Real-World Evidence for a Smartwatch-Based Parkinson's Motor Assessment App for Patients Undergoing Therapy Changes.

INTRODUCTION: Parkinson's disease (PD) is poorly quantified by patients outside the clinic, and paper diaries have problems with subjective descriptions and bias. Wearable sensor platforms; however, can accurately quantify symptoms such as tremor, dyskinesia, and bradykinesia. Commercially available smartwatches are equipped with accelerometers and gyroscopes that can measure motion for objective evaluation. We sought to evaluate the clinical utility of a prescription smartwatch-based monitoring system for PD utilizing periodic task-based motor assessment. METHODS: Sixteen patients with PD used a smartphone- and smartwatch-based monitoring system to objectively assess motor symptoms for 1 week prior to instituting a doctor recommended change in therapy and for 4 weeks after the change. After 5 weeks the participants returned to the clinic to discuss their results with their doctor, who made therapy recommendations based on the reports and his clinical judgment. Symptom scores were synchronized with the medication diary and the temporal effects of therapy on weekly and hourly timescales were calculated. RESULTS: Thirteen participants successfully completed the study and averaged 4.9 assessments per day for 3 days per week during the study. The doctor instructed 8 participants to continue their new regimens and 5 to revert to their previous regimens. The smartwatch-based assessments successfully captured intraday fluctuations and short- and long-term responses to therapies, including detecting significant improvements (p < 0.05) in at least one symptom in 7 participants. CONCLUSIONS: The smartwatch-based app successfully captured temporal trends in symptom scores following application of new therapy on hourly, daily, and weekly timescales. These results suggest that validated smartwatch-based PD monitoring can provide clinically relevant information and may reduce the need for traditional office visits for therapy adjustment.

Hypertension and progressive supranuclear palsy.

BACKGROUND: The epidemiologic evidence of whether hypertension is associated with Progressive Supranuclear Palsy (PSP) is inconsistent. The ENGENE-PSP case-control study determined various PSP risk factors including whether hypertension preceded PSP onset. METHODS: Incident PSP cases per NINDS-PSP criteria and age-, sex-, race- matched controls were recruited from similar North American geographic areas. All study participants were administered standardized interviews to obtain data on demographics, medical history and medications. STATISTICS: We used univariate and multivariate conditional logistic regression models to measure the associations between PSP and the following predictor variables: education level, hypertension, comorbid vascular conditions (diabetes mellitus and hyperlipidemia), and classes of anti-hypertensive medications using odds ratios and 95% confidence intervals. RESULTS: There were significant associations seen between PSP and hypertension (OR: 1.569; 95% CI 1.129-2.181; p-value = 0.007), education level (OR: 0.733; 95% CI 0.637-0.843; p-value<0.001) and beta-blocker use (OR: 2.000; 95% CI 1.053-3.799; p-value = 0.034). However, in the multi-variate analysis hypertension (OR: 1.492; 95% CI 1.045-2.129; p-value = 0.027) and education level (OR: 0.730; 95% CI 0.633-0.841; p-value<0.001) were the only significant associations. CONCLUSION: These results suggest that there is a modest, yet significant association between hypertension and PSP. Further studies will be needed to better understand the pathophysiological basis for this finding.

Motor and non-motor features of Parkinson's disease in LRRK2 G2019S carriers versus matched controls.

INTRODUCTION: LRRK2 G2019S mutation carriers with Parkinson's disease (PD) have been generally indistinguishable from those with idiopathic PD, with the exception of variable differences in some motor and non-motor domains, including cognition, gait, and balance. LRRK2 G2019S is amongst the most common genetic etiologies for PD, particularly in Ashkenazi Jewish (AJ) populations. METHODS: This cross-sectional data collection study sought to clarify the phenotype of LRRK2 G2019S mutation carriers with PD. Primary endpoints were the Movement Disorder Society Unified Parkinson Disease Rating Scale (MDS-UPDRS) and Montreal Cognitive Assessment (MoCA). Other motor and non-motor data were also assessed. The Mann-Whitney U Test was utilized to compare LRRK2 G2019S carriers with PD (LRRK2+) with non-carrier PD controls who were matched for age, gender, education, and PD duration. Survival analyses and log rank tests were utilized to compare interval from onset of PD to development of motor and non-motor complications. RESULTS: We screened 251 subjects and 231 completed the study, of whom 9 were LRRK2+, including 7 AJ subjects. 22.73% of AJ subjects with a family history of PD (FH) and 12.96% of AJ subjects without a FH were LRRK2+. There were no significant differences between the 9 LRRK2+ subjects and 19 matched PD controls in MDS-UPDRS, MoCA, or other motor and non-motor endpoints. CONCLUSION: Prevalence of the LRRK2 G2019S mutation in AJ and non-AJ subjects in our study population in Cleveland, Ohio was comparable to other clinical studies. There were no significant motor or non-motor differences between LRRK2+ PD and matched PD controls.

Cognitive fluctuations in Parkinson's disease dementia: blood pressure lability as an underlying mechanism.

BACKGROUND: Cognitive fluctuations refer to alterations in cognition, attention, or arousal occurring over minutes to hours, most commonly in patients with dementias associated with advanced Lewy body pathology. Their pathophysiologic underpinning remains undetermined. CASE PRESENTATION: We documented serial blood pressure (BP) measurements in an 86-year-old man with Parkinson's disease dementia experiencing cognitive fluctuations during an office visit. This patient's associated dysautonomia included labile BP with orthostatic hypotension and nocturnal hypertension. A spontaneous episode of unresponsiveness occurred while his BP was 72/48. His mental status began to recover immediately as his BP increased to 84/56 when he was placed in a recumbent position; it fully returned to baseline when it reached 124/66 within 1 min. His heart rate remained in the mid-to-high 60s throughout. Subsequent treatment with midodrine markedly reduced the frequency of cognitive fluctuations. CONCLUSIONS: Paroxysmal hypotension may represent an explanatory mechanism for cognitive fluctuations, a common clinical feature in patients with Parkinson's disease dementia and dementia with Lewy bodies.

The Role of Stress as a Risk Factor for Progressive Supranuclear Palsy.

BACKGROUND: PSP, like Alzheimer's disease (AD), is a tauopathy. The etiopathogenesis of PSP is not well known and the role of stress has not yet been examined. Recent studies have shown that stress increases the risk for developing AD. This study investigates the role of stress as a risk factor for PSP. OBJECTIVE: B To examine the association between the development of progressive supranuclear palsy (PSP) and self-reported life stressors. METHODS: 76 patients diagnosed with PSP according to the NINDS-SPSP criteria and 68 age-matched unrelated controls were administered a life stressor questionnaire. Stress was quantified as total number of events, number of life changing events, and number of events characterized by self-rated severity. Conditional odds ratio (OR) was calculated for each measure, with participants in the highest quartile of each measure being defined as high-exposure in relation to all other participants. RESULTS: There were no significant differences between the reported number of total events or life-changing events in cases and controls. However, we found 24.4% of cases (N = 11) and 9.1% of controls (N = 5) had a higher exposure to high severity events, yielding an OR of 3.2 (p = 0.04). CONCLUSIONS: We found that cases have over a three times greater odds of high exposure to high-severity events than controls prior to the clinical development of PSP, while there were no differences in overall number of reported events. Our findings suggest that high exposure to highly stressful events may be associated with the development of PSP.

Understanding falls in progressive supranuclear palsy.

INTRODUCTION: Progressive supranuclear palsy (PSP) is characterized by frequent falls which worsen with disease progression, causing substantial morbidity and mortality. Few studies have investigated which factors contribute to falls in PSP, and all have involved few participants, thus lacking necessary statistical power. The aim of this study was to identify clinical parameters most significantly associated with increasing falls in PSP, using the largest sample of patients to date. METHODS: Comprehensive clinical data were collected from 339 not demented PSP patients meeting the NINDS-SPSP criteria, who were divided into two groups - Infrequent Fallers (IF; n = 118) with rare falls, and Frequent Fallers (FF; n = 221) who fell occasionally to multiple times a day. Of 198 clinical parameters, we hypothesized 38 to be correlated with an increasing risk of falls. These 38 parameters were analyzed via univariate regression analysis to determine the strength of their association with fall frequency. Unit odds ratios identified the magnitude with which each parameter resulted in an increasing risk of falls. RESULTS: Twenty-five of 38 parameters analyzed were significantly associated with fall frequency based on univariate analysis. Symptom duration, clinical measures of disease severity, and several motoric and oculomotor clinical parameters were associated with FF. Examined cognitive parameters and slowing of vertical saccades were not. CONCLUSIONS: The clinical parameters identified as associated with increased frequency of falls improve our understanding of why they occur and may help identify not demented PSP patients at risk for increasing falls.

Relationship between uric acid levels and progressive supranuclear palsy.

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.

Clinimetric Analysis of the Motor Section of the Progressive Supranuclear Palsy Rating Scale: Reliability and Factor Analysis.

INTRODUCTION: PSP is a rare degenerative disorder associated with significant morbidity. Recently, investigations of the etiology and treatment of PSP have been initiated. The aim of the present study was to validate the motor domain of the Progressive Supranuclear Palsy Rating Scale (PSPRS) as part of a larger epidemiological study. METHODS: Fifty videos of patients with PSP were rated by four trained movement disorder neurologists using the PSPRS. Reliability and construct validity of the scale were evaluated using standard methods. RESULTS: Inter-rater reliability for the total scale score was good. Internal consistency of the scale improved with the removal of three items. Four factors accounted for the majority of the variance of the scale as determined by principal components analysis. DISCUSSION: This study shows that the motor domain of the PSPRS is a reliable scale, with a factor structure that suggests construct validity, for the assessment of motor signs of the disease. Removal or modification of items may improve the clinimetric features of the motor domain of the scale.

Five-months-postoperative neuropsychological outcome from a pilot prospective randomized clinical trial of thalamic deep brain stimulation for Tourette syndrome.

OBJECTIVE: Tourette syndrome (TS) is a neuropsychiatric disorder presenting with motor and/or sonic tics associated with frontostriatal dysfunction. This study provided pilot data of the neuropsychological safety of bilateral thalamic deep brain stimulation (DBS) to treat medication-refractory TS in adults. METHOD: This study used a repeated-measures design with pretest and 3-month follow-up from start of continuous bilateral DBS. Five male patients underwent DBS surgery for medically refractory TS. Repeated-measures ANOVA was used to evaluate for any change in neuropsychological test scores, employing a false discovery rate. Outcome measures included 14 neuropsychological tests assessing psychomotor speed, attention, memory, language, visuoconstructional, and executive functions, as well as subjective mood ratings of depression and anxiety. RESULTS: Average age was 28.2 years (SD = 7.5) with 12-17 years of education. Participants were disabled by tics, with a tic frequency of 50-80 per minute before surgery. At baseline, subjects' cognitive function was generally average, although mild deficits in sequencing and verbal fluency were present, as were clinically mild obsessive-compulsive symptoms. At 3 months of continuous DBS (5 months after implantation), 3 of 5 participants had clinical reductions in motor and sonic tics. Cognitive scores generally remained stable, but declines of moderate to large effect size (Cohen's d > 0.6) in verbal fluency, visual immediate memory, and reaction time were observed. Fewer symptoms of depression and anxiety, as well as fewer obsessions and compulsions, were reported after 3 months of continuous high-frequency DBS. CONCLUSIONS: Bilateral centromedian-parafascicular thalamic DBS for medically refractory TS shows promise for treatment of medically refractory TS without marked neuropsychological morbidity. Symptoms of depression and anxiety improved.

Effective and efficient diagnosis of parkinsonism: the role of dopamine transporter SPECT imaging with ioflupane I-123 injection (DaTscan™).

Parkinson's disease (PD), the second-most common neurodegenerative disease, is characterized by motor and nonmotor symptoms. PD is often misdiagnosed; inappropriate treatment due to misdiagnosis has undesired consequences, as does delayed diagnosis. Unfortunately, most people with PD receive a diagnosis only after motor symptoms have emerged, by which time 40% to 60% of dopamine neurons have already been lost. Advances in imaging techniques have provided clinicians with increasingly sophisticated tools. In 2011, the US Food and Drug Administration approved ioflupane I-123 injection (DaTscanTM) for striatal dopamine transporter visualization using single-photon emission computed tomography (SPECT) imaging, which provides an effective tool for assessing striatal dopaminergic deficiency. Among patients with suspected parkinsonian syndromes, of which PD is one, the diagnostic sensitivity and specificity of DaTscan SPECT imaging are high. In clinical studies that were part of the DaTscan new drug application, no serious drug-related adverse events reported by the 1236 participants were attributed to DaTscan. The introduction of DaTscan imaging and its utility necessitate the development of clinical recommendations for appropriate use; thus, a multidisciplinary panel of experts was convened to develop clinical criteria and algorithms to help guide clinicians and managed care organizations in the application of DaTscan SPECT imaging. Based on the consensus of this expert panel, appropriate use of DaTscan SPECT imaging includes cases where: (1) PD diagnosis is uncertain; (2) tremor of uncertain etiology is present; and (3) nonmotor and/ or supportive symptoms and features associated with PD are present but the classical motor syndrome is absent or atypical.

Criteria for the diagnosis of corticobasal degeneration.

Current criteria for the clinical diagnosis of pathologically confirmed corticobasal degeneration (CBD) no longer reflect the expanding understanding of this disease and its clinicopathologic correlations. An international consortium of behavioral neurology, neuropsychology, and movement disorders specialists developed new criteria based on consensus and a systematic literature review. Clinical diagnoses (early or late) were identified for 267 nonoverlapping pathologically confirmed CBD cases from published reports and brain banks. Combined with consensus, 4 CBD phenotypes emerged: corticobasal syndrome (CBS), frontal behavioral-spatial syndrome (FBS), nonfluent/agrammatic variant of primary progressive aphasia (naPPA), and progressive supranuclear palsy syndrome (PSPS). Clinical features of CBD cases were extracted from descriptions of 209 brain bank and published patients, providing a comprehensive description of CBD and correcting common misconceptions. Clinical CBD phenotypes and features were combined to create 2 sets of criteria: more specific clinical research criteria for probable CBD and broader criteria for possible CBD that are more inclusive but have a higher chance to detect other tau-based pathologies. Probable CBD criteria require insidious onset and gradual progression for at least 1 year, age at onset ≥ 50 years, no similar family history or known tau mutations, and a clinical phenotype of probable CBS or either FBS or naPPA with at least 1 CBS feature. The possible CBD category uses similar criteria but has no restrictions on age or family history, allows tau mutations, permits less rigorous phenotype fulfillment, and includes a PSPS phenotype. Future validation and refinement of the proposed criteria are needed.

The floccular syndrome in herpes simplex type 1 encephalitis.

A woman with herpes simplex virus type 1 (HSV1) encephalitis had downbeat nystagmus. The nystagmus was robust in primary gaze but attenuated during upgaze, suggestive of the flocculus involvement. FLAIR and T2-sequences of the brain MRI revealed cerebral lesions typical of HSV1, but also patchy hyperintensities in bilateral flocculi. Cerebrospinal fluid polymerase chain reaction confirmed HSV1 infection. Encephalopathy and downbeat nystagmus gradually improved with acyclovir therapy.

Quantitative analysis of gait and balance response to deep brain stimulation in Parkinson's disease.

Gait and balance disturbances in Parkinson's disease (PD) can be debilitating and may lead to increased fall risk. Deep brain stimulation (DBS) is a treatment option once therapeutic benefits from medication are limited due to motor fluctuations and dyskinesia. Optimizing DBS parameters for gait and balance can be significantly more challenging than for other PD motor symptoms. Furthermore, inter-rater reliability of the standard clinical PD assessment scale, Unified Parkinson's Disease Rating Scale (UPDRS), may introduce bias and washout important features of gait and balance that may respond differently to PD therapies. Study objectives were to evaluate clinician UPDRS gait and balance scoring inter-rater reliability, UPDRS sensitivity to different aspects of gait and balance, and how kinematic features extracted from motion sensor data respond to stimulation. Forty-two subjects diagnosed with PD were recruited with varying degrees of gait and balance impairment. All subjects had been prescribed dopaminergic medication, and 20 subjects had previously undergone DBS surgery. Subjects performed seven items of the gait and balance subset of the UPDRS while wearing motion sensors on the sternum and each heel and thigh. Inter-rater reliability varied by UPDRS item. Correlation coefficients between at least one kinematic feature and corresponding UPDRS scores were greater than 0.75 for six of the seven items. Kinematic features improved (p<0.05) from DBS-OFF to DBS-ON for three UPDRS items. Despite achieving high correlations with the UPDRS, evaluating individual kinematic features may help address inter-rater reliability issues and rater bias associated with focusing on different aspects of a motor task.

Automated motion sensor quantification of gait and lower extremity bradykinesia.

The objective was to develop and evaluate algorithms for quantifying gait and lower extremity bradykinesia in patients with Parkinson's disease using kinematic data recorded on a heel-worn motion sensor unit. Subjects were evaluated by three movement disorder neurologists on four domains taken from the Movement Disorders Society Unified Parkinson's Disease Rating Scale while wearing the motion sensor unit. Multiple linear regression models were developed based on the recorded kinematic data and clinician scores and produced outputs highly correlated to clinician scores with an average correlation coefficient of 0.86. The newly developed models have been integrated into a home-based system for monitoring Parkinson's disease motor symptoms.

Influence of orbital eye position on vertical saccades in progressive supranuclear palsy.

Disturbance of vertical saccades is a cardinal feature of progressive supranuclear palsy (PSP). We investigated whether the amplitude and peak velocity (PV) of saccades are affected by the orbital position from which movements start in PSP patients and age-matched control subjects. Subjects made vertical saccades in response to ±5° vertical target jumps with their heads in one of three positions: head "center," head pitched forward ∼15°, and head pitched back ∼15°. All patients showed some effect of starting eye position, whether beginning in the upward or downward field of gaze, on saccade amplitude, PV, and net range of movement. Generally, reduction of amplitude and PV were commensurate and bidirectional in the affected hemifield of gaze. Such findings are unlikely to be because of orbital factors and could be explained by varying degrees of involvement of rostral midbrain nuclei in the pathological process.

Identification of common variants influencing risk of the tauopathy progressive supranuclear palsy.

Progressive supranuclear palsy (PSP) is a movement disorder with prominent tau neuropathology. Brain diseases with abnormal tau deposits are called tauopathies, the most common of which is Alzheimer's disease. Environmental causes of tauopathies include repetitive head trauma associated with some sports. To identify common genetic variation contributing to risk for tauopathies, we carried out a genome-wide association study of 1,114 individuals with PSP (cases) and 3,247 controls (stage 1) followed by a second stage in which we genotyped 1,051 cases and 3,560 controls for the stage 1 SNPs that yielded P ≤ 10(-3). We found significant previously unidentified signals (P < 5 × 10(-8)) associated with PSP risk at STX6, EIF2AK3 and MOBP. We confirmed two independent variants in MAPT affecting risk for PSP, one of which influences MAPT brain expression. The genes implicated encode proteins for vesicle-membrane fusion at the Golgi-endosomal interface, for the endoplasmic reticulum unfolded protein response and for a myelin structural component.

The disturbance of gaze in progressive supranuclear palsy: implications for pathogenesis.

Progressive supranuclear palsy (PSP) is a disease of later life that is currently regarded as a form of neurodegenerative tauopathy. Disturbance of gaze is a cardinal clinical feature of PSP that often helps clinicians to establish the diagnosis. Since the neurobiology of gaze control is now well understood, it is possible to use eye movements as investigational tools to understand aspects of the pathogenesis of PSP. In this review, we summarize each disorder of gaze control that occurs in PSP, drawing on our studies of 50 patients, and on reports from other laboratories that have measured the disturbances of eye movements. When these gaze disorders are approached by considering each functional class of eye movements and its neurobiological basis, a distinct pattern of eye movement deficits emerges that provides insight into the pathogenesis of PSP. Although some aspects of all forms of eye movements are affected in PSP, the predominant defects concern vertical saccades (slow and hypometric, both up and down), impaired vergence, and inability to modulate the linear vestibulo-ocular reflex appropriately for viewing distance. These vertical and vergence eye movements habitually work in concert to enable visuomotor skills that are important during locomotion with the hands free. Taken with the prominent early feature of falls, these findings suggest that PSP tauopathy impairs a recently evolved neural system concerned with bipedal locomotion in an erect posture and frequent gaze shifts between the distant environment and proximate hands. This approach provides a conceptual framework that can be used to address the nosological challenge posed by overlapping clinical and neuropathological features of neurodegenerative tauopathies.

Selective defects of visual tracking in progressive supranuclear palsy (PSP): implications for mechanisms of motion vision.

Smooth ocular tracking of a moving visual stimulus comprises a range of responses that encompass the ocular following response (OFR), a pre-attentive, short-latency mechanism, and smooth pursuit, which directs the retinal fovea at the moving stimulus. In order to determine how interdependent these two forms of ocular tracking are, we studied vertical OFR in progressive supranuclear palsy (PSP), a parkinsonian disorder in which vertical smooth pursuit is known to be impaired. We measured eye movements of 9 patients with PSP and 12 healthy control subjects. Subjects viewed vertically moving sine-wave gratings that had a temporal frequency of 16.7 Hz, contrast of 32%, and spatial frequencies of 0.17, 0.27 or 0.44 cycles/degree. We measured OFR amplitude as change in eye position in the 70-150 ms, open-loop interval following stimulus onset. Vertical smooth pursuit was studied as subjects attempted to track a 0.27 cycles/degree grating moving sinusoidally through several cycles at frequencies between 0.1 and 2.5 Hz. We found that OFR amplitude, and its dependence on spatial frequency, was similar in PSP patients (group mean 0.10 degree) and control subjects (0.11 degree), but the latency to onset of OFR was greater for PSP patients (group mean 99 ms) than control subjects (90 ms). When OFR amplitude was re-measured, taking into account the increased latency in PSP patients, there was still no difference from control subjects. We confirmed that smooth pursuit was consistently impaired in PSP; group mean tracking gain at 0.7 Hz was 0.29 for PSP patients and 0.63 for controls. Neither PSP patients nor control subjects showed any correlation between OFR amplitude and smooth-pursuit gain. We propose that OFR is spared because it is generated by low-level motion processing that is dependent on posterior cerebral cortex, which is less affected in PSP. Conversely, smooth pursuit depends more on projections from frontal cortex to the pontine nuclei, both of which are involved in PSP. The accessory optic pathway, which is heavily involved in PSP, seems unlikely to contribute to the OFR in humans.

Clinically deployable Kinesia technology for automated tremor assessment.

The objective was to design, build, and assess Kinesia, a wireless system for automated assessment of Parkinson's disease (PD) tremor. The current standard in evaluating PD is the Unified Parkinson's Disease Rating Scale (UPDRS), a qualitative ranking system typically completed during an office visit. Kinesia integrates accelerometers and gyroscopes in a compact patient-worn unit to capture kinematic movement disorder features. Objectively quantifying PD manifestations with increased time resolution should aid in evaluating efficacy of treatment protocols and improve patient management. In this study, PD subjects performed the tremor subset of the UPDRS motor section while wearing Kinesia. Quantitative kinematic features were processed and highly correlated to clinician scores for rest tremor (r(2) = 0.89), postural tremor (r(2) = 0.90), and kinetic tremor (r(2) = 0.69). The quantitative features were used to develop a mathematical model that predicted tremor severity scores for new data with low errors. Finally, PD subjects indicated high clinical acceptance.