James F. Morley

Genetic Influences on Cognitive Decline in Parkinson's Disease

The role of genetic factors in cognitive decline associated with Parkinsons disease (PD) is unclear. We examined whether variations in apolipoprotein E (APOE), microtubule‐associated protein tau (MAPT), or catechol‐O‐methytransferase (COMT) genotypes are associated with cognitive decline in PD. We performed a prospective cohort study of 212 patients with a clinical diagnosis of PD. The primary outcome was change in Mattis Dementia Rating Scale version 2 score. Linear mixed‐effects models and survival analysis were used to test for associations between genotypes and change in cognitive function over time. The ε4 allele of APOE was associated with more rapid decline (loss of 2.9; 95% confidence interval [CI]: 1.7–4.1) of more points per year; P < 0.001) in total score and an increased risk of a ≥10 point drop during the follow‐up period (hazard ratio, 2.8; 95% CI: 1.4–5.4; P = 0.003). MAPT haplotype and COMT genotype were associated with measures of memory and attention, respectively, over the entire follow‐up period, but not with the overall rate of cognitive decline. These results confirm and extend previously described genetic associations with cognitive decline in PD and imply that individual genes may exert effects on specific cognitive domains or at different disease stages. Carrying at least one APOE ε4 allele is associated with more rapid cognitive decline in PD, supporting the idea of a component of shared etiology between PD dementia and Alzheimers disease. Clinically, these results suggest that genotyping can provide information about the risk of future cognitive decline for PD patients.

Longitudinal study of normal cognition in Parkinson disease.

Objective: To report the rates and predictors of progression from normal cognition to either mild cognitive impairment (MCI) or dementia using standardized neuropsychological methods. Methods: A prospective cohort of patients diagnosed with Parkinson disease (PD) and baseline normal cognition was assessed for cognitive decline, performance, and function for a minimum of 2 years, and up to 6. A panel of movement disorders experts classified patients as having normal cognition, MCI, or dementia, with 55/68 (80.9%) of eligible patients seen at year 6. Kaplan-Meier curves and Cox proportional hazard models were used to examine cognitive decline and its predictors. Results: We enrolled 141 patients, who averaged 68.8 years of age, 63% men, who had PD on average for 5 years. The cumulative incidence of cognitive impairment was 8.5% at year 1, increasing to 47.4% by year 6. All incident MCI cases had progressed to dementia by year 5. In a multivariate analysis, predictors of future decline were male sex (p = 0.02), higher Unified Parkinsons Disease Rating Scale motor score (p ≤ 0.001), and worse global cognitive score (p < 0.001). Conclusions: Approximately half of patients with PD with normal cognition at baseline develop cognitive impairment within 6 years and all new MCI cases progress to dementia within 5 years. Our results show that the transition from normal cognition to cognitive impairment, including dementia, occurs frequently and quickly. Certain clinical and cognitive variables may be useful in predicting progression to cognitive impairment in PD.

A comparative study of Parkinson's disease and leucine-rich repeat kinase 2 p.G2019S parkinsonism

Parkinson disease is a progressive neurodegenerative disease for which leucine-rich repeat kinase 2 (LRRK2 carriers) p.G2019S confers substantial genotypic and population attributable risk. With informed consent, we have recruited clinical data from 778 patients from Tunisia (of which 266 have LRRK2 parkinsonism) and 580 unaffected subjects. Motor, autonomic, and cognitive assessments in idiopathic Parkinson disease and LRRK2 patients were compared with regression models. The age-associated cumulative incidence of LRRK2 parkinsonism was also estimated using case-control and family-based designs. LRRK2 parkinsonism patients had slightly less gastrointestinal dysfunction and rapid eye movement sleep disorder. Overall, disease penetrance in LRRK2 carriers was 80% by 70 years but women become affected a median 5 years younger than men. Idiopathic Parkinson disease patients with younger age at diagnosis have slower disease progression. However, age at diagnoses does not predict progression in LRRK2 parkinsonism. LRRK2 p.G2019S mutation is a useful aid to diagnosis and modifiers of disease in LRRK2 parkinsonism may aid in developing therapeutic targets.

Olfactory dysfunction is associated with neuropsychiatric manifestations in Parkinson's disease

Hyposmia, psychiatric disorders, and cognitive problems are common nonmotor manifestations in Parkinsons disease, but how they are related remains unclear. We investigated the relationship between olfactory dysfunction and neuropsychiatric manifestations and performed a cross‐sectional study of 248 patients at two movement disorders clinics at academic medical centers. Psychiatric measures were the Geriatric Depression Scale‐15, Inventory of Depressive Symptomatology, State Anxiety Inventory, Apathy Scale, and Parkinsons Psychosis Rating Scale. Cognitive measures were the Mini–Mental State Examination, Hopkins Verbal Learning Test–Revised, Digit Span, Tower of London‐Drexel, and the Stroop Color Word Test. Olfaction was tested with the University of Pennsylvania Smell Identification Test. There was no significant association between olfaction and mood measures, but psychotic symptoms were more common in patients with olfaction scores below the median (30% vs. 12%; P < 0.001). Worse olfaction was associated with poorer memory (Hopkins Verbal Learning Test–Revised delayed recall items: mean [standard deviation], 6.2 [3.2] vs. 8.4 [2.8]; P < 0.001) and executive performance (Tower of London total moves, 52 [38] vs. 34 [21]; P < 0.001). Odor‐identification score was a significant predictor of abnormal performance on these cognitive tests after adjustment for age, sex, and disease characteristics in logistic regression models. The relationship between hyposmia, psychosis, and specific cognitive impairments may reflect the anatomic distribution of Lewy pathology and suggests that olfactory dysfunction could be a biomarker of additional extranigral disease. Future prospective studies are warranted to assess whether hyposmia, a very early feature of Parkinsons disease, might be used to predict the appearance of other common nonmotor symptoms.

A New Cyclic AMP-independent, Gs-mediated Stimulatory Mechanism via the Adenosine A2a Receptor in the Intact Cardiac Cell

The objectives of this study were to investigate the mechanism underlying the adenosine A2a receptor (A2aR)-mediated positive inotropic response and to define its contractile function using chick embryo ventricular cells as a model. Activation of the A2aR caused a marked stimulation of calcium entry and cell contractility, which were blocked by verapamil or nifedipine. The effects elicited by maximal concentrations of the A2aR agonist 2-[4-(2-carboxyethyl)phenylethylamino]-5′-N-ethylcarboxamidoadenosine and the β-adrenergic agonist isoproterenol were additive, indicating that the two receptors do not share a common stimulatory mechanism. The cAMP antagonist (Rp)-adenosine cyclic 3′:5′-monophosphorothioate was ineffective in inhibiting the A2aR-mediated stimulation of contractility or the L-type calcium channel, while it completely abolished the isoproterenol effects. Activation of the A2aR had no effect on Na+/Ca2+ exchange or inositol 1,4,5-trisphosphate accumulation. Blocking of the A2aR resulted in unopposed A1 receptor-mediated inhibitory effects and led to an inhibition of basal contractility and an enhanced anti-adrenergic effect by A1 agonist. The adenosine A2a receptor mediates a new cyclic AMP-independent mechanism and a new contractile function in the cardiac cell.

Olfactory impairment predicts cognitive decline in early Parkinson's disease

OBJECTIVE To evaluate the association between baseline olfaction and both cross-sectional and longitudinal cognitive assessments, motor symptoms, non-motor symptoms (NMS), and CSF biomarkers in early Parkinsons disease (PD). METHODS Parkinsons Progression Markers Initiative (PPMI) participants underwent baseline olfactory testing with the University of Pennsylvania Smell Identification Test (UPSIT). Serial assessments included measures of motor symptoms, NMS, neuropsychological assessment, and CSF biomarkers. Up to three years follow-up data were included. RESULTS At baseline, worse olfaction (lowest tertile) was associated with more severe NMS, including anxiety and autonomic symptoms. Those in the lowest olfactory tertile were more likely to report cognitive impairment (37.4%) compared to those in the middle (24.4%) and highest olfactory tertiles (14.2%, p < 0.001). Aβ1-42 was significantly lower, and tau/Aβ1-42 ratio was higher in those with worse olfaction. In longitudinal analyses, lower UPSIT score was associated with greater decline in MoCA score (β = 0.02 [0.01, 0.03], p = 0.001) over time, as were composite measures of UPSIT score and either Aβ1-42 or tau/Aβ1-42 ratio. In a Cox proportional hazards model, a composite measure of olfaction and Aβ1-42 was a significant predictor of conversion from normal cognition to mild cognitive impairment (MCI; i.e., MoCA < 26), with subjects most impaired on both measures being 87% more likely to develop incident MCI (HR = 1.87 [1.16, 3.01], p = 0.01). CONCLUSIONS Worse baseline olfaction is associated with long-term cognitive decline. The addition of AD CSF biomarkers to olfactory testing may increase the likelihood of identifying those at highest risk for cognitive decline and progression to MCI.

Olfaction as a biomarker in Parkinson's disease

Olfactory dysfunction in Parkinsons disease is common and of interest, both as a clinical finding and potential biomarker. In this article, we discuss studies characterizing the olfactory deficit in Parkinsons disease and pathological analysis that suggests the olfactory system is a likely induction site of the neurodegenerative process. These studies have enabled research to explore the potential of olfactory dysfunction as a key component in early diagnostic strategies, as a biomarker for diagnostic purposes, a predictor of clinical outcomes and a potential therapy-independent marker of disease progression.

Current understanding and management of Parkinson disease Five new things

PubMed query for “Parkinson disease” yields more than 2,000 articles per year for each of the last 5 years. That is a daunting pile of bedside reading for even the most diligent neurologist. This review highlights 5 emerging topics that are changing our current understanding and management of Parkinson disease (PD). When using the term PD, we mean Lewy body parkinsonism as defined by the clinical criteria of the United Kingdom Parkinsons Disease Society Brain Bank. Other parkinsonian syndromes, such as progressive supranuclear palsy and multiple system atrophy, are beyond the scope of this review. Clinicians are frequently faced with the question, posed by a newly diagnosed patient or family member: “Is Parkinsons genetic?” This apparently simple question has a complex answer. In a small minority of cases, there are defined genes that, when mutated, cause PD. For example, mutations in α-synuclein ( SNCA ), leucine-rich repeat kinase-2 ( LRRK2 ), Parkin , PTEN-induced kinase-1 ( PINK1 ), and DJ-1 have been convincingly demonstrated to cause familial PD but often without a typically Mendelian pattern of inheritance. Families with clear autosomal recessive and dominant patterns are rare. Yet the relative risk of developing PD is more than 3 times higher for an asymptomatic individual when a first-degree relative is affected with sporadic PD.1 Even where there is clear familial clustering of cases, a causative gene may not be identified. What is the source of this “missing heritability”? Some insight has come from recent genome-wide association studies2,3 of large numbers of patients. These analyses—essentially case-control studies where “exposures” are defined by genotyping individuals over a large number of sites of variation in the genome—have identified a number of novel “risk genes” that contribute to the overall chance of developing PD. Importantly, some of these were loci already implicated in familial PD ( SNCA, LRRK2 …

High patient satisfaction with telehealth in Parkinson disease: A randomized controlled study

Background:Parkinson disease (PD) is a complex neurodegenerative disorder that benefits from specialty care. Telehealth is an innovative resource that can enhance access to this care within a patient-centered framework. Research suggests that telehealth can lead to increased patient satisfaction, equal or better clinical outcomes, and cost savings, but these outcomes have not been well-studied in PD. Methods:We conducted a dual active-arm 12-month randomized controlled trial to assess patient satisfaction, clinical outcomes, travel burden, and health care utilization in PD using video telehealth for follow-up care with specialty providers. Telehealth visits took place either at a facility nearer to the patient (satellite clinic arm) or in the patients home (home arm). Each control group received usual in-person care. Patient satisfaction, assessed by quantitative questionnaires, was the primary outcome. Results:Eighty-six men were enrolled (home arm: 18 active, 18 control; satellite clinic arm: 26 active, 24 control) with a mean age of 73 years (range 42–87). There were no differences in baseline characteristics between the active group and the controls in each arm (p > 0.05). A significant difference in overall patient satisfaction was not found; however, high levels of patient satisfaction were found in all groups. Greater satisfaction for the telehealth modality was found in assessments of convenience and accessibility/distance. Clinical outcomes were similar between groups, travel burden was reduced using telehealth, and health care utilization was largely similar in both groups. Conclusions:As the need for PD subspecialty care increases, innovative patient-centered solutions to overcoming barriers to access, such as video telehealth, will be invaluable to patients and may provide high patient satisfaction.

Olfactory dysfunction in Parkinson's disease: Positive effect of cigarette smoking.

There is compelling evidence from over 60 epidemiological studies that smoking significantly reduces the risk of Parkinsons disease (PD). In general, those who currently smoke cigarettes, as well as those with a past history of such smoking, have a reduced risk of PD compared to those who have never smoked. Recently it has been suggested that a cardinal nonmotor sensory symptom of PD, olfactory dysfunction, may be less severe in PD patients who smoke than in PD patients who do not, in contrast to the negative effect of smoking on olfaction described in the general population.