Citations

ABSTRACT Background : The aim of this postmortem study was to compare, in Parkinson's disease subjects with and without bilateral subthalamic nucleus deep brain stimulation (STN‐DBS), the loss of pigmented neurons within the substantia nigra and pathological alpha‐synuclein density within the SN and other brain regions. Methods : PD subjects were identified from the Arizona Study of Aging and Neurodegenerative Disorders database (STN‐DBS = 11, non‐DBS = 156). Pigmented neuron loss scores within the substantia nigra as well as alpha‐synuclein density scores within the substantia nigra and 9 other brain regions were compared, the latter individually and in summary as the Lewy body brain load score. Results : DBS subjects had higher alpha‐synuclein density scores within the substantia nigra, olfactory bulb, and locus ceruleus, as well as higher total Lewy body brain load scores when compared with non‐DBS subjects. No differences in substantia nigra pigmented neuron loss scores were found. Conclusions : STN‐DBS subjects tend to have higher alpha‐synuclein density scores, but do not have a differential loss of substantia nigra pigmented neurons. © 2016 International Parkinson and Movement Disorder Society

ABSTRACTIntroductionQuantitative EEG features have been identified as surrogates and predictors of cognitive decline/dementia, a common feature of progressive PD. The biochemical correlates for altered quantitative EEG features are unknown. Our primary objective was to test the hypothesis that quantitative EEG measures correlate with cortical levels of phosphorylated α‐synuclein, a modified form of the synaptic protein α‐synuclein, in PD cases, in contrast to other pathology‐associated proteins. A secondary objective was to explore the same correlations among cellular fractions of these proteins.MethodsWe used posterior cingulate cortex autopsy tissue from 44 PD subjects with various degrees of cognitive decline, who had undergone EEG. In this brain region, which is a major hub of the default mode network, biochemical measurements for levels of phosphorylated α‐synuclein, unmodified α‐synuclein, amyloid beta peptide, phosphorylated tau, and key synaptic proteins were analyzed and data correlated with spectral EEG measures.ResultsFindings revealed significant correlations between background rhythm peak frequency and all bandpower values (highest in delta bandpower) with total phosphorylated α‐synuclein, but not any correlation with total α‐synuclein, phosphorylated tau protein, amyloid beta peptide, or synaptic proteins. Certain fractions of synaptosomal‐associated protein 25 showed correlation with some quantitative EEG measures.ConclusionsThese data show an association between increased phosphorylation of α‐synuclein and the abnormal EEG signatures of cognitive decline. Results suggest that quantitative EEG may provide an in vivo approximation of phosphorylated α‐synuclein in PD cortex. This adds to previous evidence that quantitative EEG measures can be considered valid biomarkers of PD cognitive decline. © 2016 International Parkinson and Movement Disorder Society

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.

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

Abstract Background Hyposmia is common in Parkinson's disease (PD) and is also observed with normal aging. It can be ascertained through objective testing, but it is unclear whether patients are aware of deficits and whether this has implications for cognitive status. Methods Subjects in the Arizona Study of Aging and Neurodegenerative Disorders were studied with annual motor and cognitive testing with objective smell testing (University of Pennsylvania Smell Identification Test; UPSIT ) done every third year beginning in 2002. Those with a baseline UPSIT <25th percentile (hyposmia) were studied for presence of unawareness of hyposmia and cognitive status. Results There were 75 subjects with PD and 143 nonparkinsonian controls with hyposmia. Lack of awareness of hyposmia was present in 16% of PD subjects and 47% of those without PD . In PD , there was no increase in unawareness in PD with dementia. In non‐ PD controls, unawareness was correlated with presence of dementia. Unawareness of hyposmia correlated most strongly with the neuropsychiatric tests of learning and memory. In controls without dementia or PD , 48% were unaware. Conclusions Querying patients about anosmia might be useful in parkinsonian disorders without objective testing. However, in elderly controls, it should be followed by objective testing and lack of awareness has implications for worsened cognitive status.

AbstractThe 2013 American Thoracic Society/European Respiratory Society consensus classification update of the idiopathic interstitial pneumonias (IIP) included several important modifications to the organization and spectrum of the diseases that were proposed in an earlier multidisciplinary consensus document in 2002. The histopathology of the now ‘major’ and ‘rare’ IIP is presented here with exposition of the newly included entity of a distinctive upper lobe fibrotic lung disease referred to as idiopathic pleuroparenchymal fibroelastosis. The ‘rare histological patterns’ of acute fibrinous and organizing pneumonia and bronchiolocentric patterns of interstitial pneumonia are illustrated and discussed.