Marta S. Mendiondo

Modeling the Association between 43 Different Clinical and Pathological Variables and the Severity of Cognitive Impairment in a Large Autopsy Cohort of Elderly Persons

We evaluated the association between mini‐mental status examination (MMSE) scores proximal to death and the values of 43 different clinical and pathological parameters. Studies were performed using data from 334 elderly, longitudinally evaluated research subjects who had undergone autopsy and satisfied inclusion criteria from an initial study group of 501. Interindividual variance in MMSE scores was used as a surrogate for the severity of cognitive impairment linked to aging (CILA). A statistical linear regression‐based model provided a framework for assessing the parameters with significant, direct impact on CILA severity. Strong association between CILA and Alzheimers disease (AD) pathology, especially isocortical neurofibrillary tangles, was evident. The pattern of association between AD lesion densities with cognitive impairment severity was biologically informative, with neuritic plaques having more impact in relatively high‐functioning individuals. Abundant isocortical Lewy bodies tended to be an additive pathology correlating with final MMSE scores approximately 10 points lower. In a subset of cases we found evidence for association between TDP‐43‐related pathology and CILA severity, independent of AD or hippocampal sclerosis. There was no support for independent association between CILA severity and most evaluated indices including diffuse plaques, argyrophilic grains, heart disease, education level, apolipoprotein E alleles or diabetes.

Risk factors for transitions from normal to mild cognitive impairment and dementia

Objective: To identify risk factors associated with transitions from cognitively normal to various forms of mild cognitive impairment (MCI) and then from MCI into early dementia with death as a competing state. Methods: Cognitive assessments from 554 subjects participating in a longitudinal study at the University of Kentucky AD Center were used to classify individuals into one of three transient states at any visit: cognitively normal, amnestic MCI, or mixed MCI. Between visits subjects could die or become demented. A series of polytomous logistic models were used to model transitions among these states over time and to determine how the log odds of these transitions vary with age, education, sex, family history of dementia, and APOE status. Results: Age affects all transitions among transient states as well as those to dementia or death. Presence of at least one apolipoprotein 4 allele affects transitions from cognitively normal into amnestic MCI or into dementia. At most 12 years of education affects transitions into mixed MCI. Transitions do not vary with sex or family history. Conclusion: Aside from age, the usual risk factors associated with conversion from cognitively normal into dementia are likely risk factors for transitions into mild cognitive impairment.

Modelling Mini Mental State Examination changes in Alzheimer's disease

The Mini Mental State Examination (MMSE) is widely used to measure dementia severity in Alzheimers disease patients. While changes over time in the MMSE due to dementia have been studied, the relationship between MMSE scores and the duration of disease course is less well understood. Using the Consortium to Establish a Registry for Alzheimers Disease (CERAD) data, we modelled change in MMSE as a function of time for this population. For this purpose we used the interval between consecutive MMSE assessments as the time factor. We also investigated the impact of sex, education and age at testing on the resulting model. Analyses showed that Alzheimers disease progression over time (ADP) can be modelled using a cubic or a logarithmic function of MMSE score. From these curves ADP can be obtained as a function of MMSE. These models demonstrate that there are different rates of change for various ranges of the MMSE. Additional analyses suggest that patient factors affect rates of ADP, younger patients and more educated patients progress more rapidly, while sex has little impact on ADP. Such estimations of disease course are useful when comparing different populations for both clinical and research purposes.

Improving dementia care: The role of screening and detection of cognitive impairment

The value of screening for cognitive impairment, including dementia and Alzheimers disease, has been debated for decades. Recent research on causes of and treatments for cognitive impairment has converged to challenge previous thinking about screening for cognitive impairment. Consequently, changes have occurred in health care policies and priorities, including the establishment of the annual wellness visit, which requires detection of any cognitive impairment for Medicare enrollees. In response to these changes, the Alzheimers Foundation of America and the Alzheimers Drug Discovery Foundation convened a workgroup to review evidence for screening implementation and to evaluate the implications of routine dementia detection for health care redesign. The primary domains reviewed were consideration of the benefits, harms, and impact of cognitive screening on health care quality. In conference, the workgroup developed 10 recommendations for realizing the national policy goals of early detection as the first step in improving clinical care and ensuring proactive, patient‐centered management of dementia.

University of Kentucky Sanders-Brown Healthy Brain Aging Volunteers: Donor Characteristics, Procedures and Neuropathology

Cognitively intact elderly research volunteers at the University of Kentucky have been recruited, followed longitudinally, and autopsied with extensive neuropathological evaluations since 1989. To date, the cohort has recruited 1,030 individuals with 552 participants being actively followed, 363 deceased, and 273 autopsied. An extensive database has been constructed with continuous updates that include textured clinical, neuropsychological, neuroimaging, and pathological information. The history, demographics, clinical observations, and pathological features of this research cohort are described. We also explain some of the evolving methodologies and the academic contributions that have been made due to this motivated group of older Kentuckians.

Sexual predators who target elders: findings from the first national study of sexual abuse in care facilities

ABSTRACT This article reports research findings concerning 119 alleged sexual perpetrators who were reported to state authorities for abusing elderly individuals residing in care facilities. The largest group of accused was employees of the facilities, followed by facility residents. Family members of the alleged victims and visitors to the facilities also were among those reported as sexually abusive. Investigation of the allegations by Adult Protective Services and regulatory staff resulted in 32 of these individuals being confirmed as sexual perpetrators against vulnerable elders. Male and female alleged and confirmed sexual perpetrators were identified as well as both male and female elderly sexual abuse victims. Perpetrator characteristics, victim vulnerabilities, abuse acts, locations of assaults, and available case outcomes are presented. Implications of the findings are discussed.

The emotional ramifications of unmet need in dementia caregiving

Using a unique measure of unmet need that taps into several dimensions of informal long-term care, the present study included data from 694 informal caregivers of persons suffering from dementia at different times in the caregiving career (e.g., at home, following institutionalization, following the death of the care recipient). Multivariate regression models found that unmet need for either confidante or formal support had key implications for caregivers’ emotional distress in each of the care situations. The findings suggest that conceptual models should incorporate unmet need as a viable predictor of caregiving outcomes and that assessment of unmet need may provide guidance in the development of more refined psychosocial and community-based intervention protocols.

Designing a Brief Alzheimer Screen (BAS)

CONTEXT With advances in the treatment of Alzheimers disease (AD), clinical focus has shifted to early patient identification. Memory recall tests and category fluency distinguish normal individuals from early AD patients. OBJECTIVE Develop a brief test for general practitioners to screen for AD. Design. Examination of items from the MMSE and category fluency. SETTING AND PARTICIPANTS A Brief Alzheimer Screen (BAS) was developed from cognitive assessments on 406 normal subjects and 342 mild AD patients in the CERAD (Consortium to Establish a Registry for AD) dataset. The derived measure was then applied to a second validation sample. MAIN OUTCOME MEASURE Logistic regression was used to derive a predictive equation, which was then applied to two validation samples to estimate sensitivity and specificity. RESULTS The resulting logistic model for discriminating between mild AD and controls included: recall of 3 words, number of animals named in 30 seconds, date, and spelling of WORLD backwards, (p < 0.001 for each) accounting for 77% of the variance. When applied to the validation samples, sensitivity and specificity were over 99% and 87%, respectively. CONCLUSIONS These data support the use of the BAS as a potential screen of patients over 60 years of age.

Rating the severity of ALS by caregivers over the telephone using the ALSFRS-R.

We tested the hypothesis that the ALSFRS‐R can be accurately administered exclusively to the spouse/caregiver over the telephone (phone) in 31 patients with clinically possible, probable, or definite ALS (El Escorial criteria) by comparing the phone response to the consensus assessment during a clinic visit using a standardized script. We also compared the responses of the spouse/caregiver, during a private assessment, to the consensus assessment. Both the phone and private assessments were highly correlated with the consensus assessment, even considering that the evaluations were performed by multiple phone assessors and, in three instances, multiple home assessors. These results suggest the possibility of using this approach to conduct research in ALS.

A randomized controlled Alzheimer’s disease Prevention trial’s evolution into an exposure trial: The Preadvise trial

OBJECTIVES To summarize the ongoing prevention of Alzheimers disease (AD) by vitamin E and selenium (PREADViSE) trial as an ancillary study to SELECT (a large prostate cancer prevention trial) and to present the blinded results of the first year as an exposure study. DESIGN PREADViSE was designed as a double blind randomized controlled trial (RCT). SETTING SELECT terminated after median of 5.5 years of exposure to supplements due to a futility analysis. Both trials then converted into an exposure study. PARTICIPANTS In the randomized component PREADViSE enrolled 7,547 men age 62 or older (60 if African American). Once the trial terminated 4,246 of these men volunteered for the exposure study. Demographics were similar for both groups with exposure volunteers having baseline mean age 67.3 ± 5.2 years, 15.3 ± 2.4 years of education, 9.8% African Americans, and 22.0% reporting a family history of dementia. INTERVENTION In the RCT men were randomly assigned to either daily doses of 400 IU of vitamin E or placebo and 200 µg of selenium or placebo using a 2x2 factorial structure. MEASUREMENTS In the RCT, participants completed the memory impairment screen (MIS), and if they failed, underwent a longer screening (based on an expanded Consortium to Establish a Registry in AD [CERAD] battery). CERAD failure resulted in visits to their clinician for medical examination with records of these examinations forwarded to the PREADViSE center for further review. In the exposure study, men are contacted by telephone and complete the telephone version of the memory impairment screen (MIS-T) screen. If they fail the MIS-T, a modified telephone interview of cognitive status (TICS-M) exam is given. A failed TICS-M exam also leads to a visit to their clinician for an in-depth examination and forwarding of records for a centralized consensus diagnosis by expert clinicians. A subgroup of the men who pass the MIS-T also take the TICS-M exam for validation purposes. RESULTS While this ancillary trial was open to all 427 SELECT clinical sites, only 130 (30.0%) of the sites chose to participate in PREADViSE. Staff turnover at the sites presented challenges when training persons unfamiliar with cognitive testing procedures to conduct the memory screens. In the RCT few participants (1.6%) failed the MIS screen and among those who passed this screen a significant practice effect was encountered. In the exposure study 3,581 men were reached by phone in year 1, 15.7% could not be reached after 5 calls, and of those contacted 6.0% refused the screen even after consenting to the procedures at their clinical site. Most notable is that the failure rate for the MIS-T increased fourfold to 7.2%. Of the 257 men who took the TICS-M, 84.0% failed and were asked to contact their physicians for a more detailed memory assessment, and approximately half of these had some form of dementia or cognitive impairment. Several of these dementia cases are not AD. CONCLUSION Partnering with SELECT led to an AD prevention trial conducted at a very reasonable cost by taking advantage of the experience and efficient clinical trial management found in a cancer cooperative group (Southwest Oncology Group or SWOG). Once unblinded, the RCT and exposure study data have the potential to yield new information on long term exposure to antioxidant supplements under controlled conditions.