Conjugal Synucleinopathies: A Clinicopathologic Study.

BACKGROUND: While preclinical studies have shown that alpha-synuclein can spread through cell-to-cell transmission whether it can be transmitted between humans is unknown. OBJECTIVES: The aim was to assess the presence of a synucleinopathy in autopsied conjugal couples. METHODS: Neuropathological findings in conjugal couples were categorized as Parkinson's disease (PD), dementia with Lewy bodies (DLB), Alzheimer's disease with Lewy bodies (ADLB), incidental Lewy body disease (ILBD), or no Lewy bodies. RESULTS: Ninety conjugal couples were included; the mean age of death was 88.3 years; 32 couples had no Lewy bodies; 42 couples had 1 spouse with a synucleinopathy: 10 PD, 3 DLB, 13 ADLB, and 16 ILBD; 16 couples had both spouses with a synucleinopathy: in 4 couples both spouses had PD, 1 couple had PD and DLB, 4 couples had PD and ADLB, 2 couples had PD and ILBD, 1 couple had DLB and ADLB, in 3 couples both had ADLB, and 1 couple had ADLB and ILBD. No couples had both spouses with ILBD. CONCLUSIONS: This large series of 90 autopsied conjugal couples found 16 conjugal couples with synucleinopathies, suggesting transmission of synucleinopathy between spouses is unlikely. © 2024 International Parkinson and Movement Disorder Society.

Generalization of In-Place Balance Perturbation Training in People With Parkinson Disease.

BACKGROUND AND PURPOSE: Reactive balance training improves reactive postural control in people with Parkinson disease (PwPD). However, the extent to which reactive balance training generalizes to a novel, unpracticed reactive balance task is unknown. This study aimed to determine whether reactive training stepping through support surface translations can be generalized to an unpracticed, instrumented tether-release task. METHODS: Twenty-five PwPD (70.52 years ± 7.15; Hoehn and Yahr range 1-3) completed a multiple baseline, open-label, uncontrolled pre-post intervention study. Stepping was trained through a 2-week (6-session) intervention with repeated support surface translations. Performance on an untrained tether-release task (generalization task) was measured at 2 baseline assessments (B1 and B2, 2 weeks apart), immediately after the intervention (P1), and 2 months after training (P2). The tether-release task outcomes were the anterior-posterior margin of stability (MOS), step length, and step latency during backward and forward steps. RESULTS: After support surface translation practice, tether-release stepping performance improved in MOS, step length, and step latency for both backward and forward steps compared to baseline (P < 0.05). Improvements in MOS and step length during backward and forward steps in the tether-release task, respectively, were related to stepping changes in the practiced task. However, the improvements in the generalization task were not retained for 2 months. DISCUSSION AND CONCLUSIONS: These findings support short-term generalization from trained balance tasks to novel, untrained tasks. These findings contribute to our understanding of the effects and generalization of reactive step training in PwPD.Video Abstract available for more insights from the authors (see the Video, Supplemental Digital Content available at http://links.lww.com/JNPT/A465).

Symmetry of synuclein density in autopsied Parkinson's disease submandibular glands.

BACKGROUND: Peripheral tissue biopsy in Parkinson's disease (PD) may be valuable for clinical care, biomarker validation, and as research enrollment criteria. OBJECTIVE: Determine whether submandibular gland pathologic alpha-synuclein (aSyn) density is symmetrical and whether previous needle biopsy caused tissue damage. METHODS: Thirty autopsy-confirmed PD cases having fixed submandibular gland tissue from one side and frozen submandibular gland tissue from the contralateral side were studied. Tissue was stained for phosphorylated aSyn and density (0-4 semiquantitative scale) was determined. Three previously biopsied cases were also assessed for tissue damage at subsequent autopsy. RESULTS: Mean (SD) age was 80.9 (5.5) years and disease duration 12.5 (9.3). Submandibular gland aSyn staining had a mean score of 2.13 for both the initially fixed and the initially frozen submandibular glands. The correlation between aSyn density of the two sides was r = 0.63. Correlation of aSyn density, in the originally fixed submandibular gland, with disease duration was good (r = 0.49, p =.006). No permanent tissue damage was found in the three previously biopsied cases. CONCLUSIONS: This study found good correlation between aSyn density in both submandibular glands of patients with PD and found no evidence of significant tissue damage in previously biopsied subjects.

Stability Changes in Fall-Prone Individuals With Parkinson Disease Following Reactive Step Training.

BACKGROUND AND PURPOSE: Poor reactive steps may lead to falls in people with Parkinson disease (PwPD). However, whether reactive steps can be improved in PwPD at risk for falls or whether step training reduces falls remains unclear. This study aimed to determine whether 2 weeks of reactive step training result in (1) immediate and retained improvements in stepping and (2) fewer prospective falls in PwPD at fall risk. METHODS: Twenty-five PwPD (70.52 years ± 7.15; Hoehn & Yahr range 1-3) at risk for falls completed a multiple baseline, open-label, uncontrolled pre-/postintervention study. Stepping performance was assessed at 2 baseline assessments (B1 and B2) followed by a 2-week, 6-session training protocol. Stepping was assessed immediately (P1) and 2 months after training (P2). Primary outcomes were anterior-posterior margin of stability (MOS), step length, and step latency during backward stepping. Fall frequency was measured for 2 months before and after training. RESULTS: MOS during backward steps was significantly larger (better) after training ( P < 0.001, d = 0.83), and improvements were retained for 2 months ( P = 0.04, d = 0.66). Step length was not statistically significant different after training ( P = 0.13, d = 0.46) or at follow-up ( P = 0.08, d = 0.62), although effect sizes were medium and large, respectively. Step latency improved after initial exposure ( P = 0.01, d = 0.60) but not following training ( P = 0.43, d = 0.35). Twelve participants experienced fewer falls after training than before (10 = no change, 5 = increase; P = 0.12). Greater improvements in MOS were related to fewer falls ( P = 0.04). DISCUSSION AND CONCLUSIONS: Two weeks of reactive step training resulted in immediate and retained improvements in some reactive stepping outcomes in PwPD at risk for falls and may reduce fall risk. Reactive step training may be a viable approach to reduce falls in PwPD.

Disease progression modelling reveals heterogeneity in trajectories of Lewy-type α-synuclein pathology.

Lewy body (LB) disorders, characterized by the aggregation of misfolded α-synuclein proteins, exhibit notable clinical heterogeneity. This may be due to variations in accumulation patterns of LB neuropathology. By applying data-driven disease progression modelling to regional neuropathological LB density scores from 814 brain donors, we describe three inferred trajectories of LB pathology that were characterized by differing clinicopathological presentation and longitudinal antemortem clinical progression. Most donors (81.9%) showed earliest pathology in the olfactory bulb, followed by accumulation in either limbic (60.8%) or brainstem (21.1%) regions. The remaining donors (18.1%) exhibited the first abnormalities in brainstem regions. Early limbic pathology was associated with Alzheimer's disease-associated characteristics. Meanwhile, brainstem-first pathology was associated with progressive motor impairment and substantial LB pathology outside of the brain. Our data provides evidence for heterogeneity in the temporal spread of LB pathology, possibly explaining some of the clinical disparities observed in LBDs.

Cognitive Predictors of Responsiveness to Reactive Step Training in People with Parkinson's Disease at Fall-Risk.

Reactive stepping can be improved in people with Parkinson's Disease (PwPD). However, there is variability in the responsiveness to such training. This study examined if cognition could predict the responsiveness of PwPD to a two-week reactive step training intervention. 25 PwPD (70.52 years ± 7.15; Hoehn & Yahr range 1-3) at risk for falls completed a multiple baseline, open-label, uncontrolled pre-post intervention study. Reactive stepping was trained through a two-week (six-session) intervention with repeated support surface translations. Stepping performance was measured at two baseline assessments (B1 and B2), immediately after the intervention (P1), and two months after training (P2). Primary stepping outcomes were anterior-posterior margin of stability (MOS), step length, and step latency during backward steps. The primary aim assessed whether global cognition (Scales for Outcomes in Parkinson's Disease-Cognition - SCOPA-COG, & Montreal Cognitive Assessment - MoCA) was related to two-month retention of improvements in reactive stepping after practice. The secondary aim explored whether specific cognitive domains predicted retained stepping improvements, including attention/working memory, executive function, language, memory, and visuospatial function. Greater baseline global cognition was related to better two-month retention of step length improvements (SCOPA-COG: p = 0.002, f2 = 0.31; MoCA: p = 0.002, f2 = 0.38). However, only SCOPA-COG retained statistical significance after p-value adjustment for multiple comparisons (p = 0.04). Optimal cut-point analysis revealed that a SCOPA-COG threshold of 31 or higher was optimal for identifying individuals likely to retain improvement. Specific cognitive domains did not predict changes in reactive stepping outcomes. Participants with greater baseline global cognition, particularly as measured by SCOPA-COG, demonstrated greater retention of improvements in reactive stepping. In this cohort, a SCOPA-COG threshold of 31 could predict individuals likely to benefit from the intervention. These findings highlight the potential of cognitive screening to identify people more or less likely to benefit from reactive balance training.

Longitudinal motor decline in dementia with Lewy bodies, Parkinson disease dementia, and Alzheimer's dementia in a community autopsy cohort.

INTRODUCTION: We examined the progression of extrapyramidal symptoms and signs in autopsy-confirmed dementia with Lewy bodies (DLB), Parkinson's disease dementia (PDD), and Alzheimer's disease dementia (AD). METHODS: Longitudinal data were obtained from Arizona Study of Aging and Neurodegenerative Disease, with PDD (n = 98), AD (n = 47) and DLB (n = 48) further sub-grouped as with or without parkinsonism (DLB+ and DLB-). Within-group Unified Parkinson's Disease Rating Scale (UPDRS) -II and UPDRS-III trajectories were analyzed using non-linear mixed effects models. RESULTS: In DLB, 65.6% had parkinsonism. Baseline UPDRS-II and III scores (off-stage) were highest (P < 0.001) for PDD (mean ± SD 14.3 ± 7.8 and 27.4 ± 16.3), followed by DLB+ (6.0 ± 8.8 and 17.2 ± 17.1), DLB- (1.1 ± 1.3 and 3.3 ± 5.5) and AD (3.2 ± 6.1 and 8.2 ± 13.6). Compared to PDD, the DLB+ group had faster UPDRS-III progression over 8-years (Cohen's-d range 0.98 to 2.79, P < 0.001), driven by gait (P < 0.001) and limb bradykinesia (P = 0.02) subscales. DISCUSSION: Motor deficits progress faster in DLB+ than PDD, providing insights about expected changes in motor function. HIGHLIGHTS: Dementia with Lewy bodies has faster motor progression than Parkinson's disease dementia Linear and non-linear mixed modeling analysis of longitudinal data was utilized Findings have implications for clinical prognostication and trial design.

Low clinical sensitivity and unexpectedly high incidence for neuropathologically diagnosed progressive supranuclear palsy.

The objective of this study was to determine the prevalence, incidence, and clinical diagnostic accuracy for neuropathologically diagnosed progressive supranuclear palsy (PSP) with data from a longitudinal clinicopathological study using Rainwater criteria to define neuropathological PSP. Of 954 autopsy cases, 101 met Rainwater criteria for the neuropathologic diagnosis of PSP. Of these, 87 were termed clinicopathological PSP as they also had either dementia or parkinsonism or both. The prevalence of clinicopathologically defined PSP subjects in the entire autopsy dataset was 9.1%, while the incidence rate was estimated at 780 per 100 000 persons per year, roughly 50-fold greater than most previous clinically determined PSP incidence estimates. A clinical diagnosis of PSP was 99.6% specific but only 9.2% sensitive based on first examination, and 99.3% specific and 20.7% sensitive based on the final clinical exam. Of the clinicopathologically defined PSP cases, 35/87 (∼40%) had no form of parkinsonism at first assessment, while this decreased to 18/83 (21.7%) at final assessment. Our study confirms a high specificity but low sensitivity for the clinical diagnosis of PSP. The low clinical sensitivity for PSP is likely primarily responsible for previous underestimates of the PSP population incidence rate.

Cerebral white matter rarefaction has both neurodegenerative and vascular causes and may primarily be a distal axonopathy.

Cerebral white matter rarefaction (CWMR) was considered by Binswanger and Alzheimer to be due to cerebral arteriolosclerosis. Renewed attention came with CT and MR brain imaging, and neuropathological studies finding a high rate of CWMR in Alzheimer disease (AD). The relative contributions of cerebrovascular disease and AD to CWMR are still uncertain. In 1181 autopsies by the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND), large-format brain sections were used to grade CWMR and determine its vascular and neurodegenerative correlates. Almost all neurodegenerative diseases had more severe CWMR than the normal control group. Multivariable logistic regression models indicated that Braak neurofibrillary stage was the strongest predictor of CWMR, with additional independently significant predictors including age, cortical and diencephalic lacunar and microinfarcts, body mass index, and female sex. It appears that while AD and cerebrovascular pathology may be additive in causing CWMR, both may be solely capable of this. The typical periventricular pattern suggests that CWMR is primarily a distal axonopathy caused by dysfunction of the cell bodies of long-association corticocortical projection neurons. A consequence of these findings is that CWMR should not be viewed simply as "small vessel disease" or as a pathognomonic indicator of vascular cognitive impairment or vascular dementia.

Postmortem Cerebellar Volume Is Not Reduced in Essential Tremor: A Comparison with Multiple System Atrophy and Controls.

BACKGROUND: Essential tremor (ET) is a common movement disorder in which cerebellar microscopic and volume alterations have been repeatedly reported although with disagreement between studies. However, pronounced heterogeneity was found with regard to cerebellar volume alterations. OBJECTIVE: This study aimed to assess postmortem cerebellar volume in subjects with or without ET, as compared with subjects with multiple system atrophy (MSA), a well-established cerebellar neurodegeneration. METHODS: Cases with ET (n = 29), MSA (n = 7), and non-demented control cases without any movement disorder (n = 22) were selected from the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND), a longitudinal clinicopathological study with annual research-dedicated clinical assessments by neuropsychologists, subspecialist movement disorders, and cognitive/behavioral neurologists, with comprehensive neuropathological examinations after death. Group comparisons were controlled for common age-related neurodegenerative and cerebrovascular pathologies. Cerebellar volumes were calculated using digital images of slices taken at the time of autopsy, immediately after brain removal and before fixation. RESULTS: Cerebellar volume was not reduced in ET subjects compared to controls. The two groups did not differ in terms of incidental cerebrovascular and Alzheimer's disease neuropathology. In contrast, cerebellar volume was significantly reduced in subjects with MSA when compared to ET and control subjects. CONCLUSION: In a well-characterized cohort, postmortem cerebellar volume measurements suggest that there are no volume alterations in ET when compared to controls, in contrast to significant cerebellar atrophy in subjects with MSA.

Clinicopathologic Correlations of Jaw Tremor in a Longitudinal Aging Study.

Background and Objectives: The aim of this study is to assess clinical and pathologic correlations of jaw tremor in 3 cohorts enrolled in a long-term aging study. Jaw/lip tremor has been described in various movement disorders but the impact of seeing a jaw tremor on clinician diagnosis and whether the presence of isolated jaw tremor is correlated with subsequent phenoconversion to a different movement disorder are unclear. Methods: Data from the Arizona Study of Aging and Neurodegenerative Disease, a longitudinal clinicopathologic study, were used. Control subjects (n = 708) did not have any tremor or parkinsonism. At initial evaluation, 276 subjects who had jaw tremor were categorized as isolated jaw tremor (jaw tremor without limb action tremor or parkinsonism), suspect/possible PD (1 or 2 cardinal features of PD without a history of dopaminergic treatment), parkinsonism (probable PD and other parkinsonian disorders), or nonparkinsonian tremor (e.g., essential tremor). Initial clinical diagnosis was compared with "final diagnosis" based on longitudinal assessments and with clinicopathologic diagnosis when available. Results: In subjects with jaw tremor, we identified 45 isolated jaw tremor, 92 nonparkinsonian tremor, 56 suspect/possible PD, and 83 parkinsonism cases at baseline and followed longitudinally. Neuropathologic diagnosis was available for 137 cases. The mean time from initial to final assessment or autopsy was 6.8 years (SD 4.4). Of the subjects with follow-up data, only 15.4% of those with isolated jaw tremor (6/39) and 8.8% of those with nonparkinsonian tremor (6/68) evolved into a clinical parkinsonian disorder. Neither of these groups was associated with clinicopathologic PD: isolated jaw tremor (1/18) and nonparkinsonian tremor (1/43). Those with jaw tremor initially classified into a parkinsonian group were more highly associated with clinicopathologic PD: 27 of 51 subjects with parkinsonism other and 4 of 25 possible PD. Discussion: The presence of either jaw tremor in isolation or associated with nonparkinsonian tremor does not portend a neurodegenerative diagnosis.

Effect of STN/GPi DBS on swallowing function in Parkinson's disease as assessed by Video fluoroscopy: A retrospective study.

INTRODUCTION: The goal of the study is to objectively assess changes in swallowing (using "gold standard" video fluoroscopy (VFS)) following Deep Brain Stimulation (DBS) surgery in Parkinson's disease (PD) patients. There are few studies on the effect of DBS on swallowing in PD. We use VFS to assess swallowing function pre- and post-DBS. METHODS: Our study participants underwent pre- and post-DBS VFS (6 months later) in the practically defined on state. We converted VFS reports into an objective numerical scale. Higher scores denote more severe dysphagia. We used non-parametric test (Wilcoxon signed rank test) to test if the difference between pre- and post-DBS swallow score is significantly different from 0. RESULTS: Fifty-four PD patients completed pre- and post-DBS evaluations. Twenty-five patients had bilateral GPi DBS (46.3%) and 29 had bilateral STN DBS (53.7%). The mean (SD) post-DBS swallow score is 1.9 (2.0) and pre-DBS swallow score is 1.6 (1.3). The difference is not significantly different from 0 (p = 0.16). In our study, swallow scores for majority of the patients (39 out of 54) did not change after DBS regardless of lead location. Six (11.1%) PD patients had post-DBS swallow score decrease on average by 1 (SD: 0) points. 9 (16.7%) patients had post-DBS swallow score increase on average by 2.7 (SD: 2.3) points. CONCLUSION: There was no statistically significant change in the swallow scores pre-and 6 months post-DBS with VFS when assessed in the practically defined on state, regardless of the site of bilateral lead implantation. Hence, we believe that DBS does not improve or reduce swallow function in a clinically meaningful way in PD.

SARS-CoV-2 Brain Regional Detection, Histopathology, Gene Expression, and Immunomodulatory Changes in Decedents with COVID-19.

Brains of 42 COVID-19 decedents and 107 non-COVID-19 controls were studied. RT-PCR screening of 16 regions from 20 COVID-19 autopsies found SARS-CoV-2 E gene viral sequences in 7 regions (2.5% of 320 samples), concentrated in 4/20 subjects (20%). Additional screening of olfactory bulb (OB), amygdala (AMY) and entorhinal area for E, N1, N2, RNA-dependent RNA polymerase, and S gene sequences detected one or more of these in OB in 8/21 subjects (38%). It is uncertain whether these RNA sequences represent viable virus. Significant histopathology was limited to 2/42 cases (4.8%), one with a large acute cerebral infarct and one with hemorrhagic encephalitis. Case-control RNAseq in OB and AMY found more than 5000 and 700 differentially expressed genes, respectively, unrelated to RT-PCR results; these involved immune response, neuronal constituents, and olfactory/taste receptor genes. Olfactory marker protein-1 reduction indicated COVID-19-related loss of OB olfactory mucosa afferents. Iba-1-immunoreactive microglia had reduced area fractions in cerebellar cortex and AMY, and cytokine arrays showed generalized downregulation in AMY and upregulation in blood serum in COVID-19 cases. Although OB is a major brain portal for SARS-CoV-2, COVID-19 brain changes are more likely due to blood-borne immune mediators and trans-synaptic gene expression changes arising from OB deafferentation.

Olfactory Bulb Amyloid-ß Correlates With Brain Thal Amyloid Phase and Severity of Cognitive Impairment.

The Alzheimer disease (AD) neuropathological hallmarks amyloid ß (Aß) and tau neurofibrillary (NF) pathology have been reported in the olfactory bulb (OB) in aging and in different neurodegenerative diseases, which coincides with frequently reported olfactory dysfunction in these conditions. To better understand when the OB is affected in relation to the hierarchical progression of Aß throughout the brain and whether OB pathology might be an indicator of AD severity, we assessed the presence of OB Aß and tau NF pathology in an autopsy cohort of 158 non demented control and 173 AD dementia cases. OB Aß was found in less than 5% of cases in lower Thal phases 0 and 1, in 20% of cases in phase 2, in 60% of cases in phase 3 and in more than 80% of cases in higher Thal phases 4 and 5. OB Aß and tau pathology significantly predicted a Thal phase greater than 3, a Braak NF stage greater than 4, and an MMSE score lower than 24. While OB tau pathology is almost universal in the elderly and therefore is not a good predictor of AD severity, OB Aß pathology coincides with clinically-manifest AD and might prove to be a useful biomarker of the extent of brain spread of both amyloid and tau pathology.

Effect of olfactory bulb pathology on olfactory function in normal aging.

Decline of olfactory function is frequently observed in aging and is an early symptom of neurodegenerative diseases. As the olfactory bulb (OB) is one of the first regions involved by pathology and may represent an early disease stage, we specifically aimed to evaluate the contribution of OB pathology to olfactory decline in cognitively normal aged individuals without parkinsonism or dementia. This clinicopathological study correlates OB tau, amyloid ß (Aß) and α-synuclein (αSyn) pathology densities and whole brain pathology load to olfactory identification function as measured with the University of Pennsylvania Smell Identification Test (UPSIT) and clinical data measured proximate to death in a large autopsy study including 138 cases considered non-demented controls during life. Tau pathology was frequently observed in the OB (95% of cases), while both Aß (27% of cases) and αSyn (20% of cases) OB pathologies were less commonly observed. A weak correlation was only observed between OB tau and olfactory performance, but when controlled for age, neither OB tau, Aß or αSyn significantly predict olfactory performance. Moreover, whole brain tau and αSyn pathology loads predicted olfactory performance; however, only αSyn pathology loads survived age correction. In conclusion, OB tau pathology is frequently observed in normally aging individuals and increases with age but does not appear to independently contribute to age-related olfactory impairment suggesting that further involvement of the brain seems necessary to contribute to age-related olfactory decline.

In Patients With Functional Movement Disorders, Is Specialized Physical Therapy Effective in Improving Motor Symptoms?: A Critically Appraised Topic.

BACKGROUND: Functional movement disorders (FMD, aka psychogenic movement disorders) are very common and frequently chronic and disabling. Despite this, there is a paucity of evidence-based treatment to manage and alleviate these conditions. Specialized physical therapy (PT), involving sequential motor relearning and redirecting attention, has shown promise as a therapeutic intervention for motor symptoms. METHODS: The objective of this study was to critically assess current evidence regarding specialized PT compared with usual care in improving motor symptoms among patients with FMD. This was addressed through the development of a structured critically appraised topic. This included a clinical scenario with a clinical question, literature search strategy, critical appraisal, results, evidence summary, commentary, and bottom-line conclusions. Participants included consultant and resident neurologists, a medical librarian, and content experts in the fields of physical medicine and rehabilitation, physical and occupational therapy, psychiatry, and psychology. RESULTS: A randomized controlled feasibility trial was identified and selected for critical appraisal. This study randomized 60 patients with FMD to a 5-day specialized outpatient PT program or to general outpatient PT referral, and measured patient-reported and clinician-measured outcomes. At 6 months, 72% of patients in the intervention group had a good outcome compared with 18% of control group patients. Patients in the specialized outpatient PT program had significantly better outcomes in 3 Short-Form 36 (SF36) domains (d=0.46 to 0.79) and multiple other scales of physical and social function as well as clinician-measured outcomes. The intervention resulted in 0.08 additional quality-adjusted life years in a cost-effective manner. CONCLUSIONS: Current evidence suggests that in patients with FMD, specialized PT improves motor symptoms in a clinically significant, sustained, and cost-effective manner. This promising intervention warrants further investigation and replication.

Olfactory Dysfunction in Incidental Lewy Body Disease and Parkinson's Disease: An Update.

Objective: Measuring olfactory dysfunction shows promise as one of a number of nonmotor biomarkers that can be used to detect clinically manifest and prodromal Parkinson's disease (PD) and dementia with Lewy bodies (DLB) and to differentiate these from nonsynucleinopathies. Using a larger sample size than in our previous study, we evaluated the relationship between olfactory dysfunction based on the University of Pennsylvania Smell Identification Test (UPSIT) to the clinicopathological findings in patients with PD (n=41), patients with incidental Lewy body disease (ILBD) (n=47), and controls with no neurodegenerative disease (n=137). Design: This study was conducted through the Arizona Study of Aging and Neurodegenerative Disease (AZSAND). We selected individuals who had an UPSIT score completed antemortem and were clinicopathologically diagnosed with PD, ILBD, or control. Various measures included density of Lewy type synucleinopathy (aSyn) in the olfactory bulb and tract, as well as connected mesial temporal lobe structures. Cases and controls were analyzed using one-way analysis of variance (ANOVA) with pairwise contrasts. Results: Compared to controls (mean: 27.8, standard deviation [SD]: 6.0), the mean UPSIT scores were lower for PD (15.8, SD: 6.0, p<0.001) and ILBD (24.1, SD: 8.6, p<0.001). The sensitivity for detecting ILBD from controls, based on a cutoff score of less than 23 (23/47), was 48.9 percent. The specificity for detecting a control was 79.6 percent with a cutoff greater than 23 (109/137). Conclusion: These findings replicate, with a larger sample size, our previously published findings that individuals with autopsy-confirmed PD and ILBD have significantly lower UPSIT scores compared to controls. These data add to the growing body of evidence supporting early olfactory dysfunction as a prodromal biomarker for the risk of developing PD and ILBD as a prodromal Lewy body disorder.

Clinical Diagnostic Accuracy of Early/Advanced Parkinson Disease: An Updated Clinicopathologic Study.

OBJECTIVE: To update data for diagnostic accuracy of a clinical diagnosis of Parkinson disease (PD) using neuropathologic diagnosis as the gold standard. METHODS: Data from the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND) were used to determine the predictive value of a clinical PD diagnosis. Two clinical diagnostic confidence levels were used, possible PD (PossPD, never treated or not responsive) and probable PD (ProbPD, 2/3 cardinal clinical signs and responsive to dopaminergic medications). Neuropathologic diagnosis was the gold standard. RESULTS: Based on the first visit to AZSAND, 15/54 (27.8%) PossPD participants and 138/163 (84.7%) ProbPD participants had confirmed PD. PD was confirmed in 24/34 (70.6%) ProbPD with <5 years and 114/128 (89.1%) with ≥5 years disease duration. Using the consensus final clinical diagnosis following death, 161/187 (86.1%) ProbPD had neuropathologically confirmed PD. Diagnostic accuracy for ProbPD improved if included motor fluctuations, dyskinesias, and hyposmia, and hyposmia for PossPD. CONCLUSIONS: This updated study confirmed lower clinical diagnostic accuracy for elderly, untreated or poorly responsive PossPD participants and for ProbPD with <5 years of disease duration, even when medication responsive. Caution continues to be needed when interpreting clinical studies of PD, especially studies of early disease, that do not have autopsy confirmation. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that a clinical diagnosis of ProbPD at the first visit identifies participants who will have pathologically confirmed PD with a sensitivity of 82.6% and a specificity of 86.0%.

Assessing the impact of dual-task reactive step practice in people with Parkinson's disease: A feasibility study.

Reactive stepping is impaired in people with Parkinson's Disease (PD) but can be improved with training. However, it is unclear if reactive steps can be improved when performing a concurrent cognitive task, a common and fall-relevant circumstance. We assessed the feasibility and preliminary effectiveness of dual-task reactive step training. Specifically, we measured whether stepping and cognitive reaction time are improved after one day of dual-task reactive step practice and if improvements are retained 24 h later. Sixteen people with PD and 13 age-matched healthy controls (HC) underwent repeated from-stance support surface perturbations that elicited a reactive step while performing an auditory Stroop task. Participants returned the following day to reassess dual-task reactive stepping performance. Cognitive, neuromuscular, and stepping outcomes were calculated. Increased step lengths were observed for both groups after practice (p < 0.001). Cognitive reaction times also improved through practice; however, this was more pronounced in the HC group (group by time interaction- p < 0.001). No changes were observed for step latency, margin of stability, or EMG onset through practice. Step length and cognitive reaction time improvements were retained 24 h after practice in both groups (step length: p < 0.001; cognitive reaction time: p = 0.05). This study provides preliminary evidence for the effectiveness of dual-task reactive step training to improve step length in people with PD. The improvements in step length without compromising cognitive reaction times suggest that participants improved reactive stepping without a robust attention shift toward the postural task. Future research is necessary to determine optimal training protocols and determine if such training protocols impact falls in PD patients.