Structural Brain Changes in Pre-Clinical FTD MAPT Mutation Carriers.

BACKGROUND: Frontotemporal dementia (FTD) is the second most common cause of early-onset neurodegenerative dementia. Several studies have focused on early imaging changes in FTD patients, but once subjects meet full criteria for FTD diagnosis, structural changes are generally widespread. OBJECTIVE: This study aims to determine the earliest structural brain changes in asymptomatic MAPT MUTATION carriers. METHODS: This is a cross-sectional multicenter study comparing global and regional brain volume and white matter integrity in a group of MAPT mutation preclinical carriers and controls. Participants belong to multiple generations of six families with five MAPT mutations. All participants underwent a medical examination, neuropsychological tests, genetic analysis, and a magnetic resonance scan (3T, scout, T1-weighted image followed by EPI (BOLD), MPRAGE, DTI, FLAIR, and ASL sequences). RESULTS: Volumes of five cortical and subcortical areas were strongly correlated with mutation status: temporal lobe (left amygdala, left temporal pole), cingulate cortex (left rostral anterior cingulate gyrus, right posterior cingulate), and the lingual gyrus in the occipital lobe. We did not find significant differences in whole brain volume, white matter hyperintensities volume, and white matter integrity using DTI analysis. CONCLUSION: Temporal lobe, cingulate cortex and the lingual gyrus seem to be early targets of the disease and may serve as biomarkers for FTD prior to overt symptom onset.

Modification of everyday activities and its association with self-awareness in cognitively diverse older adults.

Cognitive impairment (CI) in older adults is frequently accompanied by difficulty performing complex everyday activities (e.g., managing finances). However, it is unclear if and how older adults with CI modify their activities (i.e., Do individuals continue, monitor, seek help with, change their approach to, or stop different activities?). In the current study, we examined if older adults with CI are concerned about their ability to carry out complex activities, if and how they modify activities based on their concern, and the factors associated with activity modification. We hypothesized that older adults with CI will more frequently be concerned about, and modify, everyday activities than cognitively healthy (HE) older adults, and that higher awareness of memory loss in the CI group would relate to more frequent modification. The sample included 81 older adults (51 HEs; mean age 70.02 (7.34) and 30 CI; mean age 75.97 (8.12)). Compared to HEs, the CI group reported having more concern about, F(3,77) = 5.50, p = 0.02, and modifying a greater number of activities, F(3,77) = 5.02, p = 0.03. Medication management (30%) and completing taxes (33.3%) were among the most frequently modified activities for the CI and HE groups, respectively. In the CI group, higher memory awareness was associated with more concern (r = .53, p = .005) and activity modification (r = 0.55, p = .003). Findings provide novel information about how cognitively diverse older adults navigate complex activities in daily life. We propose a preliminary theoretical model by which self-awareness may influence navigation of everyday activities in the context of CI.

Cognitive Indicators of Preclinical Behavioral Variant Frontotemporal Dementia in MAPT Carriers.

OBJECTIVES: The cognitive indicators of preclinical behavioral variant Frontotemporal Dementia (bvFTD) have not been identified. To investigate these indicators, we compared cross-sectional performance on a range of cognitive measures in 12 carriers of pathogenic MAPT mutations not meeting diagnostic criteria for bvFTD (i.e., preclinical) versus 32 demographically-matched familial non-carriers (n = 44). Studying preclinical carriers offers a rare glimpse into emergent disease, environmentally and genetically contextualized through comparison to familial controls. METHODS: Evaluating personnel blinded to carrier status administered a standardized neuropsychological battery assessing attention, speed, executive function, language, memory, spatial ability, and social cognition. Results from mixed effect modeling were corrected for multiplicity of comparison by the false discovery rate method, and results were considered significant at p < .05. To control for potential interfamilial variation arising from enrollment of six families, family was treated as a random effect, while carrier status, age, gender, and education were treated as fixed effects. RESULTS: Group differences were detected in 17 of 31 cognitive scores and spanned all domains except spatial ability. As hypothesized, carriers performed worse on specific measures of executive function, and social cognition, but also on measures of attention, speed, semantic processing, and memory storage and retrieval. CONCLUSIONS: Most notably, group differences arose on measures of memory storage, challenging long-standing ideas about the absence of amnestic features on neuropsychological testing in early bvFTD. Current findings provide important and clinically relevant information about specific measures that may be sensitive to early bvFTD, and advance understanding of neurocognitive changes that occur early in the disease. (JINS, 2019, 25, 184-194).

Psychiatric symptoms in preclinical behavioural-variant frontotemporal dementia in MAPT mutation carriers.

OBJECTIVE: To characterise psychiatric symptoms in preclinical and early behavioural-variant frontotemporal dementia (bvFTD), a neurodegenerative disorder whose symptoms overlap with and are often mistaken for psychiatric illness. METHODS: The present study reports findings from a systematic, global, prospective evaluation of psychiatric symptoms in 12 preclinical carriers of pathogenic MAPT mutations, not yet meeting bvFTD diagnostic criteria, and 46 familial non-carrier controls. Current psychiatric symptoms, informant-reported symptoms and lifetime prevalence of psychiatric disorders were assessed with The Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) and the Neuropsychiatric Inventory Questionnaire. Fisher exact test was used to compare carriers and non-carriers' lifetime prevalence of six DSM-IV disorders: major depressive disorder, panic attacks, alcohol abuse, generalised anxiety disorder, panic disorder, and depressive disorder not otherwise specified. Other DSM-IV disorders had insufficient prevalence across our sample for between-group comparisons, but are reported. RESULTS: Non-carriers had greater prevalence of mood and anxiety disorders than has been reported for a general reference population. Preclinical carriers had lower lifetime prevalence of mood and anxiety disorders than non-carriers, except for depressive disorder not otherwise specified, an atypical syndrome comprising clinically significant depressive symptoms which fail to meet criteria for major depressive disorder. CONCLUSION: Findings suggest that early psychiatric symptoms of emergent bvFTD may manifest as emotional blunting or mood changes not cleanly conforming to criteria for a DSM-defined mood disorder.

Examination of the metacognitive errors that contribute to anosognosia in Alzheimer's disease.

Disordered awareness of memory loss (i.e., anosognosia) is a frequent and clinically relevant symptom of Alzheimer's disease (AD). The metacognitive errors which characterize anosognosia in AD, however, have not been fully articulated. The current study examined metamemory performance as a function of clinically defined awareness groups using different task conditions to examine the extent to which specific metacognitive deficits (i.e., detecting, integrating, or being explicitly aware of errors) contribute to anosognosia in AD (n = 49). In the prospective condition of the metamemory task, analyses examining the association between awareness group, confidence (i.e., FOK) ratings, and memory performance demonstrated an interaction effect F (1, 43) = 5.16, p = .028 with only the aware group (n = 22) providing higher FOK ratings for correct responses compared to incorrect responses (p < .001). The unaware group (n = 27) did not show this dissociation (p = .167), and also made higher FOK ratings for incorrect responses than the aware group (p = .048). There was no main effect of task condition on FOK [F (2, 66) = 1.51, p = .228] with all participants providing comparable FOK ratings for memory performance whether ratings were made prospectively, retrospectively, or in the context of examiner feedback. The overall pattern of performance in the unaware group, whereby individuals did not sufficiently lower confidence ratings in the context of memory errors, and did not benefit from either retrospective assessment or examiner feedback, appears most consistent with a primary anosognosia in which memory failures are not available in explicit awareness.

Examining the Pathways Between Self-Awareness and Well-Being in Mild to Moderate Alzheimer Disease.

OBJECTIVE: To investigate the relationship between awareness of memory loss and psychological well-being in a nonclinically depressed sample of participants with mild to moderate Alzheimer disease (AD). METHODS: Study participants (N = 104) enrolled through Columbia University Medical Center and the University of Pennsylvania completed clinical and cognitive assessments. Participants were rated with regard to their degree of awareness of memory deficits and completed questionnaires relating to their psychological well-being, including mood and quality of life (QOL). Mediating models were used to establish the relationship between awareness, depression, and QOL and to examine potential mediators of awareness and depression, including psychological distress, objective memory deficits, and negative self-ratings. RESULTS: There was a direct association between awareness of memory deficits and depressed mood but not awareness and QOL. However, there was an indirect association between awareness and QOL through depression. Neither psychological distress, memory deficits, nor negative self-ratings mediated the relationship between awareness and depression. CONCLUSION: Awareness is associated with depressed mood in nonclinically depressed participants with mild to moderate AD. However, depressed mood does not appear to reflect the direct psychological reaction to awareness of memory loss. Moreover, awareness has only an indirect association with QOL via depressed mood. These results suggest that preserved awareness does not have a direct negative impact on overall psychological well-being in AD.

Ascertaining Subjective Cognitive Decline: A Comparison of Approaches and Evidence for Using an Age-Anchored Reference Group.

BACKGROUND: Subjective cognitive decline (SCD) is increasingly considered promising to detect preclinical Alzheimer's disease. How SCD is ascertained is critical for determining its potential utility in identifying at-risk individuals, yet SCD measures differ along several dimensions. OBJECTIVE: We aimed to examine the extent to which reports of SCD in healthy elderly may be influenced by the characteristics of the SCD measures. We investigated variations in rates of SCD endorsement across different measures, including an open-ended question. We also examined the association of responses across measures, and the degree to which specific SCD items were associated with objective memory performance. METHODS: 99 healthy elderly completed a series of questionnaires from which 10 items examining SCD for memory and other aspects of cognition were drawn. We applied Cochran's Q tests to assess differences in rates of SCD, correlation analyses to examine association of SCD responses, and regression models to determine the association between SCD items and delayed verbal memory. RESULTS: Rates of SCD varied as a function of the assessment format, ranging from 1 to 7% for memory and 5 to 20% for concentration. SCD was lower for memory versus non-memory domains. SCD items were associated both within and across domains. The most accurate predictor of memory was memory-related SCD in comparison to others the same age. CONCLUSION: Characteristics of SCD items influence rates of endorsement. Querying SCD using an "age-anchored" question may provide the most accurate reflection of actual cognitive performance.

The right insula contributes to memory awareness in cognitively diverse older adults.

Unawareness of memory loss is a challenging characteristic of Alzheimer's disease (AD) and other age-related neurodegenerative conditions at their earliest stages, adversely affecting important outcomes such as patient decision making and safety. The basis of this metacognitive disturbance has been elusive; however it is almost certainly determined in part by compromise to brain regions critical for self-assessment. The subjectivity of traditional measurements of self-awareness in dementia has likely limited the rigor with which its neuroanatomic correlates can be established. Here we objectively measure memory awareness (metamemory) using a Feeling of Knowing (FOK) task in a group of cognitively diverse older adults, including 14 with mild AD and 20 cognitively healthy older adults. Performance on the metamemory task was examined in relation to the structural integrity of 14 bilateral neuroanatomic regions hypothesized to support self-awareness. Less accurate metamemory was associated only with reduced right insular volume (r=.41, p=.019). Implications of the current findings for models of metacognitive aging are discussed, with attention to the role of the insula in the conscious detection of errors.

Untimed Design Fluency in Aging and Alzheimer's Disease: Psychometrics and Normative Data.

Design fluency tests, commonly used in both clinical and research contexts to evaluate nonverbal concept generation, have the potential to offer useful information in the differentiation of healthy versus pathological aging. Although normative data for older adults (OAs) are available for multiple timed versions of this test, similar data have been unavailable for a previously published untimed test, the Graphic Pattern Generation Test (GPG). Time constraints common to almost all of the available design fluency tests may cloud interpretation of higher-level executive abilities-for example, in individuals with slow processing speed. The current study examined the psychometric properties of the GPG and presents normative data in a sample of 167 healthy OAs and 110 individuals diagnosed with Alzheimer's disease (AD). Results suggest that a brief version of the GPG can be administered reliably and that this short form has high test-retest and interrater reliability. Number of perseverations was higher in individuals with AD as compared with OAs. A cutoff score of 4 or more perseverations showed a moderate degree of sensitivity (76%) and specificity (37%) in distinguishing individuals with AD and OAs. Finally, perseverations were associated with nonmemory indexes, thereby underscoring the nonverbal nature of this error in OAs and individuals with AD.

Cognitive correlates of metamemory in Alzheimer's disease.

OBJECTIVE: Metamemory, or knowledge of one's memory abilities, is often impaired in individuals with Alzheimer's disease (AD), although the basis of this metacognitive deficit has not been fully articulated. Behavioral and imaging studies have produced conflicting evidence regarding the extent to which specific cognitive domains (i.e., executive function; memory) and brain regions contribute to memory awareness. The primary aim of this study was to disentangle the cognitive correlates of metamemory in AD by examining the relatedness of objective metamemory performance to cognitive tasks grouped by domain (executive function or memory) as well as by preferential hemispheric reliance defined by task modality (verbal or nonverbal). METHOD: Eighty-nine participants with mild AD recruited at Columbia University Medical Center and the University of Pennsylvania underwent objective metamemory and cognitive testing. Partial correlations were used to assess the relationship between metamemory and four cognitive variables, adjusted for recruitment site. RESULTS: The significant correlates of metamemory included nonverbal fluency (r = .27, p = .02) and nonverbal memory (r = .24, p = .04). CONCLUSIONS: Our findings suggest that objectively measured metamemory in a large sample of individuals with mild AD is selectively related to a set of interdomain nonverbal tasks. The association between metamemory and the nonverbal tasks may implicate a shared reliance on a right-sided cognitive network that spans frontal and temporal regions.