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Objective To assess the predictive potential of the complete response pattern from the University of Pennsylvania Smell Identification Test for the diagnosis of Parkinson's disease. Methods We analyzed a large dataset from the Arizona Study of Aging and Neurodegenerative Disorders, a longitudinal clinicopathological study of health and disease in elderly volunteers. Using the complete pattern of responses to all 40 items in each subject's test, we built predictive models of neurodegenerative disease, and we validated these models out of sample by comparing model predictions against postmortem pathological diagnosis. Results Consistent with anatomical considerations, we found that the specific test response pattern had additional predictive power compared with a conventional measure – total test score – in Parkinson's disease, but not Alzheimer's disease. We also identified specific test questions that carry the greatest predictive power for disease diagnosis. Interpretation Olfactory ability has typically been assessed with either self-report or total score on a multiple choice test. We showed that a more accurate clinical diagnosis can be made using the pattern of responses to all the test questions, and validated this against the “gold standard” of pathological diagnosis. Information in the response pattern also suggests specific modifications to the standard test that may optimize predictive power under the typical clinical constraint of limited time. We recommend that future studies retain the individual item responses for each subject, and not just the total score, both to enable more accurate diagnosis and to enable additional future insights.

This study was designed to correlate clinical findings with the extent of pathologic a-synuclein (aSyn) in the brain using the Unified Staging System for Lewy Body disorders (USSLB). Data from 280 cases from the Arizona Study of Aging and Neurodegenerative Disorders are presented. Each case had a complete USSLB staging and at least 1 full research clinical assessment, including subspecialty neurologist-administered movement and cognitive evaluation. Of the 280, 25.7% were cognitively normal, 8.6% had mild cognitive impairment, and 65.7% had dementia. All cases could be categorized into 1 of 5 USSLB stages (8.6% stage I—olfactory bulb only; 15.4% IIa—brainstem predominant; 13.6% IIb—limbic predominant; 31.8% III—brainstem and limbic; and 30.7% IV—neocortical) yet using the Braak staging system 70 cases (25.3%) could not be classified. Those with USSLB stages III and IV died at a younger age. Multiple measures of motor parkinsonism, cognitive impairment, hyposmia, and probable RBD were significantly correlated with increasing USSLB stage. We conclude that the USSLB is the most comprehensive staging system for all Lewy body disorders and allows for categorization and ranking of all brains with significant correlations to many motor and nonmotor clinical signs and symptoms.

Due to the absence of core clinical features, many subjects with neuropathologically-confirmed dementia with Lewy bodies (DLB) are never diagnosed as such during life. Most of these are diagnosed with Alzheimer’s disease dementia (ADD) or unspecified dementia. Unrecognized DLB therefore is a critical impediment to clinical studies and treatment trials of both ADD and DLB. There are numerous published studies that suggest that olfactory function tests may be able to differentiate some neurodegenerative conditions from each other and from normal subjects, but there are very few studies with neuropathological confirmation of diagnosis. We compared University of Pennsylvania Smell Identification Test (UPSIT) results in 209 subjects: 1) 29 concurrently meeting intermediate or high consensus clinicopathological criteria for both DLB and ADD 2) 96 meeting criteria for ADD without DLB 3) 84 control subjects that were non-demented and without parkinsonism at death. The DLB subjects had significantly lower (one-way ANOVA p < 0.0001, pairwise Bonferroni p < 0.05) first and mean UPSIT scores (13.7 and 13.2) than ADD (23.3 and 22.2) or controls (29.6 and 28.9). For subjects with first and mean UPSIT scores less than 20 and 17, respectively, Firth logistic regression analysis, adjusted for age, gender and mean MMSE score, conferred statistically significant odds ratios of 17.5 and 18.0 for predicting a DLB vs ADD diagnosis, as compared to 3.3 for the presence or absence of visual hallucinations throughout the clinical observation period. To our knowledge, this is the largest study to date comparing olfactory function in subjects with neuropathologically confirmed DLB and ADD. Olfactory function testing may be a convenient and inexpensive strategy for enriching dementia studies or clinical trials with DLB subjects, or conversely, reducing the inclusion of DLB subjects in ADD studies or trials.

Multiple studies suggest that females are affected by Alzheimer disease (AD) more severely and more frequently than males. Other studies have failed to confirm this and the issue remains controversial. Difficulties include differences in study methods and male versus female life expectancy. Another element of uncertainty is that the majority of studies have lacked neuropathological confirmation of the AD diagnosis. We compared clinical and pathological AD severity in 1028 deceased subjects with full neuropathological examinations. The age of dementia onset did not differ by gender but females were more likely to proceed to very severe clinical and pathological disease, with significantly higher proportions having a Mini-Mental State Examination score of 5 or less and Braak stage VI neurofibrillary degeneration. Median neuritic plaque densities were similar in females and males with AD but females had significantly greater tangle density scores. In addition, we found that AD-control brain weight differences were significantly greater for females, even after adjustment for age, disease duration, and comorbid conditions. These findings suggest that when they are affected by AD, females progress more often to severe cognitive dysfunction, due to more severe neurofibrillary degeneration, and greater loss of brain parenchyma.

Inability to accurately diagnose Lewy type alpha-synucleinopathy (LTS) pre-mortem has been a major obstacle to clinical care and research. Probable REM sleep behavior disorder (PRBD) diagnosed with support of instruments such as the Mayo Sleep Questionnaire (MSQ) may provide a cost effective means of predicting LTS. Since 2007, 602 subjects in the Arizona Study of Aging and Neurodegenerative Disorders had clinician assessment for PRBD (298 with, 304 without support of the MSQ), completed cognitive and movement examinations, and had neuropathological assessment. Mean age at death was 84.8 years. Histological evidence of LTS was found in 80/101(79.2%) cases with PRBD and 198/501 (39.5%) without PRBD (p

The Brain and Body Donation Program (BBDP) at Banner Sun Health Research Institute (http://www.brainandbodydonationprogram.org) started in 1987 with brain-only donations and currently has banked more than 1600 brains. More than 430 whole-body donations have been received since this service was commenced in 2005. The collective academic output of the BBDP is now described as the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND). Most BBDP subjects are enrolled as cognitively normal volunteers residing in the retirement communities of metropolitan Phoenix, Arizona. Specific recruitment efforts are also directed at subjects with Alzheimer's disease, Parkinson's disease and cancer. The median age at death is 82. Subjects receive standardized general medical, neurological, neuropsychological and movement disorders assessments during life and more than 90% receive full pathological examinations by medically licensed pathologists after death. The Program has been funded through a combination of internal, federal and state of Arizona grants as well as user fees and pharmaceutical industry collaborations. Subsets of the Program are utilized by the US National Institute on Aging Arizona Alzheimer's Disease Core Center and the US National Institute of Neurological Disorders and Stroke National Brain and Tissue Resource for Parkinson's Disease and Related Disorders. Substantial funding has also been received from the Michael J. Fox Foundation for Parkinson's Research. The Program has made rapid autopsy a priority, with a 3.0-hour median post-mortem interval for the entire collection. The median RNA Integrity Number (RIN) for frozen brain and body tissue is 8.9 and 7.4, respectively. More than 2500 tissue requests have been served and currently about 200 are served annually. These requests have been made by more than 400 investigators located in 32 US states and 15 countries. Tissue from the BBDP has contributed to more than 350 publications and more than 200 grant-funded projects.

Fibromyalgia (FM) has been understudied in the elderly population, a group with particular vulnerabilities to pain, reduced mobility, and sleep disruption.To characterize FM symptoms and treatments in a cohort of older subjects examined over time to determine the extent to which current, community-based treatment for older FM patients is in accord with published guidelines, and effective in reducing symptoms.A longitudinal, observational study of 51 subjects with FM (range 55-95 years) and 81 control subjects (58-95 years) performed at Banner Sun Health Research Institute in Sun City, AZ, USA. Serial history and examination data were obtained over a 6-year period. FM data included medical history, medications, physical examination, tender point examination, neuropsychological testing, sleep and pain ratings, the Physical Function Subscale of the Fibromyalgia Impact Questionnaire, and other standardized scales to evaluate depression and other psychiatric symptoms, and cognitive and functional impairment.Pain and stiffness that interfered with physical activity, sleep, and mood were reported by 80 % or more of subjects. Over time, pain involved an increasing number of body areas. Over half of subjects were treated with NSAIDs, one-quarter with opioids, and one-quarter with estrogen. Few were treated with dual-acting antidepressants or pregabalin.In this cohort of elders with suboptimally treated FM, substantial persistence of symptoms was seen over time. In general, recommended treatments were either not used or not tolerated.Age-appropriate treatments as well as education of primary care providers are needed to improve treatment of FM in the older population.

Existing reports on the frequencies of neurodegenerative diseases are typically based on clinical diagnoses. We sought to determine these frequencies in a prospectively assessed, community-based autopsy series. Included subjects had normal cognitive and movement disorder assessments at study entry. Of the 119 cases meeting these criteria, 52% were women; the median age of study entry was 83.5 years (range, 67-99 years), and the median duration from the first visit until death was 4.3 years (range, 0-10 years). At autopsy, clinicopathological diagnoses were made in 30 cases (25%). These diagnoses included 20 with Alzheimer disease (AD) (17%), 7 with vascular dementia (6%), 4 with progressive supranuclear palsy (3%), 3 with Parkinson disease and 1 each with dementia with Lewy bodies, corticobasal degeneration, or multiple system atrophy (0.8% each). Of the 87 subjects still clinically normal at death (73%), 33 had extensive AD pathology (preclinical AD) (38%), 17 had incidental Lewy bodies (20%), and 4 had incidental pathology consistent with progressive supranuclear palsy (5%). The diagnoses were not mutually exclusive. Although limited by a relatively small sample size, the neuropathological outcome of these initially normal elderly subjects represents a rough estimate of the incidence of these neurodegenerative conditions over a defined time period.

Background Clinical misdiagnosis, particularly at early disease stages, is a roadblock to finding new therapies for Lewy body disorders. Biopsy of a peripheral site might provide improved diagnostic accuracy. Previously, we reported, from both autopsy and needle biopsy, a high prevalence of submandibular gland synucleinopathy in Parkinson's disease (PD). Here, we report on an extension of these studies to subjects with dementia with Lewy bodies (DLB) and other Lewy body disorders in 228 autopsied subjects from the Arizona Study of Aging and Neurodegenerative Disorders. Objective To provide an estimate of the prevalence of histological synucleinopathy in the submandibular glands of subjects with PD and other Lewy body disorders. Methods Submandibular gland sections from autopsied subjects were stained with an immunohistochemical method for α-synuclein phosphorylated at serine 129. Included were 146 cases with CNS Lewy-type synucleinopathy (LTS), composed of 46 PD, 28 DLB, 14 incidental Lewy body disease (ILBD), 33 Alzheimer's disease with Lewy bodies (ADLB) and 2 with progressive supranuclear palsy and Lewy bodies (PSPLB). Control subjects included 79 normal elderly, 15 AD, 12 PSP, 2 conticobasal degeneration (CBD) and 2 multiple system atrophy (MSA). Results Submandibular gland LTS was found in 42/47 (89%) of the PD subjects, 20/28 (71%) DLB, 4/33 (12%) ADLB and 1/9 (11%) ILBD subjects but none of the 110 control subjects. Conclusions These results provide support for further clinical trials of in vivo submandibular gland diagnostic biopsy for PD and DLB. An accurate peripheral biopsy diagnosis would assist subject selection for clinical trials and could also be used to verify other biomarkers.

Objective: To identify a panel of peripheral inflammatory/immune mediators that could discriminate Parkinson disease with dementia (PDD) from Parkinson disease (PD) without dementia. Methods: Plasma samples from 52 patients with PD and 22 patients with PDD were prepared from freshly collected blood following an institutional review board–approved protocol. A total of 160 proteins were measured using a multiplex antibody array. Plasma α-synuclein levels were analyzed by an electrochemiluminescence immunoassay. The main objective of the statistical analyses was to identify PDD discriminants using the plasma protein profile alone or in combination with age. Results: The PD and PDD groups differed significantly in cognitive measurements (Mini-Mental State Examination, Auditory Verbal Learning Test-A7, and Clinical Dementia Rating) and age. The age-adjusted levels of thymus and activation-regulated chemokine (TARC) and platelet-derived growth factor (PDGF)-AA were significantly different between disease groups. The levels of plasma α-synuclein significantly correlated with 26 proteins; among them, PDGF-BB, TARC, PDGF-AA, and epidermal growth factor were the highest. Linear discriminant analysis with leave-one-out cross-validation identified a 14-protein panel with age as discriminants of PDD (96% sensitivity, 89% specificity, area under the curve = 0.9615). Conclusions: We showed that multiple proteins that are mediators of growth/trophic and immune response-related pathways had discriminatory power for identifying PDD in patients with PD. Validation of this discovery-based study in longitudinal population-based studies is warranted. Classification of evidence: This study provides Class III evidence that a 14-protein panel plasma assay combined with age has a sensitivity of 96% and a specificity of 89% for PDD.

Background. Pelvic floor dysfunction is a disorder predominantly affecting females. It is common and undermines the quality of lives of at least one-third of adult women and is a growing component of women's health care needs. Identifying and supporting these needs is a major public health issue with a strong psychosocial and economic basis. The importance of the interdependence of mechanical, neural, endocrine and environmental factors in the development of pelvic floor dysfunction is well recognized. There is a paucity of data investigating the true prevalence, incidence, specific risk factors, poor outcome of treatment and subsequent prevention strategies for women with multiple pelvic floor symptomatology. Aim. The aim of this paper is to present a critical review of the literature on the mechanism, presentation and management of multiple symptomatology in pelvic floor dysfunction and to propose a conceptual framework by which to consider the impact and problems women with pelvic floor dysfunction face. Methods. A comprehensive although not exhaustive literature search was carried out using medical and nursing databases BIOMED (1966–2002) NESLI (1989–2002) and EMBASE (1980–2003) CINAHL (1982–2003) and Cochrane databases using the key words ‘pelvic floor dysfunction’, ‘incontinence (urinary and faecal)’, ‘genital prolapse’, sexual dysfunction, ‘aetiology’, epidemiology’ and ‘treatment’. Retrospective and prospective studies and previous clinical reviews were considered for review. The articles retrieved were hand searched for further citations and referrals were made to relevant textbooks. Particular attention was paid to papers that focused on multiple pelvic floor symptoms. Findings. Pelvic floor dysfunction affects women of all ages and is associated with functional problems of the pelvic floor. Pelvic floor dysfunction describes a wide range of clinical problems that rarely occur in isolation. Inaccurate knowledge, myths and misconceptions of the incidence, cause and treatment of pelvic floor dysfunction abound. Given the significance of the aetiological contribution of factors such as pregnancy and obstetric trauma, ageing, hormonal status, hysterectomy and lifestyle in the development of pelvic floor disorders, the assessment, management and prevention of pelvic floor dysfunction remains a neglected part of many health care professionals educational preparation. This not only has major economic but also psychosocial implications for women, the general population and women's health care providers. A conceptual framework is also discussed that considers not only the impact and difficulties women with pelvic floor dysfunction face but also areas in which health care professionals can improve assessment and eventual treatment outcomes. Conclusion. This paper demonstrates gaps in the current provision of women's health care services. Functional pelvic floor problems are perceived to have low priority compared with other health disorders, and treatment remains sub-optimal. Inherent in achieving and promoting better health care services for women is the need for better collaborative approaches to care. There is a need to identify and develop comprehensive interdisciplinary, multi-professional strategies that improve the assessment and treatment of pelvic floor dysfunction in primary, secondary and tertiary settings. If this area of women's health care is to be improved nurses, whether community- or hospital-based, must play a front-line role in challenging and changing current practices. Education needs to be given greater priority and the development of a specialist pelvic floor nurse role explored. Such strategies could substantially influence a more effective approach to women's health care needs, result in improved treatment outcomes and liberate women from the embarrassment, social and sexual isolation, restriction to employment and leisure opportunities and potential loss of independence that multiple symptomatology can generate.

To date there is no validated peripheral biomarker to assist with the clinical diagnosis of Alzheimer’s disease (AD). Platelet proteins have been studied as AD biomarkers with relative success. In the present study we investigated whether platelet BACE1 levels differ between AD and cognitively normal (CN) control patients. Using a newly developed ELISA method, we found that BACE1 levels were significantly lower in AD compare to CN subjects. These data were supported by the observation that several BACE1 isoforms, identified by Western blotting, were also lower in AD platelets. This proof-of-concept study provides evidence for testing platelet BACE1 levels as a peripheral AD biomarker using a novel, sensitive and inexpensive method.