Spirituality in Parkinson's Disease within a Sample from the USA.

Spirituality and religious beliefs are important for coping with medical conditions. The dopaminergic system is involved in reward behavior, and its dysfunction in Parkinson Disease (PD) raises questions about religiosity and spirituality in people with PD. This study examines the association between levels of spirituality and religiosity and the severity of PD motor and non-motor symptoms. The secondary aim investigates the perceived impact of PD diagnosis on spirituality and religiosity. This was a cross-sectional analysis of demographic, physical, mental, and spirituality and religiosity status in patients with PD recruited for the Health Outcomes Measurement (HOME) Study at the University of Maryland Parkinson Disease and Movement Disorders Center, Baltimore, USA. Spirituality and religiosity were assessed using the Spiritual Well-being Scale, and the World Health Organization Quality of Life Spiritual Religious and Personal Belief field-test instrument. The sample size was 85 PD patients. The mean age (standard deviation) was 65.5 (9.4) years and 67.1% were male. Higher levels of spirituality and religiosity were associated with younger age, sex (female), less education, religious affiliation (Christian), and mental health status. After adjusting for age, education, gender, race, marital status, religion, physical health, mental health, and comorbidity, only anxiety was associated with all of the spirituality/religiosity assessments. The majority of patients reported no change in their religious or spiritual beliefs following diagnosis. Greater spirituality and religiosity were associated with less anxiety. Also, younger women with PD showed higher levels of spirituality and religiosity. Longitudinal studies on more diverse populations are needed.

Conditional disruption of calpain in the CNS alters dendrite morphology, impairs LTP, and promotes neuronal survival following injury.

Ubiquitous classical (typical) calpains, calpain-1 and calpain-2, are Ca(+2)-dependent cysteine proteases, which have been associated with numerous physiological and pathological cellular functions. However, a clear understanding of the role of calpains in the CNS has been hampered by the lack of appropriate deletion paradigms in the brain. In this study, we describe a unique model of conditional deletion of both calpain-1 and calpain-2 activities in mouse brain, which more definitively assesses the role of these ubiquitous proteases in brain development/function and pathology. Surprisingly, we show that these calpains are not critical for gross CNS development. However, calpain-1/calpain-2 loss leads to reduced dendritic branching complexity and spine density deficits associated with major deterioration in hippocampal long-term potentiation and spatial memory. Moreover, calpain-1/calpain-2-deficient neurons were significantly resistant to injury induced by excitotoxic stress or mitochondrial toxicity. Examination of downstream target showed that the conversion of the Cdk5 activator, p35, to pathogenic p25 form, occurred only in the presence of calpain and that it played a major role in calpain-mediated neuronal death. These findings unequivocally establish two central roles of calpain-1/calpain-2 in CNS function in plasticity and neuronal death.

Development and characterization of a new Parkinson's disease model resulting from impaired autophagy.

Parkinson's disease (PD) is a progressive neurodegenerative disease caused by the interaction of genetic and environmental factors. However, the etiology of PD remains largely unknown. Macroautophagy is known to play an essential role in the degradation of abnormal proteins and organelles. Furthermore, the loss of autophagy-related (Atg) genes results in neurodegeneration and abnormal protein accumulation. Since these are also pathologic features of Parkinson's disease, the conditional impairment of autophagy may lead to improved animal models for the study of PD. Using transgenic mice expressing Cre recombinase under the control of either the dopamine transporter or the engrailed-1 promoters, we generated mice with the conditional deletion of Atg7 in the dopamine neurons of the substantia nigra pars compacta, other regions of the midbrain, and also the hindbrain. This conditional impairment of autophagy results in the age-related loss of dopaminergic neurons and corresponding loss of striatal dopamine, the accumulation of low-molecular-weight α-synuclein, and the presence of ubiquitinated protein aggregates, recapitulating many of the pathologic features of PD. These conditional knock-out animals provide insight into the process of autophagy in Parkinson's disease pathology.

The in vivo response of stem and other undifferentiated spermatogonia to the reversible inhibition of glial cell line-derived neurotrophic factor signaling in the adult.

Maintaining adequate numbers of spermatogonial stem cells is required for the production of the millions of sperm required for male fertility. To date, however, the mechanisms that regulate the size of this pool in the adult are poorly defined. Glial cell line-derived neurotrophic factor (GDNF) is required for establishing this pool in the prepubertal animal, but its in vivo function in the normal adult testis has never been examined directly. We used a chemical-genetic approach to address this issue. We generated mice carrying a single amino acid mutation (V805A) in Ret, the kinase subunit of the GDNF receptor. This mutation does not affect normal GDNF signaling but renders it susceptible to inhibition by the ATP competitive inhibitor, NA-PP1. When GDNF signaling was blocked in adults for 11 days, only a few cells remained that expressed the stem spermatogonial markers, Gfrα1 and Zbtb16, and testicular Ret mRNA content was reduced markedly. These decreases were associated with depletion of functional stem spermatogonia; some were lost when GDNF signaling was inhibited for only 2 days while others survived for up to 11 days. However, when signaling was restored, the remaining stem cells proliferated, initiating tissue restoration. In conclusion, these results provide the first direct proof that GDNF acutely regulates the number of spermatogonial stem cells in the normal adult testis. Additionally, these results demonstrate different sensitivities among subpopulation of these stem cells to inhibition of GDNF signaling.

S-nitrosylation of XIAP compromises neuronal survival in Parkinson's disease.

Inhibitors of apoptosis (IAPs) are a family of highly-conserved proteins that regulate cell survival through binding to caspases, the final executioners of apoptosis. X-linked IAP (XIAP) is the most widely expressed IAP and plays an important function in regulating cell survival. XIAP contains 3 baculoviral IAP repeats (BIRs) followed by a RING finger domain at the C terminal. The BIR domains of XIAP possess anticaspase activities, whereas the RING finger domain enables XIAP to function as an E3 ubiquitin ligase in the ubiquitin and proteasomal system. Our previous study showed that parkin, a protein that is important for the survival of dopaminergic neurons in Parkinson's disease (PD), is S-nitrosylated both in vitro and in vivo in PD patients. S-nitrosylation of parkin compromises its ubiquitin E3 ligase activity and its protective function, which suggests that nitrosative stress is an important factor in regulating neuronal survival during the pathogenesis of PD. In this study we show that XIAP is S-nitrosylated in vitro and in vivo in an animal model of PD and in PD patients. Nitric oxide modifies mainly cysteine residues within the BIR domains. In contrast to parkin, S-nitrosylation of XIAP does not affect its E3 ligase activity, but instead directly compromises its anticaspase-3 and antiapoptotic function. Our results confirm that nitrosative stress contributes to PD pathogenesis through the impairment of prosurvival proteins such as parkin and XIAP through different mechanisms, indicating that abnormal S-nitrosylation plays an important role in the process of neurodegeneration.

Confirming Parkinson Disease Diagnosis: Patterns of Diagnostic Changes by Movement Disorder Specialists.

Background: The American Academy of Neurology Parkinson Disease (PD) quality measures include an annual diagnostic review. Objective: To investigate the frequency and pattern of changes in diagnoses between PD and other causes of parkinsonism. Methods: This prospective longitudinal cohort study included consented patients diagnosed with PD at least once and a minimum of two times at the Movement Disorders Center between 2002 and 2017. Movement disorder specialists confirmed and documented diagnoses at every visit. Longitudinal changes in diagnoses were identified across visits. Results: Of 1567 patients with parkinsonism, 174 had non-PD parkinsonism with no change over time. Of 1393 patients diagnosed with PD at least once, 94% (N = 1308) had no change of diagnosis over time and 6% (N = 85) had a change of diagnosis including PD ⟷ drug-induced parkinsonism (DIP) (27.1%), PD ⟷ multiple system atrophy (MSA) (20.0%), PD ⟷ progressive supranuclear palsy (PSP) (18.8%), PD ⟷ Lewy body dementia (DLB) (16.5%), PD⟷ vascular parkinsonism (9.4%), more than two diagnoses (4.7%), and PD ⟷ corticobasal syndrome (CBS) (3.5%). The direction of diagnostic switches was as follows: PD ⟶ other parkinsonism diseases (36.5%), other parkinsonism diseases ⟶ PD (31.8%), and 31.8% of multiple switches. There were no significant differences in duration of follow-up, age at first visit, gender, race, marital status, education, income, cognition, or employment between the stable and unstable groups. Diagnostic change was associated with greater PD severity and greater medical comorbidity. Conclusion: Over a 15-year period, movement disorder specialists changed their clinical diagnosis of PD in 6% of patients. The most common diagnostic switches, to or from PD, were DIP, MSA, PSP, and DLB. This study describes routine clinical diagnostic patterns in the absence of pathologic confirmation. The presence of diverse diagnostic changes over time underscores the value of confirming PD diagnosis.

Genome Sequencing in the Parkinson Disease Clinic.

Background and Objectives: Genetic variants affect both Parkinson disease (PD) risk and manifestations. Although genetic information is of potential interest to patients and clinicians, genetic testing is rarely performed during routine PD clinical care. The goal of this study was to examine interest in comprehensive genetic testing among patients with PD and document reactions to possible findings from genome sequencing in 2 academic movement disorder clinics. Methods: In 203 subjects with PD (age = 63 years, 67% male), genome sequencing was performed and filtered using a custom panel, including 49 genes associated with PD, parkinsonism, or related disorders, as well as a 90-variant PD genetic risk score. Based on the results, 231 patients (age = 67 years, 63% male) were surveyed on interest in genetic testing and responses to vignettes covering (1) familial risk of PD (LRRK2); (2) risk of PD dementia (GBA); (3) PD genetic risk score; and (4) secondary, medically actionable variants (BRCA1). Results: Genome sequencing revealed a LRRK2 variant in 3% and a GBA risk variant in 10% of our clinical sample. The genetic risk score was normally distributed, identifying 41 subjects with a high risk of PD. Medically actionable findings were discovered in 2 subjects (1%). In our survey, the majority (82%) responded that they would share a LRRK2 variant with relatives. Most registered unchanged or increased interest in testing when confronted with a potential risk for dementia or medically actionable findings, and most (75%) expressed interest in learning their PD genetic risk score. Discussion: Our results highlight broad interest in comprehensive genetic testing among patients with PD and may facilitate integration of genome sequencing in clinical practice.

A hierarchical NGF signaling cascade controls Ret-dependent and Ret-independent events during development of nonpeptidergic DRG neurons.

NGF controls survival, differentiation, and target innervation of both peptidergic and nonpeptidergic DRG sensory neurons. The common receptor for GDNF family ligands, Ret, is highly expressed in nonpeptidergic neurons, but its function during development of these neurons is unclear. Here, we show that expression of Ret and its coreceptors GFRalpha1 and GFRalpha2 is dependent on NGF. GFR/Ret signaling, in turn, autoregulates expression of both GFRalpha1 and GFRalpha2 and promotes expression of TrpA1, MrgA1, MrgA3, and MrgB4, acquisition of normal neuronal size, axonal innervation of the epidermis, and postnatal extinction of the NGF receptor TrkA. Moreover, NGF controls expression of several other genes characteristic of nonpeptidergic neurons, such as TrpC3, TrpM8, MrgD, and the transcription factor Runx1, via a Ret-independent signaling pathway. These findings support a model in which NGF controls maturation of nonpeptidergic DRG neurons through a combination of GFR/Ret-dependent and -independent signaling pathways.

Extreme task specificity in writer's cramp.

BACKGROUND: Focal hand dystonia may be task specific, as is the case with writer's cramp. In early stages, task specificity can be so specific that it may be mistaken for a psychogenic movement disorder. METHODS: We describe 4 patients who showed extreme task specificity in writer's cramp. They initially only had problems writing either a single letter or number. Although they were largely thought to be psychogenic, they progressed to typical writer's cramp. CONCLUSIONS: Early recognition of this condition may provide an opportunity for early initiation of treatment.

Comparison of Mini-Mental State Examination and Montreal Cognitive Assessment Ratings Across Levels of Parkinson's Disease Severity.

BACKGROUND: Cognitive impairment (CI) is common in Parkinson's disease (PD) and an important cause of disability. Screening facilitates early detection of CI and has implications for management. Preclinical disability is when patients have functional limitations but maintain independence through compensatory measures. OBJECTIVE: The objective of this study was to investigate the relationship between scores on the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) with levels of PD severity and disability. METHODS: PD patients (n = 2,234) in a large observational study were stratified by disease severity, based on Total Unified Parkinson's Disease Rating Scale (Total UPDRS) and Hoehn and Yahr (HY) stage. Using MMSE (n = 1,184) or MoCA (n = 1,050) and basic (ADL) and instrumental activities of daily living (IADL) scales for disability, linear regression analysis examined associations between cognitive status and disability. RESULTS: Cognition and disability were highly correlated, with the strongest correlation between IADL and MoCA. Only 16.0% of mean MMSE scores were below threshold for CI (28) and only in advanced PD (Total UPDRS 60+, HY≥3). MoCA scores fell below CI threshold (26) in 66.2% of the sample and earlier in disease (Total UPDRS 30+, HY≥2), corresponding with impairments in ADLs. CONCLUSION: In a large clinical dataset, a small fraction of MMSE scores fell below cutoff for CI, reinforcing that MMSE is an insensitive screening tool in PD. MoCA scores indicated CI earlier in disease and coincided with disability. This study shows that MoCA, but not MMSE is sensitive to the emergence of early cognitive impairment in PD and correlates with the concomitant onset of disability.

Weight loss and weight gain in Parkinson disease.

INTRODUCTION: Parkinson disease (PD) has been associated with both weight loss and gain in different stages of the disease. Our study aimed to determine the prevalence and associations with weight change over two years based on 3% and 5% weight change. METHODS: In this longitudinal analysis, weight at baseline and follow-up was used to classify patients into groups of weight loss, stable, and weight gain. Differences between these groups at baseline and then with change over time were tested. RESULTS: The sample was 668 patients with mean(SD) age 66.1(10) and disease duration 5.3(5.4) years. Using 3% weight change criteria: 32.6% lost, 23.1% gained, and 55.7% had stable weight. Using 5% criteria: 22.6% lost, 15.7% gained, and 61.7% had stable weight. Age was associated with both 3% and 5% change in weight. Other associations with 5% weight change were disease duration, Total and Motor Unified Parkinson's Disease Rating Scale, Older Americans Resource and Services disability, and Hoehn & Yahr staging. The effects of 3% weight loss on Motor UPDRS, IADLs, and depression, and the effects of 5% weight loss on IADLs remained statistically significant when controlling for baseline differences in age, levodopa use, and Total UPDRS. CONCLUSION: PD patients are more likely to experience 3% than 5% weight change and this lower threshold of weight change was associated with greater disease severity and disability over time. Attention to more subtle weight change may help identify those at greater risk of disability.

Ghrelin promotes and protects nigrostriatal dopamine function via a UCP2-dependent mitochondrial mechanism.

Ghrelin targets the hypothalamus to regulate food intake and adiposity. Endogenous ghrelin receptors [growth hormone secretagogue receptor (GHSR)] are also present in extrahypothalamic sites where they promote circuit activity associated with learning and memory, and reward seeking behavior. Here, we show that the substantia nigra pars compacta (SNpc), a brain region where dopamine (DA) cell degeneration leads to Parkinson's disease (PD), expresses GHSR. Ghrelin binds to SNpc cells, electrically activates SNpc DA neurons, increases tyrosine hydroxylase mRNA and increases DA concentration in the dorsal striatum. Exogenous ghrelin administration decreased SNpc DA cell loss and restricted striatal dopamine loss after 1-methyl-4-phenyl-1,2,5,6 tetrahydropyridine (MPTP) treatment. Genetic ablation of ghrelin or the ghrelin receptor (GHSR) increased SNpc DA cell loss and lowered striatal dopamine levels after MPTP treatment, an effect that was reversed by selective reactivation of GHSR in catecholaminergic neurons. Ghrelin-induced neuroprotection was dependent on the mitochondrial redox state via uncoupling protein 2 (UCP2)-dependent alterations in mitochondrial respiration, reactive oxygen species production, and biogenesis. Together, our data reveal that peripheral ghrelin plays an important role in the maintenance and protection of normal nigrostriatal dopamine function by activating UCP2-dependent mitochondrial mechanisms. These studies support ghrelin as a novel therapeutic strategy to combat neurodegeneration, loss of appetite and body weight associated with PD. Finally, we discuss the potential implications of these studies on the link between obesity and neurodegeneration.

Management of Visual Dysfunction in Patients with Parkinson's Disease.

Parkinson's disease (PD) is a movement disorder with many symptoms responsive to treatment with dopamine agonists, anti-cholinergics and the dopamine precursor, levodopa. The cardinal features of PD include tremor, rigidity, bradykinesia, and postural instability. There also are non-motor features that include sleep disorders, cognitive and affective dysfunction, hyposmia, pain and dysautonomia (constipation, bloating, orthostasis, urinary symptoms, sexual dysfunction, dysphagia). Among these non-motor features are signs and symptoms of visual system impairment that range from subtle examination findings to those causing severe disability. In this review we describe common PD-related abnormalities in the visual system, how they present, and potential treatments.

COVID-19 in Pediatric Long-Term Care: How Infection Control and Prevention Practices Minimized the Impact of the Pandemic on Healthcare Providers and Residents.

Children in pediatric long-term care (LTC) facilities are commonly infected with respiratory tract viruses as they have many high-risk co-morbidities and require significant interactions with the healthcare team. From previous studies, we know that infected staff can often be the source of transmission of infection to the children. If instituted quickly, infection control practices can help mitigate the spread of infection. We will describe how Sunshine Children's Home and Rehabilitation Center responded to federal and state infection control and prevention mandates in LTC for COVID-19. We will report our practice changes, staff and resident screening, and testing results as well as outcomes of the COVID-19-infected cases. The outcomes for COVID-19 infection among pediatric LTC staff and residents are in stark contrast to the data available for the adult providers and residents in adult nursing homes. Implementation and change in infection control practices and procedures resulted in much fewer cases of COVID-19 infection in our pediatric LTC residents.

Diagnosis and treatment of Parkinson disease: molecules to medicine.

Parkinson disease (PD) is a relatively common disorder of the nervous system that afflicts patients later in life with tremor, slowness of movement, gait instability, and rigidity. Treatment of these cardinal features of the disease is a success story of modern science and medicine, as a great deal of disability can be alleviated through the pharmacological correction of brain dopamine deficiency. Unfortunately these therapies only provide temporary, though significant, relief from early symptoms and do not halt disease progression. In addition, pathological changes outside of the motor system leading to cognitive, autonomic, and psychiatric symptoms are not sufficiently treated by current therapies. Much as the discovery of dopamine deficiency led to powerful treatments for motor symptoms, recent discoveries concerning the role of specific genes in PD pathology will lead to the next revolution in disease therapy. Understanding why and how susceptible cells in motor and nonmotor regions of the brain die in PD is the first step toward preventing this cell death and curing or slowing the disease. In this review we discuss recent discoveries in the fields of diagnosis and treatment of PD and focus on how a better understanding of disease mechanisms gained through the study of monogenetic forms of PD has provided novel therapeutic targets.

Parkinson's Disease.

The diagnosis of Parkinson disease (PD) is based on the presence of bradykinesia and either resting tremor or rigidity and there should be no features from the history or examination to suggest an alternative cause of parkinsonism. In addition to the motor manifestations of PD, there is a long list of nonmotor symptoms, several of which occur before motor signs and are considered "prodromal" PD. These are classified as neuropsychiatric, autonomic, sleep, and sensory. There are many medical options for the treatment of PD but levodopa remains the mainstay. Deep brain stimulation and other advanced therapies are also available.

Treatment of Visual Disorders in Parkinson Disease.

PURPOSE OF REVIEW: This article discusses visual disorders in both Parkinson disease (PD) and other Parkinsonian disorders. It is organized largely by the anatomical site of pathology and emphasizes practical treatments. Targeted treatment options include medications, surgery, occupational, and physical therapies as well as optical aids. RECENT FINDINGS: The causes of visual complaints in Parkinson disease and other similar disorders are being more clearly identified. A new medication approved specifically to treat hallucinations in PD now is available. There is increased understanding of the important role that an ophthalmologist can play in the care of these patients. Finally, research and therapeutic development are unmet needs in accessing and treating visual complaints in PD and Parkinsonian disorders. A better understanding of Parkinson-related visual complaints and of available treatment options is important to optimize patient safety and quality of life. Vision impairment leads to difficulties in many common activities including reading, ambulating, and driving. Falls and injuries, made more likely because of impaired vision, result in an early loss of independence. Awareness of the problem, patient education, ophthalmologic care, selected therapeutics, physical therapy, and occupational therapy are crucial to maximizing quality of life in these patients.

Inclusion body formation and neurodegeneration are parkin independent in a mouse model of alpha-synucleinopathy.

Mutations in the genes coding for alpha-synuclein and parkin cause autosomal-dominant and autosomal-recessive forms of Parkinson's disease (PD), respectively. Alpha-synuclein is a major component of Lewy bodies, the proteinaceous cytoplasmic inclusions that are the pathological hallmark of idiopathic PD. Lewy bodies appear to be absent in cases of familial PD associated with mutated forms of parkin. Parkin is an ubiquitin E3 ligase, and it may be involved in the processing and/or degradation of alpha-synuclein, as well as in the formation of Lewy bodies. Here we report the behavioral, biochemical, and histochemical characterization of double-mutant mice overexpressing mutant human A53T alpha-synuclein on a parkin null background. We find that the absence of parkin does not have an impact on the onset and progression of the lethal phenotype induced by overexpression of human A53T alpha-synuclein. Furthermore, all major behavioral, biochemical, and morphological characteristics of A53T alpha-synuclein-overexpressing mice are not altered in parkin null alpha-synuclein-overexpressing double-mutant mice. Our results demonstrate that mutant alpha-synuclein induces neurodegeneration independent of parkin-mediated ubiquitin E3 ligase activity in nondopaminergic systems and suggest that PD caused by alpha-synuclein and parkin mutations may occur via independent mechanisms.

Bcl-x is required for proper development of the mouse substantia nigra.

Recent findings have uncovered a role for the Bcl-x gene in the survival of dopaminergic neurons. The exact nature of this role has been difficult to examine because of the embryonic lethality of Bcl-x gene disruption in mouse models. Here we report the generation catecholaminergic cell-specific conditional Bcl-x gene knock-out mice using Cre-lox recombination technology. First we produced transgenic mice that express Cre recombinase from an exogenous rat tyrosine hydroxylase promoter (TH-Cre mice). These mice were crossed to Z/AP and Z/EG reporter mouse strains to verify catecholaminergic (TH-positive) cell-specific Cre expression. The TH-Cre mice then were mated to mice possessing the Bcl-x gene flanked by loxP sites, thereby producing offspring with Bcl-x deletion limited to catecholaminergic cells. The resulting mice are viable but have one-third fewer catecholaminergic neurons than do control animals. They demonstrate a deficiency in striatal dopamine and also tend to be smaller and have decreased brain mass when compared with controls. Surprisingly, surviving neurons were found that lacked Bcl-x immunoreactivity, thereby demonstrating that this gene is dispensable for the ongoing survival of a subpopulation of catecholaminergic cells.

Cis and trans RET signaling control the survival and central projection growth of rapidly adapting mechanoreceptors.

RET can be activated in cis or trans by its co-receptors and ligands in vitro, but the physiological roles of trans signaling are unclear. Rapidly adapting (RA) mechanoreceptors in dorsal root ganglia (DRGs) express Ret and the co-receptor Gfrα2 and depend on Ret for survival and central projection growth. Here, we show that Ret and Gfrα2 null mice display comparable early central projection deficits, but Gfrα2 null RA mechanoreceptors recover later. Loss of Gfrα1, the co-receptor implicated in activating RET in trans, causes no significant central projection or cell survival deficit, but Gfrα1;Gfrα2 double nulls phenocopy Ret nulls. Finally, we demonstrate that GFRα1 produced by neighboring DRG neurons activates RET in RA mechanoreceptors. Taken together, our results suggest that trans and cis RET signaling could function in the same developmental process and that the availability of both forms of activation likely enhances but not diversifies outcomes of RET signaling.