There is clinical and phenotypic heterogeneity in
G2019S Parkinson disease (PD), including loss of smell. Olfactory scores have defined subgroups of
PD at baseline. We now extend this work ...longitudinally to better determine features associated with olfactory classes and to gain further insight into this heterogeneity.
Evaluation of 162 patients with
PD and 198 patients with idiopathic PD (IPD) from the
Ashkenazi Jewish Consortium was performed, with follow-up available for 92 patients with
PD and 74 patients with IPD. Olfaction (University of Pennsylvania Smell Identification Test UPSIT), motor function (Unified Parkinson Disease Rating Scale), and cognition (Montreal Cognitive Assessment), as well as sleep, nonmotor, and mood, were measured. Gaussian mixture models were applied on the UPSIT percentile score to determine subgroups based on olfactory performance. Linear mixed effects models, using PD duration as the time scale, assessed the relationship between UPSIT subgroup membership and motor/cognitive change.
Baseline olfaction was better in
PD compared with IPD (mean UPSIT ± SD: 24.2 ± 8.8 vs 18.9 ± 7.6), with higher mean percentile scores (difference: 15.3 ± 11.6) (
< 0.001) and less frequent hyposmia (55.6% vs 85.4%;
< 0.001). Analysis suggested 3 classes among
PD. Age at onset in
PD was earlier in the worst olfaction group (group 1), compared with groups 2 and 3 (54.5 ± 11.1 vs 61.7 ± 9.3) (
= 0.012), and separately in the hyposmic group overall (55.0 ± 11.3 vs 61.7 ± 9.1) (
< 0.001). Longitudinal motor deterioration in
PD was also significantly faster in the worst UPSIT group than the best UPSIT group (group 3 vs group 1: B = 0.31, SE = 0.35 vs B = 0.96, SE = 0.28) (rate difference = -0.65, SE = 0.29) (
= 0.03). However, olfactory group membership was not significantly associated with cognitive decline.
In this large
cohort with longitudinal analysis, we extend prior work demonstrating subgroups defined by olfaction in
G2019S PD and show that the worst olfaction group has earlier age at PD onset and more rapid motor decline. This supports a subgroup of
PD that might show more rapid change in a clinical trial of
-related agents and highlights the need to integrate careful phenotyping into allocation schema in clinical trials of
-related agents.
This study provides Class II evidence that worse olfactory scores were associated with an earlier age at symptomatic onset and a faster rate of motor deterioration in patients with
PD.
The search for a biomarker for Parkinson's disease (PD) has led to a surge in literature describing peripheral α-synuclein (aSyn) in both biofluids and biopsy/autopsy tissues. Despite encouraging ...results, attempts to capitalize on this promise have fallen woefully short. The Systemic Synuclein Sampling Study (S4) is uniquely designed to identify a reproducible diagnostic and progression biomarker for PD. S4 will evaluate aSyn in multiple tissues and biofluids within the same subject and across the disease spectrum to identify the optimal biomarker source and provide vital information on the evolution of peripheral aSyn throughout the disease. Additionally, S4 will correlate the systemic aSyn profile with an objective measure of nigrostriatal dopaminergic function furthering our understanding of the pathophysiological progression of PD.
Objectives
The objectives of this study were to determine if hypertensive patients with comorbid diabetes mellitus (DM) and/or chronic kidney disease (CKD) receiving a pharmacist intervention had a ...greater reduction in mean blood pressure (BP) and improved BP control at 9 months compared with those receiving usual care; and compare Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) guideline and 2014 guideline (JNC 8) BP control rates in patients with DM and/or CKD.
Methods
This cluster randomized trial included 32 medical offices in 15 states. Clinical pharmacists made treatment recommendations to physicians at intervention sites. This post hoc analysis evaluated mean BP and BP control rates in the intervention and control groups.
Main results
The study included 335 patients (227 intervention, 108 control) when mean BP and control rates were evaluated by JNC 7 inclusion and control criteria. When JNC 8 inclusion and control criteria were applied, 241 patients (165 intervention, 76 control) remained and were included in the analysis. The pharmacist‐intervention group had significantly greater mean systolic blood pressure reduction compared with usual care at 9 months (8.64 mm Hg; 95% confidence interval CI −12.8 to −4.49, p<0.001). The pharmacist‐intervention group had significantly higher BP control at 9 months than usual care by either the JNC 7 or JNC 8 inclusion and control groups (adjusted odds ratio OR 1.97, 95% CI 1.01–3.86, p=0.0470 and OR 2.16, 95% CI 1.21–3.85, p=0.0102, respectively).
Principal conclusions
This study demonstrated that a physician‐pharmacist collaborative intervention was effective in reducing mean systolic BP and improving BP control in patients with uncontrolled hypertension with DM and/or CKD, regardless of which BP guidelines were used.
Background:
The SPRINT-MS trial demonstrated benefit of ibudilast on brain atrophy over 96 weeks in progressive multiple sclerosis (MS). Optical coherence tomography (OCT) was performed in all trial ...participants.
Objective:
Report the OCT results of the SPRINT-MS trial.
Methods:
OCT was obtained at baseline and every 6 months using spectral domain OCT and analyzed by an OCT reading center. Change in each OCT outcome measure by treatment group was estimated using linear mixed models.
Results:
Change in pRNFL thickness was +0.0424 uM/year (95% confidence interval (CI): −0.3091 to 0.3939) for ibudilast versus −0.2630 uM (95% CI: −0.5973 to 0.0714) for placebo (n = 244, p = 0.22). Macular volume change was −0.00503 mm3/year (−0.02693 to 0.01688) with ibudilast versus −0.03659 mm3/year (−0.05824 to −0.01494) for placebo in the Spectralis cohort (n = 61, p = 0.044). For the Cirrus cohort, macular volume change was −0.00040 mm3/year (−0.02167, 0.020866) with ibudilast compared to −0.02083 mm3/year (−0.04134 to −0.00033) for placebo (n = 183, p = 0.1734). Ganglion cell-inner plexiform layer thickness change, available from Cirrus, was −0.4893 uM/year (−0.9132, −0.0654) with ibudilast versus −0.9587 uM/year (−1.3677, −0.5498) with placebo (n = 183, p = 0.12).
Conclusion:
Retinal thinning in MS may be attenuated by ibudilast. Sample size estimates suggest OCT can be a viable outcome measure in progressive MS trials if a therapy has a large treatment effect.
Trial registration:
NN102/SPRINT-MS ClinicalTrials.gov number, NCT01982942.
Although, for patients with cancer, comorbidity can affect the timing of cancer detection, treatment, and prognosis, there is little information relating to the question of whether the choice of ...comorbidity index affects the results of studies. Therefore, to compare the association of comorbidity with mortality after surgery for colon cancer, this study evaluated the Adult Comorbidity Evaluation-27 (ACE-27), the National Institute on Aging (NIA) and National Cancer Institute (NCI) Comorbidity Index, and the Charlson Comorbidity Index (CCI).
The study population consisted of colon cancer patients (N = 496) who underwent surgery at the University of Alabama at Birmingham Hospital from 1981 to 2002. Hazard ratios (HRs) with 95% CIs were obtained using the method of Cox proportional hazards for the three comorbidity indices in predicting overall and colon cancer-specific mortality. The point estimates obtained for comorbidity and other risk factors across the three models were compared.
For each index, the highest comorbidity burden was significantly associated with poorer overall survival (ACE-27: HR = 1.63; 95% CI, 1.24 to 2.15; NIA/NCI: HR = 1.83; 95% CI, 1.29 to 2.61; CCI: HR = 1.46; 95% CI, 1.14 to 1.88) as well as colon cancer-specific survival. For the other risk factors, there was little variation in the point estimates across the three models.
The results obtained from these three indices were strikingly similar. For patients with severe comorbidity, all three indices were statistically significant in predicting shorter survival after surgery for colon cancer.
We sought to examine whether levels of soluble alpha-synuclein (α‐syn), amyloid-beta (Aβ42), phosphorylated tau (p-tau), and total tau (t-tau), as measured in cerebrospinal fluid (CSF), are ...associated with changes in brain volume in Parkinson's disease.
We assessed the 4-year change in total brain volume (n = 99) and baseline CSF α‐syn, Aβ42, p-tau, and t-tau of Parkinson Progression Markers Initiative participants. We used linear mixed models to assess the longitudinal effect of baseline CSF biomarkers on total and regional brain volume and thickness as well as linear regression for cross-sectional analyses at baseline and year 2. All models were adjusted for age and gender; brain volume models also adjusted for baseline intracranial volume. Bonferroni correction was applied.
The 4-year change in total brain volume was −21.2 mm3 (95% confidence interval, −26.1, −16.3). There were no significant associations between the 4-year change in total brain volume and baseline levels of any CSF biomarker (all p-values > 0.05). On cross-sectional analyses, CSF Aβ42 was linearly associated with total brain volume at baseline (R2 = 0.60, p = 0.0004) and at year 2 (R2 = 0.66, p < 0.0001), with CSF Aβ42 < 1100 pg/ml, the threshold for brain amyloid pathology, associated with smaller total brain volume at baseline (p = 0.0010) and at year 2 (p = 0.0002). CSF α‐syn was linearly associated with total brain volume at baseline (R2 = 0.58, p = 0.0044) but not at year 2 (R2 = 0.58, p = 0.1342).
Reduction in soluble Aβ42 is associated with lower total brain volume in Parkinson's disease.
•CSF Aβ42 levels at baseline are linearly associated with brain volume in Parkinson’ disease.•CSF Aβ42 < 1100 pg/ml was associated with smaller brain volume compared with CSF Aβ42 > 1100 pg/ml.•Brain amyloidosis was not associated with brain atrophy at 4 years of follow-up.
A direct antidepressant effect has been reported for certain dopaminergic medications used in the treatment of Parkinson's disease (PD).
To examine whether dopaminergic medications may exert ...differential effects on mood in early PD.
We analyzed prospectively-collected 5-year data on 405 early, drug-naïve (at baseline) PD patients enrolled in the Parkinson's Progression Markers Initiative (PPMI) cohort study, initiated on levodopa, dopamine agonists (DAs), or monoamine-oxidase type B inhibitors (iMAO-B) under naturalistic conditions. The outcome for depressive symptoms was the 15-item Geriatric Depression Scale (GDS-15) score. Potential motor and cognitive confounders were measured using the Unified Parkinson's disease Rating Scale (MDS-UPDRS-III) and the Montreal Cognitive Assessment (MoCA). Three statistical models were used to determine medication effects on GDS-15 scores: unadjusted, adjusted, and a marginal structural model.
One-third of patients in this cohort met GDS-15 threshold for clinically-significant depressive symptoms (GDS-15 ≥ 5). There was a marginal positive effect on GDS-15 scores after iMAO-B treatment initiation (−0.35 95%; CI: −0.73, 0.04; p = 0.08). There were no significant interactions between any of the three medication groups, but robust interactions between MoCA scores and both DAs (p = 0.005) and iMAO-B (p = 0.03) use on GDS-15 scores. Specifically, as MoCA scores worsened, DAs yielded a steeper worsening of GDS-15 scores while iMAO-B a moderating effect on GDS-15.
Dopaminergic medications have no direct effect on mood in early, unselected PD patients.
•Mood effects by dopaminergic effects are confounded by cognitive and motor function.•There was no adjusted mood stabilizing or enhancing effect by any dopaminergic drug.•As cognition worsens, dopamine agonists are associated with worse depression scores.•MAO-B inhibitors may have a modest attenuating effect in the cognition-depression link.
Objective
To determine the evolution of numerous neuropsychiatric symptoms and cognitive abilities in Parkinson disease from disease onset.
Methods
Prospectively collected, longitudinal (untreated, ...disease onset to year 5), observational data from Parkinson's Progression Markers Initiative annual visits was used to evaluate prevalence, correlates, and treatment of 10 neuropsychiatric symptoms and cognitive impairment in Parkinson disease participants and matched healthy controls.
Results
Of 423 Parkinson disease participants evaluated at baseline, 315 (74.5%) were assessed at year 5. Eight neuropsychiatric symptoms studied increased in absolute prevalence by 6.2–20.9% at year 5 relative to baseline, and cognitive impairment increased by 2.7–6.2%. In comparison, the frequency of neuropsychiatric symptoms in healthy controls remained stable or declined over time. Antidepressant and anxiolytic/hypnotic use in Parkinson disease were common at baseline and increased over time (18% to 27% for the former; 13% to 24% for the latter); antipsychotic and cognitive‐enhancing medication use was uncommon throughout (2% and 5% of patients at year 5); and potentially harmful anticholinergic medication use was common and increased over time. At year 5 the cross‐sectional prevalence for having three or more neuropsychiatric disorders/cognitive impairment was 56% for Parkinson disease participants versus 13% for healthy controls, and by then seven of the examined disorders had either occurred or been treated at some time point in the majority of Parkinson disease patients. Principal component analysis suggested an affective disorder subtype only.
Interpretation
Neuropsychiatric features in Parkinson disease are common from the onset, increase over time, are frequently comorbid, and fluctuate in severity.
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