It is “normal” for old age to be associated with gradual decline in memory and brain mass. However, there are anecdotal reports of individuals who seem immune to age-related memory impairment, but these individuals have not been studied systematically. This study sought to establish that such cognitive SuperAgers exist and to determine if they were also resistant to age-related loss of cortical brain volume. SuperAgers were defined as individuals over age 80 with episodic memory performance at least as good as normative values for 50- to 65-year-olds. Cortical morphometry of the SuperAgers was compared to two cognitively normal cohorts: age-matched elderly and 50- to 65-year-olds. The SuperAgers’ cerebral cortex was significantly thicker than their healthy age-matched peers and displayed no atrophy compared to the 50- to 65-year-old healthy group. Unexpectedly, a region of left anterior cingulate cortex was significantly thicker in the SuperAgers than in both elderly and middle-aged controls. Our findings identify cognitive and neuroanatomical features of a cohort that appears to resist average age-related changes of memory capacity and cortical volume. A better understanding of the underlying factors promoting this potential trajectory of unusually successful aging may provide insight for preventing age-related cognitive impairments or the more severe changes associated with Alzheimer’s disease. (JINS, 2012, 18, 1081–1085)
Structural magnetic resonance imaging (MRI); Neuropsychology; Dementia; Freesurfer; Elderly; Neuroimaging
Emerging evidence suggests the relationship between health literacy and health outcomes could be explained by cognitive abilities.
To investigate to what degree cognitive skills explain associations between health literacy, performance on common health tasks, and functional health status.
Two face-to-face, structured interviews spaced a week apart with three health literacy assessments and a comprehensive cognitive battery measuring ‘fluid’ abilities necessary to learn and apply new information, and ‘crystallized’ abilities such as background knowledge.
An academic general internal medicine practice and three federally qualified health centers in Chicago, Illinois.
Eight hundred and eighty-two English-speaking adults ages 55 to 74.
Health literacy was measured using the Rapid Estimate of Adult Literacy in Medicine (REALM), Test of Functional Health Literacy in Adults (TOFHLA), and Newest Vital Sign (NVS). Performance on common health tasks were globally assessed and categorized as 1) comprehending print information, 2) recalling spoken information, 3) recalling multimedia information, 4) dosing and organizing medication, and 5) healthcare problem-solving.
Health literacy measures were strongly correlated with fluid and crystallized cognitive abilities (range: r = 0.57 to 0.77, all p < 0.001). Lower health literacy and weaker fluid and crystallized abilities were associated with poorer performance on healthcare tasks. In multivariable analyses, the association between health literacy and task performance was substantially reduced once fluid and crystallized cognitive abilities were entered into models (without cognitive abilities: β = −28.9, 95 % Confidence Interval (CI) -31.4 to −26.4, p; with cognitive abilities: β = −8.5, 95 % CI −10.9 to −6.0).
Cross-sectional analyses, English-speaking, older adults only.
The most common measures used in health literacy studies are detecting individual differences in cognitive abilities, which may predict one’s capacity to engage in self-care and achieve desirable health outcomes. Future interventions should respond to all of the cognitive demands patients face in managing health, beyond reading and numeracy.
health literacy; cognitive abilities; health tasks; patient-reported outcomes; physical health; mental health
Primary progressive aphasia is a neurodegenerative syndrome characterized by gradual dissolution of language but relative sparing of other cognitive domains, especially memory. It is associated with asymmetric atrophy in the language-dominant hemisphere (usually left), and differs from typical Alzheimer-type dementia where amnesia is the primary deficit. Various pathologies have been reported, including the tangles and plaques of Alzheimer’s disease. Identification of Alzheimer pathology in these aphasic patients is puzzling since tangles and related neuronal loss in Alzheimer’s disease typically emerge in memory-related structures such as entorhinal cortex and spread to language-related neocortex later in the disease. Furthermore, Alzheimer pathology is typically symmetric. How can a predominantly limbic and symmetric pathology cause the primary progressive aphasia phenotype, characterized by relative preservation of memory and asymmetric predilection for the language-dominant hemisphere? Initial investigations into the possibility that Alzheimer pathology displays an atypical distribution in primary progressive aphasia yielded inconclusive results. The current study was based on larger groups of patients with either primary progressive aphasia or a typical amnestic dementia. Alzheimer pathology was the principal diagnosis in all cases. The goal was to determine whether Alzheimer pathology had clinically-concordant, and hence different distributions in these two phenotypes. Stereological counts of tangles and plaques revealed greater leftward asymmetry for tangles in primary progressive aphasia but not in the amnestic Alzheimer-type dementia (P < 0.05). Five of seven aphasics had more leftward tangle asymmetry in all four neocortical regions analysed, whereas this pattern was not seen in any of the predominantly amnestic cases. One aphasic case displayed higher right-hemisphere tangle density despite greater left-hemisphere hypoperfusion and atrophy during life. Although there were more tangles in the memory-related entorhinal cortex than in language-related neocortical areas in both phenotypes (P < 0.0001), the ratio of neocortical-to-entorhinal tangles was significantly higher in the aphasic cases (P = 0.034). Additionally, overall numbers of tangles and plaques were greater in the aphasic than amnestic cases (P < 0.05), especially in neocortical areas. No significant hemispheric asymmetry was found in plaque distribution, reinforcing the conclusion that tangles have greater clinical concordance than plaques in the spectrum of Alzheimer pathologies. The presence of left-sided tangle predominance and higher neocortical-to-entorhinal tangle ratio in primary progressive aphasia establishes clinical concordance of Alzheimer pathology with the aphasic phenotype. The one case with reversed asymmetry, however, suggests that these concordant clinicopathological relationships are not universal and that individual primary progressive aphasia cases with Alzheimer pathology exist where distributions of plaques and tangles do not account for the observed phenotype.
neurodegenerative disorders; primary progressive aphasia; AD pathology; hemispheric differences; stereology
Word class naming deficits are commonly seen in aphasia resulting from stroke (StrAph) and primary progressive aphasia (PPA), with differential production of nouns (objects) and verbs (actions) found based on StrAph type or PPA variant for some individuals. Studies to date, however, have not compared word class naming (or comprehension) ability in the two aphasic disorders. In addition, there are no available measures for testing word class deficits, which control for important psycholinguistic variables across language domains. This study examined noun and verb production and comprehension in individuals with StrAph and PPA using a new test, the Northwestern Naming Battery (NNB; Thompson & Weintraub, experimental version), developed explicitly for this purpose. In addition, we tested verb type effects, based on verb argument structure characteristics, which also is addressed by the NNB.
Fifty-two participants with StrAph (33 agrammatic, Broca’s (StrAg); 19 anomic (StrAn)) and 28 PPA (10 agrammatic (PPA-G); 14 logopenic (PPA-L); 4 semantic (PPA-S)) were included in the study. Nouns and verbs were tested in the Confrontation Naming and Auditory Comprehension subtests of the NNB, with scores used to compute noun to verb ratios as well as performance by verb type. Performance patterns within and across StrAph and PPA groups were then examined. The external validity of the NNB also was tested by comparing (a) NNB Noun Naming scores to the Boston Naming Test (BNT; Kaplan, Goodglass, & Weintraub, 1983) and Western Aphasia Battery (WAB-R, Kertesz, 2007) Noun Naming subtest scores, (b) NNB Verb Naming scores to the Boston Diagnostic Aphasia Examination (BDAE; Goodglass, Kaplan & Barresi, 2001) Action Naming score (for StrAph participants only), and (c) NNB Comprehension subtest scores to WAB-R Auditory Comprehension subtest scores.
Outcomes and Results
Both agrammatic (StrAg and PPA-G) groups showed significantly greater difficulty producing verbs compared to nouns, but no comprehension impairment for either word class. Whereas, three of the four PPA-S participants showed poorer noun compared to verb production, as well as comprehension. However, neither the StrAn or PPA-L participants showed significant differences between the two word classes in production or comprehension. In addition, similar to the agrammatic participants, the StrAn participants showed a significant transitivity effect, producing intransitive (one-argument) verbs with greater accuracy than transitive (two- and three-argument) verbs. However, no transitivity effects were found for the PPA-L or PPA-S participants. There were significant correlations between NNB scores and all external validation measures.
These data indicate that the NNB is sensitive to word class deficits in stroke and neurodegenerative aphasia. This is important both clinically for treatment planning and theoretically to inform both psycholinguistic and neural models of language processing.
primary progressive aphasia (PPA); word class deficits; naming deficit patterns; verb argument structure production
The characteristics of early and mild disease in primary progressive aphasia are poorly understood. This report is based on 25 patients with aphasia quotients >85%, 13 of whom were within 2 years of symptom onset. Word-finding and spelling deficits were the most frequent initial signs. Diagnostic imaging was frequently negative and initial consultations seldom reached a correct diagnosis. Functionality was preserved, so that the patients fit current criteria for single-domain mild cognitive impairment. One goal was to determine whether recently published classification guidelines could be implemented at these early and mild disease stages. The quantitative testing of the recommended core and ancillary criteria led to the classification of ∼80% of the sample into agrammatic, logopenic and semantic variants. Biological validity of the resultant classification at these mild impairment stages was demonstrated by clinically concordant cortical atrophy patterns. A two-dimensional template based on orthogonal mapping of word comprehension and grammaticality provided comparable accuracy and led to a flexible road map that can guide the classification process quantitatively or qualitatively. Longitudinal evaluations of initially unclassifiable patients showed that the semantic variant can be preceded by a prodromal stage of focal left anterior temporal atrophy during which prominent anomia exists without word comprehension or object recognition impairments. Patterns of quantitative tests justified the distinction of grammar from speech abnormalities and the desirability of using the ‘agrammatic’ designation exclusively for loss of grammaticality, regardless of fluency or speech status. Two patients with simultaneous impairments of grammatical sentence production and word comprehension displayed focal atrophy of the inferior frontal gyrus and the anterior temporal lobe. These patients represent a fourth variant of ‘mixed’ primary progressive aphasia. Quantitative criteria were least effective in the distinction of the agrammatic from the logopenic variant and left considerable latitude to clinical judgement. The widely followed recommendation to wait for 2 years of relatively isolated and progressive language impairment before making a definitive diagnosis of primary progressive aphasia has promoted diagnostic specificity, but has also diverted attention away from early and mild disease. This study shows that this recommendation is unnecessarily restrictive and that quantitative guidelines can be implemented for the valid root diagnosis and subtyping of mildly impaired patients within 2 years of symptom onset. An emphasis on early diagnosis will promote a better characterization of the disease stages where therapeutic interventions are the most likely to succeed.
aphasia; logopenic; semantic; agrammatic; anomic
Many studies have investigated factors associated with the rate of decline and evolution from mild cognitive impairment to Alzheimer’s disease (AD) dementia in elderly patients. In this analysis we compared the rates of decline to dementia estimated from three common global measures of cognition: Mini Mental Status Examination (MMSE) score, Clinical Dementia Rating sum of boxes score (CDR-SB), and a neuropsychological tests composite score (CS).
A total of 2,899 subjects in the National Alzheimer’s Coordinating Center Uniform Data Set age 65+ years diagnosed with amnestic mild cognitive impairment (aMCI) were included in this analysis. Population-averaged decline to dementia rates were estimated and compared for standardized MMSE, CDR-SB, and Composite scores using Generalized Estimating Equations (GEE). Associations between rate of decline and several potential correlates of decline were also calculated and compared across measures.
The CDR-SB had the steepest estimated slope, with a decline of .49 standard deviations (SD) per year, followed by the MMSE with .22 SD/year, and finally the CS with .07 SD/year. The rate of decline of the three measures differed significantly in a global test for differences (p<.0001). Age at visit, BMI at visit, APOE ε4 allele status, and race (black vs. white) had significantly different relationships with rate of decline in a global test for difference among the three measures.
These results suggest that both the rate of decline and the effects of AD risk factors on decline to dementia can vary depending on the evaluative measure used.
neuropsychological testing; Alzheimer’s Disease; cognitive assessment; aging
This study examined the time course of object naming in 21 individuals with primary progressive aphasia (PPA) (8 agrammatic (PPA-G); 13 logopenic (PPA-G)) and healthy age-matched speakers (n=17) using a semantic interference paradigm with related and unrelated interfering stimuli presented at stimulus onset asynchronies (SOAs) of −1000, −500, −100 and 0 ms. Results showed semantic interference (SI) (i.e. significantly slower RTs in related compared to unrelated conditions) for all groups at −500, −100 and 0 ms, indicating timely spreading activation to semantic competitors. However, both PPA groups showed a greater magnitude of SI than normal across SOAs. The PPA-L group and six PPA-G participants also evinced SI at −1000 ms, suggesting an abnormal time course of semantic interference resolution, and concomitant left hemisphere cortical atrophy in brain regions associated with semantic processing. These subtle semantic mapping impairments in non-semantic variants of PPA may contribute to the anomia of these patients.
primary progressive aphasia; semantic interference; word interference paradigms; naming deficits in primary progressive aphasia; Free Surfer; cortical thickness
Classical aphasiology, based on the study of stroke sequelae, fuses speech fluency and grammatical ability. Nonfluent (Broca's) aphasia often is accompanied by agrammatism; whereas in the fluent aphasias grammatical deficits are not typical. The assumption that a similar relationship exists in primary progressive aphasia (PPA) has led to the dichotomization of this syndrome into fluent and nonfluent subtypes.
This study compared elements of fluency and grammatical production in the narrative speech of individuals with PPA to determine if they can be dissociated from one another.
Speech samples from 37 individuals with PPA, clinically assigned to agrammatic (N=11), logopenic (N=20) and semantic (N=6) subtypes, and 13 cognitively healthy control participants telling the “Cinderella Story” were analyzed for fluency (i.e., words per minute (WPM) and mean length of utterance in words (MLU-W)) and grammaticality (i.e., the proportion of grammatically correct sentences, open-to-closed-class word ratio, noun-to-verb ratio, and correct production of verb inflection, noun morphology, and verb argument structure.) Between group differences were analyzed for each variable. Correlational analyses examined the relation between WPM and each grammatical variable, and an off-line measure of sentence production.
Outcomes And Results
Agrammatic and logopenic groups both had lower scores on the fluency measures and produced significantly fewer grammatical sentences than did semantic and control groups. However, only the agrammatic group evinced significantly impaired production of verb inflection and verb argument structure. In addition, some semantic participants showed abnormal open-to-closed and noun-to-verb ratios in narrative speech. When the sample was divided on the basis of fluency, all the agrammatic participants fell in the nonfluent category. The logopenic participants varied in fluency but those with low fluency showed variable performance on measures of grammaticality. Correlational analyses and scatter plots comparing fluency and each grammatical variable revealed dissociations within PPA participants, with some nonfluent participants showing normal grammatical skill.
Grammatical production is a complex construct comprised of correct usage of several language components, each of which can be selectively affected by disease. This study demonstrates that individuals with PPA show dissociations between fluency and grammatical production in narrative speech. Grammatical ability, and its relationship to fluency, varies from individual to individual, and from one variant of PPA to another, and can even be found in individuals with semantic PPA in whom a fluent aphasia is usually thought to accompany preserved ability to produce grammatical utterances.
This study provides empirical evidence on whether polypharmacy and potentially inappropriate prescription medications (PIRx, as defined by the 2003 Beers criteria) increase the likelihood of functional decline among community-dwelling older adults with dementia. Data were from the National Alzheimer’s Coordinating Center, Uniform Data Set (9/2005–9/2009). Study sample included 1994 community-dwelling participants aged ≥65 with dementia at baseline. Results showed that participants having ≥5 medications were more likely to have functional decline than participants having <5 medications. However, the increased likelihood was only apparent in participants who did not have PIRx. Instead of magnifying the associated risk as hypothesized, PIRx appeared to have a protective effect albeit marginally statistically significant. Therefore, increased medication burden may be associated with functional decline in community-dwelling older adults with dementia who are not prescribed with PIRx. More research is needed to understand which classes of medications have the most deleterious effect on this population.
Beers criteria; Alzheimer’s disease; prescription drug utilization
Whereas patients with Alzheimer's disease (AD) experience difficulties forming and retrieving memories, their memory impairments may also partially reflect an unrecognized dysfunction in sleep-dependent consolidation that normally stabilizes declarative memory storage across cortical areas. Patients with amnestic mild cognitive impairment (aMCI) exhibit circumscribed declarative memory deficits, and many eventually progress to an AD diagnosis. Whether sleep is disrupted in aMCI and whether sleep disruptions contribute to memory impairment is unknown. We measured sleep physiology and memory for two nights and found that aMCI patients had fewer stage-2 spindles than age-matched healthy adults. Furthermore, aMCI patients spent less time in slow-wave sleep and showed lower delta and theta power during sleep compared to controls. Slow-wave and theta activity during sleep appear to reflect important aspects of memory processing, as evening-to-morning change in declarative memory correlated with delta and theta power during intervening sleep in both groups. These results suggest that sleep changes in aMCI patients contribute to memory impairments by interfering with sleep-dependent memory consolidation.
Long-term memory; Memory consolidation; Mild cognitive impairment; Slow-wave sleep; Polysomnography; Aging
The value of self-reported memory complaints for identifying or predicting future cognitive decline or dementia is controversial, but observations from a third party, or “informant”, may prove more useful. The relationship between Informant and Self ratings of cognitive status and neuropsychological test scores was examined in a cohort of 384 non-demented, community-dwelling women, aged sixty and older, participating in a single-site Women’s Health Initiative ancillary study. Each participant and her respective informant separately completed the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE)1. Participants also underwent neuropsychological testing and responded to questionnaires on depression and functioning in complex activities of daily living. All neuropsychological test scores were significantly correlated (p-values <.05 to <.01) with Informant IQCODE ratings while Self ratings overestimated cognitive functioning in some domains. Furthermore, the Self and Informant ratings were both positively correlated with depression and negatively correlated with participants’ activity level. Therefore, Informant judgments of functional abilities are robust predictors of cognitive status in high functioning non-demented women. These results suggest that informants may be sensitive to changes that are not clinically significant but that may represent an incipient trend for decline.
Normal Aging; IQCODE; Informant-rating; Self-rating; Cognitive impairment; Screening
Based on the recent literature and collective experience, an international consortium developed revised guidelines for the diagnosis of behavioural variant frontotemporal dementia. The validation process retrospectively reviewed clinical records and compared the sensitivity of proposed and earlier criteria in a multi-site sample of patients with pathologically verified frontotemporal lobar degeneration. According to the revised criteria, ‘possible’ behavioural variant frontotemporal dementia requires three of six clinically discriminating features (disinhibition, apathy/inertia, loss of sympathy/empathy, perseverative/compulsive behaviours, hyperorality and dysexecutive neuropsychological profile). ‘Probable’ behavioural variant frontotemporal dementia adds functional disability and characteristic neuroimaging, while behavioural variant frontotemporal dementia ‘with definite frontotemporal lobar degeneration’ requires histopathological confirmation or a pathogenic mutation. Sixteen brain banks contributed cases meeting histopathological criteria for frontotemporal lobar degeneration and a clinical diagnosis of behavioural variant frontotemporal dementia, Alzheimer’s disease, dementia with Lewy bodies or vascular dementia at presentation. Cases with predominant primary progressive aphasia or extra-pyramidal syndromes were excluded. In these autopsy-confirmed cases, an experienced neurologist or psychiatrist ascertained clinical features necessary for making a diagnosis according to previous and proposed criteria at presentation. Of 137 cases where features were available for both proposed and previously established criteria, 118 (86%) met ‘possible’ criteria, and 104 (76%) met criteria for ‘probable’ behavioural variant frontotemporal dementia. In contrast, 72 cases (53%) met previously established criteria for the syndrome (P < 0.001 for comparison with ‘possible’ and ‘probable’ criteria). Patients who failed to meet revised criteria were significantly older and most had atypical presentations with marked memory impairment. In conclusion, the revised criteria for behavioural variant frontotemporal dementia improve diagnostic accuracy compared with previously established criteria in a sample with known frontotemporal lobar degeneration. Greater sensitivity of the proposed criteria may reflect the optimized diagnostic features, less restrictive exclusion features and a flexible structure that accommodates different initial clinical presentations. Future studies will be needed to establish the reliability and specificity of these revised diagnostic guidelines.
behavioural variant frontotemporal dementia; diagnostic criteria; frontotemporal lobar degeneration; FTD; pathology
The goal of this study was to determine if the apolipoprotein ε (ApoE) gene, which is a well-established susceptibility factor for Alzheimer’s disease (AD) pathology in typical amnestic dementias, may also represent a risk factor in the language-based dementia, primary progressive aphasia (PPA). Apolipoprotein E genotyping was obtained from 149 patients with a clinical diagnosis of PPA, 330 cognitively healthy individuals (NC) and 179 patients with a clinical diagnosis of probable Alzheimer’s disease (PrAD). Allele frequencies were compared among the groups. Analyses were also completed by gender and in two subsets of PPA patients, one where patients were classified by subtype (logopenic, agrammatic and semantic) and another where pathologic data were available. The allele frequencies for the PPA group (ε2:5%, ε3:79.5%, and ε4:15.4%) showed a distribution similar to the NC group but significantly different from the PrAD group. The presence of an ε4 allele did not influence the age of symptom onset or aid in the prediction of AD pathology in PPA. These data show that the ε4 polymorphism, which is a well-known risk factor for AD pathology in typical amnestic dementias, has no similar relationship to the clinical syndrome of PPA or its association with AD pathology.
Neuropsychological assessment has featured prominently over the past 30 years in the characterization of dementia associated with Alzheimer disease (AD). Clinical neuropsychological methods have identified the earliest, most definitive cognitive and behavioral symptoms of illness, contributing to the identification, staging, and tracking of disease. With increasing public awareness of dementia, disease detection has moved to earlier stages of illness, at a time when deficits are both behaviorally and pathologically selective. For reasons that are not well understood, early AD pathology frequently targets large-scale neuroanatomical networks for episodic memory before other networks that subserve language, attention, executive functions, and visuospatial abilities. This chapter reviews the pathognomonic neuropsychological features of AD dementia and how these differ from “normal,” age-related cognitive decline and from other neurodegenerative diseases that cause dementia, including cortical Lewy body disease, frontotemporal lobar degeneration, and cerebrovascular disease.
Alzheimer disease (AD) targets neuroanatomical networks for episodic memory before those for language, executive functions, and visuospatial abilities. Therefore, amnestic dementia is strongly associated with early AD pathology.
The National Institute on Aging and the Alzheimer’s Association charged a workgroup with the task of revising the 1984 criteria for Alzheimer’s disease (AD) dementia. The workgroup sought to ensure that the revised criteria would be flexible enough to be used by both general healthcare providers without access to neuropsychological testing, advanced imaging, and cerebrospinal fluid measures, and specialized investigators involved in research or in clinical trial studies who would have these tools available. We present criteria for all-cause dementia and for AD dementia. We retained the general framework of probable AD dementia from the 1984 criteria. On the basis of the past 27 years of experience, we made several changes in the clinical criteria for the diagnosis. We also retained the term possible AD dementia, but redefined it in a manner more focused than before. Bio-marker evidence was also integrated into the diagnostic formulations for probable and possible AD dementia for use in research settings. The core clinical criteria for AD dementia will continue to be the cornerstone of the diagnosis in clinical practice, but biomarker evidence is expected to enhance the pathophysiological specificity of the diagnosis of AD dementia. Much work lies ahead for validating the biomarker diagnosis of AD dementia.
Alzheimer’s disease; Dementia; Diagnosis; Magnetic resonance brain imaging; Position emission tomography; Cerebrospinal fluid
Primary progressive aphasia (PPA) is a clinical dementia syndrome characterized by progressive decline in language function but relative sparing of other cognitive domains. There are three recognized PPA variants: agrammatic, semantic, and logopenic. Although each PPA subtype is characterized by the nature of the principal deficit, individual patients frequently display subtle impairments in additional language domains. The present study investigated the distribution of atrophy related to performance in specific language domains (i.e., grammatical processing, semantic processing, fluency, and sentence repetition) across PPA variants to better understand the anatomical substrates of language. Results showed regionally specific relationships, primarily in the left hemisphere, between atrophy and impairments in language performance. Most notable was the neuroanatomical distinction between fluency and grammatical processing. Poor fluency was associated with regions dorsal to the traditional boundaries of Broca’s area in the inferior frontal sulcus and the posterior middle frontal gyrus, whereas grammatical processing was associated with more widespread atrophy, including the inferior frontal gyrus and supramarginal gyrus. Repetition performance was correlated with atrophy in the posterior superior temporal gyrus. The correlation of atrophy with semantic processing impairment was localized to the anterior temporal poles. Atrophy patterns were more closely correlated with domain-specific performance than with subtype. These results show that PPA reflects a selective disruption of the language network as a whole, with no rigid boundaries between subtypes. Further, these atrophy patterns reveal anatomical correlates of language that could not have been surmised in patients with aphasia resulting from cerebrovascular lesions.
Sleep is important for declarative memory consolidation in healthy adults. Sleep disruptions are typical in Alzheimer’s disease, but whether they contribute to memory impairment is unknown. Sleep has not been formally examined in amnestic mild cognitive impairment (aMCI), which is characterized by declarative-memory deficits without dementia and can signify prodromal Alzheimer’s disease. We studied 10 aMCI patients and 10 controls over 2 weeks using daily sleep surveys, wrist-worn activity sensors, and daily recognition tests. Recognition was impaired and more variable in aMCI patients, whereas sleep was similar across groups. However, lower recognition of items learned the previous day was associated with lower subjective sleep quality in aMCI patients. This correlation was not present for information learned the same day, thus did not reflect nonspecific effects of poor sleep on memory. These results indicate that inadequate memory consolidation in aMCI patients is related to declines in subjective sleep indices. Furthermore, participants with greater across-night sleep variability exhibited lower scores on a standardized recall test taken prior to the 2-week protocol, suggesting that consistent sleep across nights also contributes to successful memory. Physiological analyses are needed to further specify which aspects of sleep in neurological disorders impact memory function and consolidation.
declarative memory; sleep; amnestic mild cognitive impairment; memory consolidation
With the recent publication of new criteria for the diagnosis of preclinical Alzheimer's disease (AD), there is a need for neuropsychological tools that take premorbid functioning into account in order to detect subtle cognitive decline. Using demographic adjustments is one method for increasing the sensitivity of commonly used measures. We sought to provide a useful online z-score calculator that yields estimates of percentile ranges and adjusts individual performance based on sex, age and/or education for each of the neuropsychological tests of the National Alzheimer's Coordinating Center Uniform Data Set (NACC, UDS). In addition, we aimed to provide an easily accessible method of creating norms for other clinical researchers for their own, unique data sets.
Data from 3,268 clinically cognitively-normal older UDS subjects from a cohort reported by Weintraub and colleagues (2009) were included. For all neuropsychological tests, z-scores were estimated by subtracting the raw score from the predicted mean and then dividing this difference score by the root mean squared error term (RMSE) for a given linear regression model.
For each neuropsychological test, an estimated z-score was calculated for any raw score based on five different models that adjust for the demographic predictors of SEX, AGE and EDUCATION, either concurrently, individually or without covariates. The interactive online calculator allows the entry of a raw score and provides five corresponding estimated z-scores based on predictions from each corresponding linear regression model. The calculator produces percentile ranks and graphical output.
An interactive, regression-based, normative score online calculator was created to serve as an additional resource for UDS clinical researchers, especially in guiding interpretation of individual performances that appear to fall in borderline realms and may be of particular utility for operationalizing subtle cognitive impairment present according to the newly proposed criteria for Stage 3 preclinical Alzheimer's disease.
Alzheimer's disease; cognitive aging; MCI; memory; norms
While normal aging is associated with a marked decline in cognitive abilities, such as memory and executive functions, recent evidence suggests that control processes involved in regulating responses to emotional stimuli may remain well-preserved in the elderly. However, neither the precise nature of these preserved control processes, nor their domain-specificity with respect to comparable non-emotional control processes, are currently well-established. Here, we tested the hypothesis of domain-specific preservation of emotional control in the elderly by employing two closely matched behavioral tasks that assessed the ability to shield the processing of task-relevant stimulus information from competition by task-irrelevant distracter stimuli that could be either non-emotional or emotional in nature. The efficacy of non-emotional versus emotional task-set shielding, gauged via the ‘conflict adaptation effect’, was compared between cohorts of healthy young adults, healthy elderly adults, and individuals diagnosed with probable Alzheimer’s disease (PRAD), age-matched to the elderly subjects. It was found that, compared to the young adult cohort, the healthy elderly displayed deficits in task-set shielding in the non-emotional but not in the emotional task, whereas PRAD subjects displayed impaired performance in both tasks. These results provide new evidence that healthy aging is associated with a domain-specific preservation of emotional control functions, specifically, the shielding of a current task-set from interference by emotional distracter stimuli. This selective preservation of function supports the notion of partly dissociable affective control mechanisms, and may either reflect different time-courses of degeneration in the neuroanatomical circuits mediating task-set maintenance in the face of non-emotional versus emotional distracters, or a motivational shift towards affective processing in the elderly.
aging; cognitive control; emotional control; conflict adaptation; face-word Stroop task; probable Alzheimer’s disease
Dementia of the Alzheimer’s type (DAT) is a major public health threat in developed countries where longevity has been extended to the eighth decade of life. Estimates of prevalence and incidence ofDAT vary with what is measured, be it change from a baseline cognitive state or a clinical diagnostic endpoint, such as Alzheimer’s disease. Judgment of what is psychometrically “normal” at the age of 80 years implicitly condones a decline from what is normal at the age of 30. However, because cognitive aging is very heterogeneous, it is reasonable to ask “Is ‘normal for age’ good enough to screen forDAT or its earlier precursors of cognitive impairment?” Cost containment and accessibility of ascertainment methods are enhanced by well-validated and reliable methods such as screening for cognitive impairment by telephone interviews. However, focused assessment of episodic memory, the key symptom associated with DAT, might be more effective at distinguishing normal from abnormal cognitive aging trajectories. Alternatively, the futuristic “Smart Home,” outfitted with unobtrusive sensors and data storage devices, permits the moment-to-moment recording of activities so that changes that constitute risk for DAT can be identified before the emergence of symptoms.
This cross-sectional study examines the association between total prescription medication use and potentially inappropriate medication use (PIRx) among community-dwelling elderly patients with and without dementia. Data (9/2005-9/2007) were from the NIA-funded National Alzheimer's Coordinating Center Uniform Data Set (UDS). The study analyzed the UDS initial visits of 4,518 community-dwelling subjects aged 65+ with and without dementia (2,665 and 1,853, respectively). PIRx was defined using a partial list of the 2003 Beers criteria. Generalized linear mixed models were applied to estimate the association between PIRx and polypharmacy. In both groups (with and without dementia), subjects who received PIRx on average took more medications than those taking no PIRx. As the total number of medications used increased, the odds of having PIRx also increased, controlling for dementia diagnosis and other subject characteristics. Our key findings were consistent after considering two definitions of PIRx (with or without oral estrogens) and accounting for missing data. In summary, the total number of medications used is associated with PIRx among ADC's community-dwelling elderly patients with and without dementia, with polypharmacy increasing the risk of PIRx. Ensuring appropriate medication use in this population is clinically important because of the significant risks for institutionalization.
prescription drugs; Beers criteria; Alzheimer's disease
Primary progressive aphasia (PPA), a selective neurodegeneration of the language network, frequently causes object naming impairments. We examined the N400 event-related potential (ERP) to explore interactions between object recognition and word processing in 20 PPA patients and 15 controls. Participants viewed photographs of objects, each followed by a word that was either a match to the object, a semantically related mismatch, or an unrelated mismatch. Patients judged whether word– object pairs matched with high accuracy (94% PPA group; 98% control group), but they failed to exhibit the normal N400 category effect (N400c), defined as a larger N400 to unrelated versus related mismatch words. In contrast, the N400 mismatch effect (N400m), defined as a larger N400 to mismatch than match words, was observed in both groups. N400m magnitude was positively correlated with neuropsychological measures of word comprehension but not fluency or grammatical competence, and therefore reflected the semantic component of naming. After ERP testing, patients were asked to name the same set of objects aloud. Trials with objects that could not be named were found to lack an N400m, although the name had been correctly recognized at the matching stage. Even accurate overt naming did not necessarily imply normal semantic processing, as shown by the absent N400c. The N400m was preserved in one patient with postsemantic anomia, who could write the names of objects she could not verbalize. N400 analyses can thus help dissect the multiple cognitive mechanisms that contribute to object naming failures in PPA.
To provide a quantitative algorithm for classifying primary progressive aphasia (PPA) into agrammatic (PPA-G), semantic (PPA-S) and logopenic (PPA-L) variants, each of which is known to have a different probability of association with Alzheimer’s disease (AD) versus frontotemporal lobar degeneration (FTLD).
Prospectively and consecutively enrolled 16 PPA patients tested with neuropsychological instruments and magnetic resonance imaging (MRI).
University medical center.
PPA patients recruited nationally in the USA as part of a longitudinal study.
A two-dimensional template, reflecting performance on tests of syntax (Northwestern Anagram Test) and lexical semantics (Peabody Picture Vocabulary Test), classified all 16 patients in concordance with a clinical diagnosis that had been made prior to the administration of the quantitative tests. All three subtypes had distinctly asymmetrical atrophy of the left perisylvian language network. Each subtype also had distinctive peak atrophy sites. Only PPA-G had peak atrophy in the IFG (Broca’s area), only PPA-S had peak atrophy in the anterior temporal lobe, and only PPA-L had peak atrophy in area 37.
Once an accurate root diagnosis of PPA is made, subtyping can be quantitatively guided using a two-dimensional template based on orthogonal tasks of grammatical competence and word comprehension. Although the choice of tasks and precise cut-off levels may evolve in time, this set of 16 patients demonstrates the feasibility of using a simple algorithm for clinico-anatomical classification in PPA. Prospective studies will show whether this suptyping can improve the clinical prediction of underlying neuropathology.
Pathogenic mutations in the gene encoding TDP-43, TARDBP, have been reported in familial amyotrophic lateral sclerosis (FALS) and, more recently, in families with a heterogeneous clinical phenotype including both ALS and frontotemporal lobar degeneration (FTLD). In our previous study, sequencing analyses identified one variant in the 3′-untranslated region (3′-UTR) of the TARDBP gene in two affected members of one family with bvFTD and ALS and in one unrelated clinically assessed case of FALS. Since that study, brain tissue has become available and provides autopsy confirmation of FTLD-TDP in the proband and ALS in the brother of the bvFTD-ALS family and the neuropathology of those two cases is reported here. The 3′-UTR variant was not found in 982 control subjects (1,964 alleles). To determine the functional significance of this variant, we undertook quantitative gene expression analysis. Allele-specific amplification showed a significant increase of 22% (P < 0.05) in disease-specific allele expression with a twofold increase in total TARDBP mRNA. The segregation of this variant in a family with clinical bvFTD and ALS adds to the spectrum of clinical phenotypes previously associated with TARDBP variants. In summary, TARDBP variants may result in clinically and neuropathologically heterogeneous phenotypes linked by a common molecular pathology called TDP-43 proteinopathy.
Frontotemporal lobar degeneration; Frontotemporal dementia; Motor neuron disease; Amyotrophic lateral sclerosis; TDP-43; TARDBP; 3′-Untranslated region
In the present study, we have correlated plasma TDP-43 levels, as measured by ELISA, with the presence of TDP-43 pathological changes in the brains of 28 patients with frontotemporal lobar degeneration (FTLD) (14 with FTLD-TDP and 14 with FTLD-tau) and 24 patients with pathologically confirmed AD (8 with, and 16 without, TDP-43 pathological changes). Western blotting revealed full-length TDP-43, including a phosphorylated form, and a phosphorylated C-terminal fragment, in all samples examined. Both ELISA and immunohistochemistry were performed using phospho-dependent and phospho-independent TDP-43 antibodies for detection of phosphorylated and total TDP-43, respectively. Over all 52 cases, plasma levels of TDP-43, and scores of brain TDP-43 pathology, determined using TDP-43 phospho-dependent antibody correlated with the equivalent measure determined using the TDP phospho-independent antibody. In FTLD, but not AD, TDP-43 plasma levels correlated significantly with the pathology score when using the TDP-43 phospho-dependent antibody, but a similar correlation was not seen in either FTLD or AD using the TDP-43 phospho-independent antibody. With the TDP-43 phospho-independent antibody, there were no significant differences in median plasma TDP-43 levels between FTLD, or AD, patients with or without TDP-43 pathology. Using TDP-43 phospho-dependent antibody, median plasma TDP-43 levels were greater in patients with, than in those without, TDP-43 pathology for FTLD patients, though not significantly so, but not for AD patients. Present assays for TDP-43 do not differentiate between FTLD, or AD, patients with or without TDP-43 pathological changes in their brains. However, the levels of phosphorylated TDP-43 in plasma do correlate with the extent of TDP-43 brain pathology in FTLD, and therefore might be a useful surrogate marker for tracking changes in TDP-43 brain pathology during the course of this disease.
Frontotemporal lobar degeneration; Alzheimer's disease; TDP-43; ELISA; Plasma