Neuropsychiatric Symptoms In Parkinson's Disease Research Articles

Learning Objectives and Core Competencies.

Diagnosis and Treatment of Cognitive and Neuropsychiatric Symptoms in Parkinson Disease and Dementia With Lewy Bodies

Key Points for Issue.

Diagnosis and Treatment of Cognitive and Neuropsychiatric Symptoms in Parkinson Disease and Dementia With Lewy Bodies

Diagnosis and Treatment of Cognitive and Neuropsychiatric Symptoms in Parkinson Disease and Dementia With Lewy Bodies.

This article summarizes the underlying biology and current diagnostic and treatment strategies for the cognitive and neuropsychiatric features of Parkinson disease (PD) and dementia with Lewy bodies (DLB). Cognitive impairment and neuropsychiatric symptoms have been increasingly recognized in PD and DLB, leading to improved diagnosis and treatment strategies. While PD is most associated with and diagnosed by the presence of motor symptoms, nonmotor symptoms can often be the most debilitating for patients. Neuropsychiatric symptoms are highly prevalent nonmotor features and include cognitive impairment, depression, anxiety, psychosis, impulse control disorders, and apathy. Neuropsychiatric symptoms can be difficult to recognize and diagnose in patients with PD, in part because of comorbidity and symptom overlap with core PD features. Treatment strategies are a combination of pharmacologic and nonpharmacologic interventions used in the general population and those specific to PD. DLB is a clinical dementia syndrome, often with similar cognitive, behavioral, autonomic, and motor features as PD. Moreover, DLB has shared underlying pathophysiology with PD, as both are associated with postmortem findings of α-synuclein neuropathology at autopsy and have shared genetic risk and prodromal symptoms. DLB is clinically differentiated from PD by the presenting features of cognitive impairment in DLB, compared with the variable onset of cognitive impairment occurring 1 year or more after established motor onset in PD. Thus, diagnosis and treatment of cognitive impairment and neuropsychiatric symptoms in DLB are similar to that of PD and have important implications for maintaining patient independence and providing support for caregivers because motor, cognitive, and neuropsychiatric symptoms have an additive effect on patient functional disability. A careful history and physical examination are often needed to accurately diagnose and treat the heterogeneous cognitive and behavioral symptoms of PD and DLB. Accurate diagnosis and treatment of neuropsychiatric symptoms and cognitive impairment in PD and DLB are important, as these are a considerable source of patient disability and caregiver burden.

A Multisensory Deficit in the Perception of Pleasantness in Parkinson's Disease.

There is growing interest in non-motor symptoms in Parkinson's disease (PD), due to the impact on quality of life. Anhedonia, the inability to experience joy and lust, has a prevalence of up to 46% in PD. The perception of pleasantness of an odor is reduced in anhedonia without PD. We previously showed a reduced hedonic olfactory perception in PD, i.e., patients evaluated odors as less pleasant or unpleasant compared to controls. This deficit correlated with anhedonia. We aimed to confirm these findings. Moreover, we hypothesized that the perception of pleasantness in PD is affected on a multisensory level and correlates with anhedonia. Therefore, we assessed olfactory, visual and acoustic evaluation of pleasantness in PD and healthy individuals. Participants had to rate the pleasantness of 22 odors, pictures, and sounds on a nine-point Likert scale. Depression, anhedonia, and apathy were assessed by means of questionnaires. Results of the pleasantness-rating were compared between groups and correlated to scores of the questionnaires. In particular pleasant and unpleasant stimuli across all three modalities are perceived less intense in PD, suggesting that a reduced range of perception of pleasantness is a multisensory phenomenon. However, only a reduction of visual hedonic perception correlated with anhedonia in PD. A correlation of reduced perception of pleasantness with apathy or depression was not present. We provide evidence for a multisensory deficit in the perception of pleasantness. Further studies should delineate the underlying neural circuity and the diagnostic value to detect neuropsychiatric symptoms in PD.

Brainstem Pathologies Correlate With Depression and Psychosis in Parkinson's Disease

BackgroundThe pathological hallmarks of Parkinson's disease include intraneuronal Lewy bodies, neuronal loss, and gliosis. We aim to correlate Parkinson's disease neuropsychiatric symptoms, (e.g., depression, psychosis, and anxiety) with the severity of neuropathology in the substantia nigra and locus coeruleus. MethodsThe brains of 175 participants with a primary pathologic diagnosis of Parkinson's disease were analyzed semi-quantitatively to ascertain the burden of neuronal loss and gliosis and Lewy body pathology within the locus coeruleus and substantia nigra. Participants’ history of anxiety, depression, and psychosis were determined using a chart-extracted medical history or record of formal psychiatric evaluation. ResultsOf the sample, 56% (n = 98), 50% (n = 88), and 31.25% (n = 55) of subjects had a diagnosis of psychosis, depression, and anxiety, respectively. Psychosis (χ2 = 7.1, p = 0.008, df = 1) and depression (χ2 = 7.2, p = 0.007, df = 1) were associated with severe neuronal loss and gliosis in the substantia nigra but not in the locus coeruleus. No association was observed between anxiety and neuronal loss and gliosis in either region. No neuropsychiatric symptoms were associated with Lewy body score. After controlling for disease duration and dementia, psychosis (odds ratio [OR]: 3.1, 95% confidence interval [CI]: 1.5–6.4, χ2 = 9.4, p = 0.012, df = 1) and depression (OR: 2.6, 95% CI: 1.3–5.0, χ2 = 7.9, p = 0.005, df = 1) remained associated with severe neuronal loss and gliosis in the substantia nigra. ConclusionThese results suggest that psychosis and depression in Parkinson's disease are associated with the underlying neurodegenerative process and demonstrate that cell loss and gliosis may be a better marker of neuropsychiatric symptoms than Lewy body pathology.

Stress and Mindfulness in Parkinson's Disease: Clinical Effects and Potential Underlying Mechanisms.

ABSTRACTPatients with Parkinson's disease (PD) are very vulnerable to the negative effects of psychological distress: neuropsychiatric symptoms, such as anxiety and depression, are highly prevalent in PD; motor symptoms (such as tremor) typically worsen in stressful situations; and dopaminergic medication is less effective. Furthermore, animal studies of PD suggest that chronic stress may accelerate disease progression. Adequate self‐management strategies are therefore essential to reduce the detrimental effects of chronic stress on PD. Mindfulness‐based interventions encourage individuals to independently self‐manage and adapt to the challenges created by their condition. In PD, emerging clinical evidence suggests that mindfulness‐based interventions may reduce psychological distress and improve clinical symptoms, but insight into the underlying mechanisms is lacking. In this viewpoint, we provide a systematic overview of existing mindfulness trials in PD. Furthermore, we discuss the cerebral mechanisms involved in acute and chronic stress, and the impact of mindfulness‐based interventions on these networks. In addition, we delineate a hypothetical mechanistic framework of how chronic stress may increase the susceptibility for neuropsychiatric symptoms in PD and may potentially even influence disease progression. We end with offering recommendations for future research. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Mild cognitive impairment, psychiatric symptoms, and executive functioning in patients with Parkinson's disease.

Mild cognitive impairment (MCI) and psychiatric symptoms (anxiety, depression, and apathy) are common in Parkinson's disease (PD). While studies have supported the association between psychiatric symptoms and cognitive performance in PD, it is unclear if the magnitude of link between psychiatric symptoms and cognitive health is stronger by MCI status. The purpose of this study was to examine the association between cognitive performance and psychiatric symptoms in PD and whether MCI status moderates this association. Participants (N = 187) completed a comprehensive neuropsychological assessment that included measures of attention, language, executive function (EF), visuospatial ability, episodic memory, and psychiatric symptoms. Participants were classified as PD-MCI (N = 73) or PD-normal cognition (NC; N = 114). Linear regression analyses were conducted to examine the association between psychiatric symptoms and cognitive performance and the moderating effect of PD-MCI status. There were no differences in mean psychiatric symptoms between PD-MCI and PD-NC. Psychiatric symptoms were predominantly associated with worse EF. The magnitude of the association between anxiety and worse EF was larger in participants with PD-MCI compared with PD-NC. A multivariable regression analysis examining the independent contributions of each symptom demonstrated the most robust association between EF and anxiety. Symptoms of anxiety, depression, and apathy are associated with worse executive functioning in individuals with PD. PD-MCI may be important in moderating the association between cognitive performance, specifically anxiety, and EF. Factors that promote cognitive resilience may serve as key therapeutic modalities in managing neuropsychiatric symptoms in PD.

Sleep quality is associated with the severity of clinical symptoms in Parkinson's disease.

Sleep disorders are very common in Parkinson's disease (PD), being associated with several other conditions, mainly psychiatric disorders. The present study was designed to assess sleep quality in Brazilian patients with PD and to evaluate whether sleep changes are associated with clinical variables, especially neuropsychiatric symptoms in PD. Patients diagnosed with PD were subjected to a comprehensive clinical evaluation that included the assessment of motor, cognitive and psychiatric symptoms. Our study showed that sleep complaints are frequent in PD and worse sleep quality is associated with depressive and anxious symptoms, poorer cognitive performance and greater severity of PD symptoms. In the multivariate analysis, older age, greater severity of anxiety and PD remained as significant predictors of worse sleep quality. In conclusion, sleep complaints, depressive and anxiety symptoms are frequent in PD patients. Older age, disease severity and anxiety symptoms are significant predictors of poorer sleep quality in PD patients.

Characteristics, correlates, and assessment of psychosis in Parkinson disease without dementia

IntroductionConsidering that psychosis in Parkinson disease (PD) is associated with worse outcomes, including dementia, we aimed to study the characteristics, correlates, and assessment of PD psychosis in those without dementia. Methods101 PD subjects without dementia (Montreal Cognitive Assessment ≥21/30) were recruited to participate in a study of neuropsychiatric symptoms in PD. This study included a baseline standard neurological exam and common PD symptom assessments. Using the Scale for the Assessment of Positive Symptoms (SAPS) and separate assessment of visual illusions and sense of presence, NINDS-NIMH criteria for PD psychosis were applied. ResultsOf the 33 (32.7%) PD subjects who met diagnostic criteria for psychosis in PD, visual illusions were most common (72.7%), followed by visual hallucinations (39.4%). Adjusted for presence of REM sleep behavior disorder (RBD) (p = 0.097), use of dopamine agonists (OR = 3.7, p = 0.012) and greater autonomic symptom burden (OR = 1.1 (per 1-unit change in score on SCOPA-AUT), p = 0.012) were associated with greater risk of psychosis. Use of dopamine agonists (OR = 5.0, p = 0.007), higher MDS-UPDRS Part II score (OR = 1.1, p = 0.010), and presence of RBD (OR = 4.8, p = 0.012) were independent predictors of visual hallucinations and visual illusions. MDS-UPDRS item 1.2 score ≥1 had highly correlated with the SAPS score (r = 0.65, p < 0.0001), but was 42% sensitive and 96% specific for identifying psychosis. ConclusionThis study confirms the association between dopamine agonists and psychosis in PD patients without dementia. The association of RBD, autonomic symptoms, and MDS-UPDRS Part II scores with psychosis underscore its link to brainstem dysfunction and greater PD motor symptom severity.

Neuropsychiatric Symptoms in Parkinson's Disease.

Parkinson's disease (PD) is characterized by motor symptoms, but focused and extensive research in the last years has provided new knowledge in the field of non-motor symptoms. Non-motor symptoms include neuropsychiatric symptoms such as depression, anxiety, psychosis, apathy, impulse control disorders, and occur in the majority of patients with PD. They are associated with impaired quality of life for patients and relatives, additional deterioration of function and increased use of health resources. Medical and surgical therapies commonly used for treatment of PD can induce or worsen such symptoms. This paper discusses the epidemiology, clinical features and treatment approaches for neuropsychiatric symptoms (NPS) in PD in the perspective of clinical practice and management. The prevalence rates of various NPS are high, various demographic, clinical and treatment related variables have shown to be associated with higher risk of NPS. Randomized controlled trials of pharmacological and non-pharmacological treatments of NPS in PD are sparse. Current evidence supports tricyclic antidepressants as efficacious treatment of depression in PD and antipsychotic clozapine as efficacious choice for psychosis. Further studies to evaluate various other management strategies of NPS in PD are required. Neuropsychiatric symptoms in PD should be considered an integral part of the disease; hence a multidisciplinary approach is essential to improve the overall outcome of PD also through raised awareness and enriched knowledge on NPS.

Neuropsychiatric symptoms in Parkinson's disease: fronto-striatal atrophy contributions.

Neuropsychiatric symptoms (NPS) in Parkinson's disease (PD) have been mostly attributed to neurotransmitter imbalances. However, recent findings suggest that gray matter atrophy also contributes to NPS in PD. We contrast PD patients with different levels of NPS, who are well-matched for dopaminergic medication levels and disease stage, to identify the fronto-striatal gray matter atrophy areas associated with NPS in PD. Fifty mild, non-demented PD patients were included. We median-split the group via a neuropsychiatric screening tool (Cambridge Behavioural Inventory-Revised), which resulted in higher vs. lower NPS groups (n = 25 in each group). Using T1 brain scans acquired on a 3 Tesla MRI scanner, voxel-based morphometry analysis was applied to characterize the pattern of fronto-striatal gray matter atrophy associated with elevated NPS. We found that the higher NPS group was characterized by greater atrophy in the prefrontal cortex, but not striatal areas. This was further corroborated by a post-hoc analysis cross-correlating the severity of NPS with gray matter loss across the whole PD group, which revealed that atrophy in the orbitofrontal cortex and frontal pole was specifically associated with elevated NPS. Prefrontal cortex atrophy in PD has an additional effect to dopamine replacement therapy on the generation of NPS in these patients. These findings are an important step towards the delineation of atrophy vs. neurochemical imbalance in PD, and the results emphasize the importance of considering interactions between prefrontal atrophy and neurochemical dysfunction in the genesis of neuropsychiatric symptoms in PD.

Psychiatric issues in cognitive impairment.

Neuropsychiatric symptoms (NPS) such as depression, hallucinations and apathy commonly occur in Parkinson's disease (PD) and have major clinical consequences including a negative impact on quality of life. This review discusses the epidemiology, clinical features, diagnostic procedures and treatment issues of NPS in PD and related disorders in the perspective of cognitive impairment, focusing on depression, anxiety, visual hallucinations, apathy, sleep disturbances, impulse control disorder and non-motor fluctuations. The majority of NPS are more common in PD patients with dementia, possibly related to shared underlying pathologies. Recent studies also suggest that NPS are associated with mild cognitive impairment in PD, in particular with the amnestic type. Accurate diagnosis of NPS is important but can be difficult, due to overlapping symptoms and similar appearance of symptoms of motor symptoms of parkinsonism, cognitive impairment, mood disorders and apathy. There are few systematic studies focusing on the management of NPS in PD with cognitive impairment.

Neuropsychiatric Symptoms in Parkinson Disease and Dementia with Lewy Bodies: What Geriatric Psychiatry Can Learn

In an examination of the history of psychiatric and cognitive research in Parkinson disease (PD), it was noted that in the first year of publication of Movement Disorders (1986), none of the issues contained primary manuscripts that pertained to the psychiatric and cognitive complications of PD.1 The neuropsychiatric symptoms (NPS; defined here as psychiatric and cognitive complications) of PD received scant attention at that time, although there was an appreciation, present since James Parkinson’s legendary quote about the melancholic features of his defining case, that depression was common. In addition, ever since levodopa was introduced as the first dopamine replacement therapy in the 1960s, studies have documented the occurrence of psychotic symptoms in treated PD patients. In general, it was thought that the “senses” were mainly preserved, in part because the shortened life span of PD patients at that time precluded the development of dementia. When dementia (PDD) did occur, it was considered most often to represent the co-occurrence of Alzheimer disease (AD). Other psychiatric and cognitive complications in PD either were not commonly recognized or were not frequent due to the limited prevailing treatment options available. Beyond a very limited understanding of the epidemiology of these disorders, very little research was conducted on assessment, diagnosis, impact, course, neuropathophysiology, or treatment. Fast forwarding 25 years, although PD is still considered a movement disorder and is diagnosed on that basis, the high prevalence of NPS suggests it is more accurately conceptualized as a neurocognitive-psychiatric disorder. In addition to the most commonly studied aforementioned disorders, other relatively common psychiatric complications include impulse control disorders, anxiety symptoms, disorders of sleep and wakefulness, and apathy. The emergent focus on the NMS of PD over the past 25 years is exemplified by the nonlinear increase in the number of published manuscripts devoted to this topic1 and by quality improvement efforts that increasingly stress the nonmotor features of the disease.2,3 The original lack of focus on cognition in PD, particularly early in the disease course, led astute clinicians to recognize patients who presented with concomitant dementia and parkinsonism, giving rise to the new diagnosis of dementia with Lewy bodies (DLB), now considered the second most common dementia diagnosis in the developed world after AD.4 The clinical features of PDD and DLB are very similar (i.e., presence of dementia plus triad of parkinsonism, fluctuating cognition, and visual hallucinations), as is their neuropathology, and it is controversial whether they are distinct illnesses or simply the same disease with different time courses for the presentation of cognitive deficits relative to parkinsonism. When considering the diseases together, the term Lewy body disease (LBD) is typically used, because Lewy bodies and neurites (intraneuronal aggregates of misfolded α-synuclein) are the pathologic hallmarks of both diseases.

Fluoxetine rescues impaired hippocampal neurogenesis in a transgenic A53T synuclein mouse model

The accumulation of alpha-synuclein in Lewy bodies and Lewy neurites of different neuronal populations is one of the neuropathological hallmarks in Parkinson disease (PD). Overexpression of human wildtype or mutant alpha-synuclein affects the generation of new neurons in the adult dentate gyrus (DG) of the hippocampus in models of PD. Hippocampal dysfunction with reduced neurogenesis plays an important role in the pathogenesis of depression, an important non-motor symptom in PD. Moreover, effective antidepressant treatment is still an unmet need in PD. The present study explored if impaired hippocampal neurogenesis in the A53T transgenic animal model of PD may be restored by chronic oral application of the selective serotonin reuptake inhibitor (SSRI) fluoxetine. First, we determined the expression pattern of transgenic mutant A53T synuclein in developing DG neurons and showed early expression of the transgene linked to a severely impaired neurogenesis. After chronic fluoxetine treatment we observed an increased adult neurogenesis in the hippocampus of more than threefold in treated A53T mice compared with controls. The pro-neurogenic effect of chronic fluoxetine application is predominantly related to an increased proliferation of neural precursor cells in the DG, and to a lesser extent by induction of differentiation into mature neurons. Analysis of the underlying mechanisms revealed an induction of brain-derived and glial cell-derived neurotrophic factor levels as a result of fluoxetine treatment. This study underlines the large potential of SSRI-dependent mechanisms to stimulate adult hippocampal neurogenesis in alpha-synuclein models and may lead to novel means to improve neuropsychiatric symptoms in PD.

Olfactory neuron-specific expression of A30P alpha-synuclein exacerbates dopamine deficiency and hyperactivity in a novel conditional model of early Parkinson's disease stages

Mutations in the N-terminus of the gene encoding α-synuclein (α-syn) are linked to autosomal dominantly inherited Parkinson's disease (PD). The vast majority of PD patients develop neuropsychiatric symptoms preceding motor impairments. During this premotor stage, synucleinopathy is first detectable in the olfactory bulb (OB) and brain stem nuclei; however its impact on interconnected brain regions and related symptoms is still less far understood. Using a novel conditional transgenic mouse model, displaying region-specific expression of human mutant α-syn, we evaluated effect and reversibility of olfactory synucleinopathy. Our data showed that induction of mutant A30P α-syn expression increased transgenic deposition into somatodendritic compartment of dopaminergic neurons, without generating fibrillar inclusions. We found reversibly reduced levels of dopamine and metabolites in the OB, suggesting an impact of A30P α-syn on olfactory neurotransmitter content. We further showed that mutant A30P expression led to neurodegenerative changes on an ultrastructural level and a behaviorally hyperactive response correlated with novelty, odor processing and stress associated with an increased dopaminergic tone in midbrain regions. Our present data indicate that mutant (A30P) α-syn is directly implicated in reduction of dopamine signaling in OB interneurons, which mediates further alterations in brain regions without transgenic expression leading functionally to a hyperactive response. These modulations of neurotransmission may underlie in part some of the early neuropsychiatric symptoms in PD preceding dysfunction of the nigrostriatal dopaminergic system.

Atomoxetine for depression and other neuropsychiatric symptoms in Parkinson disease

Depression and antidepressant use, especially selective serotonin reuptake inhibitors (SSRIs), are common in Parkinson disease (PD). The objective of this clinical trial was to assess the efficacy of atomoxetine, a selective norepinephrine reuptake inhibitor (SNRI), for the treatment of clinically significant depressive symptoms and common comorbid neuropsychiatric symptoms in PD. A total of 55 subjects with PD and an Inventory of Depressive Symptomatology-Clinician (IDS-C) score > or = 22 were randomized to 8 weeks of atomoxetine or placebo treatment (target dosage = 80 mg/day). Depression response (> 50% decrease in IDS-C score or Clinical Global Impression-Improvement [CGI-I] score of 1 or 2) was assessed using intention-to-treat modeling procedures. Secondary outcomes included global cognition, daytime sleepiness, anxiety, apathy, and motor function. There were no between-groups differences in a priori-defined response rates. Using a more liberal response criterion of > 40% decrease in IDS score from baseline, there was a trend (p = 0.08) favoring atomoxetine. Patients receiving atomoxetine experienced significantly greater improvement in global cognition (p = 0.003) and daytime sleepiness (p = 0.001), and atomoxetine was well-tolerated. Atomoxetine treatment was not efficacious for the treatment of clinically significant depressive symptoms in PD, but was associated with improvement in global cognitive performance and daytime sleepiness. Larger studies of SNRIs in PD for disorders of mood, cognition, and wakefulness are appropriate. This interventional study provides Class II evidence that atomoxetine (target dosage = 80 mg/day) is not efficacious in improving clinically significant depression in PD.

Impaired learning and memory in Pitx3 deficient aphakia mice: A genetic model for striatum-dependent cognitive symptoms in Parkinson's disease

Disorders of the basal ganglia such as Parkinson's disease (PD) and Huntington's disease are commonly thought of primarily as motor disorders; however, the cognitive symptoms of these diseases such as executive dysfunction, learning, memory and attention deficits are prominent and often more disabling than the hallmark motor symptoms. Cognitive features of PD are often neglected in preclinical studies of PD, likely due to the lack of available animal models to study them. Aphakia mice, which are deficient in the transcription factor Pitx3, model the selective nigrostriatal DA loss in PD. Here we report that aphakia mice are impaired in striatum-dependent cognitive tasks including rotarod learning, T-maze and inhibitory avoidance tasks, but not the striatum-independent social transmission of food preference task. These results suggest that some neuropsychiatric symptoms in PD are related to the pathophysiology of the disease rather than stress associated with disease burden, or medications used to treat PD. Furthermore aphakia mice may be used as a novel model of non-motor symptoms in PD.