Background

Cognitive dysfunction is common in progressive supranuclear palsy, but the influence of genetics on cognition in this disorder has not been well studied. The objective of this study was to investigate the effect of genes previously identified as risk alleles, including microtubule-associated protein tau, myelin-associated oligodendrocyte basic protein, eukaryotic translation initiation factor 2-alpha kinase 3, and syntaxin 6, as well as apolipoprotein E, on cognitive function in progressive supranuclear palsy.

Methods

The sample was composed of 305 participants who met criteria for possible or probable progressive supranuclear palsy. Genetic information was determined by TaqMan genotyping assays. A neuropsychological battery was administered to all study participants. Measures included in the battery evaluated for general cognition, executive function, memory, attention, language, and visuospatial ability.

Results

Cognition did not vary significantly between individuals homozygous or heterozygous for the microtubule-associated protein tau H1 haplotype. However, cognition varied significantly at the subhaplotype level, with carriers of the microtubule-associated protein tau rs242557/A allele, which marks the H1c subhaplotype, performing better than noncarriers on measures of general cognitive function, executive function, and attention. No associations were found for other genes.

Conclusions

The results of the current study indicate that variations in microtubule-associated protein tau influence cognition in progressive supranuclear palsy. Although the H1c-specific rs242557/A allele is a risk factor for progressive supranuclear palsy, carriers of this allele may exhibit better cognition than non-carriers in patients with the atypical parkinsonian syndrome. Further studies are needed. © 2017 International Parkinson and Movement Disorder Society.

Introduction

Statins were proposed to be neuroprotective; however, the effects are unknown in progressive supranuclear palsy (PSP), a pure tauopathy.

Methods

Data of 284 PSP cases and 284 age-matched, sex-matched, and race-matched controls were obtained from the environmental and genetic PSP (ENGENE-PSP) study. Cases were evaluated with the PSP Rating Scale, Unified Parkinson's Disease Rating Scale, Mattis Dementia Rating Scale, and Neuropsychiatric Inventory. Statin associations with PSP risk, onset age, and disease features were analyzed.

Results

Univariate models showed lower PSP risk for type 1 statin users (simvastatin, lovastatin, pravastatin). After adjusting for confounding variables, statin use and lower PSP risk association remained only at a trend level. For PSP cases, type 1 statins were associated with 1-year older onset age; type 2 statins (atorvastatin, rosuvastatin) were associated with the lower PSP Rating Scale and Unified Parkinson's Disease Rating Scale.

Conclusion

Statins may have inverse associations with PSP risk and motor impairment. Randomized prospective studies are required to confirm this effect. © 2020 International Parkinson and Movement Disorder Society.

Introduction

The pathophysiology of both PD and PSP is characterized by a pro-oxidant state. Uric acid is an oxidative stress marker. High uric acid blood levels have been associated with a reduced risk of PD and a decreased rate of disease progression. We investigated whether a low serum concentration of uric acid is also associated with PSP.

Methods

We measured serum uric acid concentrations in a subsample of the ENGENE PSP Cohort that included 75 cases and 75 frequency-matched-by-sex healthy controls (69 spouses, 6 in-laws) from four centers willing to participate (Case Western, Rush University, University of Utah, and University of Louisville). Case severity was characterized using the total PSP-Rating Scale, UPDRS, and Mattis Dementia Rating Scale. Unconditional logistic regression, Pearson's chi-squared test, and analysis of variance were used, as appropriate.

Results

The mean uric acid level among cases (4.0 mg/dL) was not significantly lower than that of controls (4.1 mg/dL). When controlling for sex, there were no between-group statistical differences in uric acid levels. Uric acid levels were not correlated with disease severity.

Conclusions

The results of this study do not provide evidence of uric acid having a protective role in PSP, even if oxidative injury is important in the pathophysiology of this disorder. The lack of statistical significance suggests that there is no direct association between uric acid levels and PSP. However, a small inverse association cannot be excluded. © 2016 Movement Disorder Society.

Introduction

Freezing of gait (FoG) leads to falls and reduces quality of life, but little is known about FoG in progressive supranuclear palsy (PSP). This study aim was to identify the clinical parameters associated with FoG in PSP patients.

Methods

349 patients meeting the National Institute for Neurological Disorders and Society for PSP (NINDS-SPSP) clinical diagnostic criteria were divided into two groups: PSP with FoG (n = 159) and PSP without FoG (n = 190). To determine if FoG in PSP associates with demographics, motor performance, visual difficulties, and executive function, we used the Frontal Assessment Battery (FAB), Mattis Dementia Rating Scale (DRS), Unified Parkinson's Disease Rating Scale (UPDRS), PSP Rating Scale (PSPRS), Modified Hoehn & Yahr staging, and Schwab and England Activities Daily Living (S&EADL) scale. UPDRS was used to identify FoG. Individual items of each clinical assessment with p-value < 0.05 in the univariate logistic regression analyses were included in the backward stepwise multivariate regression analysis.

Results

Both groups were similar in demographics. 45.6% of patients had FoG, which was present at onset and increased with disease duration. There were no between-group significant associations between FoG and visual disturbances, executive function and overall cognition, but on univariate analyses, FoG was significantly associated with bradykinesia, rigidity, gait, and posture. In the multivariate model FoG was associated with disease duration and speech.

Conclusions

Our findings indicate that disease duration and speech have the most significant association with FoG. These findings may suggest that FoG and speech difficulties in PSP share a similar pathophysiology.

Background

Anti-inflammatory drug use, particularly ibuprofen, has been associated with a lower risk of Parkinson's disease. Microglial activation and inflammatory cytokine expression have been shown to be pathological features of progressive supranuclear palsy. We examined the association between NSAID use and risk of PSP, disease severity and age at onset.

Methods

The ENGENE-PSP multicenter case-control study recruited incident PSP cases who met the NINDS-PSP Society diagnostic criteria and age-, sex- and race-matched controls primarily from the same geographical areas. All subjects underwent standardized interviews to obtain data on demographics, residential history, medication history and lifetime occupational history. NSAID use was specifically queried by telephone interview using a standardized questionnaire.

Results

Information was obtained on anti-inflammatory drug exposure in 276 cases and 278 controls. No association was found between NSAID exposure and risk of PSP, age at onset or rate of change of UPDRS motor subscale, PSP Rating Scale or Mattis Dementia Rating Scale scores. This lack of association persisted when NSAID exposure was measured considering any NSAIDs, ibuprofen only, ASA only or non-ibuprofen, non-aspirin NSAIDs.

Conclusions

These results do not suggest an important association between NSAID use and PSP occurrence or expression. Despite the large size of our study, confidence intervals were wide. To rule out small associations, very large sample sizes will be required.

BACKGROUND:Studies suggesting a protective effect of estrogen in neurodegenerative diseases prompted us to investigate this relationship in progressive supranuclear palsy (PSP). METHODS:This case-control study evaluated the self-reported reproductive characteristics and estrogen of 150 women with PSP and 150 age-matched female controls who participated in the Environmental Genetic-PSP study. Conditional logistic regression models were generated to examine associations of PSP with estrogen. RESULTS:There was no association between years of estrogen exposure duration and PSP. There was a suggestion of an inverse association between composite estrogen score and PSP that did not reach statistical significance (P = .06). Any exposure to estrogen replacement therapy halved the risk of PSP (odds ratio = 0.52; 95% confidence interval = 0.30-0.92; P = .03). Among PSP cases, earlier age at menarche was associated with better performance on Hoehn and Yahr stage (β = -0.60; SE = 0.26; P = .02) and Unified Parkinson's Disease Rating Scale II score (β = -5.19; SE = 2.48; P = .04) at clinical examination. CONCLUSIONS:This case-control study suggests a protective role of lifetime estrogen exposure in PSP. Future studies will be needed to confirm this association. © 2018 International Parkinson and Movement Disorder Society.

Background

The cause of progressive supranuclear palsy (PSP) is largely unknown. Based on evidence for impaired mitochondrial activity in PSP, we hypothesized that the disease may be related to exposure to environmental toxins, some of which are mitochondrial inhibitors.

Methods

This multicenter case-control study included 284 incident PSP cases of 350 cases and 284 age-, sex-, and race-matched controls primarily from the same geographical areas. All subjects were administered standardized interviews to obtain data on demographics, residential history, and lifetime occupational history. An industrial hygienist and a toxicologist unaware of case status assessed occupational histories to estimate past exposure to metals, pesticides, organic solvents, and other chemicals.

Results

Cases and controls were similar on demographic factors. In unadjusted analyses, PSP was associated with lower education, lower income, more smoking pack-years, more years of drinking well water, more years living on a farm, more years living 1 mile from an agricultural region, more transportation jobs, and more jobs with exposure to metals in general. However, in adjusted models, only more years of drinking well water was significantly associated with PSP. There was an inverse association with having a college degree.

Conclusions

We did not find evidence for a specific causative chemical exposure; higher number of years of drinking well water is a risk factor for PSP. This result remained significant after adjusting for income, smoking, education and occupational exposures. This is the first case-control study to demonstrate PSP is associated with environmental factors. © 2016 International Parkinson and Movement Disorder Society.

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.

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.