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To determine whether quality-of-life (QOL) ratings are reduced in mild cognitive impairment (MCI) and analyze correlations between QOL ratings and cognitive, neuropsychiatric, and functional indices in MCI. Cross-sectional. The Easton Center for Alzheimer's Disease Research at the University of California, Los Angeles. A total of 205 individuals who met criteria for normal cognition (n = 97) or MCI (n = 108). The MCI group included amnestic (n = 72) and nonamnestic (n = 36) MCI. QOL was assessed using subject and informant ratings on the Quality of Life–Alzheimer's Disease (QOL-AD) scale. Cognitive performance was assessed with the National Alzheimer's Disease Coordinating Center Uniform Data Set neuropsychological battery. Neuropsychiatric symptoms were assessed with the Geriatric Depression Scale (GDS) and the Neuropsychiatric Inventory. Functional abilities were assessed with the Functional Activities Questionnaire (FAQ). The normal cognition group had significantly higher QOL-AD scores than the MCI group on both subject and informant assessments. Individual item analyses indicated that the largest group differences were seen on the mood and memory items. Similar QOL-AD scores were seen in the amnestic and nonamnestic MCI subgroups. Multiple regression analyses within the MCI group indicated that QOL-AD ratings were not correlated with neuropsychological performance. Subject QOL-AD ratings were inversely correlated with GDS scores and informant QOL-AD ratings were inversely correlated with GDS, Neuropsychiatric Inventory, and FAQ scores. Significant declines in QOL are seen in MCI and are associated with neuropsychiatric symptoms and functional decline. Interventions targeting mood symptoms and/or instrumental activities of daily living may improve QOL in MCI.

Background/Aims: Prior work in smaller cohorts suggests that traumatic brain injury (TBI) may be a risk factor for frontotemporal degeneration (FTD). We sought to confirm and extend these results using the National Alzheimer's Coordinating Center Uniform Data Set. Methods: We compared the TBI prevalence between FTD subjects and matched normal controls. Indices of cognitive, behavioral, functional, and global dementia severity were compared between FTD subjects with and without prior TBI. Results: Remote TBI with extended loss of consciousness (TBI-ext) was more common in individuals with FTD than in controls (OR: 1.67; 95% CI: 1.004-2.778). With TBI-ext, less functional and global impairment was seen in the behavioral variant of FTD, but more behavioral pathology was seen in the semantic variant. Conclusion: TBI may increase the FTD risk and influence clinical symptomatology and severity in FTD subtypes.

Background The role and implementation of tau PET imaging for predicting subsequent cognitive decline in Alzheimer’s disease (AD) remains uncertain. This study was designed to evaluate the relationship between baseline [ 18 F]GTP1 tau PET and subsequent longitudinal change across multiple cognitive measures over 18 months. Methods Our analyses incorporated data from 67 participants, including cognitively normal controls ( n = 10) and β-amyloid (Aβ)-positive individuals ([ 18 F] florbetapir Aβ PET) with prodromal ( n = 26), mild ( n = 16), or moderate ( n = 15) AD. Baseline measurements included cortical volume (MRI), tau burden ([ 18 F]GTP1 tau PET), and cognitive assessments [Mini-Mental State Examination (MMSE), Clinical Dementia Rating (CDR), 13-item version of the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog13), and Repeatable Battery for the Assessment of Neuropsychological Status (RBANS)]. Cognitive assessments were repeated at 6-month intervals over an 18-month period. Associations between baseline [ 18 F]GTP1 tau PET indices and longitudinal cognitive performance were assessed via univariate (Spearman correlations) and multivariate (linear mixed effects models) approaches. The utility of potential prognostic tau PET cut points was assessed with ROC curves. Results Univariate analyses indicated that greater baseline [ 18 F]GTP1 tau PET signal was associated with faster rates of subsequent decline on the MMSE, CDR, and ADAS-Cog13 across regions of interest (ROIs). In multivariate analyses adjusted for baseline age, cognitive performance, cortical volume, and Aβ PET SUVR, the prognostic performance of [ 18 F]GTP1 SUVR was most robust in the whole cortical gray ROI. When AD participants were dichotomized into low versus high tau subgroups based on baseline [ 18 F]GTP1 PET standardized uptake value ratios (SUVR) in the temporal (cutoff = 1.325) or whole cortical gray (cutoff = 1.245) ROIs, high tau subgroups demonstrated significantly more decline on the MMSE, CDR, and ADAS-Cog13. Conclusions Our results suggest that [ 18 F]GTP1 tau PET represents a prognostic biomarker in AD and are consistent with data from other tau PET tracers. Tau PET imaging may have utility for identifying AD patients at risk for more rapid cognitive decline and for stratification and/or enrichment of participant selection in AD clinical trials. Trial registration ClinicalTrials.gov NCT02640092 . Registered on December 28, 2015

Speech and language changes occur in Alzheimer's disease (AD), but few studies have characterized their longitudinal course. We analyzed open‐ended speech samples from a prodromal‐to‐mild AD cohort to develop a novel composite score to characterize progressive speech changes. Participant speech from the Clinical Dementia Rating (CDR) interview was analyzed to compute metrics reflecting speech and language characteristics. We determined the aspects of speech and language that exhibited significant longitudinal change over 18 months. Nine acoustic and linguistic measures were combined to create a novel composite score. The speech composite exhibited significant correlations with primary and secondary clinical endpoints and a similar effect size for detecting longitudinal change. Our results demonstrate the feasibility of using automated speech processing to characterize longitudinal change in early AD. Speech‐based composite scores could be used to monitor change and detect response to treatment in future research. HIGHLIGHTS Longitudinal speech samples were analyzed to characterize speech changes in early AD. Acoustic and linguistic measures showed significant change over 18 months. A novel speech composite score was computed to characterize longitudinal change. The speech composite correlated with primary and secondary trial endpoints. Automated speech analysis could facilitate remote, high frequency monitoring in AD.

Introduction Prior observational work in a heterogeneous cohort of participants with mild cognitive impairment suggests the Amsterdam Instrumental Activities of Daily Living Questionnaire (A‐IADL‐Q) may have greater sensitivity for functional decline than the more established Alzheimer's Disease Cooperative Study–Activities of Daily Living (ADCS‐ADL) scale. However, the relative utility of the A‐IADL‐Q versus the ADCS‐ADL for clinical trials in early Alzheimer's disease (AD) remains uncertain. Methods We compared baseline and longitudinal performance of the A‐IADL‐Q and ADCS‐ADL in participants with biomarker‐confirmed prodromal (pAD; n = 158) or mild (mAD; n = 283) AD enrolled in the 18‐month Tauriel study of semorinemab (NCT03289143). Results The A‐IADL‐Q exhibited numerically stronger discrimination between pAD and mAD participants at baseline per Cohen's d analyses and similar sensitivity to longitudinal decline across cohorts over 18 months relative to the ADCS‐ADL. Discussion The comparable performance of the ADCS‐ADL and A‐IADL‐Q supports the utility of the A‐IADL‐Q in early AD clinical trials. Highlights The Amsterdam Instrumental Activities of Daily Living Questionnaire (A‐IADL‐Q) may be more sensitive than the Alzheimer's Disease Cooperative Study–Activities of Daily Living Scale (ADCS‐ADL) for distinguishing prodromal and mild Alzheimer's disease (AD). A‐IADL‐Q and ADCS‐ADL are similarly sensitive to decline in early AD over 18 months. Comparable performance of these indices supports A‐IADL‐Q use in future AD trials. Additional AD clinical trial data could extend findings across more diverse cohorts.

Background Bilingualism may protect against cognitive aging and delay the onset of dementia. However, studies comparing monolinguals and bilinguals on such metrics have produced inconsistent results complicated by confounding variables and methodological concerns. Methods We addressed this issue by comparing cognitive performance in a more culturally homogeneous cohort of older Spanish-speaking monolingual ( n  = 289) and Spanish-English bilingual ( n  = 339) Mexican-American immigrants from the Sacramento Longitudinal Study on Aging. Results After adjusting for demographic differences and depressive symptoms, both groups performed similarly at baseline on verbal memory but the bilingual group performed significantly better than the monolingual group on a cognitive screening test, the Modified Mini-Mental State Examination (3MS; p  < 0.001). Group differences on the 3MS were driven by language/executive and language/praxis factors. Within the bilingual group, neither language of testing nor degree of bilingualism was significantly associated with 3MS or verbal memory scores. Amongst individuals who performed in the normal or better range on both tests at baseline and were followed for an average of 6 years, both monolinguals and bilinguals exhibited similar rates of cognitive decline on both measures. Conclusions These findings suggest that bilingualism is associated with modest benefits in cognitive screening performance in older individuals in cross-sectional analyses that persist across longitudinal analyses. The effects of bilingualism should be considered when cognitively screening is performed in aging immigrant populations.

Background Mild cognitive impairment (MCI) has an uncertain etiology and prognosis and may be challenging for clinicians to discuss with patients and families. Amyloid imaging may aid specialists in determining MCI etiology and prognosis, but creates novel challenges related to disease labeling. Methods We convened a workgroup to formulate recommendations for clinicians providing care to MCI patients. Results Clinicians should use the MCI diagnosis to validate patient and family concerns and educate them that the patient’s cognitive impairment is not normal for his or her age and education level. The MCI diagnosis should not be used to avoid delivering a diagnosis of dementia. For patients who meet Appropriate Use Criteria after standard-of-care clinical workup, amyloid imaging may position specialists to offer more information about etiology and prognosis. Clinicians must set appropriate expectations, including ensuring that patients and families understand the limitations of amyloid imaging. Communication of negative results should include that patients remain at elevated risk for dementia and that negative scans do not indicate a specific diagnosis or signify brain health. Positive amyloid imaging results should elicit further monitoring and conversations about appropriate advance planning. Clinicians should offer written summaries, including referral to appropriate social services. Conclusions In patients with MCI, there is a need to devote considerable time and attention to patient education and shared decision-making. Amyloid imaging may be a tool to aid clinicians. Careful management of patient expectations and communication of scan results will be critical to the appropriate use of amyloid imaging information.

Background/Aims: Greater cognitive and functional deficits in mild cognitive impairment (MCI) are associated with higher rates of dementia. We explored the relationship between these factors by comparing instrumental activities of daily living (IADLs) among cognitive subtypes of MCI and examining associations between IADL and neuropsychological indices. Methods: We analyzed data from 1,108 MCI and 3,036 normal control subjects included in the National Alzheimer’s Coordinating Center Uniform Data Set who were assessed with the Functional Activities Questionnaire (FAQ). Results: IADL deficits were greater in amnestic than nonamnestic MCI, but within these subgroups, did not differ between those with single or multiple domains of cognitive impairment. FAQ indices correlated significantly with memory and processing speed/executive function. Conclusions: IADL deficits are present in both amnestic MCI and nonamnestic MCI but are not related to the number of impaired cognitive domains. These cross-sectional findings support previous longitudinal reports suggesting that cognitive and functional impairments in MCI may be independently associated with dementia risk.

The hippocampus is part of a system of structures in the medial temporal lobe that are essential for memory 1 , 2 , 3 . One influential view of hippocampal function emphasizes its role in the acquisition and retrieval of spatial knowledge 4 , 5 . By this view, the hippocampus constructs and stores spatial maps and is therefore essential for learning and remembering places, including those learned about long ago. We tested a profoundly amnesic patient (E.P.), who has virtually complete bilateral damage to the hippocampus and extensive damage to adjacent structures in the medial temporal lobe. We asked him to recall the spatial layout of the region where he grew up, from which he moved away more than 50 years ago. E.P. performed as well as or better than age-matched control subjects who grew up in the same region and also moved away. In contrast, E.P. has no knowledge of his current neighbourhood, to which he moved after he became amnesic. Our results show that the medial temporal lobe is not the permanent repository of spatial maps, and support the view that the hippocampus and other structures in the medial temporal lobe are essential for the formation of long-term declarative memories, both spatial and non-spatial, but not for the retrieval of very remote memories, either spatial or non-spatial 3 , 6 .

Impairments in learning and recall have been well established in amnestic mild cognitive impairment (aMCI). However, a relative dearth of studies has examined the profiles of memory strategy use in persons with aMCI relative to those with Alzheimer's disease (AD). Participants with aMCI, nonamnestic MCI, AD, and healthy older adults were administered the California Verbal Learning Test-II (CVLT-II). Measures of semantic clustering and recall were obtained across learning and delayed recall trials. In addition, we investigated whether deficits in semantic clustering were related to progression from healthy aging to aMCI and from aMCI to AD. The aMCI group displayed similar semantic clustering performance as the AD participants, whereas the AD group showed greater impairments on recall relative to the aMCI participants. Control participants who progressed to aMCI showed reduced semantic clustering at the short delay at baseline compared to individuals who remained diagnostically stable across follow-up visits. These findings show that the ability to engage in an effective memory strategy is compromised in aMCI, before AD has developed, suggesting that disruptions in semantic networks are an early marker of the disease. (JINS, 2014, 20, 1–11)