77:211-222.
Naming and word-retrieval deficits, which are common characteristics of primary progressive aphasia (PPA), differentially affect production across word classes (e.g., nouns, verbs) in some patients. Individuals with the agrammatic variant (PPA-G) often show greater difficulty producing verbs whereas those with the semantic variant (PPA-S) show greater noun deficits and those with logopenic PPA (PPA-L) evince no clear-cut differences in production of the two word classes. To determine the source of these production patterns, the present study examined word-finding pauses as conditioned by lexical variables (i.e., word class, frequency, length) in narrative speech samples of individuals with PPA-S (n=12), PPA-G (n=12), PPA-L (n=11), and cognitively healthy controls (n=12). We also examined the relation between pause distribution and cortical atrophy (i.e., cortical thickness) in nine left hemisphere regions of interest (ROIs) linked to word production. Results showed higher overall pause rates for PPA compared to unimpaired controls; however, greater naming severity was not associated with increased pause rate. Across all groups, more pauses were produced before lower vs. higher frequency words, with no independent effects of word length after controlling for frequency. With regard to word class, the PPA-L group showed a higher rate of pauses prior to production of nouns compared to verbs, consistent with noun-retrieval deficits arising at the lemma level of word production. Those with PPA-G and PPA-S, like controls, produced similar pause rates across word classes; however, lexical simplification (i.e., production of higher-frequency and/or shorter words) was evident in the more-impaired word class: nouns for PPA-S and verbs for PPA-G. These patterns are consistent with conceptual and/or lemma-level impairments for PPA-S, predominantly affecting objects/nouns, and a lemma-level verb-retrieval deficit for PPA-G, with a concomitant impairment in phonological encoding and articulation affecting overall pause rates. The greater tendency to pause before nouns was correlated with atrophy in the left precentral gyrus, inferior frontal gyrus and inferior parietal lobule, whereas the greater tendency to pause before less frequent and longer words was associated with atrophy in left precentral and inferior parietal regions.
PMCID: PMC4609629  PMID: 26300385
primary progressive aphasia; narrative analysis; word retrieval deficits; word class effects; brain-behavior relationship
3.  Memory Improvement via Slow Oscillatory Stimulation during Sleep in Older Adults 
Neurobiology of aging  2015;36(9):2577-2586.
We examined the intriguing but controversial idea that disrupted sleep-dependent consolidation contributes to age-related memory decline. Slow-wave activity during sleep may help strengthen neural connections and provide memories with long-term stability, in which case decreased slow-wave activity in older adults could contribute to their weaker memories. One prediction from this account is that age-related memory deficits should be reduced by artificially enhancing slow-wave activity. In young adults, applying transcranial current oscillating at a slow frequency (.75 Hz) during sleep improves memory. Here, we tested whether this procedure can improve memory in older adults. In two sessions separated by 1 week, we applied either slow-oscillatory stimulation or sham stimulation during an afternoon nap in a double-blind, crossover design. Memory tests were administered before and after sleep. A larger improvement in word-pair recall and higher slow-wave activity were observed with slow-oscillatory stimulation than with sham stimulation. This is the first demonstration that this procedure can improve memory in older adults, suggesting that declarative memory performance in older adults is partly dependent on slow-wave activity during sleep.
PMCID: PMC4523433  PMID: 26116933
slow-wave sleep; aging; electrical stimulation; declarative memory
4.  Retinal nerve fiber layer thickness in amnestic mild cognitive impairment: Case-control study and meta-analysis 
Retinal structural changes in subjects with mild cognitive impairment (MCI) remain a subject of controversy.
We investigated the correlation between optical coherence tomography (OCT) of the retinal sublayers, including the retinal nerve fiber layer (RNFL), and cognitive function in subjects with amnestic MCI and compared the OCT findings with matched controls. We also performed a meta-analysis of the world literature using a random-effects model.
We found no statistically significant differences in OCT between amnestic MCI (aMCI) and controls. In aMCI subjects, we found an inverse relationship between RNFL thickness and two cognitive tests (delayed story recall and a word-list learning test and the word-list test). The meta-analysis revealed a statistically significant decrease in RNFL thickness in MCI subjects.
The inverse relationship between cognitive testing and RNFL thickness suggests that retinal involvement may include paradoxically increased thickness of the RNFL, which could suggest gliotic reactive changes.
PMCID: PMC5045947  PMID: 27722194
Alzheimer's disease; Mild cognitive impairment; Retinal nerve fiber layer; Optical coherence tomography; Biomarkers
6.  The Wernicke conundrum and the anatomy of language comprehension in primary progressive aphasia 
Brain  2015;138(8):2423-2437.
The location of Wernicke’s area remains controversial. Using structural MRI in 72 patients with primary progressive aphasia, Mesulam et al. show that word and sentence comprehension are dissociable, and that a circumscribed cortical area equally critical for word and sentence comprehension is unlikely to exist anywhere in the cerebral cortex.
The location of Wernicke’s area remains controversial. Using structural MRI in 72 patients with primary progressive aphasia, Mesulam et al. show that word and sentence comprehension are dissociable, and that a circumscribed cortical area equally critical for word and sentence comprehension is unlikely to exist anywhere in the cerebral cortex.
Wernicke’s aphasia is characterized by severe word and sentence comprehension impairments. The location of the underlying lesion site, known as Wernicke’s area, remains controversial. Questions related to this controversy were addressed in 72 patients with primary progressive aphasia who collectively displayed a wide spectrum of cortical atrophy sites and language impairment patterns. Clinico-anatomical correlations were explored at the individual and group levels. These analyses showed that neuronal loss in temporoparietal areas, traditionally included within Wernicke’s area, leave single word comprehension intact and cause inconsistent impairments of sentence comprehension. The most severe sentence comprehension impairments were associated with a heterogeneous set of cortical atrophy sites variably encompassing temporoparietal components of Wernicke’s area, Broca’s area, and dorsal premotor cortex. Severe comprehension impairments for single words, on the other hand, were invariably associated with peak atrophy sites in the left temporal pole and adjacent anterior temporal cortex, a pattern of atrophy that left sentence comprehension intact. These results show that the neural substrates of word and sentence comprehension are dissociable and that a circumscribed cortical area equally critical for word and sentence comprehension is unlikely to exist anywhere in the cerebral cortex. Reports of combined word and sentence comprehension impairments in Wernicke’s aphasia come almost exclusively from patients with cerebrovascular accidents where brain damage extends into subcortical white matter. The syndrome of Wernicke’s aphasia is thus likely to reflect damage not only to the cerebral cortex but also to underlying axonal pathways, leading to strategic cortico-cortical disconnections within the language network. The results of this investigation further reinforce the conclusion that the left anterior temporal lobe, a region ignored by classic aphasiology, needs to be inserted into the language network with a critical role in the multisynaptic hierarchy underlying word comprehension and object naming.
PMCID: PMC4805066  PMID: 26112340
language; dementia; aphasia; semantics; grammar
7.  Neuronal amyloid-β accumulation within cholinergic basal forebrain in ageing and Alzheimer’s disease 
Brain  2015;138(6):1722-1737.
Baker-Nigh et al. reveal accumulation of amyloid-β in basal forebrain cholinergic neurons throughout life, and the formation of large intraneuronal oligomers specifically in aged and Alzheimer brains. Accumulation and age-related aggregation of amyloid-β may contribute to the selective vulnerability of cholinergic neurons to degeneration in Alzheimer’s disease.
Baker-Nigh et al. reveal accumulation of amyloid-β in basal forebrain cholinergic neurons throughout life, and the formation of large intraneuronal oligomers specifically in aged and Alzheimer brains. Accumulation and age-related aggregation of amyloid-β may contribute to the selective vulnerability of cholinergic neurons to degeneration in Alzheimer’s disease.
The mechanisms that contribute to selective vulnerability of the magnocellular basal forebrain cholinergic neurons in neurodegenerative diseases, such as Alzheimer’s disease, are not fully understood. Because age is the primary risk factor for Alzheimer’s disease, mechanisms of interest must include age-related alterations in protein expression, cell type-specific markers and pathology. The present study explored the extent and characteristics of intraneuronal amyloid-β accumulation, particularly of the fibrillogenic 42-amino acid isoform, within basal forebrain cholinergic neurons in normal young, normal aged and Alzheimer’s disease brains as a potential contributor to the selective vulnerability of these neurons using immunohistochemistry and western blot analysis. Amyloid-β1–42 immunoreactivity was observed in the entire cholinergic neuronal population regardless of age or Alzheimer’s disease diagnosis. The magnitude of this accumulation as revealed by optical density measures was significantly greater than that in cortical pyramidal neurons, and magnocellular neurons in the globus pallidus did not demonstrate a similar extent of amyloid immunoreactivity. Immunoblot analysis with a panel of amyloid-β antibodies confirmed accumulation of high concentration of amyloid-β in basal forebrain early in adult life. There was no age- or Alzheimer-related alteration in total amyloid-β content within this region. In contrast, an increase in the large molecular weight soluble oligomer species was observed with a highly oligomer-specific antibody in aged and Alzheimer brains when compared with the young. Similarly, intermediate molecular weight oligomeric species displayed an increase in aged and Alzheimer brains when compared with the young using two amyloid-β42 antibodies. Compared to cortical homogenates, small molecular weight oligomeric species were lower and intermediate species were enriched in basal forebrain in ageing and Alzheimer’s disease. Regional and age-related differences in accumulation were not the result of alterations in expression of the amyloid precursor protein, as confirmed by both immunostaining and western blot. Our results demonstrate that intraneuronal amyloid-β accumulation is a relatively selective trait of basal forebrain cholinergic neurons early in adult life, and increases in the prevalence of intermediate and large oligomeric assembly states are associated with both ageing and Alzheimer’s disease. Selective intraneuronal amyloid-β accumulation in adult life and oligomerization during the ageing process are potential contributors to the degeneration of basal forebrain cholinergic neurons in Alzheimer’s disease.
PMCID: PMC4542619  PMID: 25732182
Alzheimer pathology; amyloid-β; amyloid oligomer; basal forebrain cholinergic neurons; intracellular
8.  The CARE Pathway Model for Dementia 
PMCID: PMC4635684  PMID: 25998120
Quality of life; Neurocognitive profile; Symptom-specific strategies; Clinical care model; Primary progressive aphasia; Behavioral variant frontotemporal dementia; Posterior cortical atrophy; Dementia of the Alzheimer type
9.  Benefits of Mindfulness Training for Patients with Progressive Cognitive Decline and their Caregivers 
New strategies are needed to help people cope with the repercussions of neurodegenerative disorders such as Alzheimer's disease. Patients and caregivers face different challenges, but here we investigated an intervention tailored for this combined population. The program focused on training skills such as attending to the present moment nonjudgmentally, which may help reduce maladaptive emotional responses. Patients participated together with caregivers in weekly group sessions over 8 weeks. An assessment battery was individually administered before and after the program. Pre-post analyses revealed several benefits, including increased quality-of-life ratings, fewer depressive symptoms, and better subjective sleep quality. In addition, participants indicated that they were grateful for the opportunity to learn to apply mindfulness skills and that they would recommend the program to others. In conclusion, mindfulness training can be beneficial for patients and their caregivers, it can be delivered at low-cost to combined groups, and it is worthy of further investigation.
PMCID: PMC4363074  PMID: 25154985
neurodegenerative disorders; Mild Cognitive Impairment; Alzheimer's disease; caregiver stress; Mindfulness-Based Stress Reduction (MBSR)
10.  Hippocampal subfield surface deformity in non-semantic primary progressive aphasia 
Alzheimer neuropathology (AD) is found in almost half of patients with non-semantic primary progressive aphasia (PPA). This study examined hippocampal abnormalities in PPA to determine similarities to those described in amnestic AD.
In 37 PPA patients and 32 healthy controls, we generated hippocampal subfield surface maps from structural MRIs and administered a face memory test. We analyzed group and hemisphere differences for surface shape measures and their relationship with test scores and ApoE genotype.
The hippocampus in PPA showed inward deformity (CA1 and subiculum subfields) and outward deformity (CA2-4+DG subfield) and smaller left than right volumes. Memory performance was related to hippocampal shape abnormalities in PPA patients, but not controls, even in the absence of memory impairments.
Hippocampal deformity in PPA is related to memory test scores. This may reflect a combination of intrinsic degenerative phenomena with transsynaptic or Wallerian effects of neocortical neuronal loss.
PMCID: PMC4398964  PMID: 25893207
frontotemporal dementia; lobar degeneration; multi-atlas mapping; structural magnetic resonance imaging (MRI); memory; neuroanatomy; primary progressive aphasia (PPA); Alzheimer’s disease (AD)
11.  Preliminary evidence for the feasibility of at-home online cognitive training with older adults 
Increased levels of cognitive activity may improve general cognitive function in older adults and potentially increase cognitive reserve, protecting against the onset of dementia associated with syndromes like Alzheimer's disease. To test the efficacy of cognitive training administered online, 18 participants (11 cognitively healthy; 7 mild cognitive impairment) were recruited from a clinical population of older adults to complete an online training intervention (CogniFit™). Before and after training, participants completed a separate battery of assessment measures, including measures of quality of life and competency at everyday activities, as well as a series of tests assessing cognitive function. Participants generally adhered to the online training protocol and completed a computerized assessment battery pre- and post-training. However, participants with mild cognitive impairment (MCI) were somewhat less likely to adhere to the protocol, suggesting that more direct contact is needed with this population in intervention research. Furthermore, participants demonstrated significant improvement on a measure of working memory and also in processing speed across several assessments, though these data are tentative, as no control data exist. These results, along with the generally good adherence observed, suggest that online cognitive training is feasible for this population and a potentially valuable tool for the wider dissemination of cognitive training.
PMCID: PMC4712702  PMID: 26778939
cognitive training; human factors; mild cognitive impairment
12.  Using quantile regression to create baseline norms for neuropsychological tests 
The Uniform Data Set (UDS) contains neuropsychological test scores and demographic information for participants at Alzheimer's disease centers across the United States funded by the National Institute on Aging. Mean regression analysis of neuropsychological tests has been proposed to detect cognitive decline, but the approach requires stringent assumptions.
We propose using quantile regression to directly model conditional percentiles of neuropsychological test scores. An online application allows users to easily implement the proposed method.
Scores from 13 different neuropsychological tests were analyzed for 5413 cognitively normal participants in the UDS. Quantile and mean regression models were fit using age, gender, and years of education. Differences between the mean and quantile regression estimates were found on the individual measures.
Quantile regression provides more robust estimates of baseline percentiles for cognitively normal adults. This can then serve as standards against which to detect individual cognitive decline.
PMCID: PMC4879644  PMID: 27239531
Alzheimer's disease; Neuropsychological assessment; Cognitive decline; Early detection; Quantile regression
14.  NIH Toolbox Cognition Battery (CB): Validation of Executive Function Measures in Adults 
This study describes psychometric properties of the NIH Toolbox Cognition Battery (NIHTB-CB) executive function measures in an adult sample. The NIHTB-CB was designed for use in epidemiologic studies and clinical trials for ages 3 to 85. A total of 268 self-described healthy adults were recruited at four university-based sites, using stratified sampling guidelines to target demographic variability for age (20–85 years), gender, education and ethnicity. The NIHTB-CB contains two computer-based instruments assessing executive function: the Dimensional Change Card Sort (a measure of cognitive flexibility) and a flanker task (a measure of inhibitory control and selective attention). Participants completed the NIHTB-CB, corresponding gold standard convergent and discriminant measures, and sociodemographic questionnaires. A subset of participants (N = 89) was retested 7 to 21 days later. Results reveal excellent sensitivity to age-related changes during adulthood, excellent test–retest reliability, and adequate to good convergent and discriminant validity. The NIH Toolbox EF measures can be used effectively in epidemiologic and clinical studies.
PMCID: PMC4601803  PMID: 24960301
Cognitive control; Cognitive flexibility; Inhibitory control; Lifespan development; Standardized testing; Validation
16.  Primary progressive aphasia and the evolving neurology of the language network 
Nature reviews. Neurology  2014;10(10):554-569.
Primary progressive aphasia (PPA) is caused by selective neurodegeneration of the language-dominant cerebral hemisphere; a language deficit initially arises as the only consequential impairment and remains predominant throughout most of the course of the disease. Agrammatic, logopenic and semantic subtypes, each reflecting a characteristic pattern of language impairment and corresponding anatomical distribution of cortical atrophy, represent the most frequent presentations of PPA. Such associations between clinical features and the sites of atrophy have provided new insights into the neurology of fluency, grammar, word retrieval, and word comprehension, and have necessitated modification of concepts related to the functions of the anterior temporal lobe and Wernicke’s area. The underlying neuropathology of PPA is, most commonly, frontotemporal lobar degeneration in the agrammatic and semantic forms, and Alzheimer disease (AD) pathology in the logopenic form; the AD pathology often displays atypical and asymmetrical anatomical features consistent with the aphasic phenotype. The PPA syndrome reflects complex interactions between disease-specific neuropathological features and patient-specific vulnerability. A better understanding of these interactions might help us to elucidate the biology of the language network and the principles of selective vulnerability in neurodegenerative diseases. We review these aspects of PPA, focusing on advances in our understanding of the clinical features and neuropathology of PPA and what they have taught us about the neural substrates of the language network.
PMCID: PMC4201050  PMID: 25179257
17.  Ataxin-2 as potential disease modifier in C9ORF72 expansion carriers 
Neurobiology of aging  2014;35(10):2421.e13-2421.e17.
Repeat expansions in chromosome 9 open reading frame 72 (C9ORF72) are an important cause of both motor neuron disease (MND) and frontotemporal dementia (FTD). Currently, little is known about factors that could account for the phenotypic heterogeneity detected in C9ORF72 expansion carriers. In this study, we investigated four genes that could represent genetic modifiers: ataxin-2 (ATXN2), non-imprinted in Prader-Willi/Angelman syndrome 1 (NIPA1), survival motor neuron 1 (SMN1) and survival motor neuron 2 (SMN2). Assessment of these genes, in a unique cohort of 331 C9ORF72 expansion carriers and 376 controls, revealed that intermediate repeat lengths in ATXN2 possibly act as disease modifier in C9ORF72 expansion carriers; no evidence was provided for a potential role of NIPA1, SMN1 or SMN2. The effects of intermediate ATXN2 repeats were most profound in probands with MND or FTD/MND (2.1% versus 0% in controls, P=0.013), whereas the frequency in probands with FTD was identical to controls. Though intermediate ATXN2 repeats were already known to be associated with MND risk, previous reports did not focus on individuals with clear pathogenic mutations, such as repeat expansions in C9ORF72. Based on our present findings, we postulate that intermediate ATXN2 repeat lengths may render C9ORF72 expansion carriers more susceptible to the development of MND; further studies are needed, however, to validate our findings.
PMCID: PMC4105839  PMID: 24866401
C9ORF72; ataxin-2; ATXN2; motor neuron disease; amyotrophic lateral sclerosis; frontotemporal dementia; disease modifier
18.  Asymmetry of cortical decline in subtypes of primary progressive aphasia 
Neurology  2014;83(13):1184-1191.
The aim of this study was to provide quantitative measures of changes in cortical atrophy over a 2-year period associated with 3 subtypes of primary progressive aphasia (PPA) using whole-brain vertex-wise and region-of-interest (ROI) neuroimaging methods. The purpose was to quantitate disease progression, establish an empirical basis for clinical expectations, and provide outcome measures for therapeutic trials.
Changes in cortical thickness and volume loss as well as neuropsychological performance were assessed at baseline and 2-year follow-up in 26 patients who fulfilled criteria for logopenic (8 patients), agrammatic (10 patients), and semantic (8 patients) PPA subtypes. Whole-brain vertex-wise and ROI imaging analysis were conducted using the FreeSurfer longitudinal pipeline.
Clinical deficits and cortical atrophy patterns showed distinct patterns of change among the subtypes over 2 years. Results confirmed that progression for each of the 3 subtypes showed left greater than right hemisphere asymmetry. An ROI analysis also revealed that progression was greater within, rather than outside, the language network.
Preferential neurodegeneration of the left hemisphere language network is a common denominator for all 3 PPA subtypes, even as the disease progresses. Using a focal cortical language network ROI as an outcome measure of disease progression appears to be more sensitive than whole-brain or ventricular volume measures of change and may be helpful for designing future clinical trials in PPA.
PMCID: PMC4176026  PMID: 25165386
19.  Language Measures of the NIH Toolbox Cognition Battery 
Language facilitates communication and efficient encoding of thought and experience. Because of its essential role in early childhood development, in educational achievement and in subsequent life adaptation, language was included as one of the subdomains in the NIH Toolbox for the Assessment of Neurological and Behavioral Function Cognition Battery (NIHTB-CB). There are many different components of language functioning, including syntactic processing (i.e., morphology and grammar) and lexical semantics. For purposes of the NIHTB-CB, two tests of language—a picture vocabulary test and a reading recognition test—were selected by consensus based on literature reviews, iterative expert input, and a desire to assess in English and Spanish. NIHTB-CB’s picture vocabulary and reading recognition tests are administered using computer adaptive testing and scored using item response theory. Data are presented from the validation of the English versions in a sample of adults ages 20–85 years (Spanish results will be presented in a future publication). Both tests demonstrated high test–retest reliability and good construct validity compared to corresponding gold-standard measures. Scores on the NIH Toolbox measures were consistent with age-related expectations, namely, growth in language during early development, with relative stabilization into late adulthood.
PMCID: PMC4558909  PMID: 24960128
Reading test; Vocabulary test; Neuropsychological assessment; Computer adaptive testing; Item response theory; Spanish version
20.  Measuring Mild Cognitive Impairment in Patients With Parkinson’s Disease 
We examined the frequency of Parkinson disease with mild cognitive impairment (PD-MCI) and its subtypes and the accuracy of 3 cognitive scales for detecting PD-MCI using the new criteria for PD-MCI proposed by the Movement Disorders Society. Nondemented patients with Parkinson’s disease completed a clinical visit with the 3 screening tests followed 1 to 3 weeks later by neuropsychological testing. Of 139 patients, 46 met Level 2 Task Force criteria for PD-MCI when impaired performance was based on comparisons with normative scores. Forty-two patients (93%) had multi-domain MCI. At the lowest cutoff levels that provided at least 80% sensitivity, specificity was 44% for the Montreal Cognitive Assessment and 33% for the Scales for Outcomes in Parkinson’s Disease-Cognition. The Mini-Mental State Examination could not achieve 80% sensitivity at any cutoff score. At the highest cutoff levels that provided specificity of at least 80%, sensitivities were low (≤44%) for all tests. When decline from estimated premorbid levels was considered evidence of cognitive impairment, 110 of 139 patients were classified with PD-MCI, and 103 (94%) had multi-domain MCI. We observed dramatic differences in the proportion of patients who had PD-MCI using the new Level 2 criteria, depending on whether or not decline from premorbid level of intellectual function was considered. Recommendations for methods of operationalizing decline from premorbid levels constitute an unmet need. Among the 3 screening tests examined, none of the instruments provided good combined sensitivity and specificity for PD-MCI. Other tests recommended by the Task Force Level 1 criteria may represent better choices, and these should be the subject of future research.
PMCID: PMC4524474  PMID: 23520128
Parkinson’s disease; parkinsonism; mild cognitive impairment; Montreal Cognitive Assessment
22.  Morphometric and Histologic Substrates of Cingulate Integrity in Elders with Exceptional Memory Capacity 
The Journal of Neuroscience  2015;35(4):1781-1791.
This human study is based on an established cohort of “SuperAgers,” 80+-year-old individuals with episodic memory function at a level equal to, or better than, individuals 20–30 years younger. A preliminary investigation using structural brain imaging revealed a region of anterior cingulate cortex that was thicker in SuperAgers compared with healthy 50- to 65-year-olds. Here, we investigated the in vivo structural features of cingulate cortex in a larger sample of SuperAgers and conducted a histologic analysis of this region in postmortem specimens. A region-of-interest MRI structural analysis found cingulate cortex to be thinner in cognitively average 80+ year olds (n = 21) than in the healthy middle-aged group (n = 18). A region of the anterior cingulate cortex in the right hemisphere displayed greater thickness in SuperAgers (n = 31) compared with cognitively average 80+ year olds and also to the much younger healthy 50–60 year olds (p < 0.01). Postmortem investigations were conducted in the cingulate cortex in five SuperAgers, five cognitively average elderly individuals, and five individuals with amnestic mild cognitive impairment. Compared with other subject groups, SuperAgers showed a lower frequency of Alzheimer-type neurofibrillary tangles (p < 0.05). There were no differences in total neuronal size or count between subject groups. Interestingly, relative to total neuronal packing density, there was a higher density of von Economo neurons (p < 0.05), particularly in anterior cingulate regions of SuperAgers. These findings suggest that reduced vulnerability to the age-related emergence of Alzheimer pathology and higher von Economo neuron density in anterior cingulate cortex may represent biological correlates of high memory capacity in advanced old age.
PMCID: PMC4308613  PMID: 25632151
aging; Alzheimer's pathology; cingulate cortex; cognition; histology; structural MRI
23.  The Cognition Battery of the NIH Toolbox for Assessment of Neurological and Behavioral Function: Validation in an Adult Sample 
This paper introduces a special series on validity studies of the Cognition Battery (CB) from the U.S. National Institutes of Health Toolbox for the Assessment of Neurological and Behavioral Function (NIHTB) (R. C. Gershon et al., 2013) in an adult sample. This first paper in the series describes the sample, each of the seven instruments in the NIHTB-CB briefly, and the general approach to data analysis. Data are provided on test-retest reliability and practice effects, and raw scores (mean, standard deviation, range) are presented for each instrument and the gold standard instruments used to measure construct validity. Accompanying papers provide details on each instrument, including information about instrument development, psychometric properties, age and education effects on performance, and convergent and discriminant construct validity. One paper in the series is devoted to a factor analysis of the NIHTB-CB in adults and another describes the psychometric properties of three composite scores derived from the individual measures representing fluid and crystallized abilities and their combination. The NIHTB-CB is designed to provide a brief, comprehensive, common set of measures to allow comparisons among disparate studies and to improve scientific communication.
PMCID: PMC4103959  PMID: 24959840
24.  Reliability and Validity of Composite Scores from the NIH Toolbox Cognition Battery in Adults 
This study describes psychometric properties of the NIH Toolbox Cognition Battery (NIHTB-CB) Composite Scores in an adult sample. The NIHTB-CB was designed for use in epidemiologic studies and clinical trials for ages 3 to 85. A total of 268 self-described healthy adults were recruited at four university-based sites, using stratified sampling guidelines to target demographic variability for age (20–85 years), gender, education, and ethnicity. The NIHTB-CB contains seven computer-based instruments assessing five cognitive sub-domains: Language, Executive Function, Episodic Memory, Processing Speed, and Working Memory. Participants completed the NIHTB-CB, corresponding gold standard validation measures selected to tap the same cognitive abilities, and sociodemographic questionnaires. Three Composite Scores were derived for both the NIHTB-CB and gold standard batteries: “Crystallized Cognition Composite,” “Fluid Cognition Composite,” and “Total Cognition Composite” scores. NIHTB Composite Scores showed acceptable internal consistency (Cronbach’s alphas = 0.84 Crystallized, 0.83 Fluid, 0.77 Total), excellent test–retest reliability (r: 0.86–0.92), strong convergent (r: 0.78–0.90) and discriminant (r: 0.19–0.39) validities versus gold standard composites, and expected age effects (r = 0.18 crystallized, r = − 0.68 fluid, r = − 0.26 total). Significant relationships with self-reported prior school difficulties and current health status, employment, and presence of a disability provided evidence of external validity. The NIH Toolbox Cognition Battery Composite Scores have excellent reliability and validity, suggesting they can be used effectively in epidemiologic and clinical studies.
PMCID: PMC4103963  PMID: 24960398
Neuropsychological assessment; Memory; Executive Function; Attention; Cognitive assessment; Cognitive screener
25.  Measuring Episodic Memory Across the Lifespan: NIH Toolbox Picture Sequence Memory Test 
Episodic memory is one of the most important cognitive domains that involves acquiring, storing and recalling new information. In this article, we describe a new measure developed for the NIH Toolbox, called the Picture Sequence Memory Test (PSMT) that is the first to examine episodic memory across the age range from 3 to 85. We describe the development of the measure and present validation data for ages 20 to 85. The PSMT involves presentation of sequences of pictured objects and activities in a fixed order on a computer screen and simultaneously verbally described, that the participant must remember and then reproduce over three learning trials. The results indicate good test–retest reliability and construct validity. Performance is strongly related to well-established “gold standard” measures of episodic memory and, as expected, much less well correlated with those of a measure of vocabulary. It shows clear decline with aging in parallel with a gold standard summary measure and relates to several other demographic factors and to self-reported general health status. The PSMT appears to be a reliable and valid test of episodic memory for adults, a finding similar to those found for the same measure with children.
PMCID: PMC4254833  PMID: 24960230
Episodic memory; Learning; Test development; NIH toolbox; Validation; Cognition

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