Everyday Functioning and Entorhinal and Inferior Temporal Tau Burden in Cognitively Normal Older Adults.

BACKGROUND: Performance of cognitively complex "instrumental activities of daily living" (IADL) has previously been related to amyloid deposition in preclinical Alzheimer's disease. OBJECTIVES: We aimed to investigate the relationship between IADL performance and cerebral tau accumulation in cognitively normal older adults. DESIGN: Cross-sectional. SETTING: Data was collected in the Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) and Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) studies. PARTICIPANTS: Participants (n = 447, age 71.9±4.9 years, 57.5% female) who underwent tau positron emission tomography were selected from the A4 and LEARN studies. MEASUREMENTS: IADL performance was measured using the self- and study partner-reported versions of the Alzheimer's Disease Cooperative Study Activities of Daily Living - Prevention Instrument (ADCS ADL-PI). We also investigated discordance between participants and their study partners. Cross-sectional associations between entorhinal and inferior temporal tau (independent variables) and ADCS ADL-PI total scores, item-level scores and discordance (dependent variables) were investigated in linear and logistic regressions. Analyses were adjusted for age, sex and education and a tau by amyloid interaction was also included. RESULTS: Participants and their study partners reported high levels of IADL performance. Entorhinal and inferior temporal tau were related to study partner but not to self-reported total ADCS ADL-PI scores. The association was not retained after adjustment for global cerebral amyloid burden. At the item level, greater entorhinal tau was associated with study partner-reported difficulties remembering important dates (odds ratio (OR) = 1.24, 95% confidence interval (95%CI) = [1.06, 1.45], p = 0.008) and difficulties remembering the details of TV programs and movies (OR = 1.32, 95%CI = [1.08, 1.61], p = 0.007). Greater inferior temporal tau was associated with self-reported difficulties managing to find personal belongings (OR = 1.23, 95%CI = [1.04, 1.46], p = 0.018) and study partner-reported difficulties remembering the details of TV programs and movies (OR = 1.39, 95%CI = [1.11, 1.75], p = 0.005). Discordance between participant and study partner-report was more likely with greater entorhinal (OR = 1.18, 95%CI = [1.05, 1.33], p = 0.005) and inferior temporal tau burden (OR = 1.29, 95%CI = [1.10, 1.51], p = 0.002). DISCUSSION: We found a cross-sectional relationship between study partner-reported everyday functioning and tau in cognitively normal older adults. Participants were more likely to self-report difficulties differently from their study partners when tau burden was higher. This may hint at an altered early-disease awareness of functional changes and underscores the importance of self-report of IADL functioning in addition to collateral report by a study partner.

Subjective Cognitive Decline in a Registry Sample: Relation to Psychiatric History, Loneliness, and Personality.

BACKGROUND: With the increasing focus on prevention of Alzheimer's disease, there is need for characterization of preclinical populations. Local participant registries offer an opportunity to facilitate research engagement via remote data collection, inform recruitment, and characterize preclinical samples, including individuals with subjective cognitive decline. OBJECTIVES: We sought to characterize subjective cognitive decline in a registry sample, as related to psychiatric history and related variables, including personality and loneliness, quality of life, and factors related to dementia risk (e.g., family history of dementia). DESIGN, SETTING, PARTICIPANTS: Participants were 366 individuals (mean age=67.2 (range 50-88), 65% female, 94% white, 97% non-Hispanic or Latino, 82% with at least a bachelor's degree) with no reported history of mild cognitive impairment or dementia. All participants had expressed interest in research, primarily via community outreach events and prior research involvement. Data was collected via electronic surveys, distributed using REDCap. Electronic questionnaires included questions on demographic variables, subjective cognitive decline, quality of life, loneliness, and personality. RESULTS: There was a high prevalence of risk factors for dementia in the registry sample (68% with family history of dementia, 31% with subjective cognitive decline). Subjective cognitive decline was more common in women and associated with history of depression, but not with family history of dementia. Subjective cognitive decline was also associated with lower conscientiousness and lower emotional stability, as well as higher loneliness and lower quality of life. Among participants who endorsed a psychiatric history, most reported onset more than 10 years prior, rather than within the last 10 years. CONCLUSIONS: Subjective cognitive decline in a registry sample may be more strongly associated with longstanding psychiatric and personality variables, rather than family history of dementia, adding to the literature on characterization of subjective cognitive decline across different settings. These findings highlight the acceptability of remote data collection and the potential of registries to inform recruitment by characterizing registrants, which may help to stratify dementia risk and match participants to eligible trials.

Item-Level Investigation of Participant and Study Partner Report on the Cognitive Function Index from the A4 Study Screening Data.

BACKGROUND: Greater subjective cognitive changes on the Cognitive Function Index (CFI) was previously found to be associated with elevated amyloid (Aß) status in participants screening for the A4 Study, reported by study partners and the participants themselves. While the total score on the CFI related to amyloid for both sources respectively, potential differences in the specific types of cognitive changes reported by either participants or their study partners was not investigated. OBJECTIVES: To determine the specific types of subjective cognitive changes endorsed by participants and their study partners that are associated with amyloid status in individuals screening for an AD prevention trial. DESIGN, SETTING, PARTICIPANTS: Four thousand four hundred and eighty-six cognitively unimpaired (CDR=0; MMSE 25-30) participants (ages 65-85) screening for the A4 Study completed florbetapir (Aß) Positron Emission Tomography (PET) imaging. Participants were classified as elevated amyloid (Aß+; n=1323) or non-elevated amyloid (Aß-; n=3163). MEASUREMENTS: Prior to amyloid PET imaging, subjective report of changes in cognitive functioning were measured using the CFI (15 item questionnaire; Yes/Maybe/No response options) and administered separately to both participants and their study partners (i.e., a family member or friend in regular contact with the participant). The impact of demographic factors on CFI report was investigated. For each item of the CFI, the relationship between Aß and CFI response was investigated using an ordinal mixed effects model for participant and study partner report. RESULTS: Independent of Aß status, participants were more likely to report 'Yes' or 'Maybe' compared to the study partners for nearly all CFI items. Older age (r= 0.06, p<0.001) and lower education (r=-0.08, p<0.001) of the participant were associated with higher CFI. Highest coincident odds ratios related to Aß+ for both respondents included items assessing whether 'a substantial decline in memory' had occurred in the last year (ORsp= 1.35 [95% CI 1.11, 1.63]; ORp= 1.55 [95% CI 1.34, 1.79]) and whether the participant had 'seen a doctor about memory' (ORsp= 1.56 [95% CI 1.25, 1.95]; ORp =1.71 [95% CI 1.37, 2.12]). For two items, associations were significant for only study partner report; whether the participant 'Repeats questions' (ORsp = 1.30 [95% CI 1.07, 1.57]) and has 'trouble following the news' (ORsp= 1.46[95% CI 1.12, 1.91]). One question was significant only for participant report; 'trouble driving' (ORp= 1.25 [95% CI 1.04, 1.49]). CONCLUSIONS: Elevated Aß is associated with greater reporting of subjective cognitive changes as measured by the CFI in this cognitively unimpaired population. While participants were more likely than study partners to endorse change on most CFI items, unique CFI items were associated with elevated Aß for participants and their study partners, supporting the value of both sources of information in clinical trials.

Gonadotrophin-independent precocious puberty in an eight-year-old boy due to ectopic human chorionic gonadotrophin from the central nervous system.

We present the case of an eight-year-old boy with advanced isosexual precocity associated with an elevated serum total-beta human chorionic gonadotrophin (HCG) and markedly elevated serum total testosterone. Radiological investigation discovered a lesion in the left thalamus and no peripheral tumour. Serum:cerebrospinal fluid (CSF) HCG ratio was approximately 1:1, consistent with a central nervous system source of HCG, with thalamic germinoma strongly suspected. Consent was not obtained for biopsy of the lesion. The patient underwent multiagent chemotherapy with return of serum HCG to normal. We discuss mechanisms of HCG-mediated sexual precocity in both boys and girls and the importance of CSF HCG.

White matter hyperintensities and cortical acetylcholinesterase activity in parkinsonian dementia.

OBJECTIVE: To investigate the relationship between the severity of white matter hyperintensities (WMH) and cortical acetylcholinesterase (AChE) activity in parkinsonian dementia (PDem). METHODS: PDem (n = 11) and control subjects (n = 14) underwent [11C]methyl-4-piperidinyl propionate (11C-PMP) AChE brain positron emission tomography and magnetic resonance (MR) imaging. Presence of WMH on proton density and T2 MR images was scored using a modified version of the semi-quantitative rating scale by Scheltens et al. [J Neurol Sci114 (1993)]. RESULTS: Analysis demonstrated significantly lower mean cortical (11)C-PMP k3 hydrolysis rates in PDem (-19.9%) when compared with control subjects (P < 0.0001). PDem subjects had higher mean severity of WMH (+20.1%) when compared with control subjects (P < 0.05). When WMH severity was entered into the analysis of variance model, there was no significant co-variate effect on cortical AChE activity (F = 0.24, ns). CONCLUSIONS: The concomitant presence of mild to moderate WMH in patients with PDem does not have a significant effect on cortical AChE activity.

Right prosubiculum amyloid plaque density correlates with anosognosia in Alzheimer's disease.

BACKGROUND: Anosognosia is a common manifestation of Alzheimer's disease. There is an association between impaired awareness and frontal-executive cognitive deficits. Anosognosia is also correlated with decreased metabolism in the right hemisphere, particularly in frontal lobe regions. OBJECTIVE: To investigate pathological correlates of anosognosia in Alzheimer's disease. DESIGN: 41 subjects followed longitudinally in the University of Pittsburgh memory disorders clinic and with necropsy verified Alzheimer's disease were divided into two groups, based on previous clinical assessment: +Aware (n = 23) and -Aware (n = 18). A subset analysis matching subjects for dementia severity using mini-mental state examination scores was also carried out (13 +Aware; 13 -Aware). Histopathological data from necropsy brain tissue consisted of senile plaque (SP) and neurofibrillary tangle (NFT) counts (regional density) from four different brain regions in the right and left hemispheres: superior and middle frontal gyri (SMF), superior temporal isocortex (ST), the prosubiculum of the hippocampus (PRO), and the entorhinal cortex (EC). RESULTS: SP density was greater in the right PRO region of -Aware subjects (F = 6.54, p = 0.015) than +Aware subjects. Significant differences between SP or NFT density were not observed in any other regions. In the subset analysis matching for dementia severity, SP density was again greater in the right PRO region of -Aware subjects than in the other regions (F = 12.72, p = 0.002). CONCLUSIONS: Increased SP density in the right PRO region suggests that selective pathological involvement of this area contributes to awareness deficits in Alzheimer's disease. The putative role of the PRO in self appraisal may reflect its interconnections with other medial temporal and prefrontal regions.

A coccidioidomycosis outbreak following the Northridge, Calif, earthquake.

OBJECTIVE: To describe a coccidioidomycosis outbreak in Ventura County following the January 1994 earthquake, centered in Northridge, Calif, and to identify factors that increased the risk for acquiring acute coccidioidomycosis infection. DESIGN: Epidemic investigation, population-based skin test survey, and case-control study. SETTING: Ventura County, California. RESULTS: In Ventura County, between January 24 and March 15, 1994, 203 outbreak-associated coccidioidomycosis cases, including 3 fatalities, were identified (attack rate [AR], 30 cases per 100,000 population). The majority of cases (56%) and the highest AR (114 per 100,000 population) occurred in the town of Simi Valley, a community located at the base of a mountain range that experienced numerous landslides associated with the earthquake. Disease onset for cases peaked 2 weeks after the earthquake. The AR was 2.8 times greater for persons 40 years of age and older than for younger persons (relative risk, 2.8; 95% confidence interval [CI], 2.1-3.7; P<.001). Environmental data indicated that large dust clouds, generated by landslides following the earthquake and strong aftershocks in the Santa Susana Mountains north of Simi Valley, were dispersed into nearby valleys by northeast winds. Simi Valley case-control study data indicated that physically being in a dust cloud (odds ratio, 3.0; 95% CI, 1.6-5.4; P<.001) and time spent in a dust cloud (P<.001) significantly increased the risk for being diagnosed with acute coccidioidomycosis. CONCLUSIONS: Both the location and timing of cases strongly suggest that the coccidioidomycosis outbreak in Ventura County was caused when arthrospores were spread in dust clouds generated by the earthquake. This is the first report of a coccidioidomycosis outbreak following an earthquake. Public and physician awareness, especially in endemic areas following similar dust cloud-generating events, may result in prevention and early recognition of acute coccidioidomycosis.

Methods for assessing drug use prevalence in the workplace: a comparison of self-report, urinalysis, and hair analysis.

A random sample of 1,200 employees of a steel manufacturing plant were randomly assigned to four different self-report methods of assessing illicit drug use: 1) Individual interview in the workplace, 2) group-administered questionnaire in the workplace, 3) telephone interview, and 4) individual interview off the worksite. Urine specimens were collected and analyzed on all 928 subjects participating in the study, and hair analysis was conducted on 307 of the subjects. Although self-reports produced the highest drug use prevalence rate, analyses combining the results of the three assessment methods showed that the actual prevalence rate was approximately 50% higher than the estimate produced by self-reports. The group-administered questionnaire condition produced prevalence rates that were roughly half those of the other self-report methods. The findings cast doubt on the validity of self-reports as a means of estimating drug use prevalence and suggest the need for multiple assessment methods.

Improved hemodynamic response after long-term intracavernous injection for impotence.

OBJECTIVE: To investigate the phenomenon of spontaneous erections in patients on long-term intracavernous injection therapy. METHODS: We undertook an objective assessment of the penile circulation of 35 patients; 21 used prostaglandin E1 (PGE1) alone and 14 used a combination of papaverine, phentolamine, and PGE1. All underwent duplex ultrasonography before initiation of home self-injection and again after a mean of thirty-one months of treatment (most patients performed injections once or twice a week). RESULTS: The diameter of the cavernosal arteries did not change significantly after treatment. However, the mean peak flow velocity increased highly significantly (P < 0.001): 17.9 cm/second in the right cavernous artery and 21.2 cm/second on the left before treatment; 24 cm/second on the right and 29 cm/second on the left after treatment. More than one third (13 of 35 patients [35%]) achieved functional erection without injection at least some of the time, giving clinical support to the sonographic findings. CONCLUSIONS: We suggest that the combination of vasodilatory drugs and sexual stimulation may act to improve sinusoidal and penile arteriolar smooth muscle function.

A prostaglandin E1 dose-response study in man.

Because prostaglandin E1 causes erection by smooth muscle relaxation in a receptor-dependent manner, one would expect increasing dosages to cause a progressively greater response and that, at receptor saturation, further increases would not be beneficial. To test this hypothesis a single-blind, placebo-controlled study of increasing dosages of prostaglandin E1 injected intracavernously was done. In 16 men with vasculogenic impotence erections were monitored by the RigiScan device in real time for 2 hours after injection, and rigidity, tumescence and duration of erection were measured. Summary parameters to characterize erection with each dosage were developed: maximal rigidity, maximal rigidity sustained for 30 minutes and duration of greater than 60% rigidity. The dose-response curve was similar for all 3 parameters. The initial response to escalating doses of prostaglandin E1 from 2.5 to 20 micrograms. demonstrated a steep dose-dependent increase; at greater than 20 micrograms. a plateau was reached, indicating a nonlinear response. More than 80% of the patients attained the maximal response at doses of 20 micrograms. or less and less than 20% benefited from a further increase. Based on these results, the effects of prostaglandin E1 appear to be receptor-dependent and prostaglandin E1 monotherapy for impotence could be limited to 20 micrograms. or less, since larger amounts offer little additional benefit.

Substance abuse-related spontaneous bladder rupture: report of 2 cases and review of the literature.

Spontaneous rupture of the normal bladder associated with alcohol abuse is rare, with only 20 cases reported in the English literature to which we add 2 cases. Heavy alcohol ingestion predisposes the bladder to rupture by the large volume of fluid intake, its diuretic effect and the mental obtusion it produces, clouding sensory cues to void. alpha-Sympathomimetic drugs, such as cocaine and methamphetamine, increase the resistance at the urethral sphincter and exacerbate the effects of alcohol. Cystography will be diagnostic, and prompt operative repair of intraperitoneal rupture is mandatory. Complete evaluation of the bladder, including urodynamic study, is important to eliminate underlying bladder pathological conditions. Substance abuse-related rupture demonstrates a typical constellation of clinical features that necessitate considering it a syndrome separate from other causes of spontaneous bladder rupture.

The Trauma Score as a triage tool in the prehospital setting.

Implementation of a regional trauma care system requires a field triage tool that identifies the severely injured patient and transports him to a trauma center, while preserving the flow of minimally injured patients to community hospitals. We prospectively tested the Trauma Score (TS) as a field triage tool and evaluated its accuracy against that of the Injury Severity Score (ISS), calculated after the patients' injuries were fully defined. During an 18-month period, 1106 patients admitted to the trauma center at San Francisco General Hospital had a TS determined in the field (TS1) and on arrival at the emergency department. A TS1 of 14 or less defined a subgroup of 222 patients in whom 93% of the deaths occurred. Using an ISS of 20 or more as an indicator of life-threatening injury, we determined the predictive value of TS1. There were 66 false-negatives (ISS, greater than or equal to 20; TS1, 15 or 16) and 107 false-positives (ISS, less than 20; TS1, less than or equal to 14). Using a prehospital TS of 14 or less as an indicator of serious injury, only 20% of a major urban trauma population would qualify for diversion to a trauma center.

Arterial intimal embrittlement. A possible factor in atherogenesis.

Sections of aorta, coronary artery, basilar artery and vena cava were collected at autopsy. Macroscopically normal intimal specimens were removed by stripping. Intimal collagen was measured as hydroxyproline. Intimal film embrittlement was measured in vitro by a bursting volume distensibility test developed in our laboratory. There was an average increase of over 100% in the collagen content of apparently lesion-free human arterial intima on aging over a fifty-year period. This includes an increase of 113% for aortic intima, 49% increase for coronary artery intima, and an increase of 158% in collagen in basilar artery intima. In contrast the collagen level in the vena caval intima decreases on aging, by 42% in fifty years. The large increase in collagen in arterial intima is accompanied by a large increase in intimal embrittlement. The decreasing collagen content of the venous intima on aging results in increased distensibility. Increased aortic intimal film embrittlement (lower distensibility) correlates with age (R = 0.699), but even better with intimal collagen (R = 0.911), suggesting that aortic intimal collagen level is a more important determinant of intimal embrittlement than age. Men, older than 55, have significantly higher aortic intimal collagen levels than women. Embrittlement of arterial intima should make it more susceptible to injury under the pulsatile pressure of the blood. Decreased venous intimal collagen and greater distensibility on aging could be factors in the development of venous valvular insufficiency and varicose veins. However, our study of veins was performed primarily as a control in this instance. Fundamental elements in the atherogenic process are increased intimal collagen, increased intimal brittleness, endothelial injury, followed by intimal cell proliferation. In the vena caval intima on aging there is decreased collagen, increased intimal distensibility, no injury due to increased pulse or blood pressure, and, therefore, no cell proliferation and no intimal lesion.

Renal trauma: re-evaluation of the indications for radiographic assessment.

We studied prospectively 359 consecutive patients with blunt (306) or penetrating (53) renal trauma to refine the indications for radiographic evaluation. Various factors, including the degree of hematuria, presence of shock and associated injuries easily assessable at the time of initial evaluation, were correlated with the severity of renal injury to determine whether any combination of parameters will separate patients with renal contusions from those with significant renal injuries (minor and major lacerations, and vascular injuries). We identified 3 groups: group 1-85 patients with gross hematuria or microscopic hematuria and shock after blunt trauma (including all 23 with significant renal injuries), group 2-221 patients with microscopic hematuria but no shock after blunt trauma (all with renal contusions) and group 3-53 patients with penetrating trauma. No combination of parameters was able to predict a severe injury in group 3. Our data support radiographic evaluation in groups 1 and 3. However, because all patients in group 2 had renal contusions and experienced no complications from nonoperative management we believe that excretory urography, which is time-consuming and costly, can be avoided in patients with microscopic hematuria but no shock after blunt renal trauma.