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A method for estimating progression rates in Alzheimer disease.

BACKGROUND: The ability to predict progression of disease in patients with Alzheimer disease (AD) would aid clinicians, improve the validation of biomarkers, and contribute to alternative study designs for AD therapies. OBJECTIVE: To test a calculated rate of initial decline prior to the first physician visit (preprogression rate) for its ability to predict progression during subsequent follow-up. METHODS: We calculated preprogression rates for 298 patients with probable or possible AD (using the criteria of the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Associations (NINCDS-ADRDA) with a formula using expected Mini-Mental State Examination (MMSE) scores, scores at presentation, and a standardized estimate of duration. The patients are being followed up longitudinally in our Alzheimer Disease Research Center. The time to clinically meaningful deterioration, defined as an MMSE score drop of 5 or more points, was compared for patients stratified as slow, intermediate, and rapid progressors based on the preprogression rate. Cox regression analysis was used to examine the contribution of demographic variables (age, sex, ethnicity, and level of education), initial MMSE scores, estimated symptom duration, and the calculated preprogression rate to the time it took to reach the end point across the groups. RESULTS: Both initial MMSE (hazard ratio, 0.95 (0.002); z = 4.19; P<.001) and the calculated preprogression rate (hazard ratio, 1.06 (0.019); z = 3.16; P =.002) were significant in determining time to clinically meaningful decline during longitudinal follow-up (Cox regression analysis). Slow, intermediate, and rapid progressors (based on preprogression rates) experienced significantly different time intervals to clinically meaningful deterioration, with the slow progressors taking the longest time, the intermediate progressors in the middle, and the rapid progressors reaching the end point first (log rank chi(2)(1) = 9.81, P =.002). CONCLUSION: An easily calculable rate of early disease progression can classify patients as rapid, intermediate, or slow progressors with good predictive value, even at initial presentation.

Aged↗

Attention and fluctuating attention in patients with dementia with Lewy bodies and Alzheimer disease.

BACKGROUND: Attentional deficits are described in the consensus clinical criteria for the operationalized diagnosis of dementia with Lewy bodies (DLB) as characteristic of the condition. In addition, preliminary studies have indicated that both attentional impairments and fluctuation of attentional impairments are more marked in patients with DLB than in patients with Alzheimer disease (AD), although neuropsychological function has not previously been examined in a large prospective cohort with confirmed diagnostic accuracy against postmortem diagnosis. METHODS: A detailed evaluation of attention and fluctuating attention was undertaken in 155 patients with dementia (85 with DLB and 80 with AD) from a representative hospital dementia case register and 35 elderly controls using the Cognitive Drug Research Computerized Assessment System for Dementia Patients computerized neuropsychological battery. Operationalized clinical diagnosis was made using the consensus criteria for DLB and the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria for AD. High levels of sensitivity and specificity have been achieved for the first 50 cases undergoing postmortem examination. RESULTS: The groups were well matched for severity of cognitive impairments, but the AD patients were older (mean age, 80 vs 78 years) and more likely to be female (55% vs 40%). Patients with DLB were significantly more impaired than patients with AD on all measures of attention and fluctuating attention (for all comparisons, t > or = 2.5, P<.001), and patients from both dementia groups were significantly more impaired than elderly controls for all comparisons other than cognitive reaction time, which was significantly more impaired in DLB patients than controls but was comparable in controls and AD patients. There were, however, significant associations between the severity of cognitive impairment and the severity of both attentional deficits and fluctuations in attention. CONCLUSIONS: This large prospective study confirms that slowing of cognitive processing, attention, and fluctuations of attention are significantly more pronounced in DLB and AD patients, although fluctuating attention is common in patients with moderate-to-severe AD. Deficits of cognitive reaction time appear to be specific to DLB, except in severe dementia. A detailed evaluation of attentional performance could make an important contribution to differential diagnosis, although the results need to be interpreted within the context of the overall severity of cognitive deficits.

Aged↗

Research evaluation and prospective diagnosis of dementia with Lewy bodies.

OBJECTIVE: To evaluate the relative merits of recently developed criteria for dementia with Lewy bodies (DLBs) in a longitudinal study of dementia. DESIGN: The diagnosis of DLBs was used in combination with other clinical diagnosis. Patients were classified primarily based on the NINCDS-ADRDA (National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association) clinical criteria for probable or possible Alzheimer disease, or with other disease process that can cause dementia (eg, Parkinson disease), and secondarily according to the consensus guidelines for DLBs. This "double" clinical diagnosis was implemented to capture different pathological entities. The neuropathological diagnosis of Lewy bodies was made with monoclonal antibodies against alpha-synuclein. SETTING: Multidisciplinary research clinic. RESULTS: Prospective application of the consensus guidelines for DLBs from January 1, 1997, to September 29, 2000, identified 11 patients having the diagnosis of probable DLBs and 35 having possible DLBs. The diagnosis of probable or possible DLBs was associated with probable Alzheimer disease in 34 patients, with possible Alzheimer disease in 5 patients, with Parkinson disease in 2 patients, and with other disease processes in 2 patients. Three patients were diagnosed as having probable DLBs alone. An autopsy was performed in 26 of the cases who were clinically examined during the study period. Cortical Lewy bodies were identified in 13 cases; 4 had had premortem diagnosis of DLBs (sensitivity, 30.7%; specificity, 100%). CONCLUSIONS: The prospective validation of the clinical criteria for DLBs showed poor accuracy in this series. We believe that current criteria for DLBs are useful when DLBs occur in isolation, but have low sensitivity when Lewy bodies coexist with the pathological abnormalities of Alzheimer disease.

Aged↗

Individual growth curve analysis of APOE epsilon 4-associated cognitive decline in Alzheimer disease.

BACKGROUND: The apolipoprotein E epsilon4 (APOE epsilon4) allele is associated with an increased risk of developing Alzheimer disease (AD). However, findings regarding an association between the APOE epsilon4 allele and the rate of decline in AD have been mixed. OBJECTIVE: To examine the relationship between the APOE epsilon4 allele and the rate of cognitive and functional decline in AD using individual growth curve analyses. DESIGN: Longitudinal cohort study. SETTING: Alzheimer Disease Research Center at Baylor College of Medicine. PATIENTS: A total of 189 patients meeting NINCDS-ADRDA (National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association) criteria for probable AD at baseline who underwent annual follow-up evaluations for at least 2 years. MAIN OUTCOME MEASURES: Individual growth curve parameters derived from baseline and follow-up performance on global and specific measures of cognitive and functional abilities. RESULTS: Patients with 2 APOE epsilon4 alleles exhibited a slower rate of decline on measures of global cognitive functioning and functional abilities. No significant association was detected between the APOE epsilon4 allele and the rate of decline on measures of specific cognitive functions. CONCLUSIONS: Although the APOE epsilon4 allele is associated with an increased risk of developing AD, it seems that having 2 APOE epsilon4 alleles is associated with a slower clinical course. These findings are consistent with hypotheses that the biological processes contributing to the onset of AD are different from those involved in determining its clinical course.

Activities of Daily Living↗

Rehabilitation of facial paralysis in children.

We report the experience and philosophy of the Department of Otolaryngology and Communicative Disorders at the Cleveland Clinic in rehabilitation of facial paralysis in children 12 years old and younger. The causes and evaluation of facial paralysis in children and the options available for rehabilitation are considered, and the criteria, expectations, and limitations of successful rehabilitation are outlined. Depending on the limitations imposed by the clinical situation, the aims of treatment are as follows: (1) normal resting tonus, (2) symmetry at rest, (3) symmetry in motion, (4) no synkinesis, (5) appropriate mimetic function, (6) no significant loss of adjacent function, and (7) rapid return of function. Every attempt must be made to avoid causing any significant muscular or neurologic deficit and to avoid interfering with return of function of the seventh nerve, when that possibility exists.

Child↗

Squamous cell papilloma at the tracheoesophageal puncture stoma.

Over 140 tracheoesophageal punctures were performed at the Cleveland Clinic Foundation, Department of Otolaryngology and Communicative Disorders over the last seven years. In all cases the Blom-Singer duckbill prosthesis was utilized for alaryngeal voice restoration. Of these patients, two examples were noted where squamous cell papilloma was found at the tracheoesophageal stoma site. The preoperative evaluation and surgical laser technique for surgical excision of the papilloma with postoperative care are described. The case reports of each of the patients that have been diagnosed as having squamous cell papilloma of the tracheoesophageal puncture site are reviewed.

Esophagostomy↗

The National Temporal Bone, Hearing, and Balance Pathology Resource Registry.

The National Temporal Bone, Hearing, and Balance Pathology Resource Registry has been established with funding provided by the National Institute on Deafness and Other Communication Disorders of the National Institutes of Health. The registry is meant to serve as a national resource for researchers and the public to stimulate and facilitate human otopathologic research. It will maintain a computerized database of currently active and inactive temporal bone and auditory brain-stem collections throughout the United States. In addition, it will encourage human temporal bone research by disseminating pertinent information, developing and fostering temporal bone professional educational activities, implementing a national temporal bone acquisition network, and encouraging investigative collaborations in the study of the human temporal bone and brain structures. It will also identify otopathologic collections at risk of being discarded or lost and will develop mechanisms and strategies to conserve them.

Brain↗

Earlier maturation of pregnant black and white adolescents.

A survey was made of the menarcheal age and anthropometry of 1,844 lower income, nulliparous female patients receiving prenatal care. No differences were observed between black and white patients in height and maximum pregnant weight. A significantly earlier mean menarcheal age was observed in adolescents (12 to 16 years) compared with adults (17 to 31 years). Younger adolescents (12 to 14 years) of both races were taller and heavier (prepregnancy) than National Center for Health Statistics standards and had a significantly greater weight-for-height. Menarcheal age and body habitus were consistent with other reports that younger pregnant adolescents tend to be earlier maturers than older pregnant adolescents and adults. Compared with their age-group cohorts (13 to 31 years) in the two-decades-old Collaborative Perinatal Study of the National Institute of Neurological Communicative Disorders and Stroke, these female patients were larger and had greater pregnancy weight gains. These anthropometric findings may reflect the two decades of improvements in social assistance and prenatal care for lower income women.

Adolescent↗

Schizophrenics' adopting parents. Psychiatric status.

With the exception of one finding in one experiment, adoption studies have demonstrated that genetic and not rearing factors play an etiological role in the schizophrenias. In that one study, clinical evaluations showed the biological parents of schizophrenics as more disturbed than the adopting parents of schizophrenics, who were, in turn, slightly more disturbed than the adopting parents of normal persons. Both the biological and the adopting parents of schizophrenics showed an equivalent degree of Rorschach pathology, suggesting the possible role of a learned communication disorder in the schizophrenic disorders. A replicative study were performed, employing the same design but utilizing a systematic sample. Structured interviews and tests were administered to the biological parents of nongenetic retardates. Structured clinical evaluation showed the biological parents of schizophrenics to be more disturbed than the other two groups, between whom there was no difference in psychopathology. With analysis of the Rorschach tests, the biological parents of schizophrenics showed significantly more Rorschach pathology than found in the other two groups, whose degree of disorder was the same. This study again confirms the role of genetic factors and fails to show an environmental component in the etiology of the schizophrenias.

Adoption↗

Marked reduction in the number of platelet-tritiated imipramine binding sites in geriatric depression.

The number (Bmax) and affinity (Kd) of platelet-tritiated imipramine binding sites was determined in young and middle-aged controls 50 years of age and younger (n = 25), elderly normal controls over 60 years of age (n = 18), patients who fulfilled DSM-III criteria for major depression who were under 50 years of age (n = 29), patients who fulfilled DSM-III criteria for major depression who were 60 years of age and older (n = 19), and patients who fulfilled both DSM-III criteria for primary degenerative dementia and National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria for probable Alzheimer's disease (n = 13). Both groups of depressed patients (under 50 and over 60 years of age) exhibited significant reductions (decreases 42%) in the number of platelet-tritiated imipramine binding sites with no change in affinity, when compared with their age-matched controls. There was little overlap in Bmax values between the elderly depressed patients and their controls. The patients with probable Alzheimer's disease showed no alteration in platelet-tritiated imipramine binding. There was no statistically significant relationship between postdexamethasone plasma cortisol concentrations and tritiated imipramine binding. These results indicate that platelet-tritiated imipramine binding may have potential utility as a diagnostic adjunct in geriatric depression, and moreover that the reduction in the number of platelet-tritiated imipramine binding sites is not due to hypercortisolemia.

Adolescent↗

The relationships between age, sex, and the incidence of dementia and Alzheimer disease: a meta-analysis.

BACKGROUND: Prevalence studies on dementia and Alzheimer disease (AD) have reported a positive association with age. However, the trend of the association in the oldest-old categories has been the subject of discussion. The relationship between sex and AD has been inconsistent with these studies. Prevalence rates are influenced by the survival and disease incidence. Incidence rates provide a better measure of disease risk. METHODS: English-language articles identified through a MEDLINE search on "incidence dementia" and "incidence Alzheimer's disease" were examined and references from identified articles were reviewed. Population-based studies using personal interviews, standard clinical diagnosis criteria (DSM-III for dementia, National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorder Association for AD) and reporting age-specific incidence rates were included in the meta-analysis. Data from the selected studies were extracted and verified. Mixed-effect models were used in the meta-analysis to accommodate the heterogeneity of the studies. RESULTS: Incident dementia and AD are associated with a significant quadratic age effect indicating that the increase in incidence rates slows down with the increase in age, although there is no sign of a decline in the incidence rates themselves. The odds ratios for women to develop incidence of dementia and AD relative to men are 1.18 (95% confidence interval, 0.95-1.46) and 1.56 (95% confidence interval, 1.16-2.10), respectively. CONCLUSIONS: The acceleration of incidence rates for AD and dementia slows down with the increase in age, although we find no evidence of a rate decline. Women are at higher risk of developing AD than men.

Age Factors↗

The temporal relationship between depressive symptoms and dementia: a community-based prospective study.

BACKGROUND: The temporal relationship between the appearance of depressive symptoms and the clinical onset of dementia and Alzheimer disease was evaluated in a community sample. METHODS: An original sample of 1366 subjects aged 65 years or older, selected randomly from a rural Pennsylvania community, was cognitively screened at study entry and every 2 years thereafter. A subset of 954 survivors of this cohort without dementia was screened for depressive symptoms at the second and subsequent data-collection waves. A "depression cluster" was identified by the presence of 5 or more depressive symptoms, including depressed mood, at the time of screening. Cognitively impaired subjects and a sample of unimpaired controls underwent standardized clinical evaluation to determine the presence of incident dementia (by DSM-III-R criteria) and probable or possible Alzheimer disease (by criteria of the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association) and to estimate the clinical onset of dementia symptoms. RESULTS: A highly increased probability of the depression cluster developing existed among subjects following the onset of dementia (15.4% [6/39]) and Alzheimer disease (17.6% [6/34]) compared with subjects without dementia (3.2% [23/712]). The odds ratios, after adjustment for age, sex, education level, and self reported memory loss, for the development of depression were 6.5 (95% confidence interval, 2.2-19.1) in subjects with Alzheimer disease and 5.2 (95% confidence interval, 1.8-15.2) in subjects with overall dementia. Depressive symptoms did not confer a significantly increased relative risk of dementia (1.27; 95% confidence interval, 0.55-2.93) or Alzheimer disease (1.28; 95% confidence interval, 0.51-3.20). CONCLUSION: Depressive symptoms appeared to be early manifestations, rather than predictors, of Alzheimer disease in this community sample.

Aged↗

Participation in cognitively stimulating activities and risk of incident Alzheimer disease.

CONTEXT: Frequent participation in cognitively stimulating activities has been hypothesized to reduce risk of Alzheimer disease (AD), but prospective data regarding an association are lacking. OBJECTIVE: To test the hypothesis that frequent participation in cognitive activities is associated with a reduced risk of AD. DESIGN: Longitudinal cohort study with baseline evaluations performed between January 1994 and July 2001 and mean follow-up of 4.5 years. PARTICIPANTS AND SETTING: A total of 801 older Catholic nuns, priests, and brothers without dementia at enrollment, recruited from 40 groups across the United States. At baseline, they rated frequency of participation in common cognitive activities (eg, reading a newspaper), from which a previously validated composite measure of cognitive activity frequency was derived. MAIN OUTCOME MEASURES: Clinical diagnosis of AD by a board-certified neurologist using National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's Disease and Related Disorders Association criteria and change in global and specific measures of cognitive function, compared by cognitive activity score at baseline. RESULTS: Baseline scores on the composite measure of cognitive activity ranged from 1.57 to 4.71 (mean, 3.57; SD, 0.55), with higher scores indicating more frequent activity. During an average of 4.5 years of follow-up, 111 persons developed AD. In a proportional hazards model that controlled for age, sex, and education, a 1-point increase in cognitive activity score was associated with a 33% reduction in risk of AD (hazard ratio, 0.67; 95% confidence interval, 0.49-0.92). Results were comparable when persons with memory impairment at baseline were excluded and when terms for the apolipoprotein E epsilon4 allele and other medical conditions were added. In random-effects models that controlled for age, sex, education, and baseline level of cognitive function, a 1-point increase in cognitive activity was associated with reduced decline in global cognition (by 47%), working memory (by 60%), and perceptual speed (by 30%). CONCLUSION: These results suggest that frequent participation in cognitively stimulating activities is associated with reduced risk of AD.

Aged↗

Interventions for apraxia of speech following stroke.

BACKGROUND: Apraxia of speech is a communication disorder that can affect stroke patients. Several different intervention strategies are undertaken by speech and language therapists working with this patient group. OBJECTIVES: To assess whether therapeutic interventions improve functional speech in stroke patients with apraxia of speech and which individual therapeutic interventions are effective. SEARCH STRATEGY: We searched the Cochrane Stroke Group Trials Register (searched May 2004). In addition, we searched the following databases: the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 4, 2003); MEDLINE (1966 to April 2004); EMBASE (1980 to April 2004); CINAHL (1982 to April 2004); PsycINFO (1974 to April 2004); the National Research Register (searched April 2004); and Current Controlled Trials Register (searched May 2004). We reviewed reference lists of relevant articles and contacted authors and researchers in an effort to identify published and unpublished trials. SELECTION CRITERIA: We sought to include randomised controlled trials of non-drug interventions for adults with apraxia of speech following a stroke where the primary outcome was functional speech at six months follow up. DATA COLLECTION AND ANALYSIS: One author searched the titles, abstracts and keywords. Two authors examined the abstracts that might meet the inclusion criteria. Four authors were available to assess trial quality and to extract data from eligible studies. MAIN RESULTS: No trials were identified. AUTHORS' CONCLUSIONS: There is no evidence from randomised trials to support or refute the effectiveness of therapeutic interventions for apraxia of speech. There is a need for high quality randomised trials to be undertaken in this area.

Apraxias↗

Lay perceptions of genetic risks attributable to inbreeding in Pakistan.

Pakistan along with many other West and South Asian countries has a very high prevalence of consanguineous, especially close cousin, marriages. Although there is substantial empirical information on offspring morbidity and mortality attributable to parental consanguinity, population-based information on how communities in general, and women in particular, perceive the health risks associated with consanguineous unions is limited. This paper considers community perceptions of health effects associated with consanguineous marriages using qualitative data from 15 focus group discussions and 294 in-depth interviews. The study was conducted in four low-income, multi-ethnic, and multi-religious communities in Karachi, the principal commercial center of Pakistan. The results show a general lack of awareness of the possible adverse health effects of consanguineous marriage. In cases where a link between consanguinity and ill health was acknowledged, it often centered on the familial origins of non-communicable disorders such as diabetes and hypertension or infectious diseases such as tuberculosis. Belief in fate and the "evil eye" was widespread across all ethnic and religious groups. Many respondents did not agree with medical explanations of a genetic mode of disease inheritance, even in cases where there was an affected child in the family. The absence of a uniform manifestation of disease among all children of a couple who were identified as carriers of a specific mutation added to the confusion among participants. The study highlights the need for further quantification of risks associated with consanguinity and a need for provision of appropriate information to primary-care clinicians and also to communities. The likely impact of increasing morbidity attributable to inbreeding on the health care system in resource poor settings is also discussed.

Adolescent↗

Congenital anomalies: mortality and morbidity, burden and classification.

This study has attempted to assess the burden imposed by congenital anomalies in terms of postnatal mortality and morbidity, which were in turn used to classify anomalies as severe and mild types. Factors studied were postnatal mortality through age 7 years and morbidity, as measured by neurologic and psychologic abnormalities, histories of major surgery, prolonged hospitalization, and chronic infections. The study was based on a prospective study of 52,332 liveborn singletons of the Collaborative Perinatal Project of the National Institute of Neurological and Communicative Disorders and Stroke. In general, the highest degree of burden was observed in syndromes and sequences, followed by multiple and single major anomalies. The burden due to major abnormalities as measured by attributable risk ranged from 0.436 for prolonged hospitalization up to one year, to 0.010 for chronic infections in subjects 1-7 years of age. In terms of mortality, the total attributable risk was 0.164, and the mean potential years of life lost was 5,020 per 10,000 population, which is considerably greater than that reported in other studies. An index constructed from mortality, neurologic, psychologic, and surgical variables provides a reasonable and objective means for classifying anomalies into severe and mild types.

Anthropometry↗

The incidence and prevalence of reported multiple sclerosis.

A national survey, sponsored by the National Institute of Neurological and Communicative Disorders and Stroke, to determine the incidence, prevalence, and economic impact of multiple sclerosis has just been completed. These data are the first report of the results. Based on the data gathered, it is estimated that on January 1, 1976, there were a reported 123,000 multiple sclerosis patients in the conterminous United States (a rate of 58 per 100,000). The annual incidence for the period 1970-1975 was estimated to be 8,800 (a rate of 4.2 per 100,000). The pattern of the disease being more common among females, whites, persons aged 30-50 years, and individuals living above the 37th parallel was also demonstrated. In addition to demographic characteristics, selected disease characteristics of the incidence and prevalence populations were also examined.

Adult↗

Infarcts of undetermined cause: the NINCDS Stroke Data Bank.

In a prospective study of 1,805 hospitalized patients in the Stroke Data Bank of the National Institute of Neurological and Communicative Disorders and Stroke, the 1,273 with infarction were classified into diagnostic subtypes. Diagnosis was based on the clinical history, examination, and laboratory tests including computed tomography, noninvasive vascular imaging, and where safe and relevant, angiography. Five hundred and eight cases (fully 40%) were labeled as infarcts of undetermined cause (IUC), of which 138 (27%) were evaluated with both computed tomography and angiography. The clinical syndrome and computed tomographic and angiographic findings in 91 (65.9%) of these 138 IUC cases were clearly not attributable to large-artery thrombosis and could permit reclassification of the infarct as due to some form of embolism. Failure to define a source of embolus kept them in the category of IUC. Thirty-one cases (22.5%) could be reclassified as due to stenosis or thrombosis of a large artery, and 16 (11.6%) as lacunar infarction. To determine if those selected for angiography among the IUC patients differed from those with other final diagnoses, a stepwise multiple logistic model was used. The most important characteristics were young age, presence of a superficial infarct, prior transient ischemic attack, low weakness score, and presentation with a nonlacunar syndrome. The results of the model suggest that angiography use was determined by clinical characteristics uniformly across centers and not by final diagnosis. Continued use of the category IUC may help clarify risk factors and stroke subtypes, allow new mechanisms of ischemic stroke to be uncovered, and prevent classification categories of stroke used in clinical trials from becoming too broad.

Cerebral Angiography↗