Publications by authors named "Brittany N Dugger"

61 Publications

Clinicopathological Correlation: Dopamine and Amyloid PET Imaging with Neuropathology in Three Subjects Clinically Diagnosed with Alzheimer's Disease or Dementia with Lewy Bodies.

J Alzheimers Dis 2021 ;80(4):1603-1612

Department of Neurology, Mayo Clinic College of Medicine, Scottsdale, AZ, USA.

Background: Imaging biomarkers have the potential to distinguish between different brain pathologies based on the type of ligand used with PET. AV-45 PET (florbetapir, Amyvid™) is selective for the neuritic plaque amyloid of Alzheimer's disease (AD), while AV-133 PET (florbenazine) is selective for VMAT2, which is a dopaminergic marker.

Objective: To report the clinical, AV-133 PET, AV-45 PET, and neuropathological findings of three clinically diagnosed dementia patients who were part of the Avid Radiopharmaceuticals AV133-B03 study as well as the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND).

Methods: Three subjects who had PET imaging with both AV-133 and AV-45 as well as a standardized neuropathological assessment were included. The final clinical, PET scan, and neuropathological diagnoses were compared.

Results: The clinical and neuropathological diagnoses were made blinded to PET scan results. The first subject had a clinical diagnosis of dementia with Lewy bodies (DLB); AV-133 PET showed bilateral striatal dopaminergic degeneration, and AV-45 PET was positive for amyloid. The final clinicopathological diagnosis was DLB and AD. The second subject was diagnosed clinically with probable AD; AV-45 PET was positive for amyloid, while striatal AV-133 PET was normal. The final clinicopathological diagnosis was DLB and AD. The third subject had a clinical diagnosis of DLB. Her AV-45 PET was positive for amyloid and striatal AV-133 showed dopaminergic degeneration. The final clinicopathological diagnosis was multiple system atrophy and AD.

Conclusion: PET imaging using AV-133 for the assessment of striatal VMAT2 density may help distinguish between AD and DLB. However, some cases of DLB with less-pronounced nigrostriatal dopaminergic neuronal loss may be missed.
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http://dx.doi.org/10.3233/JAD-200323DOI Listing
January 2021

Measuring peripheral markers of neuroinflammation in Alzheimer's disease - Challenges and opportunities.

Brain Behav Immun 2020 08 4;88:840-841. Epub 2020 Jun 4.

Department of Food Science and Technology, College of Agriculture and Environmental Sciences, University of California - Davis, Davis, CA, USA; NIH-West Coast Metabolomics Center, Genome Center, University of California - Davis, Davis, CA, USA. Electronic address:

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http://dx.doi.org/10.1016/j.bbi.2020.06.004DOI Listing
August 2020

Validation of machine learning models to detect amyloid pathologies across institutions.

Acta Neuropathol Commun 2020 04 28;8(1):59. Epub 2020 Apr 28.

Department of Neurology, Emory University School of Medicine, 12 Executive Park Dr NE, Atlanta, GA, 30322, USA.

Semi-quantitative scoring schemes like the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) are the most commonly used method in Alzheimer's disease (AD) neuropathology practice. Computational approaches based on machine learning have recently generated quantitative scores for whole slide images (WSIs) that are highly correlated with human derived semi-quantitative scores, such as those of CERAD, for Alzheimer's disease pathology. However, the robustness of such models have yet to be tested in different cohorts. To validate previously published machine learning algorithms using convolutional neural networks (CNNs) and determine if pathological heterogeneity may alter algorithm derived measures, 40 cases from the Goizueta Emory Alzheimer's Disease Center brain bank displaying an array of pathological diagnoses (including AD with and without Lewy body disease (LBD), and / or TDP-43-positive inclusions) and levels of Aβ pathologies were evaluated. Furthermore, to provide deeper phenotyping, amyloid burden in gray matter vs whole tissue were compared, and quantitative CNN scores for both correlated significantly to CERAD-like scores. Quantitative scores also show clear stratification based on AD pathologies with or without additional diagnoses (including LBD and TDP-43 inclusions) vs cases with no significant neurodegeneration (control cases) as well as NIA Reagan scoring criteria. Specifically, the concomitant diagnosis group of AD + TDP-43 showed significantly greater CNN-score for cored plaques than the AD group. Finally, we report that whole tissue computational scores correlate better with CERAD-like categories than focusing on computational scores from a field of view with densest pathology, which is the standard of practice in neuropathological assessment per CERAD guidelines. Together these findings validate and expand CNN models to be robust to cohort variations and provide additional proof-of-concept for future studies to incorporate machine learning algorithms into neuropathological practice.
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http://dx.doi.org/10.1186/s40478-020-00927-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7189549PMC
April 2020

Neuropathological Findings in Parkinson's Disease With Mild Cognitive Impairment.

Mov Disord 2020 05 8;35(5):845-850. Epub 2020 Feb 8.

Civin Laboratory for Neuropathology, Banner Sun Health Research Institute, Sun City, Arizona, USA.

Objective: There are few neuropathological studies on Parkinson's disease with mild cognitive impairment (PD-MCI). Those published reveal coexisting Lewy body and Alzheimer's disease pathology. Our objective is to determine the pathology that underlies PD-MCI.

Methods: We used data from the Arizona Study of Aging and Neurodegenerative Disorders, a longitudinal clinicopathological study. Of 736 autopsied subjects with standardized movement and cognitive assessments, 25 had PD-MCI. Neuropathological findings, including Lewy body and Alzheimer's disease pathology, were compared in PD subjects with amnestic MCI (A-MCI) and nonamnestic MCI (NA-MCI).

Results: Significant pathological heterogeneity within PD-MCI was found. This included varying Lewy body stages, Alzheimer's disease pathology, and cerebral amyloid angiopathy. There was a significant increase in the severity of Lewy body pathology (meeting The Unified Staging System for Lewy Body disorders neocortical stage) in nonamnestic MCI (7/1, 63%) when compared with amnestic MCI (3/14, 21%, P = 0.032).

Conclusion: Although a small study, distinct pathological changes may contribute to PD-MCI phenotype. © 2020 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.27991DOI Listing
May 2020

Unified Staging System for Lewy Body Disorders: Clinicopathologic Correlations and Comparison to Braak Staging.

J Neuropathol Exp Neurol 2019 10;78(10):891-899

Department of Biostatistics, Mayo Clinic, Scottsdale, Arizona.

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.
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http://dx.doi.org/10.1093/jnen/nlz080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6751070PMC
October 2019

Interpretable classification of Alzheimer's disease pathologies with a convolutional neural network pipeline.

Nat Commun 2019 05 15;10(1):2173. Epub 2019 May 15.

Department of Pathology and Laboratory Medicine, University of California-Davis School of Medicine, 3400A Research Building III Sacramento, Davis, CA, 95817, USA.

Neuropathologists assess vast brain areas to identify diverse and subtly-differentiated morphologies. Standard semi-quantitative scoring approaches, however, are coarse-grained and lack precise neuroanatomic localization. We report a proof-of-concept deep learning pipeline that identifies specific neuropathologies-amyloid plaques and cerebral amyloid angiopathy-in immunohistochemically-stained archival slides. Using automated segmentation of stained objects and a cloud-based interface, we annotate > 70,000 plaque candidates from 43 whole slide images (WSIs) to train and evaluate convolutional neural networks. Networks achieve strong plaque classification on a 10-WSI hold-out set (0.993 and 0.743 areas under the receiver operating characteristic and precision recall curve, respectively). Prediction confidence maps visualize morphology distributions at high resolution. Resulting network-derived amyloid beta (Aβ)-burden scores correlate well with established semi-quantitative scores on a 30-WSI blinded hold-out. Finally, saliency mapping demonstrates that networks learn patterns agreeing with accepted pathologic features. This scalable means to augment a neuropathologist's ability suggests a route to neuropathologic deep phenotyping.
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http://dx.doi.org/10.1038/s41467-019-10212-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6520374PMC
May 2019

Neuropathological Diagnoses of Demented Hispanic, Black, and Non-Hispanic White Decedents Seen at an Alzheimer's Disease Center.

J Alzheimers Dis 2019 ;68(1):145-158

Department of Neurology, University of California, Davis, Sacramento, CA, USA.

Our nation is becoming increasingly diverse; however, few autopsy studies examine multiple ethnoracial groups, especially Hispanics. We examined differences in neuropathological diagnoses of 423 deceased participants with dementia from three ethnoracial groups (35 Black, 28 Hispanic, and 360 non-Hispanic White) evaluated at the University of California Davis Alzheimer's Disease Center. We used novel applications of bootstrap resampling and logistic regression standardization to project neuropathological diagnostic rates for non-Hispanic Whites to minority sample characteristics to improve inference of findings. Alzheimer's disease (AD) without significant cerebrovascular disease (CVD) or other dementia-related pathologies (AD (non-mixed)) was present in 15 Black (43%), 4 Hispanic (14%), and 156 (43%) non-Hispanic Whites. CVD sufficient to contribute to dementia was confirmed in 14 Black (40%), 15 Hispanic (54%), and 101 (28%) non-Hispanic White decedents. The observed CVD prevalence of 40% in Blacks exceeded the predicted 29% [95% CI: 22%-36%]. Despite being outside the 95% confidence interval, the difference between observed and predicted was not statistically significant after bootstrap testing. Conversely, for Hispanics, the observed proportion at 54% exceeded significantly the predicted prevalence of 24% from non-Hispanic Whites [95% CI: 16%-34%], avg. p = 0.008). An identical analysis using AD (non-mixed) as the outcome predicted AD (non-mixed) in Blacks averaging 41% [95% CI: 34%-48%], nearly equal to observed prevalence. For Hispanics, however, the observed proportion at 14%, was well below predictions (mean = 42%, 95% CI: 32%-53%], avg. p = 0.008). We conclude mixed diagnoses and CVD are more common in Hispanic and Black decedents than Non-Hispanic Whites with dementia in our cohort. The increased prevalence of vascular co-morbidity may be a potential opportunity to intervene more effectively in dementia treatment of those individuals.
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http://dx.doi.org/10.3233/JAD-180992DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7286069PMC
June 2020

Tau immunoreactivity in peripheral tissues of human aging and select tauopathies.

Neurosci Lett 2019 03 21;696:132-139. Epub 2018 Dec 21.

Banner Sun Health Research Institute, Sun City, AZ, United States.

Many studies have been directed at understanding mechanisms of tau aggregation and therapeutics, nearly all focusing on the brain. It is critical to understand the presence of tau in peripheral tissues since this may provide new insights into disease progression and selective vulnerability. The current study sought to determine the presence of select tau species in peripheral tissues in elderly individuals and across an array of tauopathies. Using formalin fixed paraffin embedded sections, we examined abdominal skin, submandibular gland, and sigmoid colon among 69 clinicopathologically defined cases: 19 lacking a clinical neuropathological diagnosis (normal controls), 26 progressive supranuclear palsy (PSP), 21 Alzheimer's disease (AD), and 3 with corticobasal degeneration (CBD). Immunohistochemistry was performed using antibodies for "total" tau (HT7) and two phosphorylated tau species (AT8 and pT231). HT7 staining of abdominal skin revealed immunoreactivity of potential nerve elements in 5% of cases (1 AD, 1 AD/PSP, and 1 CBD out of 55 cases examined); skin sections lacked AT8 and pT231 immunoreactive nerve elements. Submandibular glands from all cases had HT7 immunoreactive nerve elements; while pT231 was present in 92% of cases, and AT8 in only 3 cases (2 AD and one AD/PSP case). In sigmoid colon, HT7 immunoreactivity was present in all but 2 cases (97%), pT231 in 54%, and AT8 was present in only 5/62 cases (8%). These data suggest select tau species in CNS tauopathies do not have a high propensity to spread to the periphery and this may hold clues for the understanding of CNS tau pathogenicity and vulnerability.
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http://dx.doi.org/10.1016/j.neulet.2018.12.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7357994PMC
March 2019

Are Clinical Certainty Ratings Helpful in the Diagnosis of Parkinson's Disease?

Mov Disord Clin Pract 2018 Mar-Apr;5(2):165-170. Epub 2018 Feb 22.

Department of Neurology Mayo Clinic Scottsdale AZ USA.

Background: Clinical diagnostic criteria for PD rely on rest tremor, bradykinesia, and rigidity. These features are non-specific and neuropathological confirmation remains the gold standard for diagnosis. This study presents data on clinical certainty ratings in autopsy-proven PD.

Methods: Subjects were assessed annually by a movement disorders specialist and assigned to a clinical certainty group for PD based on multiple clinical features before autopsy. The three groups considered for analysis are as follows: Group I 0-49% certainty, Group II 50-89% certainty, and Group III 90-100% certainty. All subjects were autopsied and had a standardized neuropathological assessment.

Results: 275 subjects were assigned a PD certainty at their last visit before death. Group I had 80 subjects, Group II 56 subjects, and Group III 139 subjects. The clinical features recorded in Group I, II, and III, were as follows: rest tremor, bradykinesia, rigidity, postural instability, asymmetric onset, persistent asymmetry, current response to dopaminergic treatment, motor fluctuations, and dyskinesia. Rigidity, postural instability, asymmetric onset, current response to dopaminergic treatment, motor fluctuation, and dyskinesia were more likely to be present in the group which was rated with higher certainty. The final diagnosis of PD was confirmed by neuropathological assessment in 85% of the patients in Group III as compared to 30% in Group II and 5% in Group I.

Conclusions: High certainty (90-100%) had strong positive predictive value (85%) for autopsy-proven PD as compared to either lower certainty groups (0-49% and 50-89%) which had lower predictive value (5% and 30% respectively).
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http://dx.doi.org/10.1002/mdc3.12589DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6174514PMC
February 2018

Lewy body pathology in Alzheimer's disease: A clinicopathological prospective study.

Acta Neurol Scand 2019 Jan 7;139(1):76-81. Epub 2018 Oct 7.

Department of Neurology, Mayo Clinic College of Medicine, Scottsdale, Arizona.

Objective: Identify clinical features predictive of Lewy body pathology in Alzheimer's disease (AD) patients in an ongoing longitudinal clinicopathologic study.

Material And Methods: We queried the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND) database for dementia cases with AD pathology (1997-2015). Subjects received longitudinal comprehensive clinical evaluations including motor/neuropsychological assessment and Apo-E4 genotyping. All cases were autopsied and had standard neuropathological assessments for AD and Lewy-type synucleinopathy (LTS). Subjects were categorized based on standardized pathological criteria with AD cases that had LTS but did not meet DLB pathologic criteria being categorized as ADLB. We performed pairwise comparison between the different diagnoses and multivariable modelling to identify clinical symptoms that predict the pathological diagnosis.

Results: We identified 32 DLB/AD, 54 ADLB, 70 AD only and 41 PDD/AD cases. AD subjects with LTS pathology had higher UPDRS II and III total scores as well as generally higher individual scores compared to AD alone. While depression scales and Trail-making Test A correlated significantly with LTS, other neuropsychological variables were not significantly different. Apo E4 occurrence was similar in all groups (40%-49%).

Conclusions: Our study suggests that the presence (or absence) of LTS influences motor and non-motor clinical findings in AD patients. These findings may lead to biomarkers that allow for more targeted treatment of AD.
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http://dx.doi.org/10.1111/ane.13028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6634943PMC
January 2019

Impaired hepatic amyloid-beta degradation in Alzheimer's disease.

PLoS One 2018 7;13(9):e0203659. Epub 2018 Sep 7.

Banner Sun Health Research Institute, Sun City, AZ, United States of America.

Extensive research strongly suggests that amyloid beta (Aβ) aggregates in the brain have a central role in Alzheimer's disease (AD) pathogenesis. Pathological Aβ deposition is likely due to an altered balance between overproduction and elimination. Rodent studies have suggested that the liver has a major role in Aβ degradation. It is possible alterations of liver function could affect brain Aβ levels through changes in blood Aβ concentration. In this study, we hypothesized hepatic Aβ degradation to be impaired in AD subjects. To test our hypothesis, an Aβ degradation assay was developed using synthetic fluorescein-labeled Aβ40 and Aβ42 spiked into human liver homogenates. Aβ degradation rates were lower in AD-derived homogenates as compared with those from non-demented (ND) control subjects, even after accounting for such covariates as age, sex, and APOE genotype. The protein expression of potential Aβ-degrading enzymes were also examined. Neprilysin levels were not different in AD liver samples, while cathepsin D and insulin-degrading enzyme were significantly altered in AD subjects. The results support the possibility that impaired hepatic Aβ degradation could be a factor contributing to increased brain Aβ accumulation and AD.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0203659PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6128628PMC
February 2019

Impact of the Presence of Select Cardiovascular Risk Factors on Cognitive Changes among Dementia Subtypes.

Curr Alzheimer Res 2018 ;15(11):1032-1044

W.P. Carey School of Business, Arizona State University, Tempe, AZ, United States.

Background: Studies have shown select associations between cardiovascular risk factors and dementia, but mostly focused on Alzheimer's Disease (AD).

Objective: We enhance these works by evaluating the relationship between the presence of cardiovascular risk factors and the rate of cognitive decline, measured using the Mini-Mental State Examination (MMSE) and Clinical Dementia Rating Sum of Boxes (CDR-SUM) on four common dementia subtypes (AD, dementia with Lewy bodies (DLB), frontotemporal dementia (FTD), and vascular dementia (VaD), as well as non-demented elderly individuals (normal)).

Method: We used generalized linear mixed models with random intercepts to account for correlation at the patient and center levels for each dementia subtype adjusting for time since initial visit, baseline cognitive score, age, and demographic factors. The cardiovascular risk factors evaluated included body mass index, diabetes, years of smoking, atrial fibrillation, hypertension, and hypercholesterolemia.

Results: Patients diagnosed with AD (n=1899), DLB (n=65), FTD (n=168), or VaD (n=13); or lacked cognitive impairment (normal) (n=3583) were evaluated using data from the National Alzheimer's Coordinating Centers. Cardiovascular risk factors were associated with select dementia subtypes including AD and FTD. Using MMSE and CDR-SUM, recent or active hypertension and hypercholesterolemia were associated with a slower cognitive decline for AD patients, while higher body mass index and years of smoking were associated with a slower cognitive decline for FTD patients. However, several cardiovascular factors demonstrated associations with more rapid cognitive decline.

Conclusion: These results demonstrate disease specific associations and can provide clinicians guidance on predicted cognitive changes at the group level using information about cardiovascular risk factors.
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http://dx.doi.org/10.2174/1567205015666180702105119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6162109PMC
October 2019

Predicting alpha-synuclein pathology by REM sleep behavior disorder diagnosis.

Parkinsonism Relat Disord 2018 10 17;55:92-96. Epub 2018 May 17.

Civin Laboratory for Neuropathology, Banner Sun Health Research Institute, Sun City, AZ, United States.

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 < 0.001). Overall sensitivity for predicting LTS by PRBD diagnosis was 28.8%, specificity 93.5%, positive predictive value (PPV) 79.2%, negative predictive value (NPV) 60.5%. Diagnosis of PRBD was less frequently present in subjects without LTS [4/105 (3.8%) of healthy controls, 42/255 (16.5%) AD, 2/33 (6.1%) progressive supranuclear palsy (PSP) without LTS] than in subjects with LTS [11/46 (23.9%) DLB, 58/104 (55.8%) PD, and 4/16 (25.0%) PSP with LTS.] PRBD was not present in any of 46 subjects with incidental Lewy body disease (ILBD). MSQ-supported diagnosis of PRBD appears useful for predicting LTS in manifest neurodegenerative disease, but not necessarily ILBD. Additional prospective autopsy research, including well-characterized polysomnogram-confirmed RBD subjects, is needed to elucidate the earliest tissue abnormalities in the "idiopathic" (premotor/pre-dementia) stage of RBD.
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http://dx.doi.org/10.1016/j.parkreldis.2018.05.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7850633PMC
October 2018

A novel vector for transgenesis in the rat CNS.

Acta Neuropathol Commun 2017 Nov 21;5(1):84. Epub 2017 Nov 21.

Institute for Neurodegenerative Diseases, Weill Institute for Neurosciences, University of California, San Francisco, Sandler Neurosciences Center, 675 Nelson Rising Lane, San Francisco, CA, 94158, USA.

The larger brain of the rat enables a much greater repertoire of complex behaviors than mice, likely making rats preferential for investigating neurodegeneration. Because molecular tools for specific expression of transgenes in the rat brain are sparse, we chose Prnp encoding the prion protein (PrP) to develop a novel vector to drive transgene expression in the rat brain. We compared the rat Prnp sequence with mouse and Syrian hamster Prnp sequences, identifying conserved genetic elements and hypothesizing that these elements would be able to drive neuronal transgene expression. We investigated this by generating a vector termed RaPrnp that encompasses portions of the rat Prnp gene. Importantly, we replaced the rat Prnp open reading frame (ORF) with a cloning site for rapid and seamless In-Fusion cloning. To validate the in vivo neuronal specificity of the RaPrnp vector in rats, we generated stable RaPrnp-LacZ/enhanced green fluorescent protein (EGFP) transgenic (Tg) rat lines, which led to robust LacZ activity and high EGFP fluorescence in the central nervous system of embryos and adult animals. Next, we restored the rat Prnp ORF and generated multiple Tg(RaPrnp-PrP) lines, demonstrating that overexpression of Prnp accelerates the onset of scrapie. While the incubation time in wild-type (WT) rats was 175 ± 3 days post inoculation (dpi), one line, Tg2919, overexpressed RaPrP at 4.4-fold and exhibited a reduced incubation time of 149 ± 2 dpi. The second line, Tg2922, overexpressed RaPrP at 9.7-fold compared with WT animals and had an incubation time of 112 ± 0 dpi. Tg2922 rats inoculated with rat RML showed extensive vacuolation of the brainstem in contrast to WT and Tg2919 animals in which vacuolation was most prominent in the hippocampus and striatum as well as the motor and sensory cortices. It is possible that construction of Tg rats with modified phenotypes will prove more advantageous than mice for neurodegeneration studies.
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http://dx.doi.org/10.1186/s40478-017-0484-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5697436PMC
November 2017

Improved diagnosis of Parkinson's disease from a detailed olfactory phenotype.

Ann Clin Transl Neurol 2017 10 8;4(10):714-721. Epub 2017 Sep 8.

Banner Sun Health Research Institute Phoenix Arizona.

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.
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http://dx.doi.org/10.1002/acn3.447DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5634345PMC
October 2017

The Impact of Aging on Brain Pituitary Adenylate Cyclase Activating Polypeptide, Pathology and Cognition in Mice and Rhesus Macaques.

Front Aging Neurosci 2017 12;9:180. Epub 2017 Jun 12.

Department of Neurology, Barrow Neurological Institute, St. Joseph's Hospital and Medical CenterPhoenix, AZ, United States.

Pituitary adenylate cyclase activating polypeptide (PACAP) is associated with Alzheimer's disease (AD), but its age-related effects are unknown. We chose the rhesus macaque due to its closeness to human anatomy and physiology. We examined four variables: aging, cognitive performance, amyloid plaques and PACAP. Delayed nonmatching-to-sample recognition memory scores declined with age and correlated with PACAP levels in the striatum, parietal and temporal lobes. Because amyloid plaques were the only AD pathology in the old rhesus macaque, we further studied human amyloid precursor protein (hAPP) transgenic mice. Aging was associated with decreased performance in the Morris Water Maze (MWM). In wild type (WT) C57BL/6 mice, the performance was decreased at age 24-26 month whereas in hAPP transgenic mice, it was decreased as early as 9-12 month. Neuritic plaques in adult hAPP mice clustered in hippocampus and adjacent cortical regions, but did not propagate further into the frontal cortex. Cerebral PACAP protein levels were reduced in hAPP mice compared to age-matched WT mice, but the genetic predisposition dominated cognitive decline. Taken together, these data suggest an association among PACAP levels, aging, cognitive function and amyloid load in nonhuman primates, with both similarities and differences from human AD brains. Our results suggest caution in choosing animal models and in extrapolating data to human AD studies.
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http://dx.doi.org/10.3389/fnagi.2017.00180DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5467357PMC
June 2017

Multisite Assessment of Aging-Related Tau Astrogliopathy (ARTAG).

J Neuropathol Exp Neurol 2017 Jul;76(7):605-619

Institute of Neurology, Medical University of Vienna, Vienna, Austria; Center for Neurodegenerative Disease Research, Institute on Aging and Department of Pathology and Laboratory Medicine of the Perelman School of Medicine at the University of Pennsylvania; and Department of Biostatistics and Epidemiology; and Department of Neurosurgery, Center for Brain Injury and Repair, University of Pennsylvania, Philadelphia, Pennsylvania; Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden; Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK; Department of Neuropathology, Institute of Pathology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary; Department of Neuroscience, Mayo Clinic, Jacksonville, Florida; Northwestern University Feinberg School of Medicine, Northwestern ADC Neuropathology Core, Chicago, Illinois; Clinical Neuropathology, King's College Hospital and London Neurodegenerative Brain Bank, London, UK; Institute of Neuropathology, University Hospital Zurich, Zurich, Switzerland; University of California San Francisco, Institute for Neurodegenerative Diseases, San Francisco, California; Neuropathology Department, Hôpital de La Salpetrière, AP-HP, UPMC-Sorbonne-University, Paris, France; Institute of Neuropathology, Bellvitge University Hospital, University of Barcelona, CIBERNED, Hospitalet de Llobregat, Barcelona, Spain; Discipline of Pathology, Sydney Medical School, The University of Sydney, Sydney, Australia; Neurological Tissue Bank of the Biobank-Hospital Clinic-IDIBAPS, Institut d'Investigacions Biomediques Pi i, Barcelona, Spain; Department of Medicine, Imperial College London, London, UK; IRCCS Foundation "Carlo Besta" Neurological Institute, Milan, Italy; Memory and Aging Center, Department of Neurology, University of California, San Francisco, California; Department of Pathology, University of Sao Paulo Medical School, LIM, São Paulo, Brazil; Brain & Mind Centre, Sydney Medical School, The University of Sydney, and UNSW Medicine & NeuRA, Sydney, Australia; Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas; Fishberg Department of Neuroscience, Friedman Brain Institute, and Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Neuropathology, John Radcliffe Hospital, Oxford, UK; Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK; Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Mental Health and Psychiatry, University Hospitals and University of Geneva School of Medicine, Geneva, Switzerland; Institute of Clinical Neurosciences, University of Bristol, Learning & Research Level 2, Southmead Hospital, Bristol, UK; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada; Department of Pathology and Molecular Medicine, Thomayer Hospital, Prague, Czech Republic; Department of Pathology, First Medical Faculty, Charles University, Prague, Czech Republic; Department of Anatomical Pathology, Alfred Hospital , Prahran, Victoria, Australia; Division of Pathology, St. Michael's Hospital, Toronto, Ontario, Canada; Department of Pathology and Sanders-Brown Center on Aging, University of Kentucky, Lexington, Kentucky; Physiopathology in Aging Lab/Brazilian Aging Brain Study Group-LIM22, University of Sao Paulo Medical School, Sao Paulo, Brazil; Behavioral and Cognitive Neurology Unit, Department of Neurology, University of São Paulo , São Paulo, Brazil; Netherlands Brainbank, Amsterdam and Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands; Department of Neurology and Neurobiology of Aging, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan; Institute of Neuroanatomy, Centre for Biomedicine and Medical Technology Mannheim, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany; Department of Neurodegenerative Diseases and Gerontopsychiatry at the University of Bonn Medical Center, Bonn, Germany; Department of Pathology, Brain Research Institute, Niigata University, Niigata, Japan; Department of Neurology, Saitama Medical University International Medical Center, Saitama, Japan; Department of Neuroscience, Katholieke Universiteit-Leuven; and Department of Pathology, Universitaire Ziekenhuizen-Leuven, Leuven, Belgium; Laboratory of Neuropathology, Department of Pathology and Neuropathology, Kepler University Hospital, Medical School, Johannes Kepler University, Linz, Austria; Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK; and Department of Pathology and Laboratory Medicine, Centre for Cancer Therapeutics, Ottawa Hospital Research Institute, University of Ottawa, Ontario, Canada.

Aging-related tau astrogliopathy (ARTAG) is a recently introduced terminology. To facilitate the consistent identification of ARTAG and to distinguish it from astroglial tau pathologies observed in the primary frontotemporal lobar degeneration tauopathies we evaluated how consistently neuropathologists recognize (1) different astroglial tau immunoreactivities, including those of ARTAG and those associated with primary tauopathies (Study 1); (2) ARTAG types (Study 2A); and (3) ARTAG severity (Study 2B). Microphotographs and scanned sections immunostained for phosphorylated tau (AT8) were made available for download and preview. Percentage of agreement and kappa values with 95% confidence interval (CI) were calculated for each evaluation. The overall agreement for Study 1 was >60% with a kappa value of 0.55 (95% CI 0.433-0.645). Moderate agreement (>90%, kappa 0.48, 95% CI 0.457-0.900) was reached in Study 2A for the identification of ARTAG pathology for each ARTAG subtype (kappa 0.37-0.72), whereas fair agreement (kappa 0.40, 95% CI 0.341-0.445) was reached for the evaluation of ARTAG severity. The overall assessment of ARTAG showed moderate agreement (kappa 0.60, 95% CI 0.534-0.653) among raters. Our study supports the application of the current harmonized evaluation strategy for ARTAG with a slight modification of the evaluation of its severity.
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http://dx.doi.org/10.1093/jnen/nlx041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6251511PMC
July 2017

Neurodegenerative Disease Transmission and Transgenesis in Mice.

Cold Spring Harb Perspect Biol 2017 Nov 1;9(11). Epub 2017 Nov 1.

Institute for Neurodegenerative Diseases, Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, California 94158.

Although the discovery of the prion protein (PrP) resulted from its co-purification with scrapie infectivity in Syrian hamsters, work with genetically defined and genetically modified mice proved crucial for understanding the fundamental processes involved not only in prion diseases caused by PrP misfolding, aggregation, and spread but also in other, much more common, neurodegenerative brain diseases. In this review, we focus on methodological and conceptual approaches used to study scrapie and related PrP misfolding diseases in mice and how these approaches have advanced our understanding of related disorders including Alzheimer's and Parkinson's disease.
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http://dx.doi.org/10.1101/cshperspect.a023549DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5666636PMC
November 2017

Pathology of Neurodegenerative Diseases.

Cold Spring Harb Perspect Biol 2017 Jul 5;9(7). Epub 2017 Jul 5.

Mayo Clinic, Jacksonville, Florida 32224.

Neurodegenerative disorders are characterized by progressive loss of selectively vulnerable populations of neurons, which contrasts with select static neuronal loss because of metabolic or toxic disorders. Neurodegenerative diseases can be classified according to primary clinical features (e.g., dementia, parkinsonism, or motor neuron disease), anatomic distribution of neurodegeneration (e.g., frontotemporal degenerations, extrapyramidal disorders, or spinocerebellar degenerations), or principal molecular abnormality. The most common neurodegenerative disorders are amyloidoses, tauopathies, α-synucleinopathies, and TDP-43 proteinopathies. The protein abnormalities in these disorders have abnormal conformational properties. Growing experimental evidence suggests that abnormal protein conformers may spread from cell to cell along anatomically connected pathways, which may in part explain the specific anatomical patterns observed at autopsy. In this review, we detail the human pathology of select neurodegenerative disorders, focusing on their main protein aggregates.
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http://dx.doi.org/10.1101/cshperspect.a028035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5495060PMC
July 2017

Guinea Pig Prion Protein Supports Rapid Propagation of Bovine Spongiform Encephalopathy and Variant Creutzfeldt-Jakob Disease Prions.

J Virol 2016 11 14;90(21):9558-9569. Epub 2016 Oct 14.

Institute for Neurodegenerative Diseases, University of California, San Francisco, San Francisco, California, USA Department of Neurology, University of California, San Francisco, San Francisco, California, USA Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, California, USA

The biochemical and neuropathological properties of bovine spongiform encephalopathy (BSE) and variant Creutzfeldt-Jakob disease (vCJD) prions are faithfully maintained upon transmission to guinea pigs. However, primary and secondary transmissions of BSE and vCJD in guinea pigs result in long incubation periods of ∼450 and ∼350 days, respectively. To determine if the incubation periods of BSE and vCJD prions could be shortened, we generated transgenic (Tg) mice expressing guinea pig prion protein (GPPrP). Inoculation of Tg(GPPrP) mice with BSE and vCJD prions resulted in mean incubation periods of 210 and 199 days, respectively, which shortened to 137 and 122 days upon serial transmission. In contrast, three different isolates of sporadic CJD prions failed to transmit disease to Tg(GPPrP) mice. Many of the strain-specified biochemical and neuropathological properties of BSE and vCJD prions, including the presence of type 2 protease-resistant PrP, were preserved upon propagation in Tg(GPPrP) mice. Structural modeling revealed that two residues near the N-terminal region of α-helix 1 in GPPrP might mediate its susceptibility to BSE and vCJD prions. Our results demonstrate that expression of GPPrP in Tg mice supports the rapid propagation of BSE and vCJD prions and suggest that Tg(GPPrP) mice may serve as a useful paradigm for bioassaying these prion isolates.

Importance: Variant Creutzfeldt-Jakob disease (vCJD) and bovine spongiform encephalopathy (BSE) prions are two of the prion strains most relevant to human health. However, propagating these strains in mice expressing human or bovine prion protein has been difficult because of prolonged incubation periods or inefficient transmission. Here, we show that transgenic mice expressing guinea pig prion protein are fully susceptible to vCJD and BSE prions but not to sporadic CJD prions. Our results suggest that the guinea pig prion protein is a better, more rapid substrate than either bovine or human prion protein for propagating BSE and vCJD prions.
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http://dx.doi.org/10.1128/JVI.01106-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5068510PMC
November 2016

Optimization of Aryl Amides that Extend Survival in Prion-Infected Mice.

J Pharmacol Exp Ther 2016 09 17;358(3):537-47. Epub 2016 Jun 17.

Institute for Neurodegenerative Diseases (K.G., D.B.B., C.C., B.N.D., Z.L., A.O., S.B., M.E., S.G., B.M.S., S.H.O., S.B.P.) and Departments of Neurology (K.G., C.C., B.N.D., Z.L., B.M.S., S.H.O., S.B.P.), Pharmaceutical Chemistry (S.G.), Bioengineering and Therapeutic Sciences (B.M.S.), and Biochemistry and Biophysics (S.B.P.), University of California, San Francisco, California

Developing therapeutics for neurodegenerative diseases (NDs) prevalent in the aging population remains a daunting challenge. With the growing understanding that many NDs progress by conformational self-templating of specific proteins, the prototypical prion diseases offer a platform for ND drug discovery. We evaluated high-throughput screening hits with the aryl amide scaffold and explored the structure-activity relationships around three series differing in their N-aryl core: benzoxazole, benzothiazole, and cyano. Potent anti-prion compounds were advanced to pharmacokinetic studies, and the resulting brain-penetrant leads from each series, together with a related N-aryl piperazine lead, were escalated to long-term dosing and efficacy studies. Compounds from each of the four series doubled the survival of mice infected with a mouse-passaged prion strain. Treatment with aryl amides altered prion strain properties, as evidenced by the distinct patterns of neuropathological deposition of prion protein and associated astrocytic gliosis in the brain; however, none of the aryl amide compounds resulted in drug-resistant prion strains, in contrast to previous studies on compounds with the 2-aminothiazole (2-AMT) scaffold. As seen with 2-AMTs and other effective anti-prion compounds reported to date, the novel aryl amides reported here were ineffective in prolonging the survival of transgenic mice infected with human prions. Most encouraging is our discovery that aryl amides show that the development of drug resistance is not an inevitable consequence of efficacious anti-prion therapeutics.
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http://dx.doi.org/10.1124/jpet.116.235556DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4998675PMC
September 2016

Graph theory network function in Parkinson's disease assessed with electroencephalography.

Clin Neurophysiol 2016 May 4;127(5):2228-36. Epub 2016 Mar 4.

Department of Neurology, Mayo Clinic, Scottsdale, AZ, USA.

Objectives: To determine what differences exist in graph theory network measures derived from electroencephalography (EEG), between Parkinson's disease (PD) patients who are cognitively normal (PD-CN) and matched healthy controls; and between PD-CN and PD dementia (PD-D).

Methods: EEG recordings were analyzed via graph theory network analysis to quantify changes in global efficiency and local integration. This included minimal spanning tree analysis. T-tests and correlations were used to assess differences between groups and assess the relationship with cognitive performance.

Results: Network measures showed increased local integration across all frequency bands between control and PD-CN; in contrast, decreased local integration occurred in PD-D when compared to PD-CN in the alpha1 frequency band. Differences found in PD-MCI mirrored PD-D. Correlations were found between network measures and assessments of global cognitive performance in PD.

Conclusions: Our results reveal distinct patterns of band and network measure type alteration and breakdown for PD, as well as with cognitive decline in PD.

Significance: These patterns suggest specific ways that interaction between cortical areas becomes abnormal and contributes to PD symptoms at various stages. Graph theory analysis by EEG suggests that network alteration and breakdown are robust attributes of PD cortical dysfunction pathophysiology.
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http://dx.doi.org/10.1016/j.clinph.2016.02.017DOI Listing
May 2016

The Presence of Select Tau Species in Human Peripheral Tissues and Their Relation to Alzheimer's Disease.

J Alzheimers Dis 2016 ;51(2):345-56

Banner Sun Health Research Institute, Sun City, AZ, USA.

Tau becomes excessively phosphorylated in Alzheimer's disease (AD) and is widely studied within the brain. Further examination of the extent and types of tau present in peripheral tissues and their relation to AD is warranted given recent publications on pathologic spreading. Cases were selected based on the presence of pathological tau spinal cord deposits (n = 18). Tissue samples from sigmoid colon, scalp, abdominal skin, liver, and submandibular gland were analyzed by western blot and enzyme-linked immunosorbent assays (ELISAs) for certain tau species; frontal cortex gray matter was used for comparison. ELISAs revealed brain to have the highest total tau levels, followed by submandibular gland, sigmoid colon, liver, scalp, and abdominal skin. Western blots with antibodies recognizing tau phosphorylated at threonine 231(pT231), serine 396 and 404 (PHF-1), and an unmodified total human tau between residues 159 and 163 (HT7) revealed multiple banding patterns, some of which predominated in peripheral tissues. As submandibular gland had the highest levels of peripheral tau, a second set of submandibular gland samples were analyzed (n = 36; 19 AD, 17 non-demented controls). ELISAs revealed significantly lower levels of pS396 (p = 0.009) and pT231 (p = 0.005) in AD cases but not total tau (p = 0.18). Furthermore, pT231 levels in submandibular gland inversely correlated with Braak neurofibrillary tangle stage (p = 0.04), after adjusting for age at death, gender, and postmortem interval. These results provide evidence that certain tau species are present in peripheral tissues. Of potential importance, submandibular gland pT231 is progressively less abundant with increasing Braak neurofibrillary tangle stage.
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http://dx.doi.org/10.3233/JAD-150859DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6074044PMC
December 2016

Peripheral Synucleinopathy in Early Parkinson's Disease: Submandibular Gland Needle Biopsy Findings.

Mov Disord 2016 Feb 22;31(2):250-6. Epub 2016 Jan 22.

Banner Sun Health Research Institute, Sun City, Arizona, USA.

Introduction: Finding 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.

Methods: Twenty-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.

Results: Mean (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.

Conclusions: Submandibular 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.
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http://dx.doi.org/10.1002/mds.26476DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4747813PMC
February 2016

Prevalence of Submandibular Gland Synucleinopathy in Parkinson's Disease, Dementia with Lewy Bodies and other Lewy Body Disorders.

J Parkinsons Dis 2016 ;6(1):153-63

Barrow Neurological Institute, Phoenix, AZ, USA.

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.
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http://dx.doi.org/10.3233/JPD-150680DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5498170PMC
January 2017

A Cross-Sectional Analysis of Late-Life Cardiovascular Factors and Their Relation to Clinically Defined Neurodegenerative Diseases.

Alzheimer Dis Assoc Disord 2016 Jul-Sep;30(3):223-9

*Banner Sun Health Research Institute, Sun City ‡Mayo Clinic, Scottsdale §Banner Alzheimer's Institute, Phoenix ∥Arizona State University, Tempe, AZ †National Alzheimer's Coordinating Center, University of Washington, Seattle, WA.

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.
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http://dx.doi.org/10.1097/WAD.0000000000000138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4940303PMC
November 2017

Aging-related tau astrogliopathy (ARTAG): harmonized evaluation strategy.

Acta Neuropathol 2016 Jan 10;131(1):87-102. Epub 2015 Dec 10.

Department of Medicine, Imperial College London, London, UK.

Pathological accumulation of abnormally phosphorylated tau protein in astrocytes is a frequent, but poorly characterized feature of the aging brain. Its etiology is uncertain, but its presence is sufficiently ubiquitous to merit further characterization and classification, which may stimulate clinicopathological studies and research into its pathobiology. This paper aims to harmonize evaluation and nomenclature of aging-related tau astrogliopathy (ARTAG), a term that refers to a morphological spectrum of astroglial pathology detected by tau immunohistochemistry, especially with phosphorylation-dependent and 4R isoform-specific antibodies. ARTAG occurs mainly, but not exclusively, in individuals over 60 years of age. Tau-immunoreactive astrocytes in ARTAG include thorn-shaped astrocytes at the glia limitans and in white matter, as well as solitary or clustered astrocytes with perinuclear cytoplasmic tau immunoreactivity that extends into the astroglial processes as fine fibrillar or granular immunopositivity, typically in gray matter. Various forms of ARTAG may coexist in the same brain and might reflect different pathogenic processes. Based on morphology and anatomical distribution, ARTAG can be distinguished from primary tauopathies, but may be concurrent with primary tauopathies or other disorders. We recommend four steps for evaluation of ARTAG: (1) identification of five types based on the location of either morphologies of tau astrogliopathy: subpial, subependymal, perivascular, white matter, gray matter; (2) documentation of the regional involvement: medial temporal lobe, lobar (frontal, parietal, occipital, lateral temporal), subcortical, brainstem; (3) documentation of the severity of tau astrogliopathy; and (4) description of subregional involvement. Some types of ARTAG may underlie neurological symptoms; however, the clinical significance of ARTAG is currently uncertain and awaits further studies. The goal of this proposal is to raise awareness of astroglial tau pathology in the aged brain, facilitating communication among neuropathologists and researchers, and informing interpretation of clinical biomarkers and imaging studies that focus on tau-related indicators.
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http://dx.doi.org/10.1007/s00401-015-1509-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4879001PMC
January 2016