Shprecher, David

Abstract Purpose Compare agreements between polysomnography-based (PSG) diagnosis of isolated REM-sleep-behavior-disorder (iRBD) and Non-REM-Hypertonia (NRH), a novel biomarker independently associated with synucleinopathy-related neurodegenerative diseases. Methods Sixteen patients with histories of dream-enactment-behavior (DEB)(women=38%; age:64.6±13.0) underwent PSG with simultaneously-recorded Sleep Profiler (SP). Two boarded sleep neurologists independently characterized iRBD. Physician1 combined abnormal qualitative REM-sleep-without-atonia (RSWA) by submental electromyography, with video-confirmation of probably DEB. Physician2 relied solely on qualitative RSWA. SP was auto-staged, technically reviewed, and reprocessed for automated abnormal NRH detection. Kappa scores measured physician and NRH agreements. Results In the 14 records with REM sleep, iRBD was characterized in: Physician1=64%, Physician2=79%, NRH=71% of the records. Across the three methods, unanimous iRBD agreement occurred in 57% of the records (positive=7, negative=1). The between-physician agreement in iRBD classifications was fair (kappa=0.32). The agreement between NRH and Physician1 was moderate (kappa=0.52) versus slight with Physician2 (kappa=0.05). NRH comparisons to consensus physician agreement yielded one false-positive and one false-negative iRBD finding. Physician2 classified: a) iRBD in two cases that were negative by Physician1 and NRH, and b) one negative case that Physician1 and NRH characterized as iRBD. Physician1 identified one negative case that was classified iRBD by Physician2 and NRH. Additionally, NRH was abnormal in one of the two records with no REM sleep. Discussion NRH may assist in iRBD risk assessment, given it agreed with at least one physician in 86% of the cases and the between-physician iRBD agreement was only fair. NRH also characterized iRBD-risk in patients with insufficient REM sleep for RSWA assessment.

Abstract Purpose Evaluate the sleep staging agreement between polysomnography (PSG) and Sleep Profiler (SP) in patients with suspected isolated REM-sleep-behavior-disorder. Methods Twenty-six patients with reported dream-enactment-behavior (Site1=16, Site2=10; 27% women; age 64±13 years) underwent a diagnostic PSG with simultaneously recorded SP. A registered sleep-technologist at each site performed PSG-staging, while SP was auto-staged and technically reviewed/edited. Across technicians, the initial staging was blinded. Site1 then performed unblinded restaging of PSG=N3(N2) vs. SP=N2(N3) epochs, while Site2 conducted a blinded, carefully-targeted restaging of N3. Statistics included Cohen’s kappa and Chi-square analyses. Results Agreement between SP and Site1 vs. Site2 were significantly different for Wake (kappa:Site1=0.816;Site2=0.650;combined=0.736), stage N1 (kappa:Site1=0.149;Site2=0.228;combined=0.188), stage N2 (kappa:Site1=0.632;Site2=0.718;combined=0.659), stage N3 (kappa:Site1=0.715;Site2=0.368;combined=0.525) and REM (kappa:Site1=0.827;Site2=0.719;combined=0.766)(all P<0.001). After restaging of N3, the kappa values improved at Site1 (unblinded:N2=0.659/N3=0.883) and Site2 (blinded:N2=0.775/N3=0.736)(combined:N2=0.735/N3=0.851). The proportion of PSG-epochs restaged from N3 to N2 was 17% at Sites1 and 38% at Site2 (P<0.001), while Site1 had fewer remaining PSG=N3 vs. SP=N2 conflicts (5.6% vs. 20.8%, P<0.001). Compared to Site2, Site1 had a superior: REM kappa due to fewer SP=N2 disagreements (8.5% vs. 16.8%, P<0.001), and Wake kappa resulting from fewer SP=N1 (6.6 vs. 15.6%, P<0.001) and SP=N2 conflicts (5.9 vs. 12.0%, P<0.001). Conversely, the Site1 N1 kappa was inferior due to greater SP=wake disagreement (41.6% vs. 19.8%, P<0.001). Discussion N3 was excessively stage by both PSG technicians before restaging. At Site1, Wake, N3, and REM had almost-perfect-agreement with SP, while N2 had substantial-agreement. At Site2 and across-site, substantial-agreement was observed for Wake, N2, N3, and REM.

Abstract Comorbid Lewy body pathology is very common in Alzheimer’s disease and may confound clinical trial design, yet there is no in vivo test to identify patients with this. Tissue (and/or radioligand imaging) studies have shown cardiac sympathetic denervation in Parkinson’s disease and dementia with Lewy bodies, but this has not been explored in Alzheimer’s subjects with Lewy bodies not meeting dementia with Lewy bodies clinicopathological criteria. To determine if Alzheimer’s disease with Lewy bodies subjects show sympathetic cardiac denervation, we analysed epicardial and myocardial tissue from autopsy-confirmed cases using tyrosine hydroxylase and neurofilament immunostaining. Comparison of tyrosine hydroxylase fibre density in 19 subjects with Alzheimer’s disease/dementia with Lewy bodies, 20 Alzheimer’s disease with Lewy bodies, 12 Alzheimer’s disease subjects without Lewy body disease, 19 Parkinson’s disease, 30 incidental Lewy body disease and 22 cognitively normal without Alzheimer’s disease or Lewy body disease indicated a significant group difference (P < 0.01; Kruskal–Wallis analysis of variance) and subsequent pair-wise Mann–Whitney U tests showed that Parkinson’s disease (P < 0.05) and Alzheimer’s disease/dementia with Lewy bodies (P < 0.01) subjects, but not Alzheimer’s disease with Lewy bodies subjects, had significantly reduced tyrosine hydroxylase fibre density as compared with cognitively normal. Both Parkinson’s disease and Alzheimer’s disease/dementia with Lewy bodies subjects also showed significant epicardial losses of neurofilament protein-immunoreactive nerve fibre densities within the fibre bundles as compared with cognitively normal subjects (P < 0.01) and both groups showed high pathologic alpha-synuclein densities (P < 0.0001). Cardiac alpha-synuclein densities correlated significantly with brain alpha-synuclein (P < 0.001), while cardiac tyrosine hydroxylase and neurofilament immunoreactive nerve fibre densities were negatively correlated with the densities of both brain and cardiac alpha-synuclein, as well as Unified Parkinson’s Disease Rating Scale scores (P < 0.05). The clear separation of Alzheimer’s disease/dementia with Lewy bodies subjects from Alzheimer’s disease and cognitively normal, based on cardiac tyrosine hydroxylase fibre density, is the first report of a statistically significant difference between these groups. Our data do not show significant sympathetic cardiac denervation in Alzheimer’s disease with Lewy bodies, but strongly confirm that cardiac nuclear imaging with a noradrenergic radioligand is worthy of further study as a potential means to separate Alzheimer’s disease from Alzheimer’s disease/dementia with Lewy bodies during life.

Abstract 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.

Background: The prevalence of dream enactment behavior and other risk factors for a parkinsonian disorder is not well documented. Methods: A survey on prevalence of parkinsonism risk factors was designed using two validated instruments (REM behavior disorder single item question, bowel movement frequency for constipation) and three exploratory instruments (for hallucinations, cognitive and olfactory complaints.) It was sent by mail and email to patients aged 50 and over at two University of Utah community clinics in Salt Lake City. A total of 7888 unique patients were sent the survey, and 1607 responses were recorded (response rate 20%). Those whose age was missing (n = 117) or less than 50 years (n = 10) were excluded from the analysis. Results: Of the 1406 without personal diagnosis of neurodegenerative disease 62.7% were female, and median age was 63. Family history (FH) of Parkinson’s disease was endorsed by 9%, constipation (defined as a bowel movement less than once per day) by 19%, mild cognitive complaints (MCI) 15.8%, dream enactment 13.7%, subjective hyposmia or anosmia 18.2%, and at least one potential psychotic symptom in 37.6%. Multivariable logistic regression showed male gender, mild cognitive complaints, hearing voices, and at least one potentially psychotic symptom to be significantly associated with dream enactment. Conclusions: This survey shows that dream enactment, a strong predictor of risk for synucleinopathy, is relatively common in the older population; because such individuals rarely come to medical attention of a sleep clinic, such survey research may be useful to identify and recruit at-risk individuals for trials aimed at preventing neurodegenerative disease.