Beach, Thomas G.

Introduction. The key mechanisms that connect Parkinson’s disease pathology with dementia are unclear. We tested the hypothesis that the quantitative spectral electroencephalographic measure, delta bandpower, correlates with Lewy type synucleinopathy on pathological examination in Parkinson’s disease. As a corollary hypothesis, we analyzed whether there would be delta bandpower electroencephalographic differences between Parkinson’s disease dementia cases with and without pathological criteria for Alzheimer’s disease. Methods. We used pathological examination results from 44 Parkinson’s disease subjects from our brain bank with various degrees of cognitive decline, who had undergone electroencephalography. Pathological grading for Lewy type synucleinopathy, plaques, tangles, and indications of vascular pathology in subcortical and cortical areas were correlated with the most associated electroencephalographic biomarker with Parkinson’s disease dementia in our laboratory, delta bandpower. Group differences for all spectral electroencephalographic measures were also analyzed between cases with and without pathological criteria for Alzheimer’s disease. Results. Findings revealed significant correlations between delta bandpower with Lewy type synucleinopathy, whereas indications of Alzheimer’s disease or vascular pathology had nonsignificant correlation. The strongest association was with delta bandpower and Lewy type synucleinopathy in the anterior cingulate region. Mean delta bandpower was higher in the group for Parkinson’s disease dementia with Alzheimer’s disease pathology criteria than without. Conclusions. Lewy type synucleinopathy severity appears to be more associated with increased delta bandpower than with Alzheimer’s disease pathology or indications of vascular pathology over all cases. However, the presence of Alzheimer’s pathology may associate with more cortex physiological disruption in a subset of cases.

Abstract Introduction Genetic loci for Alzheimer's disease (AD) have been identified in whites of European ancestry, but the genetic architecture of AD among other populations is less understood. Methods We conducted a transethnic genome‐wide association study (GWAS) for late‐onset AD in Stage 1 sample including whites of European Ancestry, African‐Americans, Japanese, and Israeli‐Arabs assembled by the Alzheimer's Disease Genetics Consortium. Suggestive results from Stage 1 from novel loci were followed up using summarized results in the International Genomics Alzheimer's Project GWAS dataset. Results Genome‐wide significant (GWS) associations in single‐nucleotide polymorphism (SNP)–based tests ( P < 5 × 10 −8 ) were identified for SNPs in PFDN1/HBEGF , USP6NL/ECHDC3 , and BZRAP1‐AS1 and for the interaction of the (apolipoprotein E) APOE ε4 allele with NFIC SNP. We also obtained GWS evidence ( P < 2.7 × 10 −6 ) for gene‐based association in the total sample with a novel locus, TPBG ( P = 1.8 × 10 −6 ). Discussion Our findings highlight the value of transethnic studies for identifying novel AD susceptibility loci.

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

AbstractObjectiveProtein phosphatase 2A (PP2A) is a heterotrimeric holoenzyme composed of a catalytic C subunit, a structural A subunit, and one of several regulatory B subunits that confer substrate specificity. The assembly and activity of PP2A are regulated by reversible methylation of the C subunit. α‐Synuclein, which aggregates in Parkinson disease (PD) and dementia with Lewy bodies (DLB), is phosphorylated at Ser129, and PP2A containing a B55α subunit is a major phospho‐Ser129 phosphatase. The objective of this study was to investigate PP2A in α‐synucleinopathies.MethodsWe compared the state of PP2A methylation, as well as the expression of its methylating enzyme, leucine carboxyl methyltransferase (LCMT‐1), and demethylating enzyme, protein phosphatase methylesterase (PME‐1), in postmortem brains from PD and DLB cases as well as age‐matched Controls. Immunohistochemical studies and quantitative image analysis were employed.ResultsLCMT‐1 was significantly reduced in the substantia nigra (SN) and frontal cortex in both PD and DLB. PME‐1, on the other hand, was elevated in the PD SN. In concert with these changes, the ratio of methylated PP2A to demethylated PP2A was markedly decreased in PD and DLB brains in both SN and frontal cortex. No changes in total PP2A or total B55α subunit were detected.InterpretationThese findings support the hypothesis that PP2A dysregulation in α‐synucleinopathies may contribute to the accumulation of hyperphosphorylated α‐synuclein and to the disease process, raising the possibility that pharmacological means to enhance PP2A phosphatase activity may be a useful disease‐modifying therapeutic approach.

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.

ABSTRACTNonmotor manifestations of Parkinson's disease (PD) can begin well before motor PD begins. It is now clear, from clinical and autopsy studies, that there is significant Lewy‐type α‐synucleinopathy present outside the nigro‐striatal pathway and that this may underlie these nonmotor manifestations. This review discusses neuropathological findings that may underlie nonmotor symptoms that either predate motor findings or occur as the disease progresses. © 2016 International Parkinson and Movement Disorder Society