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OBJECTIVE: Altered patterns of brain activity during cognitive tasks have been demonstrated using functional magnetic resonance imaging (fMRI) in mild cognitive impairment and Alzheimer's disease. However, there have been few studies of adults at genetic risk for Alzheimer's disease prior to the onset of symptoms. The purpose of this study was to determine whether brain activation patterns associated with working memory differ as a function of apolipoprotein E (APOE) genotype in cognitively intact adults. METHOD: Participants were cognitively intact, healthy adults who completed genotyping, comprehensive neuropsychological testing, and structural and functional neuroimaging. Twenty-two participants had the APOE epsilon3/epsilon3 genotype, and 13 participants had the APOE epsilon3/epsilon4 genotype. The study employed an auditory verbal N-back task to probe working memory-related brain activity. RESULTS: The epsilon3/epsilon3 and epsilon3/epsilon4 groups did not differ in demographic characteristics, cognitive ability, mood, or in-scanner task performance. The epsilon3/epsilon4 group showed greater activity during working memory in the medial frontal and parietal regions bilaterally and in the right dorsolateral prefrontal cortex. There were no regions in which the epsilon3/epsilon3 group showed greater activation than the epsilon3/epsilon4 group. CONCLUSIONS: These results indicate that differences in brain activity are evident in cognitively intact individuals who are at risk for late-onset Alzheimer's disease by virtue of their APOE allele status. As neuroprotective interventions become available, early detection will increase in importance. The combination of genetic and functional neuroimaging strategies may prove useful for monitoring individuals at risk for Alzheimer's disease before the onset of cognitive symptoms. [ABSTRACT FROM AUTHOR]

Brain network dynamics have been extensively explored in patients with subjective cognitive decline (SCD). However, these studies are susceptible to individual differences, scanning parameters, and other confounding factors. Therefore, how to reveal subtle SCD-related subtle changes remains unclear. Cross-sectional and longitudinal resting-state functional magnetic resonance imaging data from both Chinese and Western populations were analyzed. We proposed a framework of dynamic proportional loss of functional connectivity (DPLFC). After its stability was validated, the optimal parameters were applied for the clinical diagnosis of SCD. DPLFC yielded a relatively high intraclass correlation coefficient. In particular, the DPLFC of the left superior frontal gyrus (SFG) progressively decreased along the Alzheimer's disease (AD) continuum. Compared with the traditional index, the DPLFC had better classification performance between cognitively normal controls and patients with SCD. Furthermore, DPLFC was related to Aβ deposition and scale scores. Patients with lower DPLFC values had a greater risk of cognitive decline. Decreased DPLFC in the left SFG may be a potential AD-related neuroimaging biomarker at an early stage., Competing Interests: Declarations. Conflict of interest: The authors declare no competing interests., (© 2025. The Author(s), under exclusive licence to American Aging Association.)

AbstractResearch represents an avenue through which patients can contribute to the knowledge base surrounding their condition. However, persons with dementia cannot legally consent to participation in most scientific research. One possible avenue to preserve patient autonomy in the sphere of research is through an advance planning document. Scholars of medicine, ethics, and law have largely approached this topic from a theoretical angle, compelling the authors to develop and implement a tangible research-specific advance planning tool. In order to inform the creation of this novel legal instrument, the present study leveraged semistructured telephone interviews with cognitively intact older adults in the Upper Connecticut River Valley region of New Hampshire. Participants were prompted to reflect on their attitudes toward participation in scientific research, should they develop dementia. They were also asked to consider the possibility of incorporating research into their advance planning regime, their preferred format for a research-specific advance planning tool, and the potential relationship between an advance planning tool and their surrogate decision maker in the context of research participation. Qualitative analysis was employed to extract themes from interview responses, revealing a pervasive desire for an advance planning tool that embraces specificity, flexibility, practicality, and the integral role of the surrogate decision maker. Ultimately, through collaboration with physicians and an elder law attorney in the region, these findings were translated into a research-specific advance planning component within the Dartmouth Dementia Directive.

Advance directives (ADs) offer the opportunity for patients to express their desires regarding medical care in advance of any form of incapacitation. However, the efficacy of ADs in achieving care that aligns with patients' preferences is the subject of intense ethical debate. Current instructional AD formats may not allow for expression of the reasoning or values behind a patient's care preferences, limiting their utility and efficacy. Here, we review written AD formats and their limitations, and discuss video messages, as a supplement to written ADs, as a potential improvement. While video messages have limitations of their own, their potential use as a tool for better understanding patients' wishes and values suggests a need for further research and consideration of their application and integration into standard clinical practice., (Copyright 2022 The Journal of Clinical Ethics. All rights reserved.)

As dementia becomes more prevalent in the aging population, clinicians increasingly face the challenge of caring for patients who had told family members that they preferred death to life with advanced dementia. Advance directives can guide management, but usually are inadequate in caring for patients with advanced dementia. The "now" patient has very different sensibilities than the "then" patient who had expressed preferences for terminal care before dementia severely impaired cognition and executive function. Clinicians lack clear means of following a patient's directive to die rather than to live with advanced dementia. Withholding life-sustaining oral feeding or fluids is ethically problematic. Controversies remain over precedent autonomy as the justification for advance dementia directives, and the consequent legal, ethical, and practical issues clinicians face, particularly involving feeding., (Copyright © 2021. Published by Elsevier Inc.)

Dementia is a growing issue at the end of life that presents unique challenges for advance care planning. Advance directives are a useful and important component of end-of-life planning, but standard advance directives have less utility in cases of loss of capacity due to dementia. An advance directive designed to specifically address end-of-life issues in the setting of dementia can provide patients with increased autonomy and caregivers with improved information about the desires of the individual in question. The Dartmouth Dementia Directive is a dementia-specific advance directive, available online, that seeks to address common concerns of individuals who are planning for dementia-related end-of-life care. This directive was piloted in a community-based workshop, which provided important details and perspective on the best use of dementia-specific advance directives in the greater population., (Copyright 2020 The Journal of Clinical Ethics. All rights reserved.)

Despite considerable gains in public awareness of dementia, dementia patients and their caregivers continue to be stigmatized. Previous work has explored stigma and burden among adult children of persons with dementia in Israel, but no similar data exist for spousal caregivers or caregivers in general in the United States. This study examines the differences in stigma and burden experienced by spousal and adult child caregivers and male and female caregivers of persons with dementia. Eighty-two caregivers were given the Zarit Burden Inventory Short Form (ZBI) and the Caregiver Section of the Family Stigma in Alzheimer's Disease Scale (FS-ADS-C). Scores on the FS-ADS-C and ZBI were positively correlated (r s = .51, p < .001). Female caregivers reported experiencing more stigma on the FS-ADS-C (t(80) = -4.37, p < .001) and more burden on the ZBI (t(80) = -2.68, p = .009) compared to male caregivers, and adult child caregivers reported experiencing more stigma on the FS-ADS-C (t(30.8) = -2.22, p = .034) and more burden on the ZBI (t(80) = -2.65, p = .010) than spousal caregivers. These results reinforce the importance of support for caregivers, particularly adult child and female caregivers who may experience higher levels of stigma and burden.

Objective: To determine the physiological impact of treatment with donepezil (Aricept) on neural circuitry supporting episodic memory encoding in patients with amnestic mild cognitive impairment (MCI) using functional magnetic resonance imaging (fMRI)., Methods: Eighteen patients with MCI and 20 age-matched healthy controls (HC) were scanned twice while performing an event-related verbal episodic encoding task. MCI participants were scanned before treatment and after approximately 3 months on donepezil; HC were untreated but rescanned at the same interval. Voxel-level analyses assessed treatment effects on activation profiles in MCI patients relative to retest changes in non-treated HC. Changes in task-related connectivity in medial temporal circuitry were also evaluated, as were associations between brain activation, task-related functional connectivity, task performance, and clinical measures of cognition., Results: At baseline, the MCI group showed reduced activation during encoding relative to HC in the right medial temporal lobe (MTL; hippocampal/parahippocampal) and additional regions, as well as attenuated task-related deactivation, relative to rest, in a medial parietal lobe cluster. After treatment, the MCI group showed normalized MTL activation and improved parietal deactivation. These changes were associated with cognitive performance. After treatment, the MCI group also demonstrated increased task-related functional connectivity from the right MTL cluster seed region to a network of other sites including the basal nucleus/caudate and bilateral frontal lobes. Increased functional connectivity was associated with improved task performance., Conclusion: Pharmacologic enhancement of cholinergic function in amnestic MCI is associated with changes in brain activation and functional connectivity during episodic memory processing which are in turn related to increased cognitive performance. fMRI is a promising biomarker for assessing treatment related changes in brain function.

Deficits in contrast sensitivity (CS) have been reported in Alzheimer's disease (AD). However, the extent of these deficits in prodromal AD stages, including mild cognitive impairment (MCI) or even earlier, has not been investigated. In this study, CS was assessed using frequency doubling technology in older adults with AD (n = 10), amnestic MCI (n = 28), cognitive complaints without performance deficits (CC; n = 20), and healthy controls (HC; n = 29). The association between CS and cognition was also evaluated. Finally, the accuracy of CS measures for classifying MCI versus HC was evaluated. CS deficits were found in AD and MCI, while CC showed intermediate performance between MCI and HC. Upper right visual field CS showed the most significant difference among groups. CS was also associated with cognitive performance. Finally, CS measures accurately classified MCI versus HC. The CS deficits in AD and MCI, and intermediate performance in CC, indicate that these measures are sensitive to early AD-associated changes. Therefore, frequency doubling technology-based measures of CS may have promise as a novel AD biomarker., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Visual cortical surface area varies two- to threefold between human individuals, is highly heritable, and has been correlated with visual acuity and visual perception. However, it is still largely unknown what specific genetic and environmental factors contribute to normal variation in the area of visual cortex. To identify SNPs associated with the proportional surface area of visual cortex, we performed a genome-wide association study followed by replication in two independent cohorts. We identified one SNP (rs6116869) that replicated in both cohorts and had genome-wide significant association (P(combined) = 3.2 × 10(-8)). Furthermore, a metaanalysis of imputed SNPs in this genomic region identified a more significantly associated SNP (rs238295; P = 6.5 × 10(-9)) that was in strong linkage disequilibrium with rs6116869. These SNPs are located within 4 kb of the 5' UTR of GPCPD1, glycerophosphocholine phosphodiesterase GDE1 homolog (Saccharomyces cerevisiae), which in humans, is more highly expressed in occipital cortex compared with the remainder of cortex than 99.9% of genes genome-wide. Based on these findings, we conclude that this common genetic variation contributes to the proportional area of human visual cortex. We suggest that identifying genes that contribute to normal cortical architecture provides a first step to understanding genetic mechanisms that underlie visual perception.

Background: White matter changes measured using diffusion tensor imaging have been reported in Alzheimer's disease and amnestic mild cognitive impairment, but changes in earlier pre-mild cognitive impairment stages have not been fully investigated., Methods: In a cross-sectional analysis, older adults with mild cognitive impairment (n=28), older adults with cognitive complaints but without psychometric impairment (n=29) and healthy controls (n=35) were compared. Measures included whole-brain diffusion tensor imaging, T1-weighted structural magnetic resonance imaging, and neuropsychological assessment. Diffusion images were analyzed using Tract-Based Spatial Statistics. Voxel-wise fractional anisotropy and mean, axial, and radial diffusivities were assessed and compared between groups. Significant tract clusters were extracted in order to perform further region of interest comparisons. Brain volume was estimated using FreeSurfer based on T1 structural images., Results: The mild cognitive impairment group showed lower fractional anisotropy and higher radial diffusivity than controls in bilateral parahippocampal white matter. When comparing extracted diffusivity measurements from bilateral parahippocampal white matter clusters, the cognitive complaint group had values that were intermediate to the mild cognitive impairment and healthy control groups. Group difference in diffusion tensor imaging measures remained significant after controlling for hippocampal atrophy. Across the entire sample, diffusion tensor imaging indices in parahippocampal white matter were correlated with memory function., Conclusions: These findings are consistent with previous results showing changes in parahippocampal white matter in Alzheimer's disease and mild cognitive impairment compared to controls. The intermediate pattern found in the cognitive complaint group suggests the potential of diffusion tensor imaging to contribute to earlier detection of neurodegenerative changes during prodromal stages. This article is part of a Special Issue entitled: Imaging Brain Aging and Neurodegenerative disease., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Hierarchical clustering is frequently used for grouping results in expression or haplotype analyses. These methods can elucidate patterns between measures that can then be applied to discerning their validity in discriminating between experimental conditions. Here a hierarchical clustering method is used to analyze the results of an imaging genetics study using multiple brain morphology and cognitive testing endpoints for older adults with amnestic mild cognitive impairment (MCI) or cognitive complaints (CC) compared to healthy controls (HC). The single nucleotide polymorphisms (SNPs) are a subset of those included on a larger array that are found in a reported Alzheimer's disease (AD) and neurodegeneration pathway. The results indicate that genetic models within the endpoints cluster together, while there are 4 distinct sets of SNPs that differentiate between the endpoints, with most significant results associated with morphology endpoints rather than cognitive testing of patients' reported symptoms. The genes found in at least one cluster are ABCB1, APBA1, BACE1, BACE2, BCL2, BCL2L1, CASP7, CHAT, CST3, DRD3, DRD5, IL6, LRP1, NAT1, and PSEN2. The greater associations with morphology endpoints suggests that changes in brain structure can be influenced by an individual's genetic background in the absence of dementia and in some cases (Cognitive Complaints group) even without those effects necessarily being detectable on commonly used clinical tests of cognition. The results are consistent with polygenic influences on early neurodegenerative changes and demonstrate the effectiveness of hierarchical clustering in identifying genetic associations among multiple related phenotypic endpoints., ((c) 2010 Wiley-Liss, Inc.)

We investigated regional gray matter (GM) reduction as a predictor of judgment ability in 120 non-depressed older adults with varying degrees of cognitive complaints and/or impairment (including those with MCI and mild AD). Participants underwent neuropsychological assessment, including the Test of Practical Judgment (TOP-J), a recently developed instrument that evaluates judgment and problem solving related to safety, medical, social/ethical, and financial issues. Structural MR scanning included T1-weighted SPGR volumes acquired at 1.5 Tesla. We used voxel-based morphometry to analyze the relationship between GM density and TOP-J scores, controlling for age, education, gender, intracranial volume, verbal memory, and crystallized knowledge. Consistent with our hypothesis, judgment ability correlated with GM density in prefrontal regions (left inferior and superior frontal gyri). Findings extend previous observations of frontal involvement in higher-order cognitive abilities/executive functions and provide initial validation of the TOP-J's sensitivity to the integrity of these brain regions in individuals at risk for dementia.

Episodic memory is the first and most severely affected cognitive domain in Alzheimer's disease (AD), and it is also the key early marker in prodromal stages including amnestic mild cognitive impairment (MCI). The relative ability of memory tests to discriminate between MCI and normal aging has not been well characterized. We compared the classification value of widely used verbal memory tests in distinguishing healthy older adults (n = 51) from those with MCI (n = 38). Univariate logistic regression indicated that the total learning score from the California Verbal Learning Test-II (CVLT-II) ranked highest in terms of distinguishing MCI from normal aging (sensitivity = 90.2; specificity = 84.2). Inclusion of the delayed recall condition of a story memory task (i.e., WMS-III Logical Memory, Story A) enhanced the overall accuracy of classification (sensitivity = 92.2; specificity = 94.7). Combining Logical Memory recognition and CVLT-II long delay best predicted progression from MCI to AD over a 4-year period (accurate classification = 87.5%). Learning across multiple trials may provide the most sensitive index for initial diagnosis of MCI, but inclusion of additional variables may enhance overall accuracy and may represent the optimal strategy for identifying individuals most likely to progress to dementia.

Background: Telephone interviews are widely used in geriatric settings to identify eligible research participants and to perform brief follow-up assessments of cognition. This article reports on the development and validation of the Memory and Aging Telephone Screen (MATS), a structured interview for older adults with mild cognitive impairment and/or significant memory complaints. We also developed three alternate forms of the MATS objective memory test to reduce practice effects engendered by multiple administrations., Methods: Participants were enrolled in a longitudinal study that included 120 older adults with amnestic mild cognitive impairment, subjective cognitive complaints but without deficit on neuropsychological tests, and demographically matched healthy controls. An additional 15 patients with mild probable Alzheimer's disease completed the alternative forms study. All participants received the original MATS version, and a subset (n = 90) later received two of three alternate forms., Results: The MATS was sensitive to group differences, and the alternate forms were equivalent. MATS objective memory test scores showed adequate stability during a period of 1 year and were moderately correlated with scores on a widely used list-learning test (California Verbal Learning Test, Second Edition)., Conclusions: The MATS, a repeatable telephone screen that includes objective and subjective memory assessments, is useful for detecting individuals in the preclinical and early stages of dementia. Results encourage use of the MATS as a reliable and valid cognitive screening tool in research and clinical settings. Longitudinal assessments are being performed to investigate the predictive validity of the MATS for cognitive progression in mild cognitive impairment.

The goal of the present study was to determine if there are global or regionally specific decreases in callosal area in early Alzheimer's disease (AD) and mild cognitive impairment (MCI). In addition, this study examined the corpus callosum of healthy older adults who have subjective cognitive complaints (CC) but perform within normal limits on neuropsychological tests. We used a semi-automated procedure to examine the total and regional areas of the corpus callosum in 22 patients with early AD, 28 patients with amnestic MCI, 28 healthy older adults with cognitive complaints, and 50 demographically matched healthy controls (HC). The AD, MCI, and CC groups all showed a significant reduction of the posterior region (isthmus and splenium) relative to healthy controls. The AD group also had a significantly smaller overall callosum than the controls. The demonstration of callosal atrophy in older adults with cognitive complaints suggests that callosal changes occur very early in the dementing process, and that these earliest changes may be too subtle for detection by neuropsychological assessments, including memory tests.

The fornix and mammillary bodies are important limbic structures that have not been systematically investigated in the earliest stages of preclinical dementia. The present study examined volumetric changes in the fornix and mammillary bodies and improved previously established tracing guidelines to increase reliability and provide more comprehensive measurements. Volumetric measurements were made in euthymic older adults, including 16 patients with mild Alzheimer's disease (AD), 20 patients with amnestic mild cognitive impairment (MCI), 20 individuals with cognitive complaints (CC) but normal neuropsychological test performance, and 20 demographically matched healthy controls (HC). Structural magnetic resonance imaging included a T1-weighted 1.5-mm coronal volume, acquired on a GE 1.5T LX scanner. After adjustment for total intracranial volume (ICV), significant volume reductions were observed in the fornix and mammillary bodies in patients with AD as compared with HC, CC, and MCI participants. No volume differences were seen between the HC, CC, and MCI groups. Study findings are consistent with previous research showing volume decreases of the fornix and mammillary bodies in AD, and provide new data on the relative preservation of these structures in preclinical disease stages. Results suggest that atrophy of the fornix and mammillary bodies becomes apparent at the point of conversion from MCI to AD. Longitudinal assessments are needed to delineate the time course and extent of the observed volumetric changes.

Cholinesterase inhibitors positively affect cognition in Alzheimer's disease (AD) and other conditions, but no controlled functional MRI studies have examined where their effects occur in the brain. We examined the effects of donepezil hydrochloride (Aricept) on cognition and brain activity in patients with amnestic mild cognitive impairment (MCI), a diagnosis associated with a high risk of developing AD. Nine older adults with MCI were compared with nine healthy, demographically matched controls. At baseline, patients showed reduced activation of frontoparietal regions relative to controls during a working memory task. After stabilization on donepezil (5.7 +/- 1.7 weeks at 10 mg) patients showed increased frontal activity relative to unmedicated controls, which was positively correlated with improvement in task performance (r = 0.49, P = 0.05) as well as baseline hippocampal volume (r = 0.62, P < 0.05). The patients' overall cognitive function was stable or improved throughout the study. Short-term treatment with a cholinesterase inhibitor appears to enhance the activity of frontal circuitry in patients with MCI, and this increase appears to be related to improved cognition and to baseline integrity of the hippocampus. These relationships have implications for understanding the mechanisms by which cognition-enhancing medications exert their effects on brain function and for the use of functional MRI in early detection and treatment monitoring of AD and MCI., (Copyright 2004 Guarantors of Brain)

Functional MRI has recently been used to examine activation associated with aging and dementia, yet little is known regarding the effect of cerebral atrophy on fMRI signal. The purpose of this study was to examine the relationship between measures of global and regionally specific atrophy and fMRI activation in normal aging and in Alzheimer disease (AD). Two groups of subjects were studied with echoplanar imaging and quantitative structural volumetry: healthy controls spanning a broad age and atrophy range (n = 16) and patients with mild AD (n = 8). Results from a semantic task previously found to activate left inferior frontal (LIFG) and left superior temporal (LSTG) gyri were analyzed. The correlations between clusters of activation in the LIFG and LSTG and measures of local atrophy in the LIFG and LSTG regions were evaluated. For control subjects, there was no significant correlation between activation and regional or total brain atrophy (for LIFG r = -0.03, NS; for LSTG r = 0.20, NS). In contrast, for AD patients, there was a significant positive correlation between atrophy and activation in LIFG (r = 0.70, P = 0.05) but not LSTG (r = 0.00, NS). These results suggest that activation of language regions and atrophy within those regions may be independent among healthy adults spanning a broad age and atrophy range. However, in AD, a relationship exists in the LIFG that may reflect compensatory recruitment of cortical units or disease-specific changes in the hemodynamic response., (Copyright 2000 Academic Press.)

Impairment in semantic processing occurs early in Alzheimer's disease (AD) and differential impact on subtypes of semantic relations have been reported, yet there is little data on the neuroanatomic basis of these deficits. Patients with mild AD and healthy controls underwent 3 functional MRI auditory stimulation tasks requiring semantic or phonological decisions (match-mismatch) about word pairs (category-exemplar, category-function, pseudoword). Patients showed a significant performance deficit only on the exemplar task. On voxel-based fMRI activation analyses, controls showed a clear activation focus in the left superior temporal gyrus for the phonological task; patients showed additional foci in the left dorsolateral prefrontal and bilateral cingulate areas. On the semantic tasks, predominant activation foci were seen in the inferior and middle frontal gyrus (left greater than right) in both groups but patients showed additional activation suggesting compensatory recruitment of locally expanded foci and remote regions, for example, right frontal activation during the exemplar task. Covariance analyses indicated that exemplar task performance was strongly related to signal increase in bilateral medial prefrontal cortex. The authors conclude that fMRI can reveal similarities and differences in functional neuroanatomical processing of semantic and phonological information in mild AD compared to healthy elderly, and can help to bridge cognitive and neural investigations of the integrity of semantic networks in AD.

A multisite field trial was conducted at 11 institutions to test the clinical reliability of a 29-item consultation-liaison (C-L) psychiatry assessment instrument. Twenty-five raters viewed videotapes of two "trainees" conducting clinical interviews with a simulated patient. One trainee was a medical student, the other was a fellow in psychiatry. Raters completed the 29-item assessment instrument for each trainee. The mean value scores reflected the skill of each trainee. The medical student had a mean score of 1.93, whereas the C-L fellow had a mean score of 3.13 which parallels the expected level of skill for the two interviewers. Eighty-six percent of the items (25/29) had a standard deviation (SD) of less than 1.0. Each of the remaining four items (14%) had a SD minimally greater than 1.0. These results reflect clear wording of items with measurable parameters defined for assessing trainees' skills. The authors present different uses for the assessment instrument, including giving feedback to trainees regarding interviewing techniques and skills; setting "gold" and "lead" standards for clinical C-L interviewing skills; and training supervisors in evaluation using a standardized assessment instrument.