Associations of Stages of Objective Memory Impairment with Cerebrospinal Fluid and Neuroimaging Biomarkers of Alzheimer's Disease.

OBJECTIVE: To investigate cerebrospinal fluid (CSF) and neuroimaging correlates of Stages of Objective Memory Impairment (SOMI) based on Free and Cued Selective Reminding Test (FCSRT) performance, and to evaluate the effect of APOE ε4 status on this relationship. METHODS: Data from 586 cognitively unimpaired individuals who had FCSRT, CSF, and volumetric magnetic resonance imaging (MRI) measures available was used. We compared CSF measures of ß-amyloid (Aß42/Aß40 ratio), phosphorylated tau (p-Tau181), total tau (t-Tau), hippocampal volume, and PIB-PET mean cortical binding potential with partial volume correction (MCBP) among SOMI groups in the whole sample and in subsamples stratified by APOE ε4 status. RESULTS: Participants had a mean age of 67.4 (SD=9.1) years, had 16.1 (SD=2.6) years of education, 57.0% were female, and 33.8% were APOE ε4 positive. In the entire sample, there was no significant difference between SOMI stages in Aß42/Aß40 ratio, p-Tau181, t-Tau, or PIB-PET MCBP when adjusted for age, sex, and education. However, higher SOMI stages had smaller hippocampal volume (F=3.29, p=0.020). In the stratified sample based on APOE ε4 status, in APOE ε4 positive individuals, higher SOMI stages had higher p-Tau181 (F=2.94, p=0.034) higher t-Tau (F=3.41, p=0.019), and smaller hippocampal volume (F=5.78, p<0.001). There were no significant differences in CSF or imaging biomarkers between SOMI groups in the APOE ε4 negative subsample. CONCLUSION: Cognitively normal older individuals with higher SOMI stages have higher in-vivo tau and neurodegenerative pathology only in APOE ε4 carriers. These original results indicate the potential usefulness of the SOMI staging system in assessing of tau and neurodegenerative pathology.

Sensitivity of the Preclinical Alzheimer's Cognitive Composite (PACC), PACC5, and Repeatable Battery for Neuropsychological Status (RBANS) to Amyloid Status in Preclinical Alzheimer's Disease -Atabecestat Phase 2b/3 EARLY Clinical Trial.

BACKGROUND: Cognitive composites commonly serve as primary outcomes in Alzheimer's disease (AD) secondary prevention trials. OBJECTIVE: To evaluate the association between amyloid (Aß) burden level (+/-) and performance on three separate composite endpoints: Preclinical Alzheimer's Cognitive Composite (PACC), PACC+Semantic Fluency (PACC5), and Repeatable Battery for Neuropsychological Status (RBANS). DESIGN: Screening data from the randomized, double-blind, placebo-controlled, phase 2b/3 atabecestat EARLY study in preclinical AD participants were used in this analysis. SETTING: The EARLY study was conducted at 143 centers across 14 countries. PARTICIPANTS: 3,569 cognitively unimpaired older adults (Clinical Dementia Rating of 0; aged 60-85 years) screened for inclusion in the EARLY study with Aß status and at least PACC or RBANS at screening were included. Participants were categorized as those with non-pathological Aß levels (Aß-, n=2,824) and those with pathological Aß levels (Aß+, n=745) based on florbetapir uptake or levels of cerebrospinal fluid Aß1-42. MEASUREMENTS: Analysis of Covariance models controlling for age, sex, and education were used to examine the difference in PACC, PACC5, and RBANS between Aß groups. Nonparametric bootstrap was used to compare sensitivity of composites to differentiate between Aß status. RESULTS: Of 3,569 participants, 2,116 were women (59%); 3,006 were Caucasian (84%); mean (SD) age was 68.98 (5.28) years. Aß+ participants performed worse versus Aß- participants on all cognitive composites though the magnitude of the Aß effect was generally small. The Aß+/- effect size for the PACC (Cohen's d=-0.15) was significantly greater than the RBANS (d=-0.097) while the PACC5 effect size (d=-0.139) was numerically larger than the RBANS. When examining subscores from the composites, memory tests (i.e., Free and Cued Selective Reminding Test, Figure Recall) and speed of processing (i.e., Digit-Symbol/Coding on the PACC/RBANS) exhibited the largest Aß+/- effect sizes. CONCLUSIONS: Cross-sectional relationships between Aß and cognition among clinically unimpaired older adults are detectable on multi-domain cognitive composites but are relatively small in magnitude. The Aß+/- group effect was statistically larger for PACC and marginally larger for PACC5 versus RBANS. However, interpretation of composite sensitivity to Aß status cross-sectionally cannot be generalized to sensitivity to change over time.

The quantitative ADAM questionnaire: a new tool in quantifying the severity of hypogonadism.

Androgen deficiency is a pervasive problem in the older male population and is thought to be responsible for many symptoms once considered to be the result of normal aging. Numerous methods have been proposed to facilitate the detection of men at risk for androgen deficiency. In this article, we propose a novel screening tool, the quantitative Androgen Deficiency in the Aging Male (qADAM) questionnaire and report its successful use in quantifying the severity of androgen deficiency in a group of older men. Fifty-seven males scheduled to undergo radical prostatectomy for prostate cancer completed the qADAM as well as the Sexual Health Inventory for Men (SHIM) and the Expanded Prostate Cancer Index Composite hormonal/sexual (EPICh/EPICs) questionnaires. Thirty-four men also had serum testosterone levels measured for comparison. The qADAM showed statistically significant correlation to the SHIM (P=0.001), EPICh (P=0.016), EPICs (P= <0.001), and serum testosterone (P=0.046). The qADAM represents a viable alternative to existing questionnaires used to detect androgen deficiency and to assess response to treatment.

Correlation between simultaneous PSA and serum testosterone concentrations among eugonadal, untreated hypogonadal and hypogonadal men receiving testosterone replacement therapy.

The primary objective of this study was to correlate simultaneous measures of prostate-specific antigen (PSA) and serum testosterone among large samples of eugonadal, untreated hypogonadal and hypogonadal men treated with testosterone replacement therapy (TRT). From 2001 to 2007, laboratory records were reviewed to identify men who underwent simultaneous measurement of PSA and serum testosterone levels. The data were stratified based on three groups of men: group 1 consisted of eugonadal men (T>300 ng per 100 ml) evaluated for BPH, reproductive failure or sexual dysfunction; group 2 consisted of untreated hypogonadal men (T<300 ng per 100 ml); and group 3 comprised symptomatic hypogonadal men receiving TRT. Correlations were found between PSA (total and free fractions) and total serum testosterone levels among the three groups. Group 1: eugonadal men (n=385 patients), mean PSA and serum testosterone were 1.60 ng ml(-1) and 484 ng 100 ml, respectively. There was no significant correlation between PSA and total serum testosterone levels (r=-0.01, P=0.8). Group 2: untreated hypogonadal men (n=229 patients), mean PSA and serum testosterone were 1.49 ng ml(-1) and 269 ng per 100 ml, respectively. There was no significant correlation between PSA and total serum testosterone levels (r=0.03, P=0.6). Group 3: hypogonadal men on TRT (n=229 patients and 994 individual samples analyzed) mean PSA and serum testosterone were 1.50 ng ml(-1) and 555 ng per 100 ml, respectively. There was no significant correlation between PSA and serum testosterone levels (r=-0.005, P=0.9). Mean total serum testosterone levels were increased significantly (P<0.001) following treatment. Mean PSA levels did not increase in a statistically or clinically significant manner following TRT (mean PSA increase from baseline 0.05 ng ml(-1), P=0.6). In conclusion, TRT does not appear to significantly influence serum PSA expression and no significant correlation was identified between PSA and serum testosterone among eugonadal, untreated hypogonadal and hypogonadal men receiving TRT.

Efficacy of changing testosterone gel preparations (Androgel or Testim) among suboptimally responsive hypogonadal men.

The study objective was to evaluate the efficacy of changing testosterone gel preparations among suboptimally responsive hypogonadal men. The records of all hypogonadal men on gel (Testim or Androgel) testosterone replacement therapy (TRT) were reviewed to identify men who underwent a brand substitution in gel TRT due to initial suboptimal response. Total and free serum testosterone levels and the presence of hypogonadal symptoms (ADAM) were compared pre- and post-gel substitution. Of the 370 hypogonadal men on testosterone gel replacement therapy, 75 (20%) underwent a brand substitution. Prior to substitution, among patients initially treated with Androgel, the mean total and free testosterone levels were 311 ng dl(-1) and 10.4 pg ml(-1), respectively. Total testosterone levels were below 300 ng dl(-1) in 58% of these patients. Following a change to Testim, mean total and free testosterone levels increased to 484 ng dl(-1) (P<0.001) and 14.6 pg ml(-1) (P=0.01), respectively. Total testosterone levels remained below 300 ng dl(-1) in only 17% of these patients. Among patients initially treated with Testim, the mean total and free testosterone levels were 544 ng dl(-1) and 18.0 pg ml(-1), respectively. Total testosterone levels were below 300 ng dl(-1) in 15% of men. Following testosterone gel change to Androgel, mean total and free testosterone levels were 522 ng dl(-1) (P=0.7) and 16.1 pg ml(-1) (P=0.6), respectively. Total testosterone levels remained below 300 ng dl(-1) in 27% of these patients. Hypogonadal symptoms improved in a significant proportion of men who underwent a brand substitution following an initial suboptimal biochemical or symptomatic response. A change in testosterone gel preparation among initially unresponsive hypogonadal men is justified prior to abandoning or considering more invasive TRT. Changing from Androgel to Testim offers hypogonadal men the potential for improved clinical and biochemical responsiveness. Changing from Testim to Androgel is indicated to eliminate or minimize unwanted side effects.

Getting teams to talk: development and pilot implementation of a checklist to promote interprofessional communication in the OR.

BACKGROUND: Pilot studies of complex interventions such as a team checklist are an essential precursor to evaluating how these interventions affect quality and safety of care. We conducted a pilot implementation of a preoperative team communication checklist. The objectives of the study were to assess the feasibility of the checklist (that is, team members' willingness and ability to incorporate it into their work processes); to describe how the checklist tool was used by operating room (OR) teams; and to describe perceived functions of the checklist discussions. METHODS: A checklist prototype was developed and OR team members were asked to implement it before 18 surgical procedures. A research assistant was present to prompt the participants, if necessary, to initiate each checklist discussion. Trained observers recorded ethnographic field notes and 11 brief feedback interviews were conducted. Observation and interview data were analyzed for trends. RESULTS: The checklist was implemented by the OR team in all 18 study cases. The rate of team participation was 100% (33 vascular surgery team members). The checklist discussions lasted 1-6 minutes (mean 3.5) and most commonly took place in the OR before the patient's arrival. Perceived functions of the checklist discussions included provision of detailed case related information, confirmation of details, articulation of concerns or ambiguities, team building, education, and decision making. Participants consistently valued the checklist discussions. The most significant barrier to undertaking the team checklist was variability in team members' preoperative workflow patterns, which sometimes presented a challenge to bringing the entire team together. CONCLUSIONS: The preoperative team checklist shows promise as a feasible and efficient tool that promotes information exchange and team cohesion. Further research is needed to determine the sustainability and generalizability of the checklist intervention, to fully integrate the checklist routine into workflow patterns, and to measure its impact on patient safety.

Communication failures in the operating room: an observational classification of recurrent types and effects.

BACKGROUND: Ineffective team communication is frequently at the root of medical error. The objective of this study was to describe the characteristics of communication failures in the operating room (OR) and to classify their effects. This study was part of a larger project to develop a team checklist to improve communication in the OR. METHODS: Trained observers recorded 90 hours of observation during 48 surgical procedures. Ninety four team members participated from anesthesia (16 staff, 6 fellows, 3 residents), surgery (14 staff, 8 fellows, 13 residents, 3 clerks), and nursing (31 staff). Field notes recording procedurally relevant communication events were analysed using a framework which considered the content, audience, purpose, and occasion of a communication exchange. A communication failure was defined as an event that was flawed in one or more of these dimensions. RESULTS: 421 communication events were noted, of which 129 were categorized as communication failures. Failure types included "occasion" (45.7% of instances) where timing was poor; "content" (35.7%) where information was missing or inaccurate, "purpose" (24.0%) where issues were not resolved, and "audience" (20.9%) where key individuals were excluded. 36.4% of failures resulted in visible effects on system processes including inefficiency, team tension, resource waste, workaround, delay, patient inconvenience and procedural error. CONCLUSION: Communication failures in the OR exhibited a common set of problems. They occurred in approximately 30% of team exchanges and a third of these resulted in effects which jeopardized patient safety by increasing cognitive load, interrupting routine, and increasing tension in the OR.

Interpretation of three-dimensional structure from two-dimensional endovascular images: implications for educators in vascular surgery.

PURPOSE: Endovascular therapy has had a major effect on vascular surgery; surgeons perform tasks in three dimensions (3D) while viewing two-dimensional (2D) displays. This fundamental change in how surgeons perform operations has educational implications related to learning curves and patient safety. We studied the effects of experience, training, and visual-spatial ability on 3D perception of 2D angiographic images of abdominal aortic aneurysms (AAA). METHODS: A novel computer-based method was developed to produce 3D depth maps based on subjects' interpretations of 2D images. Seven experts (certified vascular surgeons) and 20 novices (medical or surgical trainees) were presented with a 2D AAA angiographic image. With software specifically designed for this study, a depth map representing each subject's 3D interpretation of the 2D angiogram was produced. The novices were then randomized into a control group and a treatment group, who received a 5-minute AAA anatomy educational session. All subjects repeated the exercise on a second AAA image. Finally, all novices were given tests of visual-spatial ability, including the Surface Development Test and the Mental Rotations Test. Comparisons between experts and novices were made with depth map comparison, a subject's perception of overall object contour. RESULTS: The depth maps were significantly different (depth map comparison, P <.001) between the expert and both novice groups for the first image. After the educational intervention, the control group and the treatment group exhibited significantly different depth maps (depth map comparison, P <.001), with treatment group depth maps more similar to those of the expert group. There were no significant correlations between the visual-spatial tests and the novice depth map comparison with the expert group. CONCLUSIONS: This is the first study to examine perception of endovascular images in an educational context. Perception of overall surface contour of 3D structures from 2D angiographic images is affected by experience and training. With application of methods of vision science to an important problem in surgery, this research represents a first step in understanding the nature of visual perceptual processes involved in execution of an increasingly common clinical task. These results have implications for understanding and studying the endovascular learning curve. CLINICAL RELEVANCE: This research represents a unique collaboration in an effort to understand and solve one of the greatest problems facing surgical educators and surgeons. This research uses applied tools in vision science to understand the perceptual constraints involved in minimally invasive surgery. Specifically, we examined the mental three-dimensional maps experts use when viewing two-dimensional displays. Furthermore, we compared experts with novices in an effort to assist surgical trainees.

The relative frequency of "dementia of unknown etiology" increases with age and is nearly 50% in nonagenarians.

CONTEXT: With the recent change in pathological criteria for Alzheimer disease (AD), a group of patients has emerged who do not meet pathological criteria for any well-characterized degenerative dementias. Whether these unclassified patients have vascular dementia or some other form of dementia is not known. OBJECTIVE: To determine the clinical characteristics, pathological substrate, and relative frequency of dementia not caused by well-characterized degenerative dementias. DESIGN/SETTING: Clinicopathological study of a prospectively observed sample of elderly nondemented and demented subjects recruited from our urban community. METHODS: In our series of 128 subjects with prospective neuropsychological evaluations as well as neuropathology, we identified 35 clinically nondemented subjects and 20 demented patients who did not meet pathological criteria for well-characterized degenerative dementias such as AD or dementia with Lewy bodies. The 20 demented patients were grouped together under the term dementia of unknown etiology (DUE). We compared clinical, genetic, neuropsychological, pathological, and neurochemical characteristics of the nondemented group, patients with DUE, and 28 patients with AD and no other pathological abnormality. RESULTS: Mean age at death for patients with DUE was 89.1 +/- 5.8 years compared with 79.9 +/- 11.4 years for AD (P<.001). Patients with AD and DUE did not differ in sex, risk factors, apolipoprotein E genotype, neuropsychological features, or neurological features. Hippocampal sclerosis (in 11 patients with dementia and no controls) and leukoencephalopathy (in 7 patients with dementia and 1 control) were associated with cognitive impairment; other vascular markers were not. Dementia of unknown etiology accounted for 5% of all cases of dementia among patients dying in their 70s, 21% for patients dying in their 80s, and 48% for patients dying in their 90s. CONCLUSIONS: A significant percentage of demented patients older than 80 years do not meet pathological criteria for AD or dementia with Lewy bodies. Hippocampal sclerosis and leukoencephalopathy are common in these patients but rare in clinically nondemented subjects.

Occupational exposure to methyl isobutyl ketone causes lasting impairment in working memory.

The authors describe serial evaluations of a 44-year-old man who became cognitively impaired during a 6-year period of repeated exposure to high levels of methyl isobutyl ketone (MIBK). Neuropsychological tests administered six times over 10 years demonstrated a stable pattern of cognitive impairment. Dynamic imaging studies suggested persistent CNS dysfunction. The authors conclude that chronic, high-level, occupational MIBK exposure can cause a persistent cognitive syndrome best explained by impaired working memory.

Memory impairment on free and cued selective reminding predicts dementia.

OBJECTIVE: To estimate the relative rates of dementia in initially nondemented subjects with and without memory impairment defined by baseline free recall from the Free and Cued Selective Reminding (FCSR) test. BACKGROUND: Our approach to identifying persons at high risk for future dementia is to show the presence of memory impairment not caused by other cognitive deficits by using a memory test that controls attention and cognitive processing. When the conditions of testing are not adequately controlled, prediction is reduced because age-associated memory deficits due to other cognitive deficits are confused with dementia-associated memory deficits. METHODS: Longitudinal evaluation of 264 initially nondemented, elderly community volunteers from the Einstein Aging Study with clinical and psychometric examinations every 12 to 18 months for up to 10 years. MAIN OUTCOME MEASURES: Dementia was defined by an algorithmic definition that required a Blessed Information Memory and Concentration score >8 and clinical evidence of functional decline. RESULTS: Thirty-two incident cases of dementia developed during follow-up. Survival analyses indicated that subjects with impaired free recall at baseline had dementia develop (relative risk = 75.2, 95% CI = 9.9 to 567) over 5 years of follow-up at dramatically higher rates than subjects with intact free recall after adjusting for age, gender, and education. CONCLUSION: Poor performance on free recall from FCSR predicts future dementia. These findings support the existence of a preclinical phase of dementia characterized by memory impairment, which is present for at least 5 years before diagnosis.

Memory and mental status correlates of modified Braak staging.

We assessed the relationships of performance on memory and mental status tests and neuropathologic stage of Alzheimer's disease as defined by Braak and Braak in 29 patients from a prospective clinicopathologic series. We predicted that memory changes would occur at an earlier Braak stage than mental status changes. Staging was accomplished by matching the topographic distribution of neurofibrillary lesions detected with tau immunocytochemistry to the best fitting diagram published by Braak and Braak. Higher Braak stages were associated with decrements in performance on both memory and mental status tests. As predicted, memory performance declined from stages II to III and mental status did not decline until stages III to IV. The association between memory and Braak stage was unchanged after adjusting for neocortical senile plaques, whereas adjustments for Braak stage eliminated the association between cognitive functioning and amyloid burden. We conclude that Braak staging provides a useful summary of Alzheimer's disease neuropathology, which is associated with both memory and mental status performance.

Demographic influences on free and cued selective reminding performance in older persons.

This study evaluated the influence of age, gender, race, and education on learning and memory in older persons. Free and Cued Selective Reminding (FCSR) was administered to a community-based sample of 216 Caucasian and 50 African American seniors as part of a larger medical and neuropsychological battery. Although age, education, and gender influenced FCSR performance, race did not. The study suggests that memory performance is not influenced by race and that race-adjustment may not be necessary in the norming of memory tests.

Free and cued selective reminding and selective reminding in the elderly.

Free and Cued Selective Reminding (FCSR) differs from Selective Reminding (SR) because of a study procedure which controls cognitive processing and a reminding procedure which allows for cued recall. Performance on FCSR and SR was compared in two studies to determine which test produces better recall and to identify the factors that account for the superior recall. When the tests were administered to very elderly normal subjects using the standard clinical protocol, twice as many words were retrieved from long-term memory in FCSR than SR. The second experiment, which manipulated study and reminding conditions in a younger sample of normal elderly, suggests that the improvement in free recall was due to the study procedure and the method of reminding.

Learning and retention in preclinical and early Alzheimer's disease.

Accelerated forgetting has been proposed as the first sign in preclinical and early Alzheimer's disease (AD). The authors investigated learning and retention in participants who later developed AD with free and cued selective reminding (FCSR; H. Buschke, 1984; E. Grober & H. Buschke, 1987), a test that maximizes learning by inducing deep semantic processing and by controlling study and test conditions. AD patients in the preclinical stage recalled significantly fewer words than did matched control participants, indicating an impairment of learning; nonetheless, patients' retention was identical to that of control participants. A retention deficit was documented 3 years later for AD patients but not for control participants, whose retention was still perfect. Thus, a retention deficit is not present in preclinical AD when hallmark learning deficits can be documented. Detection of preclinical and very early AD may be best accomplished by using robust learning tests that control cognitive processing.

Ethylene oxide neurotoxicity: a cluster of 12 nurses with peripheral and central nervous system toxicity.

Ethylene oxide (EO) is commonly used to sterilize heat-sensitive products used by hospital patients and personnel. Ethylene chlorohydrin (EC), a by-product, is considered highly toxic. We report a cluster of 12 operating-room nurses and technicians who developed symptoms after a 5-month exposure to high levels of EO and EC in disposable surgical gowns. All patients reported a rash on the wrist where contact was made with the gowns, headaches, and hand numbness with weakness. Ten of 12 patients complained of memory loss. Neurologic evaluation revealed neuropathy on examination in nine of the 12 patients, elevated vibration threshold in four of nine, abnormal pressure threshold in 10 of 11, atrophy on head MRI in three of 10, and neuropathy on conduction studies in four of 10. Neuropsychological testing demonstrated mild cognitive impairment in four of six patients. Sural nerve biopsy in the most severely affected patient showed findings of axonal injury. Several patients in this group display signs of peripheral and CNS dysfunction following exposure to EO. Possible mechanisms of neurotoxicity include direct exposure of peripheral nerves through cutaneous absorption and central involvement through inhalation and vascular dissemination. The frequency of central and peripheral nervous system symptoms, supported by objective testing in these EO-exposed patients, suggests other healthcare personnel may be at similar risk.

Hippocampal sclerosis: a common pathological feature of dementia in very old (> or = 80 years of age) humans.

In a neuropathological study of 81 brains of prospectively studied subjects of 80 years of age or older at the time of death, 13 cases (16%), including 4 men and 9 women, had hippocampal sclerosis (HpScl) affecting the vulnerable region of the hippocampus. In demented subjects of 80 years of age or older, the frequency of HpScl was even higher, 26%. Cases with HpScl had significantly fewer hippocampal senile plaques (SP) and neurofibrillary tangles (NFT) and parahippocampal NFT than cases without HpScl, but did not differ significantly in any of the other measured pathological parameters. Enzyme-linked analysis of synaptic protein immunoreactivity in a subset of 33 cases demonstrated significant decreases in the hippocampus, but not in frontal, temporal, parietal or parahippocampal cortices. All but 1 of the cases with HpScl had Blessed information, memory and concentration scores (BIMC) of 8 or more, and all were considered to be demented. In some patients memory disturbance was disproportionate to deficits in other cognitive areas. All but 4 of the cases with HpScl had many non-neuritic, amyloid plaques in the neocortex meeting NIA criteria for Alzheimer's disease (AD); however, given the advanced age of the subjects, amyloid plaques were considered to represent age-related cerebral amyloid deposition ("pathological aging") in most cases. Only 3 cases had both many SP and NFT in multiple cortical regions consistent with AD. Another case had brain stem and cortical Lewy bodies consistent with diffuse Lewy body disease (DLBD). A few ballooned neurons were present in the limbic cortices in 3 cases, including one case of dementia with argyrophilic grains (DAG) in limbic and orbital frontal and temporal cortices. The 8 cases without AD, DLBD or DAG included 4 cases in which no other obvious cause of dementia was detected and 4 cases in which HpScl was accompanied by either multiple cerebral infarcts or leukoencephalopathy, or both, that could have contributed to dementia. Patients with HpScl had risk factors, clinical signs and post-mortem pathological findings of cardiovascular disease, but due to the high prevalence of these conditions in very old humans, no significant correlation with HpScl was detected. This study demonstrates that HpScl is a common post-mortem finding in demented, but not normal, elderly subjects. It may contribute to. or be a marker for, the increased risk of dementia in subjects with documented cardiovascular disease or a history of myocardial infarction.

Pathological markers associated with normal aging and dementia in the elderly.

We investigated the associations of pathological markers of Alzheimer's disease (AD) and diffuse Lewy body disease as well as possible markers of vascular dementia with cognitive function in a sample of 20 nondemented and 35 demented subjects (median age of both groups, 88 years) who had been studied prospectively for 4.0 +/- 2.1 years. Very old demented subjects almost always had nonneuritic senile plaques, but over half had no neuritic senile plaques and little other AD pathology. Five subjects had cortical Lewy bodies; all were demented. We propose that hippocampal sclerosis, leukoencephalopathy, and multiple lacunae are possible markers of vascular dementia. When grouped together, these markers were significantly associated with dementia and occurred in 40% of demented subjects. As the relative frequency of neuritic markers of AD (and possibly AD itself) declines in the tenth decade, vascular dementia may become an increasingly important type of dementia.