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The Parkinson Associated Risk Syndrome (PARS) study was designed to evaluate whether screening with olfactory testing and dopamine transporter (DAT) imaging could identify participants at risk for developing Parkinson's disease (PD).Hyposmia on a single test has been associated with increased risk of PD, but, taken alone, lacks specificity. We evaluated whether repeating olfactory testing improves the diagnostic characteristics of this screening approach.Participants completed up to 10 years of clinical and imaging evaluations in the PARS cohort. Olfaction was assessed with the University of Pennsylvania Smell Identification Test at baseline and on average 1.4 years later. Multiple logistic regression and Cox proportional hazards regression were used to estimate the hazard of development of clinical PD or abnormal DAT imaging.Of 186 participants who were initially hyposmic, 28% reverted to normosmia on repeat testing (reverters). No initially normosmic subjects and only 2% of reverters developed DAT imaging progression or clinical PD, compared to 29% of subjects with persistent hyposmia who developed abnormal DAT and 20% who developed clinical PD. The relative risk of clinical conversion to PD was 8.3 (95% CI:0.92-75.2, p = 0.06) and of abnormal DAT scan was 12.5 (2.4-156.2, p = 0.005) for persistent hyposmia, compared to reversion.Persistent hyposmia on serial olfactory testing significantly increases the risk of developing clinical PD and abnormal DAT imaging, compared to hyposmia on a single test. Repeat olfactory testing may be an efficient and cost-effective strategy to improve identification of at-risk patients for early diagnosis and disease modification studies.

ObjectiveTo determine whether patients with Lewy body dementia (LBD) with likely Alzheimer disease (AD)–type copathology are more impaired on confrontation naming than those without likely AD-type copathology.MethodsWe selected 57 patients with LBD (dementia with Lewy bodies [DLB], n = 38; Parkinson disease dementia [PDD], n = 19) with available AD CSF biomarkers and neuropsychological data. CSF β-amyloid1-42 (Aβ42), phosphorylated-tau (p-tau), and total-tau (t-tau) concentrations were measured. We used an autopsy-validated CSF cut point (t-tau:Aβ42 ratio > 0.3, n = 43), or autopsy data when available (n = 14), to categorize patients as having LBD with (LBD + AD, n = 26) and without (LBD − AD, n = 31) likely AD-type copathology. Analysis of covariance tested between-group comparisons across biologically defined groups (LBD + AD, LBD − AD) and clinical phenotypes (DLB, PDD) on confrontation naming (30-item Boston Naming Test [BNT]), executive abilities (letter fluency [LF], reverse digit span [RDS]), and global cognition (Mini-Mental State Examination [MMSE]), with adjustment for age at dementia onset, time from dementia onset to test date, and time from CSF to test date. Spearman correlation related cognitive performance to CSF analytes.ResultsPatients with LBD + AD performed worse on BNT than patients with LBD − AD (F = 4.80, p = 0.03); both groups performed similarly on LF, RDS, and MMSE (all p > 0.1). Clinically defined PDD and DLB groups did not differ in performance on any of these measures (all p > 0.05). A correlation across all patients showed that BNT score was negatively associated with CSF t-tau (ρ = −0.28, p < 0.05) and p-tau (ρ = −0.26, p = 0.05) but not Aβ42 (p > 0.1).ConclusionMarkers of AD-type copathology are implicated in impaired language performance in LBD. Biologically based classification of LBD may be advantageous over clinically defined syndromes to elucidate clinical heterogeneity.

Motor features of Parkinson’s disease (PD) are heterogeneous and well-studied; non-tremor features of postural instability and gait dysfunction (PIGD) have been linked to worse outcomes and Alzheimer’s disease (AD) co-pathology. However, these features are understudied in Lewy body dementias (LBD). Here we perform retrospective analysis of a unique cohort of LBD (n=30) with Unified Parkinson’s Disease Rating Scale (UPDRS) data collected at baseline in proximity to cerebrospinal fluid collection to test the hypothesis that LBD patients with a positive AD biomarker profile (LBD+AD=13) would have higher PIGD burden compared with LBD patients without AD biomarker positivity (LBD−AD=17). We find novel evidence for selective impairment of PIGD burden in LBD+AD vs LBD−AD (OR=1.95, 95%CI=1.02-3.70, p=0.04) and a direct association of increasing CSF tau/Aβ(1-42) ratio with increasing PIGD disability in the total cohort (β=0.23, SE=0.08, p=0.01). This unique biomarker stratification approach suggests AD co-pathology may contribute to PIGD motor signs in LBD.

ObjectivesTo investigate the impact of Alzheimer's disease (AD) co-pathology on an in vivo structural measure of neurodegeneration in Lewy body disorders (LBD).MethodsWe studied 72 LBD patients (Parkinson disease (PD)=2, PD-MCI=25, PD with dementia=10, dementia with Lewy bodies=35) with either CSF analysis or neuropathological examination and structural MRI during life. The cohort was divided into those harboring significant AD co-pathology, either at autopsy (intermediate/high AD neuropathologic change) or with CSF signature indicating AD co-pathology (t-tau/Aβ1-42 >0.3) (LBD+AD, N=19), and those without AD co-pathology (LBD-AD, N=53). We also included a reference group of 25 patients with CSF biomarker-confirmed amnestic AD. We investigated differences in MRI cortical thickness estimates between groups, and in the 21 autopsied LBD patients (LBD-AD=14, LBD+AD=7), directly tested the association between antemortem MRI and post-mortem burdens of tau, Aβ, and alpha-synuclein using digital histopathology in five representative neocortical regions.ResultsThe LBD+AD group was characterized by cortical thinning in anterior/medial and lateral temporal regions (P&nbsp

Objective The objective of this study was to determine the frequency and impact of subjective cognitive complaint (SCC) in Parkinson's disease (PD) patients with normal cognition. Methods Patients with PD with expert consensus-determined normal cognition at baseline were asked a single question regarding the presence of SCC. Baseline (N = 153) and longitudinal (up to 4 follow-up visits during a 5-year period; N = 121) between-group differences in patients with PD with (+SCC) and without (-SCC) cognitive complaint were examined, including cognitive test performance and self-rated and informant-rated functional abilities. Results A total of 81 (53%) participants reported a cognitive complaint. There were no between-group differences in global cognition at baseline. Longitudinally, the +SCC group declined more than the -SCC group on global cognition (Mattis Dementia Rating Scale-2 total score, F1,431 = 5.71, P = 0.02), processing speed (Symbol Digit Modalities Test, F1,425 = 7.52, P = 0.006), and executive function (Trail Making Test Part B, F1,419 = 4.48, P = 0.04), although the results were not significant after correction for multiple testing. In addition, the +SCC group was more likely to progress to a diagnosis of cognitive impairment over time (hazard ratio = 2.61, P = 0.02). The +SCC group also demonstrated significantly lower self-reported and knowledgeable informant-reported cognition-related functional abilities at baseline, and declined more on an assessment of global functional abilities longitudinally. Conclusions Patients with PD with normal cognition, but with SCC, report poorer cognition-specific functional abilities, and are more likely to be diagnosed with cognitive impairment and experience global functional ability decline long term. These findings suggest that SCC and worse cognition-related functional abilities may be sensitive indicators of initial cognitive decline in PD. © 2020 International Parkinson and Movement Disorder Society.

The last decade has seen development of numerous novel antipsychotic drugs with unique mechanisms including long-acting formulations for clinical use. A comparative assessment of these new drugs with each other and previous antipsychotics have not been performed with regards to risk for drug-induced movement disorders (DIMD).Medline was searched from January 2010 to February 2022 for primary research articles and review articles in English using the search terms "extrapyramidal" and "tardive" with individual drug names of novel antipsychotics.We identified articles describing the risk of DIMD with 6 novel antipsychotics, 4 novel formulations, and 3 experimental antipsychotics. Both short- and long-term data generally showed comparable to lower risk of DIMD with novel antipsychotics and recent long-acting formulations compared to previously marketed antipsychotics.Several novel antipsychotics, particularly lumateperone and pimavanserin, show promise in being able to treat psychosis while reducing the risk of DIMD. Long-acting paliperidone may reduce risk of DIMD while other long-acting injectable formulations of SGA have similar risk of DIMD compared to oral formulations. New drug targets for treating psychosis without dopamine blockade also show promise.

Olfactory impairment is a common and early sign of Parkinson's disease (PD) and Alzheimer's disease (AD), the two most prevalent neurodegenerative conditions in the elderly. This phenomenon corresponds to pathologic processes emerging in the olfactory system prior to the onset of typical clinical manifestations. Clinically available tests can establish hyposmia through odor identification assessment, discrimination, and odor detection threshold. There are significant efforts to develop preventative or disease-modifying therapies that slow down or halt the progression of PD and AD. Due to the convenience and low cost of its assessment, olfactory impairment could be used in these studies as a screening instrument. In the clinical setting, loss of smell may also help to differentiate PD and AD from alternative causes of Parkinsonism and cognitive impairment, respectively. Here, we discuss the pathophysiology of olfactory dysfunction in PD and AD and how it can be assessed in the clinical setting to aid in the early and differential diagnosis of these disorders.

Given the increasing recognition that neurodegeneration begins decades before the appearance of motor symptoms of Parkinson disease (PD), recent attention has turned to methods of preclinical or prodromal diagnosis. Accurate preclinical diagnosis of individuals at high risk of developing manifest motor PD can improve clinical counseling as well as provide an enriched cohort for studies of possible disease-modifying therapies. In this review article, the authors synthesize the myriad clinical, radiographic, and biochemical signatures of preclinical PD, with an emphasis on biomarkers that may provide accurate population screening for the disease. As individual biomarkers have relatively lowsensitivity and specificity, any population-based approach to preclinical diagnosis will likely combine multiple biomarkers to improve both negative and positive predictive value.

Altres ajuts: Projekt DEAL; German Research Foundation (Grant KFO 219). To identify predictors of 36-month follow-up quality of life (QoL) outcome after bilateral subthalamic nucleus deep brain stimulation (STN-DBS) in Parkinson's disease (PD). In this ongoing, prospective, multicenter international study (Cologne, Manchester, London) including 73 patients undergoing STN-DBS, we assessed the following scales preoperatively and at 6-month and 36-month follow-up: PD Questionnaire-8 (PDQ-8), NMSScale (NMSS), Scales for Outcomes in PD (SCOPA)-motor examination, -activities of daily living, and -complications, and levodopa equivalent daily dose (LEDD). We analyzed factors associated with QoL improvement at 36-month follow-up based on (1) correlations between baseline test scores and QoL improvement, (2) step-wise linear regressions with baseline test scores as independent and QoL improvement as dependent variables, (3) logistic regressions and receiver operating characteristic curves using a dichotomized variable "QoL responders"/"non-responders". At both follow-ups, NMSS total score, SCOPA-motor examination, and -complications improved and LEDD was reduced significantly. PDQ-8 improved at 6-month follow-up with subsequent decrements in gains at 36-month follow-up when 61.6% of patients were categorized as "QoL non-responders". Correlations, linear, and logistic regression analyses found greater PDQ-8 improvements in patients with younger age, worse PDQ-8, and worse specific NMS at baseline, such as 'difficulties experiencing pleasure' and 'problems sustaining concentration'. Baseline SCOPA scores were not associated with PDQ-8 changes. Our results provide evidence that 36-month QoL changes depend on baseline neuropsychological and neuropsychiatric non-motor symptoms burden. These findings highlight the need for an assessment of a wide range of non-motor and motor symptoms when advising and selecting individuals for DBS therapy.

Background: A composite measure that assesses both cognitive and functional abilities in Parkinson’s disease (PD) would be useful for diagnosing mild cognitive impairment (MCI) and PD dementia (PDD) and as an outcome measure in randomized controlled trials. The Clinical Dementia Rating Scale Sum of Boxes (CDR-SOB) was designed to assess both cognition and basic-instrumental activities of daily living in Alzheimer’s disease but has not yet been validated in PD. Objective: To validate the CDR-SOB as a composite cognitive-functional measure for PD patients, as well as to assess its sensitivity to change. Methods: The CDR-SOB and a comprehensive cognitive and functional battery was administered to 101 PD patients at baseline (39 normal cognition [NC], 41 MCI and 21 PDD by expert consensus panel), and re-administered to 64 patients after 1-2 years follow-up (32 NC and 32 cognitive impairment [CI] at baseline). Results: Cross-sectionally, CDR-SOB and domain scores were correlated with corresponding neuropsychological or functional measures and were significantly different between cognitive subgroups both at baseline and at follow-up. In addition, CDR-SOB ROC curves distinguished between normal cognition and dementia with high sensitivity, but did not distinguish well between NC and MCI. Longitudinal changes in the CDR-SOB and domain scores were not significant and were inconsistent in predicting change in commonly-used cognitive and functional tests. Conclusion: The CDR-SOB detects dementia-level cognitive impairment in PD but may not be appropriate for predicting longitudinal combined cognitive-functional changes in patients without significant cognitive impairment at baseline.

Olfactory impairment is a common and early sign of Parkinson's disease (PD) and Alzheimer's disease (AD), the two most prevalent neurodegenerative conditions in the elderly. This phenomenon corresponds to pathologic processes emerging in the olfactory system prior to the onset of typical clinical manifestations. Clinically available tests can establish hyposmia through odor identification assessment, discrimination, and odor detection threshold. There are significant efforts to develop preventative or disease-modifying therapies that slow down or halt the progression of PD and AD. Due to the convenience and low cost of its assessment, olfactory impairment could be used in these studies as a screening instrument. In the clinical setting, loss of smell may also help to differentiate PD and AD from alternative causes of Parkinsonism and cognitive impairment, respectively. Here, we discuss the pathophysiology of olfactory dysfunction in PD and AD and how it can be assessed in the clinical setting to aid in the early and differential diagnosis of these disorders.

Amantadine, an aliphatic primary amine with complex actions on neurotransmitter systems in the basal ganglia, is approved for treating Parkinson's disease and drug-induced movement disorders (DIMDs). These disorders have a significant impact on clinical outcomes and quality of life in patients receiving antipsychotic treatment.We searched PubMed up to June 1, 2019 to identify relevant studies. The following search terms were used: "amantadine" AND "dystonia," "parkinsonism, " "akathisia," "tardive dyskinesia," "catatonia," "neuroleptic malignant syndrome." Reference lists were reviewed for additional material.Evidence from multiple, small, controlled trials supports the efficacy of amantadine as a treatment for drug-induced parkinsonism. Studies show amantadine has a more favorable tolerability profile than anticholinergic medications in these patients. Clinical evidence from observational studies and case reports suggests that further trials might be warranted to support use of amantadine in select patients for preventing dystonic reactions and as a second-line agent for treating catatonia, neuroleptic malignant syndrome, and tardive dyskinesia. Evidence is lacking on the use of amantadine specifically for akathisia relative to other treatments.Amantadine is an evidence-based pharmacologic strategy for treating drug-induced parkinsonism and might be an alternative treatment for other DIMDs in select patients. Additional randomized controlled trials are needed.

BACKGROUND: Cognitive impairment (CI) is one of the most feared and debilitating complications of PD. No therapy has been shown to slow or prevent CI in PD. OBJECTIVE: To determine associations between modifiable comorbidities, including cardiovascular disease risk factors, mood disorders, and sleep characteristics, and rate of cognitive decline in Parkinson's disease (PD). METHODS: Data from the Parkinson's Progression Markers Initiative (PPMI) cohort was queried for baseline cardiovascular disease risk factors, mood disorders, and sleep characteristics. Linear mixed‐ effects models (LME) were used to examine the association between baseline factors and change in cognition, evaluated by the Montreal Cognitive Assessment (MoCA) over time. Baseline comorbidities found to affect MoCA decline were assessed for an association with focal cognitive domains using LME. RESULTS: Higher Body Mass Index (BMI) (β = −0.009, P = 0.039), State Trait Anxiety Inventory (STAI) (β = −0.005, P

Background Physical activity and exercise improve outcomes in Parkinson disease (PD), however little is known about activity levels in early PD patients. Objective and methods We examined self-reported activity scores and examined associations with clinical characteristics in 383 PD subjects and 175 healthy controls from the Parkinson Progression Markers Initiative (PPMI). Results Activity scores were 8% lower for PD subjects than HC (162.6±86.2 vs 175.0±78.5, p = 0.10). Higher scores were associated with younger age and male sex. Only 47% of PD subjects and 44% of HC reported activity consistent with standard recommendations for adults. Conclusions Our findings highlight the need to encourage exercise even in early PD.

The 40-item University of Pennsylvania Smell Identification Test (UPSIT) is an effective instrument to detect olfactory dusfunction in Parkinson’s disease (PD). It is not clear, however, whether tests of this length are necessary to detect such dysfunction. Several studies have suggested that detection of certain odors is selectively compromised in PD, and that a test comprised of these odors could be shorter and more specific for this purpose. Therefore, we attempted to identify a subset of UPSIT odors that distinguish PD from controls with similar or improved test characteristics compared to the full test. The discriminatory power of each odor was examined using UPSIT data from a discovery cohort of 314 PD patients and 314 matched controls and ranked using multiple methods (including odds ratios, regression coefficients and discriminant analysis). To validate optimally discriminant subsets, we calculated test characteristics using data from two independent cohorts (totaling 306 PD and 343 controls). In the discovery cohort, multiple novel 12-item subsets (and the previously described Brief Smell Identification Test-B) performed similarly or improved upon the UPSIT and were better than 12 random items. However, in validation studies from independent cohorts, multiple subsets retained test characteristics similar to the full UPSIT, but did not outperform 12 random items. Differential discriminatory power of individual items is not conserved across independent cohorts arguing against selective hyposmia in PD. However, multiple 12-item subsets performed as well as the full UPSIT. These subsets could form the basis for shorter olfactory tests in the clinical evaluation of Parkinsonism., Non-motor symptoms: sniffing for a faster diagnosis A short test of olfactory function could aid the early diagnosis of Parkinson’s disease (PD). An international study led by James F. Morley at the University of Pennsylvania, USA, examined the ability of 314 PD patients and 314 matched controls to perceive 40 odors in the University of Pennsylvania Smell Identification Test (UPSIT). They used various statistical methods to determine whether tests based on a subset of these odors could distinguish PD patients from controls. Although they were not able to identify a consistent subset of smells that differentiates patients from controls, which supports the idea that there is not a PD-specific pattern of smell loss, they demonstrate that a shorter 12-item version of the UPSIT is specific and sensitive enough to detect olfactory dysfunction in PD.

Background The relationship between statins and cognition in Parkinson's disease (PD) is poorly understood. Objectives Analyses were performed to determine associations between statin use and cross-sectional and longitudinal cognitive performance in PD. Methods Neuropsychological tests, medication logs, and ratings of functional abilities were collected from 313 PD participants longitudinally. Results At baseline, statin users (SU; N = 129) were older, more likely male, and had shorter PD duration than non-statin users (NSU; N = 184). In Cross-sectional analysis, SU performed better on global cognition, Trails B, semantic fluency, and phonemic fluency tasks. Rate of long-term global cognitive (Dementia Rating Scale-2 and MoCA) decline was significantly less in SU.

Early and accurate identification and management of veterans at risk for Parkinson disease is an important priority area for the US Department of Veterans Affairs because of the substantial impact on quality of life and disability-adjusted life years.

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 patient9s 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.

Introduction Physical activity is critical in Parkinson disease (PD) management, but barriers and motivators of activity in Veterans with PD may be unique. We examined activity habits, including barriers and motivators, in this population. Methods Participants completed the Physical Activity Scale in the Elderly (PASE). Compliance with American Heart Association (AHA) recommendations was assessed. Veterans also completed the Exercise Perceptions Questionnaire (EPQ), assessing knowledge, barriers, and motivators of activity. Free-text barriers/motivators were analyzed by the overlapping clusters method. Results Seventy-five Veterans were recruited; mean age (standard deviation [SD]) was 70.5 (8.2) years and mean disease duration (SD) was 5.4 (5.2) years. Raw median PASE was 120.4 (interquartile range [IQR] 68.8–165.7); age-adjusted median PASE was 135.3. Only 9 Veterans (14.3%) were AHA-compliant. There were trends toward negative association between PASE and UPDRS-3 (r = −0.24, p = 0.06) and between PASE and PDQ-8 (r = −0.23, p = 0.08). Sixty-three subjects (84%) completed the EPQ; 27 (42.9%) preferred scheduled exercise, and only 33 (53.2%) reported that they preferred to exercise with others. Common themes of 46 free-text responses included desire to improve PD symptoms (n = 15, 32.6%) and social engagement (n = 12, 26.1%). Conclusions Self-reported activity in Veterans with PD is low, with less than 15% of subjects meeting recommended activity targets. Qualitative analysis of barriers and motivators revealed that although many Veterans enjoy the social aspects of group exercise, they may not feel comfortable in general exercise classes aimed at younger participants without chronic illnesses. These data will be useful in designing Veteran- and/or PD-specific interventions to increase activity levels.

Olfactory dysfunction is common in Parkinson’s disease (PD) and often predates the diagnosis by years, reflecting early deposition of Lewy pathology, the histologic hallmark of PD, in the olfactory bulb. Clinical tests are available that allow for the rapid characterization of olfactory dysfunction, including tests of odor identification, discrimination, detection, and recognition thresholds, memory, and tests assessing the build-up of odor intensity across increasing suprathreshold stimulus concentrations. The high prevalence of olfactory impairment, along with the ease and low cost of assessment, has fostered great interest in olfaction as a potential biomarker for PD. Hyposmia may help differentiate PD from other causes of parkinsonism, and may also aid in the identification of “pre-motor” PD due to the early pathologic involvement of olfactory pathways. Olfactory function is also correlated with other non-motor features of PD and may serve as a predictor of cognitive decline. In this article, we summarize the existing literature on olfaction in PD, focusing on the potential for olfaction as a biomarker for early or differential diagnosis and prognosis.

BACKGROUND Methods to detect early cognitive decline and account for heterogeneity of deficits in Parkinson's disease (PD) are needed. Quantitative methods such as latent class analysis (LCA) offer an objective approach to delineate discrete phenotypes of impairment. OBJECTIVE To identify discrete neurocognitive phenotypes in PD patients without dementia. METHODS LCA was applied to a battery of 8 neuropsychological measures to identify cognitive subtypes in a cohort of 199 non-demented PD patients. Two measures were analyzed from each of four domains: executive functioning, memory, visuospatial abilities, and language. Additional analyses compared groups on clinical characteristics and cognitive diagnosis. RESULTS LCA identified 3 distinct groups of PD patients: an intact cognition group (54.8%), an amnestic group (32.2%), and a mixed impairment group with dysexecutive, visuospatial and lexical retrieval deficits (13.1%). The two impairment groups had significantly lower instrumental activities of daily living ratings and greater motor symptoms than the intact group. Of those diagnosed as cognitively normal according to MDS criteria, LCA classified 23.2% patients as amnestic and 9.9% as mixed cognitive impairment. CONCLUSIONS Non-demented PD patients exhibit distinct neuropsychological profiles. One-third of patients with LCA-determined impairment were diagnosed as cognitively intact by expert consensus, indicating that classification using a statistical algorithm may improve detection of initial and subtle cognitive decline. This study also demonstrates that memory impairment is common in non-demented PD even when cognitive impairment is not clinically apparent. This study has implications for predicting eventual emergence of significant cognitive decline, and treatment trials for cognitive dysfunction in PD.

Background There is compelling evidence from over 60 epidemiological studies that smoking significantly reduces the risk of Parkinson’s 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 non-motor 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.

Drug-induced Parkinsonism (DIP) secondary to antipsychotics and other dopamine antagonists is common and can be clinically indistinguishable from idiopathic Parkinson's disease (PD). Making the correct diagnosis is essential as it has important implications both for management of the underlying psychiatric condition and potentially lifelong therapy with antiparkinsonian agents. Additionally, because Parkinsonism does not always resolve with withdrawal of the offending agent or can recur years later, DIP may sometimes represent unmasking of incipient PD. The problem is increasing in scope as antipsychotic drugs are prescribed for a widening variety of indications, and understanding the factors that distinguish pharmacologic from degenerative Parkinsonism represents a significant unmet need. In this review, we discuss the rationale and evidence for using pre-clinical manifestations of PD, particularly non-motor symptoms, to distinguish between the conditions.

Drug-induced parkinsonism (DIP) is common, and the motor symptoms can be indistinguishable from Parkinson's disease (PD). When symptoms persist after drug withdrawal, this may represent “unmasking” of underlying PD. We previously reported that hyposmia, a common nonmotor feature of PD, was associated with persistent DIP. Here, we report on a series of 33 consecutive patients who underwent dopamine transporter imaging to evaluate DIP. We examined the clinical correlates of underlying dopaminergic denervation by comparing subjects with normal and abnormal scans. Imaging was abnormal in 7 of 33 (21%) cases. Motor features were similar in patients with normal and abnormal scans. Olfactory testing was available for 30 subjects and was concordant with imaging in 27 of 30 (odds ratio = 63; 95% confidence interval: 4.8–820; P = 0.002). Olfactory testing may be a simple screen to help identify DIP patients with underlying dopaminergic denervation, consistent with unmasking of incipient PD.

SUMMARY Management of Parkinson’s disease (PD) is currently based primarily on dopamine-replacement therapy for the alleviation of motor symptoms. Current medical and surgical therapies can provide long-lasting symptomatic benefit, but they do not modify progression of the disease. Research is ongoing to find a therapy that can provide neuroprotection, defined herein as preventing vulnerable neurons from dying. Studies of neuroprotection are limited by a lack of adequate biomarkers of PD progression and by the confounding symptomatic effects of many putative neuroprotective therapies. Studies have shown that levodopa prolongs life, but they have not clearly shown that it modifies disease progression. Trials of dopamine agonists have demonstrated symptomatic effect but no unequivocal neuroprotective benefits. While some studies of monamine oxidase B inhibitors have been promising, they have not conclusively proven disease modification. Exercise provides many benefits to patients with PD, may modify the progression of the disease and should be part of each patient’s treatment plan.

The role of genetic factors in cognitive decline associated with Parkinson's 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 e4 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 e4 allele is associated with more rapid cognitive decline in PD, supporting the idea of a component of shared etiology between PD dementia and Alzheimer's disease. Clinically, these results suggest that genotyping can provide information about the risk of future cognitive decline for PD patients.

Hyposmia, psychiatric disorders, and cognitive problems are common nonmotor manifestations in Parkinson's 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 Parkinson's 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 Parkinson's disease, might be used to predict the appearance of other common nonmotor symptoms.

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 Parkinson's 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 Parkinson's 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 …

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 Parkinson's disease (PD).Parkinson's Progression Marker's 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.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%, p0.001). 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., MoCA26), 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).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.

Background Lightheadedness on standing is a disabling symptom in Parkinson's disease associated with orthostatic hypotension and is thought to represent cardiovascular autonomic dysfunction. Traditional orthostatic blood pressures are normal in some patients with lightheadedness and other measures of cardiovascular dysautonomia can be insensitive. In this study, we used continuous non-invasive arterial pressure monitoring to measure beat-to-beat changes in blood pressure and heart rate on standing and during Valsalva as a potential marker of autonomic dysfunction. Methods Subjects had a diagnosis of Parkinson's disease with or without documented orthostatic hypotension. Each participant underwent traditional measurement of orthostatic blood pressure and heart rate as well as measurement of beat-to-beat blood pressure and heart rate using continuous non-invasive arterial pressure monitoring during Valsalva maneuver and in response to standing. Orthostatic change in blood pressure and heart rate, and frequencies of normal and abnormal blood pressure responses to Valsalva maneuver were analyzed. Results In subjects without documented orthostatic hypotension, there was a higher proportion of abnormal blood pressure responses to Valsalva in subjects with symptoms of lightheadedness or dizziness upon standing compared to those without symptoms (p = 0.03). Additionally, the proportion of abnormal blood pressure responses during Valsalva observed in symptomatic subjects without orthostatic hypotension was indistinguishable from those with documented orthostatic hypotension (p = 0.7). Conclusions Our findings suggest that continuous non-invasive arterial pressure monitoring may be more sensitive than traditional measurement of orthostatic blood pressure to detect subtle cardiac dysautonomia in Parkinson's disease and helpful in the diagnosis of unexplained lightheadedness.

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 Parkinson9s Disease Rating Scale motor score ( p ≤ 0.001), and worse global cognitive score ( p 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.

The correlation between longevity and stress resistance observed in long-lived mutant animals suggests that the ability to sense and respond to environmental challenges could be important for the regulation of life span. We therefore examined the role of heat shock factor (HSF-1), a master transcriptional regulator of stress-inducible gene expression and protein folding homeostasis, in the regulation of longevity. Down-regulation of hsf-1 by RNA interference suppressed longevity of mutants in an insulin-like signaling (ILS) pathway that functions in the nervous system of Caenorhabditis elegans to influence aging. hsf-1 was also required for temperature-induced dauer larvae formation in an ILS mutant. Using tissue-specific expression of wild-type or dominant negative HSF-1, we demonstrated that HSF-1 acts in multiple tissues to regulate longevity. Down-regulation of individual molecular chaperones, transcriptional targets of HSF-1, also decreased longevity of long-lived mutant but not wild-type animals. However, suppression by individual chaperones was to a lesser extent, suggesting an important role for networks of chaperones. The interaction of ILS with HSF-1 could represent an important molecular strategy to couple the regulation of longevity with an ancient genetic switch that governs the ability of cells to sense and respond to stress.

There is compelling evidence from over 60 epidemiological studies that smoking significantly reduces the risk of Parkinson's 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.We evaluated University of Pennsylvania Smell Identification Test (UPSIT) scores from 323 PD patients and 323 controls closely matched individually on age, sex, and smoking history (never, past, or current).Patients exhibited much lower UPSIT scores than did the controls (P 0.0001). The relative decline in dysfunction of the current PD smokers was less than that of the never- and past-PD smokers (respective Ps = 0.0005 and 0.0019). Female PD patients outperformed their male counterparts by a larger margin than did the female controls (3.66 vs. 1.07 UPSIT points; respective Ps 0.0001 and 0.06). Age-related declines in UPSIT scores were generally present (P 0.0001). No association between the olfactory measure and smoking dose, as indexed by pack-years, was evident.PD patients who currently smoke do not exhibit the smoking-related decline in olfaction observed in non-PD control subjects who currently smoke. The physiological basis of this phenomenon is yet to be defined.

Prolonged status epilepticus (SE) can be refractory to conventional interventions, with high rates of subsequent morbidity and mortality. A high fat, low protein, low carbohydrate ketogenic diet (KD) has been used successfully to treat intractable epilepsy. However, its possible role in prolonged SE has not been well described. We report successful use of the KD in two adult patients with prolonged nonconvulsive SE (NCSE) refractory to multiple other interventions. Our observations suggest induction of ketosis may be a novel strategy to safely and effectively treat status in adults even after weeks to months of refractory seizures. Although there are few data regarding the use of the ketogenic diet in the treatment of adult epilepsy syndromes, it may be an option for the treatment of adults with refractory, prolonged SE.

Background Drug-induced Parkinsonism is common, causes significant morbidity, and can be clinically indistinguishable from idiopathic Parkinson's disease. Additionally, drug-induced Parkinsonism may, in some cases, represent “unmasking” of incipient Parkinson's disease. Clinical features or tests that distinguish degenerative from pharmacologic Parkinsonism are needed. Methods We performed a retrospective case-control study of 97 drug-induced Parkinsonism subjects and 97 age-matched patients with Parkinson's disease. We compared the frequency of subjective motor and non-motor complaints, objective motor findings (Unified Parkinson's Disease Rating Scale Part III) and, where available, objective olfactory tests. We also performed a nested case-control study wherein we compared these same features between drug-induced Parkinsonism patients based on whether or not they recovered after changing the offending agent. Results Non-motor symptoms including constipation and sexual dysfunction were more common in Parkinson's disease than in drug-induced Parkinsonism. While total motor scores were similar between groups, Postural Instability-Gait Difficulty scores were also higher in Parkinson's disease. Features that were significantly different or showed a trend towards significance in both comparisons included subjective loss of facial expression, dream-enactment behavior, autonomic complaints and Postural Instability-Gait Difficulty scores. Hyposmia was more common in Parkinson's disease and was strongly predictive of persistent drug-induced Parkinsonism after therapy change (odds ratio 30.3, 95% confidence interval: 1.5–500, p = 0.03). Conclusions A constellation of motor and non-motor features may differentiate unmasked Parkinson's disease from drug-induced Parkinsonism. In particular, olfactory testing may offer a simple and inexpensive method to help predict outcomes in drug-induced Parkinsonism and, potentially, identify a cohort of pre-motor Parkinson's disease.

An 80-year-old man with Parkinson disease underwent DaTscan imaging, which showed no detectable uptake in the basal ganglia but normal background uptake in other parts of the brain and in the chest and abdomen. It was later found that the patient was taking methylphenidate. The second study performed 3 weeks later after discontinuing methylphenidate for 48 hours showed good uptake in the striatum. Our results indicate that methylphenidate may completely block physiologic uptake of DaTscan in the striatum and that this effect can be effectively reversed after discontinuing the medication for a short period.

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.

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-ethylcarboxamidoadenos ine and the beta-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.

Objective: To determine whether evidence of neuronal dysfunction or demise preceded deposition of Lewy pathology in vulnerable neurons in Parkinson disease (PD). Methods: We examined the extent of nigral dysfunction and degeneration among 63 normal, incidental Lewy body disease (ILBD), and PD cases based on tyrosine hydroxylase (TH) immunoreactivity and neuron densities, respectively. The relationship between these markers and Lewy pathology (LP) burden in the substantia nigra (SN) and Braak PD stage was assessed. Results: Compared with normal subjects, ILBD cases displayed a significantly higher percentage of TH-negative cells and lower neuronal densities in the SN as early as Braak PD stages 1 and 2, before LP deposition in the nigrostriatal system. ILBD nigral neuron densities were intermediate between normal subjects and PD cases, and TH-negative percentages were higher in ILBD than either normal or PD cases. Furthermore, neuron density and neuronal dysfunction levels remained relatively constant across Braak PD stages in ILBD. Conclusions: These results suggest that significant neurodegeneration and cellular dysfunction precede LP in the SN, challenging the pathogenic role of LP in PD and the assumption that ILBD always represents preclinical PD.

The role of genetic factors in cognitive decline associated with Parkinson's 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; P0.001) 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 Alzheimer's disease. Clinically, these results suggest that genotyping can provide information about the risk of future cognitive decline for PD patients.

Olfactory impairment is a common early non-motor manifestation in Parkinson's disease that has garnered interest as a clinical biomarker for early “pre-motor” diagnosis and prediction of associated clinical phenotypes. Whether olfactory impairment correlates well with motor symptoms is not yet clear, and recent interest has focused on the relationship between hyposmia and other non-motor symptoms. In this paper, we will review emerging evidence for a relationship between hyposmia and neuropsychiatric manifestations, discussing the potential pathophysiology together with challenges and opportunities for future research.

Hyposmia, psychiatric disorders, and cognitive problems are common nonmotor manifestations in Parkinson's 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 Parkinson's 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%; P0.001). 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]; P0.001) and executive performance (Tower of London total moves, 52 [38] vs. 34 [21]; P0.001). 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 Parkinson's disease, might be used to predict the appearance of other common nonmotor symptoms.

Olfactory dysfunction in Parkinson’s 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 Parkinson’s 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.