Nonsteroidal Anti-inflammatory Use and LRRK2 Parkinson's Disease Penetrance.

BACKGROUND: The penetrance of leucine rich repeat kinase 2 (LRRK2) mutations is incomplete and may be influenced by environmental and/or other genetic factors. Nonsteroidal anti-inflammatory drugs (NSAIDs) are known to reduce inflammation and may lower Parkinson's disease (PD) risk, but their role in LRRK2-associated PD is unknown. OBJECTIVES: The objective of this study is to evaluate the association of regular NSAID use and LRRK2-associated PD. METHODS: Symptomatic ("LRRK2-PD") and asymptomatic ("LRRK2-non-PD") participants with LRRK2 G2019S, R1441X, or I2020T variants (definitely pathogenic variant carriers) or G2385R or R1628P variants (risk variant carriers) from 2 international cohorts provided information on regular ibuprofen and/or aspirin use (≥2 pills/week for ≥6 months) prior to the index date (diagnosis date for PD, interview date for non-PD). Multivariate logistic regression was used to evaluate the relationship between regular NSAID use and PD for any NSAID, separately for ibuprofen and aspirin in all carriers and separately in pathogenic and risk variant groups. RESULTS: A total of 259 LRRK2-PD and 318 LRRK2-non-PD participants were enrolled. Regular NSAID use was associated with reduced odds of PD in the overall cohort (odds ratio [OR], 0.34; 95% confidence interval [CI], 0.21-0.57) and in both pathogenic and risk variant carriers (ORPathogenic , 0.38; 95% CI, 0.21-0.67 and ORRiskVariant , 0.19; 95% CI, 0.04-0.99). Similar associations were observed for ibuprofen and aspirin separately (ORIbuprofen , 0.19; 95% CI, 0.07-0.50 and ORAspirin , 0.51; 95% CI, 0.28-0.91). CONCLUSIONS: Regular NSAID use may be associated with reduced penetrance in LRRK2-associated PD. The LRRK2 protein is involved in inflammatory pathways and appears to be modulated by regular anti-inflammatory use. Longitudinal observational and interventional studies of NSAID exposure and LRRK2-PD are needed to confirm this association. © 2020 International Parkinson and Movement Disorder Society.

Design and validation of a new instrument to assess fear of falling in Parkinson's disease.

BACKGROUND: Fear of falling may be significantly associated with falls in Parkinson's disease (PD) and may have a negative impact on quality of life. Nevertheless, there are no valid and reliable tools to examine this condition in PD. The objective of this study was to design and determine the psychometric attributes of an instrument to assess fear of falling in PD. METHODS: A prospective 1-year, 2-phase study was conducted to validate the Fear of Falling Scale, a self-assessed instrument for assessing fear of falling in PD. During phase 1, we designed a scale to measure the severity of fear of falling and determine its baseline psychometric characteristics, whereas phase 2 was a 1-year follow-up study to assess the frequency of falls and other clinical factors linked to fear of falling. Convergent and discriminant validity were assessed against the Fear of Falling Measure and the Starkstein Apathy Scale, respectively. RESULTS: The Fear of Falling Scale showed high internal consistency, test-retest reliability, and strong convergent and discriminant validity. There was a significant association between fear of falling score and the presence of both generalized anxiety disorder and major depression, poor balance-related motor ability, increased nonmotor symptoms of PD, more severe impairments in activities of daily living, and increased motor fluctuations. Finally, generalized anxiety disorder was a significant predictor of number of falls during a 12-month follow-up period. CONCLUSIONS: The Fear of Falling Scale is a valid and reliable instrument to assess fear of falling in PD. Fear of falling in PD is associated with specific psychiatric and motor disorders and is significantly related to the performance of balance-related motor functions. © 2019 International Parkinson and Movement Disorder Society.

The neuroimaging basis of apathy: Empirical findings and conceptual challenges.

Apathy, usually defined as loss of motivation, is common in both neurodegenerative conditions such as Alzheimer's disease, and acute neurological disorders such as stroke. Neuroradiological studies on the imaging correlates of apathy have used a variety of methods such as structural and functional magnetic resonance imaging, diffusion tensor imaging, and single photon and positron emission tomography to assess brain metabolic activity and specific synaptic receptors. Dysfunction of the anterior cingulate cortex (ACC) is the strongest anatomical correlate of apathy in Alzheimer's disease, whereas lesions of the basal ganglia are the most common correlates of apathy in cerebrovascular disorders. These findings should be considered in the context of important conceptual and empirical limitations. There are diverging definitions of apathy, and this behavioural disorder has not yet been validated in most neurological conditions. Moreover, apathy may be related not only to specific brain dysfunction, but to relevant contextual confounders which deserve further study.

The Structured Interview for Insight and Judgment in Dementia: Development and validation of a new instrument to assess awareness in patients with dementia.

INTRODUCTION: Poor insight about their cognitive and functional deficits is highly prevalent in patients with Alzheimer's disease (AD); however, there is a lack of reliable, valid instrumentation to measure this construct. The aim of this study was to develop and validate a semistructured interview to assess insight and judgment in patients with AD and to provide information regarding the assessment of competency and risk in this population. METHODS: We validated the Structured Clinical Interview for Insight and Judgment in Dementia (SIJID) in a consecutive series of 124 patients with probable AD. The following psychometric properties were evaluated: internal consistency, test-retest reliability, interrater reliability, and convergent and predictive validity. RESULTS: The SIJID demonstrated high test-retest, interrater reliability and also showed strong discriminant and convergent validity. It showed good predictive validity based on 1-year follow-up information of the patient's clinical outcomes, with a significant association between higher SIJID total scores at baseline, and more severe neuropsychiatric symptoms and more severe caregiver distress at follow-up. Moreover, higher scores of dangerous behaviors at baseline were significantly correlated with a higher frequency of hospitalization and placement in residential care 1 year later. CONCLUSION: The SIJID is a reliable and valid instrument to assess insight and judgment in patients with AD and is a valuable tool for assessing presence and severity of dangerous behaviors, determining risk, and providing critical information for the assessment of competency.

Management of Depression in Parkinson's Disease: A Systematic Review.

BACKGROUND: Depression is a frequent psychiatric condition in Parkinson's disease (PD). The treatment of depression has been examined in several randomized controlled trials and meta-analyses, but no clear guidelines are available. METHODS: We carried out a systematic review of pharmacological and non-pharmacological treatments for depression in patients with PD using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We searched main medical databases up to December 12, 2016, and included randomized controlled trials, patient-control studies, and case series with data on treatment modality, outcome measures, and side effects. RESULTS: Selective serotonergic reuptake inhibitors and tricyclic antidepressants may have efficacy for the treatment of depression in patients with PD, although the evidence is not strong. The antidepressant efficacy of dopamine agonists is still controversial, and initial results were positive for pramipexole but not for rotigotine. Cognitive-behavioral therapy showed promising results in two recent randomized controlled trials, but further evidence is required. Studies using repetitive transcranial magnetic stimulation produced conflicting results, and the efficacy results for this treatment have been inconsistent. On the other hand, electroconclusive therapy produced strong positive results in patients with severe depression, but no randomized controlled trials are available. CONCLUSION: Selective serotonergic reuptake inhibitors and cognitive-behavioral therapy are currently first-line treatments for depression in patients with PD, although the evidence is still weak. The heterogeneity among contributory factors for depression in PD should be considered for the most effective treatment of depression in this condition.

Amygdala Volumetric Change Following Psychotherapy for Posttraumatic Stress Disorder.

The authors investigated the impact of eye movement desensitization and reprocessing (EMDR) and prolonged exposure (PE) on the volumes of the amygdala and hippocampus, structures known to be important in fear conditioning, in 20 patients with posttraumatic stress disorder (PTSD). Patients were randomly allocated to either EMDR or PE. Volumes were assessed before and after treatment via magnetic resonance imaging (MRI). Both groups showed significant improvements in PTSD symptoms. Left amygdala mean volume increased significantly following EMDR treatment only. No significant volumetric changes were found for the hippocampus.

A Randomized, Placebo-Controlled, Double-Blind Efficacy Study of Nefiracetam to Treat Poststroke Apathy.

BACKGROUND: To evaluate the efficacy of treatment with nefiracetam compared to placebo in poststroke apathy. METHODS: A parallel group, randomized, placebo-controlled, double-blind two-center trial in patients with recent stroke and apathy was conducted in 2 tertiary teaching hospitals in Perth, Western Australia, between March 2010 and October 2014. Consenting patients hospitalized with stroke were screened for participation at the time of hospitalization and, if diagnosed with apathy 8-36 weeks later, they were randomized to 12 weeks of 900 mg/day nefiracetam or placebo. The primary efficacy parameter was change in apathy at 12 weeks defined by the 14-item Apathy Scale (AS). RESULTS: Of 2514 patients screened, only 377 (15%) were eligible for the study after the first screening, 233 declined further participation, and 144 were assessed for apathy at 8-36 weeks post stroke to confirm eligibility. Twenty patients out of 106 with a complete psychiatric assessment had apathy (19%). Of this sample, 13 patients were randomized. Overall, the AS score decreased by a mean of 7.0 points (95% CI = -14.6 to .6), but there was no significant between-group difference at week 12 (mean paired t-tests, P > .14). CONCLUSIONS: Treatment with nefiracetam did not prove to be more efficacious than placebo in ameliorating apathy in stroke. The main limitation was the very small sample randomized, highlighting the limitations of conducting drug trials for behavioral problems among stroke patients. Pharmacological studies of apathy in stroke will require a large multicenter study and a massive sample of patients.

The impact of emotional distress on motor blocks and festination in Parkinson's disease.

Recent studies suggest that depression and anxiety in patients with Parkinson's disease may predispose them to freezing. Although festination is also frequent, the association with emotional disorders has not been examined. The aim of the authors was to clarify the association between freezing and festination with anxiety, depressive disorders, and emotional distress. The authors examined a consecutive series of 95 patients with Parkinson's disease using comprehensive psychiatric assessments and a new instrument specifically designed to assess the severity of freezing, festination, and emotional distress (Motor Blocks and Festination Scale). All patients were assessed with the Motor Blocks and Festination Scale, the Mini International Neuropsychiatric Interview, and scales to measure the severity of mood and anxiety disorders. A linear regression analysis showed that both motor blocks and festination were significantly associated with emotional distress and deficits on activities of daily living. Conversely, there was no significant association between motor blocks or festination and generalized anxiety disorder, panic disorder, agoraphobia, social phobia, or depression. Motor blocks and festination are significantly associated with emotional distress, but no significant associations were found with anxiety or affective disorders.

Clinical issues in the treatment of anxiety and depression in older adults with Parkinson's disease.

A significant proportion of persons affected by Parkinson's disease (PD) are over age 65 years. Mental health issues are often less a focus of treatment in this population than physical manifestations of the illness. Anxiety or depression alone, as well as comorbid depression and anxiety, are underrecognized in patients with PD and are associated with deleterious effects on physical and interpersonal functioning, negatively impacting quality of life and well-being. We offer a brief overview of salient clinical points with respect to assessment and treatment approaches to enhance efficacy of the treatment of mental health symptoms in older adults with PD. Cognitive behavior therapy involves the patient learning to overcome behavioral avoidance associated with anxiety and challenge unhelpful negative cognitions. It is suggested that cognitive behavior therapy is an effective approach to treatment of anxiety and depression in PD and should be offered as a treatment to patients.

Psychiatric syndromes in Parkinson's disease.

PURPOSE OF REVIEW: To examine progress about relevant behavioural and psychiatric disorders in Parkinson's disease, such as depression, apathy, psychosis, and impulse control disorder. RECENT FINDINGS: Several recent studies have characterized the phenomenology of depression in Parkinson's disease, and randomized controlled trials have demonstrated the efficacy of tricyclics, selective serotonin reuptake inhibitors and psychotherapy for depression in Parkinson's disease. Apathy is a valid behavioural syndrome in Parkinson's disease and is associated with depression and cognitive deficits. Psychosis is highly prevalent in the late stages of the disease, but there are few effective therapeutic modalities for this psychiatric condition. Impulse control disorders are also relatively frequent in Parkinson's disease, and are associated with comorbid psychiatric disorders. SUMMARY: Standardized criteria should be used to diagnose depression and apathy in Parkinson's disease. Psychotherapy and pharmacotherapy are useful treatment modalities for affective disorders in Parkinson's disease. Clozapine is still the most effective, albeit rarely used, treatment for psychosis in Parkinson's disease. Impulse control disorders are relatively frequent in Parkinson's disease and all patients should be screened for this complex disorder.

Diagnostic criteria for depression in Parkinson's disease: a study of symptom patterns using latent class analysis.

Although major depression is one of the most frequent psychiatric disorders among patients with Parkinson's disease, diagnostic criteria have yet to be validated. The main aim of our study was to validate depressive symptoms using latent class analysis for use as diagnostic criteria for major depression in Parkinson's disease. We examined a consecutive series of 259 patients with Parkinson's disease admitted to 2 movement disorders clinics for regular follow-ups. All patients were assessed with a comprehensive psychiatric interview that included structured assessments for depression, anxiety, and apathy. The main finding was that all 9 Diagnostic and Statistical Manual (4th edition) diagnostic criteria for major depression (ie, depressed mood, diminished interest or pleasure, weight or appetite changes, sleep changes, psychomotor changes, loss of energy, feelings of worthlessness or inappropriate guilt, poor concentration, and suicidal ideation) identified a patient class (severe depression group) with high statistical significance. Latent class analysis also demonstrated a patient class with minimal depressive symptoms (no-depression group), and a third patient class with intermediate depressive symptoms (moderate depression). Anxiety and apathy were both significant comorbid conditions of moderate and severe depression. Taken together, our findings support the use of the full Diagnostic and Statistical Manual (4th edition) criteria for major depression for use in clinical practice and research in Parkinson's disease and suggest that anxiety may be included as an additional diagnostic criterion.

Diagnostic criteria for depression in Alzheimer disease: a study of symptom patterns using latent class analysis.

CONTEXT: Although depression in Alzheimer disease (AD) has a negative emotional and functional impact on patients and caregivers, specific criteria to diagnose depression in AD are still to be validated. OBJECTIVE: To validate a set of diagnostic criteria for major depression in AD. DESIGN: Cross-sectional design using latent cluster analysis (LCA). SETTING: Participants were recruited from consecutive referrals to a Memory Clinic of a tertiary hospital. PARTICIPANTS: A consecutive series of 971 outpatients with probable AD. MAIN OUTCOME MEASURE: Clusters of patients with or without major depression as determined with LCA. RESULTS: A LCA demonstrated three clusters that were considered to represent major depression, minor depression, and no depression. All nine Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria for major depression were significantly associated with the major depression cluster. Although a diagnosis of generalized anxiety disorder (GAD) and apathy were also associated with the major depression cluster, irritability was not. CONCLUSIONS: The DSM-IV criteria for major depression should be used unmodified to diagnose depression in AD. Future studies should determine whether GAD should be included as an additional diagnostic criterion.

Apathy and Parkinson's disease.

OPINION STATEMENT: Apathy, a frequent finding in Parkinson's disease (PD), is significantly associated with depression and dementia. Few studies have examined the efficacy of psychotropic or psychological treatments of apathy in PD, and adequate randomized controlled trials are still lacking. There is anecdotal evidence that dopaminergic agonists may be a useful treatment modality. Levodopa may improve the loss of motivation in the "off" motor state, and dopaminergic agonists could be useful to treat apathy after the withdrawal of dopaminergic treatment in patients undergoing deep brain stimulation of the subthalamic nucleus. On the other hand, the selective norepinephrine reuptake inhibitor atomoxetine did not demonstrate efficacy in improving apathy in a randomized controlled trial with apathy as a secondary efficacy measure. Given the significant association between apathy and both depression and cognitive decline, future studies should examine whether improving mood and cognition may also have a positive impact upon apathy in PD. For those PD patients with "pure" apathy, specific psychotherapeutic techniques should be developed.

Anosognosia is a significant predictor of apathy in Alzheimer's disease.

Anosognosia and apathy are among the most common behavioral and psychological disorders of Alzheimer's disease and are significantly associated in cross-sectional studies. The aim for this study was to carry out for the first time a longitudinal assessment of this association with the aim of clarifying the predictive role between anosognosia and apathy in Alzheimer's disease. A consecutive series of 213 patients with probable Alzheimer's disease were assessed for the presence of apathy and anosognosia using a specific neuropsychiatry assessment. One hundred fifty four of the patients (72%) had a follow-up assessment between 1 and 4 years after the baseline evaluation. Patients with anosognosia at baseline had a significant increase in apathy scores during follow-up relative to patients without anosognosia at both assessments. Conversely, patients with or without apathy had an increase of similar magnitude in anosognosia scores. In conclusion, anosognosia is a significant predictor of apathy in Alzheimer's disease. This may be related to a specific pattern of progression of neuropathology and/or to poor adjustment of Alzheimer's disease patients with poor insight into their functional deficits.

Neuroimaging correlates of apathy and depression in Alzheimer's disease.

A consecutive series of 79 patients with probable Alzheimer's disease were assessed with a structured psychiatric evaluation, and diagnoses of apathy and depression were made using standardized criteria. Three-dimensional MRI scans were obtained from all patients, and images were segmented into gray matter, white matter, and CSF. White matter hyperintensities were edited on segmented images, and lobar assignments (frontal, temporal, parietal, and occipital) were made based on Talairach coordinates. Patients with apathy showed a significantly larger volume of frontal white matter hyperintensities than patients without apathy. Patients with depression had a significantly larger volume of right parietal white matter hyperintensities than patients without depression. However, neither apathy nor depression was significantly associated with lobar gray or white matter atrophy. Frontal and right parietal white matter hyperintensities are the strongest brain structural correlates of apathy and depression in Alzheimer's disease.

The syndromal validity and nosological position of apathy in Parkinson's disease.

Although apathy is among the most frequent behavioral changes in Parkinson's disease (PD), its diagnosis is still problematic, and the overlap with depression and dementia poorly studied. Aim of the study was validate specific criteria to diagnose apathy in PD, and to examine its association with subsyndromes of depression and dementia. A series of 164 patients with PD, 44 patients with "primary" depression and no PD, 23 patients with Alzheimer's disease, and 26 age-comparable healthy controls underwent a comprehensive psychiatric assessment that included a structured psychiatric interview and the Apathy Scale. A set of seven diagnostic criteria showed high sensitivity and specificity for clinically diagnosed apathy. Fifty-two of the 164 patients with PD (32%) met diagnostic criteria for apathy. Eighty-three percent of patients with apathy had comorbid depression and 56% had dementia. Only 5 of the 40 PD patients (13%) with neither depression nor dementia had apathy. We validated a set of standardized criteria for the diagnosis of apathy in PD. About one third of a series of patients attending a Movement Disorders Clinic showed apathy. Both depression and dementia were the most frequent comorbid conditions of apathy in PD.

Apathy predicts more severe parkinsonism in Alzheimer's disease.

OBJECTIVES: Parkinsonian signs are frequent in Alzheimer disease (AD) and are associated with a faster cognitive decline, worse quality of life, and early nursing home admission. Cross-sectional studies in AD reported a significant association between parkinsonism and apathy. The aim of this study was to assess the chronological association between apathy and parkinsonism in AD. DESIGN: Longitudinal study of a consecutive series of patients with AD. SETTING: Dementia clinic from a tertiary clinical center. PARTICIPANTS: One hundred sixty-nine patients meeting diagnostic criteria for AD. INTERVENTION: A consecutive series of 169 patients with probable AD were assessed for the presence of parkinsonism, cognitive deficits, apathy, and depression with the Unified Parkinson's Disease Rating Scale and a comprehensive neuropsychiatry assessment. One hundred thirty-six (80%) of the patients had a follow-up assessment between 1 and 4 years after the baseline evaluation. MEASUREMENTS: Scores on apathy, parkinsonism, and depression scales at follow-up were the main outcome measures. RESULTS: Patients with apathy at baseline or those who developed apathy during follow-up had a significant increase in parkinsonism at follow-up when compared with patients with no apathy at both assessments. The association between apathy and increasing parkinsonism was unrelated to age, gender, the severity of cognitive deficits, the presence of depression, or use of psychotropic medications. On the other hand, neither the presence of parkinsonism nor depression at baseline was significantly associated with more severe apathy at follow-up. CONCLUSION: Apathy may be an early manifestation of a more aggressive AD phenotype characterized by loss of motivation, increasing parkinsonism, a faster cognitive and functional decline, and more severe depression.

A validation study of depressive syndromes in Parkinson's disease.

The validity, sensitivity, and specificity of depressive symptoms for the diagnosis of major depression, minor depression, dysthymic disorder, and subsyndromal depression in Parkinson's disease (PD) were examined. A consecutive series of 173 patients with PD attending a Movement Disorders Clinic underwent a comprehensive psychiatric and neurological assessment. The symptoms of loss of interest/pleasure, changes in appetite or weight, changes in sleep, low energy, worthlessness or inappropriate guilt, psychomotor retardation/agitation, concentration deficits, and suicide ideation were all significantly associated with the presence of the DSM-IV depressed mood criterion for major depression. The symptoms of changes in appetite, changes in sleep, low energy, low self-esteem, poor concentration, and hopelessness were all significantly associated with the presence of the DSM-IV criterion of sad mood for dysthymic disorder. Thirty percent of our sample met DSM-IV diagnostic criteria for major depression, 20% met diagnostic criteria for dysthymic disorder, 10% met diagnostic criteria for minor depression, and 8% met clinical criteria for subsyndromal depression. Patients with either major or minor depression had significantly more severe deficits in activities of daily living, more severe cognitive impairments, and more severe Parkinsonism than patients with either dysthymic disorder or no depression. This study provides validation to the DSM-IV diagnostic criteria for major depression and dysthymic disorder for use in PD. The categories of minor and subsyndromal depression may need further validation.