Ahlskog, J. Eric

AbstractProgressive supranuclear palsy with predominant cerebellar ataxia (PSP-C) has been reported as a rare clinical subtype, but the underlying pathology of its cerebellar ataxia remains unclear. Here, we report a patient with the coexistence of PSP with pontocerebellar atrophy and myotonic dystrophy type 1 (DM1). A 73-year-old man who was an asymptomatic carrier of DM1 (66 CTG repeats) started developing ataxic gait with multiple falls, visual blurring, double vision, and word finding difficulty at age 62 and was initially diagnosed with multiple system atrophy (MSA). Subsequently, the diagnosis was changed to PSP due to hypometric downward gaze, reduced blink frequency, symmetric bradykinesia, rigidity, and the absence of autonomic dysfunction. He eventually developed delayed grip opening with percussion myotonia at age 72. At autopsy, severe neuronal degeneration and astrogliosis in the pontocerebellar structures suggested MSA, but immunohistochemistry for α-synuclein did not reveal neuronal or glial cytoplasmic inclusions. Immunohistochemistry for phospho-tau and 4-repeat tau confirmed a neuropathological diagnosis of PSP with exceptionally numerous coiled bodies and threads in the pontine base and cerebellar white matter. This unusual distribution of 4-repeat tau pathology and neuronal degeneration with astrogliosis is a plausible clinicopathological substrate of PSP-C.

Objective. Autonomic symptoms are common in α-synuclein disorders: multiple system atrophy (MSA), Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and Parkinson’s disease with dementia (PDD). These symptoms may precede the motor findings/clinical diagnosis by years. Erectile dysfunction (ED) is an autonomic symptom that has rarely been studied in these α-synuclein disorders. In this population-based, case-control study, we investigated the association between premonitory erectile dysfunction surfacing prior to the clinical-motor manifestations of these α-synucleinopathies. Methods. We used the medical record-linkage system of the Rochester Epidemiology Project to identify cases of α-synucleinopathies in Olmsted County from 1991 to 2010. Each male case was matched by age (±1 year) of symptom onset and sex to a control. We reviewed complete medical records of cases and controls to detect erectile dysfunction prior to the clinical-motor onset of α-synucleinopathies of any type. We used conditional logistic regression to calculate the odds ratio of all α-synucleinopathies, as well as by type, adjusting for diabetes, coffee, and smoking. Results. A history of male erectile dysfunction was associated with 1.5-fold increased odds of an α-synucleinopathy diagnosis of any type in univariate analyses (p=0.06). When stratifying α-synucleinopathies by type, early erectile dysfunction was most frequent in MSA cases than matched controls (45% vs. 9%). Premotor phase ED was next most frequent among the DLB cases (46% vs. 27% among the controls; OR = 2.83, p=0.03; when adjusted for diabetes, smoking, and coffee, OR = 2.98, p=0.04). Premotor phase ED was not significantly associated with PD or PDD. Conclusions. Early erectile dysfunction may be a premotor symptom of MSA and DLB, reflecting premonitory dysautonomia. It was not associated with premotor PD or PDD.

Abstract Background In 2017, the International Parkinson and Movement Disorder Society put forward new clinical criteria for the diagnosis of PSP, recognizing diverse PSP phenotypes. In this study, we compared the sensitivity and specificity of the new criteria with the National Institutes of Neurological Disease and Society for Progressive Supranuclear Palsy criteria at different times. Methods Patients with clinical parkinsonism, clinical and/or neuropathological diagnosis of PSP, were identified from the Society for Progressive Supranuclear Palsy brain bank. All patients had neuropathologic diagnoses and detailed clinical examination performed by a neurologist at 1 of the 3 Mayo Clinic sites, in Florida, Arizona, and Minnesota. Clinical symptoms and signs were abstracted retrospectively in a blinded fashion and used to determine whether patients met either diagnostic criterion. Patients were divided into early and late disease stage groups using a 3‐year cutoff. Results A total of 129 patients were included, of whom 66 had PSP pathology (51%). The remainder had other neurodegenerative diseases. The overall sensitivity of the International Parkinson and Movement Disorder Society criteria was 87.9%, compared with 45.5% for the National Institutes of Neurological Disease and Society for Progressive Supranuclear Palsy criteria, whereas the specificity of the International Parkinson and Movement Disorder Society probable PSP criteria was 85.7%, compared with 90.5% for the National Institutes of Neurological Disease and Society for Progressive Supranuclear Palsy. Individual patients were noted to have features of multiple PSP phenotypes. Conclusion The International Parkinson and Movement Disorder Society criteria recognize several phenotypes of progressive supranuclear palsy and hence have higher sensitivity than the previous criteria. © 2019 International Parkinson and Movement Disorder Society

AbstractBackgroundElevated uptake of the [18F]AV‐1451 tau‐PET ligand has been observed cross‐sectionally in subjects with progressive supranuclear palsy (PSP). However, it is unknown how the ligand performs longitudinally in PSP. We aimed to determine how regional measures of change on [18F]AV‐1451 PET perform as longitudinal biomarkers of PSP compared with the more established biomarker of rate of midbrain atrophy.MethodsSixteen subjects with PSP underwent 2 serial [18F]AV‐1451 tau‐PET scans and 3‐Tesla MRI over 12 months and were age‐ and sex‐matched to 39 healthy controls with longitudinal [18F]AV‐1451 PET. Median [18F]AV‐1451 uptake was calculated for each scan for regions of interest across the brain and divided by uptake in cerebellar crus to create standard uptake value ratios. Midbrain volume on MRI was also calculated for each scan. Sample sizes required to power placebo‐controlled treatment trials were calculated.ResultsRate of midbrain atrophy was significantly increased in PSP compared with controls. [18F]AV‐1451 regional change measures were significantly increased in PSP compared with controls in the pallidum, precentral cortex, dentate nucleus of the cerebellum, and midbrain. Change over time in the PSP Rating Scale correlated with change in midbrain volume but did not correlate with change in the [18F]AV‐1451 measures. Smallest sample‐size estimates were obtained with rate of midbrain atrophy, followed by the PSP Rating Scale, with both outperforming [18F]AV‐1451 measures.Conclusions[18F]AV‐1451 tau‐PET measures increase over time in subjects with PSP, but longitudinal [18F]AV‐1451 measures may not perform as well as rate of midbrain atrophy as biomarkers for PSP clinical trials. © 2018 International Parkinson and Movement Disorder Society

Abstract Background Cognitive impairment is one of the core features of progressive supranuclear palsy. This study aimed to clarify the profile of cognitive impairment and its underlying pathology in progressive supranuclear palsy. Methods We retrospectively reviewed medical records to evaluate the pattern and severity of cognitive impairment in 121 autopsy‐confirmed progressive supranuclear palsy patients. A subset of 37 patients underwent neuropsychological evaluation as part of their clinical workup. The burden of progressive supranuclear palsy‐related tau pathology (neurofibrillary tangles/pretangles, coiled bodies, tufted astrocytes, and threads) was semiquantitatively scored in 20 vulnerable brain regions. Concurrent pathologies potentially associated with cognitive impairment, such as Alzheimer's‐type pathology, were also assessed. To evaluate possible genetic risk factors for cognitive impairment, genetic analysis for APOE and MAPT was performed. Results Ninety patients (74%) had documented cognitive impairment based on neurologic evaluation. In a subgroup with neuropsychological testing (n = 37), executive functioning was the most severely impaired cognitive domain. A global cognitive impairment index (Spearman's rho, −0.49; P = 0.005) and executive functioning were negatively correlated with total tau burden (Spearman's rho, −0.51; P = 0.003), but not correlated with the Alzheimer's‐type pathology. APOE ɛ4 carriers had more severe amyloid pathology, but total tau burden and a global cognitive impairment index did not differ from APOE ɛ4 noncarriers. Conclusion Cognitive impairment in progressive supranuclear palsy, most notably executive dysfunction, is associated with severity of progressive supranuclear palsy‐related tau pathology. © 2017 International Parkinson and Movement Disorder Society

ABSTRACT Background Epidemiological studies of drug‐induced parkinsonism remain limited. Objectives To investigate the incidence and time trends of drug‐induced parkinsonism over 30 years in a geographically defined American population. Methods We used the medical records‐linkage system of the Rochester Epidemiology Project to identify all persons in Olmsted County, Minnesota, who received a screening diagnostic code for parkinsonism from 1976 through 2005. A movement disorders specialist reviewed the complete medical records of each person to confirm the presence of drug‐induced parkinsonism associated with dopamine‐blocking or dopamine‐depleting medications. Results Among 906 incident cases of parkinsonism from 1976 to 2005, 108 persons had drug‐induced parkinsonism (11.9%). The average annual incidence rate of drug‐induced parkinsonism was 3.3 per 100,000 person‐years, was higher in women, and increased with older age. Drug‐induced parkinsonism was the fifth‐most common type of parkinsonism overall; however, it was the most common type among persons younger than age 40 years. Typical antipsychotic drugs were the most common class of drugs associated with parkinsonism, whereas atypical antipsychotic drugs were rarely involved. The incidence rate of drug‐induced parkinsonism decreased 32.0% per decade (relative risk = 0.68; 95% confidence interval: 0.49–0.94) and 68.6% over the 30 years of the study. The decrease was similar in men (65.2%) and women (69.4%); however, the trend was significant only in women. Conclusions The incidence of drug‐induced parkinsonism increased with older age and was higher in women at all ages. Typical antipsychotic drugs were the most common cause. The incidence of drug‐induced parkinsonism decreased over the 30 years of the study because of changes in drug use. © 2016 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.