Dugger, Brittany N.

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.

ABSTRACTIntroductionFinding a peripheral tissue biopsy site to diagnose early PD would be of value for clinical care, biomarker validation, and as research enrollment criteria. Whereas autopsy and advanced PD studies suggest that the submandibular gland is an important biopsy site, there are no studies in early PD. The aim of this study was to determine whether needle biopsy of the submandibular gland reveals Lewy type alpha‐synucleinopathy in early PD.MethodsTwenty‐five early PD (duration < 5 years) and 10 controls underwent transcutaneous needle core biopsies of the submandibular gland. Tissue was stained for phosphorylated alpha‐synuclein, reviewed blind to clinical diagnosis, and only nerve element staining was considered positive.ResultsMean (standard deviation) age was 69.5 (8.3) for the PD group, 64.8 (8.0) years for controls, and disease duration 2.6 (1.1) years. Six PD and 1 control subject had inadequate glandular tissue. Positive staining was found in 14 of 19 (74%) PD and 2 of 9 (22%) control subjects. PD‐positive and ‐negative cases did not differ clinically. Adverse events (mainly swelling and bruising) were common (77% of cases), but were minor and transient.ConclusionsSubmandibular gland needle biopsies identified phosphorylated alpha‐synuclein staining in 74% of early PD subjects. False positives may be true false positives or may represent prodromal PD. If confirmed in larger studies with eventual autopsy confirmation, the potential value of submandibular gland biopsies for early PD may be to aid in clinical trial inclusion/exclusion and eventually serve as a gold standard for biomarker studies short of autopsy confirmation. © 2016 International Parkinson and Movement Disorder Society

Studies have demonstrated associations between cardiovascular factors and Alzheimer disease (AD) with minimal focus on other neurodegenerative diseases. Utilizing cross-sectional data from 17,532 individuals in the National Alzheimer’s Coordinating Center, Uniform Data Set, we compared the presence of cardiovascular factors [body mass index (BMI), atrial fibrillation, hypertension, hyperlipidemia, and diabetes] in individuals carrying a diagnosis of Probable AD (ProbAD), Possible AD, vascular dementia, dementia with Lewy bodies (DLB), frontotemporal dementia, Parkinson disease, progressive supranuclear palsy, or corticobasal degeneration, with that of normals. Generalized linear mixed models were fitted with age at visit, gender, and cardiovascular factors as fixed effects and Alzheimer’s Disease Centers as random effects. In late life, only BMI of ProbAD and DLB patients was statistically significantly lower than that in normals (P–values <0.001). When accounting for colinearity within cardiovascular factors, a low BMI was a comorbidity of certain dementia etiologies as compared with normals. These data support a concept of disease-specific associations with certain cardiovascular factors.

Background and purposeIt is believed that progressive Lewy‐type synucleinopathy (LTS) is primarily responsible for the worsening of motor and non‐motor Parkinson's disease (PD) signs and symptoms. Characterization of quantitative electroencephalography (QEEG) abnormalities across the spectrum of LTS to PD dementia (PD‐D) may provide insight into the pathophysiology of PD cortical dysfunction. Here our enlarged EEG database was leveraged to characterize spectral QEEG abnormalities in asymptomatic autopsy‐defined groups of control participants and incidental Lewy body disease (ILBD) and three clinically defined groups of participants with PD (cognitively normal PD, mild cognitive impairment PD, and PD‐D).MethodsThe PD cohort was studied as part of the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND). AZSAND utilizes its Brain and Body Donation Program to perform prospective, standardized, regular longitudinal pre‐mortem assessments until death. Resting EEG from subjects was analyzed for spectral domain QEEG measures of background rhythm frequency and global relative power in delta, theta, alpha and beta bands.ResultsThe various spectral QEEG measures showed differential changes specific to the groups compared. Important findings were background rhythm frequency showing the most pairwise differences across the groups, and this also was the only significant difference between control and ILBD. An increase in delta bandpower was characteristic of worsening cognitive deficits.ConclusionsDifferent patterns of change amongst QEEG measures across LTS and PD cognitive states suggest that they correlate with heterogeneous pathophysiologies of cortical dysfunction within the PD clinical spectrum. In addition, the biomarker application of a specific spectral QEEG measure needs to be selectively suited to its study purpose.

AbstractIntroductionRapid eye movement (REM) sleep behavior disorder (RBD) in Parkinson's disease (PD) is associated with differences in clinical phenotype, including dementia, autonomic loss, and gait dysfunction. The pathological basis for this remains unclear.MethodsParkinson's disease subjects in a longitudinal clinicopathologic study were screened for probable RBD with the Mayo Sleep Questionnaire. After death, semiquantitative analyses were conducted for synuclein, amyloid, neurofibrillary tangles, and cerebrovascular lesions.ResultsForty cases had probable RBD (PD+RBD), and 41 did not (PD‐RBD). Despite similar age at death (∼80 y) and disease duration (∼14.5 y), PD+RBD had increased synuclein deposition in all regions examined, with nine of 10 regions significantly different. The Lewy body 10‐region total score (scale = 0‐40) was 29.5 in PD+RBD versus 24.5 in PD‐RBD (Cohen‐d effect size = 0.79, P = 0.002). Cerebrovascular lesion burden was slightly higher in PD‐RBD.ConclusionsAlthough overlap occurs between groups, PD patients with probable RBD may have greater density and range of synuclein pathology on autopsy. © 2015 International Parkinson and Movement Disorder Society

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.

Abstract The pathologic changes of Parkinson's disease ( PD ) and Progressive Supranuclear Palsy (PSP) have been reported to coexist, but whether PSP pathology modifies the clinical course of those individuals is unknown. The aim of this study was to determine whether clinical features of pathologically confirmed PD subjects with concomitant PSP pathology differ from those with PD alone. Subjects enrolled in the Arizona Study of Aging and Neurodegenerative Disorders had annual movement and cognitive evaluations from enrollment until death/autopsy. All cases between 1997 and 2014 with a final clinicopathological diagnosis of PD with or without PSP at autopsy were analyzed. Overall, 12 of the 125 cases with pathologically confirmed PD had coexisting PSP pathology (9.6%). Those with PD ‐ PSP had more‐prominent postural instability, body bradykinesia, difficulty arising from a chair, and falls; asymmetric onset was less common in this group. Downgaze palsy and square wave jerks were infrequent in both groups. Gender, age at death, disease duration, rate of dementia, and presence of rest tremor did not differ between groups. Only 58% of subjects in the PD ‐ PSP group were correctly given a final diagnosis in life of PD, compared to 91% of those with PD alone. The combination of PD and PSP pathology yields a heterogeneous clinical syndrome that often resembles PD, but may be more symmetric at onset and have more‐prominent postural instability and falls. Our observations suggest that coexisting PSP pathology may be an important factor contributing to the clinical heterogeneity in PD and a potential confounder in diagnosis.

ABSTRACT There has been controversy as to whether there is an underlying neurodegenerative process of the cerebellum in essential tremor (ET). The aim of this study was to examine whether ET is associated with Purkinje cell (PC) loss. Prospectively categorized ET and control subjects who were longitudinally examined in the Arizona Study for Aging and Neurodegenerative Disorders and came to autopsy between 1998 and 2013 underwent standardized neuropathological assessment of the brain. PC linear density of the cerebellar hemisphere was calculated in a blinded manner. There were 56 ET cases and 62 age‐matched controls free of dementia and other neurodegenerative disorders included in the study. Mean PC linear density was 3.80 ± 0.81 cells per mm for tremor cases and 3.82 ± 0.91 cells per mm for controls ( Δ 0.02; 95% confidence interval [CI]: −0.30‐0.34). PC counts were not associated with tremor duration (r = 0.06; 95% CI: −0.21‐0.32). These data demonstrate that ET is not associated with cerebellar PC loss. © 2014 International Parkinson and Movement Disorder Society