Novel VCP mutations in inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia.

Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia (IBMPFD, OMIM 167320) has recently been attributed to eight missense mutations in valosin-containing protein (VCP). We report novel VCP mutations N387H and L198W in six individuals from two families who presented with proximal muscle weakness at a mean age of diagnosis of 40 years, most losing the ability to walk within a few years of onset. Electromyographic studies in four individuals were suggestive of 'myopathic' changes, and neuropathic pattern was identified in one individual in family 1. Muscle biopsy in four individuals showed myopathic changes characterized by variable fiber size, two individuals showing rimmed vacuoles and IBM-type cytoplasmic inclusions in muscle fibers, and electron microscopy in one individual revealing abundant intranuclear inclusions. Frontotemporal dementia associated with characteristic behavioral changes including short-term memory loss, language difficulty, and antisocial behavior was observed in three individuals at a mean age of 47 years. Detailed brain pathology in one individual showed cortical degenerative changes, most severe in the temporal lobe and hippocampus. Abundant ubiquitin-positive tau-, alpha-synuclein-, polyglutamine repeat-negative neuronal intranuclear inclusions and only rare intracytoplasmic VCP positive inclusions were seen. These new mutations may cause structural changes in VCP and provide some insight into the functional effects of pathogenic mutations.

Ataxia associated with Hashimoto's disease: progressive non-familial adult onset cerebellar degeneration with autoimmune thyroiditis.

UNLABELLED: Acquired cerebellar ataxia has been described with hypothyroidism, and is typically reversible by thyroid hormone replacement therapy. The cerebellar dysfunction has been attributed to metabolic and physiological effects of the endocrine disorder. In a few patients, however, ataxia has persisted despite thyroid replacement therapy. Other mechanisms may be involved in ataxia associated with thyroid disorders. OBJECTIVE: To document progressive non-familial adult onset cerebellar degeneration (PNACD) occurring in six patients with raised antithyroid antibodies (Hashimoto's/autoimmune thyroiditis), and other autoimmune manifestations, in the absence of hypothyroidism; and to document the independence of the cerebellar disorder from the endocrine dysfunction. METHODS: A case study of six patients with PNACD reviewing the clinical course and relation to endocrine and autoimmune status. RESULTS: All six patients were euthyroid when they developed their symptoms; had raised antithyroid antibodies consistent with Hashimoto's autoimmune thyroiditis; and had strong personal or family histories of organ specific autoimmune diatheses. Brain MRI disclosed atrophy of the cerebellar vermis in four patients and olivopontocerebellar atrophy in two. Other possible causes of cerebellar degeneration were excluded. De novo treatment (two patients) or continued treatment (three patients) with L-thyroxine did not modify the progression of the ataxia. CONCLUSIONS: Cerebellar degeneration in these patients with raised antithyroid antibodies may be immune mediated. The presence of antithyroid antibodies may signal or cause the autoimmune process producing cerebellar degeneration. "Hashimoto's associated ataxia" seems to represent a recognisable and not uncommon condition; a trial of immunomodulating therapy should be considered in these patients.

Psychological features in persons at risk for familial Alzheimer's disease.

Persons at risk for inherited neurodegenerative diseases may experience symptoms of anxiety and depression because of concern over the possibility of developing the disease in the future. The purpose of this study was to assess psychological and emotional symptoms in persons at the age of risk for developing early-onset familial Alzheimer's disease (FAD). Their responses on a psychiatric rating scale (SCL-90-R) were compared with four groups: patients with mild FAD; head injury patients; patients with clinically diagnosed depression; and healthy control subjects. Mean scores of the at-risk FAD group were not statistically different than those of the controls. In contrast, the head injury and depressed groups had significantly elevated scores across the clinical scales. These results suggest that depression and anxiety are not prominent features in persons at genetic risk for early-onset familial Alzheimer's disease. Similar results have been found in studies of persons at risk for developing Huntington's disease, another autosomal dominant neurodegenerative disease.

Postmenopausal estrogen replacement therapy and the risk of Alzheimer disease.

BACKGROUND: Previous studies have examined the relation between postmenopausal estrogen replacement therapy (ERT) and the risk of Alzheimer disease (AD). The findings have been inconsistent, since some studies have been interpreted as showing a protective effect while others have reported no effect. OBJECTIVE: To determine whether exposure to ERT is associated with a reduced risk of AD. DESIGN: Population-based nested case-control study. SETTING: The United Kingdom-based General Practice Research Database. PATIENTS: The base cohort consisted of women who were recipients of ERT (n = 112 481) and a similar cohort of women who did not use estrogens (n = 108 925). The 2 cohorts were restricted to women born on or before January 1, 1950. From the 2 cohorts, we identified and verified 59 newly diagnosed cases of AD and 221 matched control subjects. MAIN OUTCOME MEASURE: Prior and current use of ERT in cases compared with controls. RESULTS: Among the 59 newly diagnosed cases of AD, 15 (25%) were current estrogen users, while among the controls, 53 (24%) were current users. The adjusted odds ratio comparing all current estrogen recipients with nonrecipients was 1.18 (95% confidence interval, 0.59-2.37). In estrogen users who took the drug for 5 years or longer compared with nonusers, the odds ratio was 1.05 (95% confidence interval, 0.32-3.44). Odds ratios were similar for estrogen recipients who received estrogens alone and recipients who received combined estrogen-progestin treatment. CONCLUSION: The use of ERT in women after the onset of menopause was not associated with a reduced risk of developing AD.

Statins and the risk of dementia.

BACKGROUND: Dementia affects an estimated 10% of the population older than 65 years. Because vascular and lipid-related mechanisms are thought to have a role in the pathogenesis of Alzheimer's disease and vascular dementia, we did an epidemiological study of the potential effect of HMGCoA (3 hydroxy-3methylglutaryl-coenzyme A) reductase inhibitors (statins) and other lipid-lowering agents on dementia. METHODS: We used a nested case-control design with information derived from 368 practices which contribute to the UK-based General Practice Research Database. The base study population included three groups of patients age 50 years and older: all individuals who had received lipid-lowering agents (LLAs); all individuals with a clinical diagnosis of untreated hyperlipidaemia; and a randomly selected group of other individuals. From this base population, all cases with a computer-recorded clinical diagnosis of dementia were identified. Each case was matched with up to four controls derived from the base population on age, sex, practice, and index date of case. FINDINGS: The study encompassed 284 cases with dementia and 1080 controls. Among controls 13% had untreated hyperlipidaemia, 11% were prescribed statins, 7% other LLAs, and 69% had no hyperlipidaemia or LLA exposure. The relative risk estimates of dementia adjusted for age, sex, history of coronary-artery disease, hypertension, coronary-bypass surgery and cerebral ischaemia, smoking and body mass index for individuals with untreated hyperlipidaemia (odds ratio 0.72 [95% CI 0.45-1.14]), or treated with nonstatin LLAs (0.96 [0.47-1.97], was close to 1.0 and not significant compared with people who had no diagnosis of hyperlipidaemia or exposure to other lipid-lowering drugs. The adjusted relative risk for those prescribed statins was 0.29 (0.13-0.63; p=0.002). INTERPRETATION: Individuals of 50 years and older who were prescribed statins had a substantially lowered risk of developing dementia, independent of the presence or absence of untreated hyperlipidaemia, or exposure to nonstatin LLAs. The available data do not distinguish between Alzheimer's disease and other forms of dementia.

Familial Alzheimer's disease: site of mutation influences clinical phenotype.

Alzheimer's disease (AD) is caused by multiple genetic and/or environmental etiologies. Because differences in the genetically determined pathogenesis may cause differences in the phenotype, we examined age at onset and age at death in 90 subjects with dominantly inherited AD due to different mutations (amyloid precursor protein, presenilin-1, and presenilin-2 genes). We found that among patients with dominantly inherited AD, genetic factors influence both age at onset and age at death.

Aging and the brain: a new frontier.

With aging, both "normal" senescent age-related changes (ARCs) and late-onset diseases affect the brain, producing declines in performance. The brain as a postmitotic structure is particularly vulnerable to ARCs, and senescence is by far the most powerful risk factor for neurological diseases of the elderly such as sporadic Alzheimer's disease. The concept of senescence as an immutable result of the passage of time is yielding to understanding of the biology of ARCs. Both individual and species differences in longevity illustrate the variable effects of time. Whereas human life expectancy has been extended by prevention and treatment of specific diseases, life span can be altered by modifying the processes producing ARCs. Models of prolonged life span (eg, modifications of Caenorhabditis elegans longevity genes, restricted caloric intake) demonstrate the feasibility of extending longevity throughout the phylogenetic spectrum. Both programmed and variable factors produce ARCs. Cell survival depends on a balance of opposing factors--oncogene and anti-oncogene products, cyclins, growth factors, and so on; apoptotic death results when the balance shifts. Variable factors, including accumulation of oxygen free radicals, protein conformational changes, decline in chaperone functions, and secondary loss of mitochondrial energy production, can also result in neuronal degeneration. To prevent the increased neuronal vulnerability of senescence, ARCs must be modified. The "new frontier" in neurology is the challenge of understanding the changes of aging, both to determine their impact on disease and to prevent their consequences.

Screening for dementia: Cognitive Assessment Screening Test (CAST).

The Cognitive Assessment Screening Test (CAST) is a self-administered paper-and-pencil test that can be used to screen geriatric patients for dementia. The test is composed of three one-page sections; Part A has 10 simple questions; Part B has five more demanding questions, and Part C has 13 self-report questions. Parts A and B determine whether cognition falls within the normal range or below the threshold for dementia. Part C assesses the patient's perception of a decline in memory and competence. Designed for office use, the CAST requires minimal examiner time and little training or experience to administer. This test is as sensitive and specific as other relatively brief screening instruments for dementia.

The cognitive assessment screening test (CAST) for dementia.

The purpose of this study was to assess the usefulness, the sensitivity, and the specificity of the Cognitive Assessment. Screening Test (CAST), a paper-and-pencil self-administered cognitive test designed to screen elderly people for possible dementia, for use in general physicians' offices, requiring little expertise or staff time. CAST consists of three parts: part A (relatively easy), part B (more demanding), and part C (self-report of concerns). CAST was administered in two studies to: (1) 19 patients known to be mildly to moderately demented versus 24 age-matched normal controls (to establish cutoff standards); and (2) a "real world" sample of 26 elderly patients not known to be demented, attending a general medicine clinic. The sensitivity and specificity of CAST were compared with the Mini-Mental State Examination (MMSE) and the Blessed Dementia Scale cognitive portion (BDS-cog). In study 1, controls were given a detailed neuropsychological battery; in study 2, all patients were given the neuropsychological battery, which served as the "gold standard" to identify individuals with cognitive impairment. In study 1, the cutoff scores for dementia using CAST (Parts A and B) were established. CAST discriminated demented patients from controls with a sensitivity of 95% and a specificity of 88%; the MMSE had a sensitivity of 74% and a specificity of 100%; and the BDS-cog had a sensitivity of 100% and a specificity of 96%. In study 2, CAST discriminated cognitive impairment with a sensitivity of 88% and a specificity of 100%, the MMSE had a sensitivity of 38% and a specificity of 100%; and the BDS-cog had a sensitivity of 50% and a specificity of 94%. Part C was not used to discriminate demented from normal elderly individuals, but to screen for those concerned about their cognitive functioning. CAST is highly useful as a dementia screening test, with sensitivity and specificity equal to or better than the MMSE and BDS-cog, yet requiring minimal examiner time and little training or experience to administer.

Benchmarking surgeon satisfaction at academic health centers: a nationwide comparative survey.

BACKGROUND: Forty-six academic health centers (AHCs) belonging to the University HealthSystem consortium joined forces to compare the efficiency of their surgical services and to identify best practices. In addition to measures of operational performance, surgeon satisfaction with the surgical services provided was measured by using a standardized questionnaire. METHODS: From hospital records, indicators of the efficiency of surgical services were collected in three main areas: scheduling, preoperative testing and assessment, and the intraoperative process. Responding to a mail questionnaire, a sample of surgeons rated their satisfaction with key aspects of surgical services including scheduling, operating room staff, and equipment/supplies. On the basis of a review of the operational measures and the survey results, high performers were identified. Site visits were made to several of these high performers to uncover the critical factors responsible for their success. RESULTS: The survey revealed distinct variations in surgeon satisfaction across the participating institutions. Numerical benchmarks were obtained for surgeon satisfaction with each key component of surgical services. Scheduling was the most important component of overall surgeon satisfaction, explaining 71% of the variance in the rating of overall satisfaction with surgical services. High operational efficiency and high surgeon satisfaction were not incompatible. Several of the participating institutions were able to achieve both. These results were disseminated to all of the participants at a national meeting as well as in written form. CONCLUSIONS: The surgeon satisfaction survey allowed the participants to establish benchmarks for surgeon satisfaction for each key component of the surgical services they receive. The site visits revealed several common characteristics of highly efficient surgical services. Taken by themselves, the participating institutions might have been reluctant to consider adopting these best practices for fear of alienating the surgical staff. The availability of data on surgeon satisfaction showed the participants that these best practices can coexist with high levels of surgeon satisfaction. This has helped to promote their adoption by the other participating institutions.

Benchmarking patient satisfaction at academic health centers.

BACKGROUND: In 1991 the University HealthSystem Consortium (UHC), an alliance of 70 academic health centers, began its patient satisfaction benchmarking project. The survey, adapted from the Picker Institute survey, was pilot tested in 1992 and has been in use since 1993. Each year the project's steering committee refines the survey on the basis of member needs and survey item performance. KEY FINDINGS: Findings have shown that the survey can document the effects of specific quality improvement efforts, that patients from different medical services report different levels of satisfaction with their care, and that physician and nursing care have had the greatest impact on overall satisfaction. USING THE RESULTS: Each participating organization receives concise narrative reports of the survey results, with priorities for improvement efforts clearly highlighted. A five-to six-page Executive Summary provides the organization's executive team with a quick overview of the results, as well as a summary of the areas where quality improvements are most needed. A longer Managers' Report provides a more detailed analysis of the findings for quality managers and department heads. Sections for each major area of care can be copied and distributed as "stand alone" reports to the appropriate decision makers. For example, the section on nursing care can be distributed to the chief nursing officer and nurse managers. For each key aspect of the patient's experience, best practices for maintaining patient satisfaction are identified from across the hospitals and compiled into a catalogue. LESSONS LEARNED: The UHC patient satisfaction benchmarking program has created ongoing communication among the participating hospitals, whose staff members have been willing to share problems encountered and possible solutions.

Familial and sporadic Alzheimer's disease: neuropathology cannot exclude a final common pathway.

Whether all etiologic forms of Alzheimer's disease (AD) share a final common pathway is a major issue. We determined the severity and regional distribution of neuronal loss, amyloid plaques, neuritic plaques (NPs), and neurofibrillary tangles (NFTs), and calculated the ratio of neuronal loss to NPs and NFTs in brains of 19 familial AD (FAD) patients with linkage to chromosome 14, six AD patients with mutations of chromosome 21 (codon 717 of the beta-amyloid percursor protein gene), and 11 sporadic AD (SAD) patients. There was no difference in the pattern of distribution of the various pathologic features or in the ratio of neuronal loss to NPs or NFTs in any AD group. However, FAD groups could be distinguished from SAD by the greater severity and the lack of influence of apolipoprotein E genotype on pathology. These differences may reflect differences in age at onset rather than different etiopathologic mechanisms. The similarity of pathologic findings in the different AD groups provides evidence for a final common pathophysiologic pathway in AD.

Rate of progression in familial Alzheimer's disease.

The clinical course of early-onset, dominantly inherited, familial Alzheimer's disease (FAD) was contrasted with late-onset, sporadic Alzheimer's disease (AD). Eight FAD and 23 sporadic AD patients were followed over a mean of 63 months from estimated disease onset. The two groups did not differ notably in duration of symptoms from onset, global disease severity, or degree of cognitive deficits on initial evaluation. The Kaplan-Meier lifetable method was used to assess time from estimated disease onset to dependence in self-care, institutionalization, and death. A greater percentage of FAD patients became dependent in self-care and died earlier than did sporadic AD patients. The lifetable results suggest that FAD may have a more rapid course than dose late-onset sporadic AD.