Fatigue in early Parkinson’s disease. Minor inconvenience or major distress?

Background and purpose: Although fatigue is recognized as a common and debilitating symptom in patients with Parkinson’s disease (PD), little is known on how and when this symptom emerges during disease progression. The aim of the study was to explore the presence and severity of fatigue in patients with PD at the time of diagnosis, before dopaminergic treatment has been instituted. Methods: The present study is part of the Norwegian ParkWest project, a large cohort study of patients with incident PD in Norway. PD was diagnosed according to the Gelb criteria. The study population comprised 199 patients with untreated, newly diagnosed PD and 172 control subjects, matched for gender and age. Fatigue was measured by the Fatigue Severity Scale (FSS). Results: Fifty‐five percent of the patients with PD had clinical significant fatigue (FSS > 4), compared with about 20% of the controls (RR = 2.9). The mean score in patients on the FSS was 4.4 (SD 1.7) and in controls 3.1 (SD 1.3). In addition, there were highly significant differences between patients and controls in each of the nine FSS items. In a regression analysis, only the Montgomery and Åsberg Depression Rating Scale and Unified Parkinson’s Disease Rating Scale‐Activities of Daily Living scores were significantly associated with fatigue. There was no correlation between fatigue and cognitive impairment and hypersomnia. Conclusion: Fatigue is a common symptom in PD, also in patients with early, untreated disease, and it has a negative impact on these patients’ activity of daily living. Also in early PD, fatigue is an important consideration in the management of patients with the disease.     

Are there ethnic differences in impulsive/compulsive behaviors in Parkinson’s disease?

Background and purpose: Recent studies have suggested increased prevalence of impulsive/compulsive behaviors (ICB) in patients with Parkinson’s disease (PD) as compared to general population in different ethnic groups. The spectrum of these behaviors includes dopamine dysregulation syndrome (DDS), punding, pathological gambling (PG), hypersexuality (HS), binge eating (BE), and compulsive shopping (CS). Methods: Two hundred and seventy‐eight consecutive patients with idiopathic PD regularly followed‐up at an outpatient clinic were interviewed and screened for the ICB between September 2008 and December 2008 using designated diagnostic criteria. All patients who screened positive for ICB or obsessive‐compulsive disorder (OCD) were further confirmed by an experienced psychiatrist. Results: Of all the studied patients, 15 patients confirmed to have ICB (lifetime prevalence: 5.60%), 3 (1.12%) were diagnosed to have DDS, 1 (0.37%) punding, 4 (1.49%) PG, 8 (2.99%) HS, 1 (0.37%) BE, 0 (0%) CS. OCD was found in one patient (0.37%). Conclusions: The prevalence of ICB is lower in Taiwan as compared with the Caucasians, with similar risk factors. The possible reasons include differences in ethnicity, environmental, cultural, and social factors as well as the dosage and selection of dopaminergic medications.     

Response to sensory uncertainty in Parkinson’s disease: a marker of cerebellar dysfunction?

Motor performance is profoundly influenced by sensory information, yet sensory input can be noisy and uncertain. The basal ganglia and the cerebellum are important in processing sensory uncertainty, as the basal ganglia incorporate the uncertainty of predictive reward cues to reinforce motor programs, and the cerebellum and its connections mitigate the effect of ambiguous sensory input on motor performance through the use of forward models. Although Parkinson's disease (PD) is classically considered a primary disease of the basal ganglia, alterations in cerebellar activation are also observed, which may have consequences for the processing of sensory uncertainty. The aim of this study was to investigate the effect of visual uncertainty on motor performance in 15 PD patients and ten age-matched control subjects. Subjects performed a visually guided tracking task, requiring large-amplitude arm movements, by tracking with their index finger a moving target along a smooth trajectory. To induce visual uncertainty, the target position randomly jittered about the desired trajectory with increasing amplitudes. Tracking error was related to target ambiguity to a significantly greater degree in PD subjects off medication compared with control subjects, indicative of susceptibility to visual uncertainty in PD. l-Dopa partially ameliorated this deficit. We interpret our findings as suggesting an inability of PD subjects to create adequate forward models and/or de-weight less informative visual input. As these computations are normally associated with the cerebellum and connections, we suggest that alterations in normal cerebellar functioning may be a significant contributor to altered motor performance in PD.     

The emerging role of probiotics in neurodegenerative diseases: new hope for Parkinson’s disease?

Neurodegenerative disease etiology is still unclear, but different contributing factors, such as lifestyle and genetic factors are involved. Altered components of the gut could play a key role in the gut-brain axis, which is a bidirectional system between the central nervous system and the enteric nervous system. Variations in the composition of the gut microbiota and its function between healthy people and patients have been reported for a variety of human disorders comprising metabolic, autoimmune, cancer, and, notably, neurodegenerative disorders. Diet can alter the microbiota composition, affecting the gut-brain axis function. Different nutraceutical interventions have been devoted to normalizing gut microbiome dysbiosis and to improving biological outcomes in neurological conditions, including the use of probiotics. Preclinical and clinical investigations discussed in this review strengthen the correlation between intestinal microbiota and brain and the concept that modifying the microbiome composition may improve brain neurochemistry, modulating different pathways. This review will discuss the potential use of probiotics for Parkinson’s disease prevention or treatment or as adjuvant therapy, confirming that gut microbiota modulation influences different pro-survival pathways. Future investigations in Parkinson’s disease should consider the role of the gut-brain axis and additional comprehension of the underlying mechanisms is extremely necessary.     

Kennedy’s disease: a triplet repeat disorder or a motor neuron disease?

Two definite genetic causes of adult motor neuron degeneration have been identified to date: CAG repeat expansion in the androgen receptor gene in Kennedy’s disease and point mutations in the SOD1 gene, encoding the enzyme, Cu/Zn superoxide dismutase, in some familial forms of amyotrophic lateral sclerosis. Although both have unrelated genetic causes, Kennedy’s disease and SOD1-linked amyotrophic lateral sclerosis share several pathogenic features. First, expanded androgen receptor and mutant Cu/Zn superoxide dismutase have a propensity to aggregate into insoluble complexes and form inclusion bodies in affected neurons. Deposits of mutant proteins could be detrimental to neuronal viability by interfering with the normal housekeeping functions of chaperones and of the ubiquitin/proteasome system. Secondly, cytoskeletal function may be impaired in both diseases as decreased transactivational activity of expanded androgen receptor may cause an abnormal pattern of tubulin expression in motor neurons in Kennedy’s disease and disruption of neurofilament organisation is a hallmark of amyotrophic lateral sclerosis. The concept of activation of overlapping cell death cascades by two distinct genetic defects could help elucidating downstream pathogenic processes and may provide novel targets for pharmacological intervention or gene therapy for the treatment of motor neuron disorders.     

Depressive illness in Parkinson’s disease – indication of a more advanced and widespread neurodegenerative process?

Objective –  The aims were to study if the type and complexity of Parkinsonian symptoms, as well as treatment, could be related to the occurrence and severity of later depressive symptoms. Furthermore, the aim was to study if there is a different depressive symptomatology in Parkinson's disease (PD) patients compared with depressive illness in an age-matched group of patients with major depression but without Parkinson's disease.
Methods –  Eleven PD-patients with major depression (MD) were compared to 14 PD-patients without depression and to 12 MD patients without PD.
Results –  PD patients who later developed a depressive illness were younger at the debut of PD than patients without depression ( P < 0.05). At inclusion the depressed PD patients were more disabled than PD patients without depression with higher level in the H&Y scale ( P <0.05), and they had more involuntary movements according to Unified Parkinson's Disease Rating Scale (UPDRS IV) ( P < 0.01). A family history of depression was found in one third of the depressed non-parkinsonian patients but in none of the PD groups. Sleep disturbances were significantly more common among depressed PD patients than in PD patients without depression but even more common in depressed patients without PD.
Conclusions –  Depressed PD patients had a longer duration of PD and more severe motor symptoms than PD patients without depression, although tremor as an initial symptom seemed to be more common in PD without a later depression. It cannot be excluded that depression in PD reflects a more advanced and widespread neurodegeneration, including serotonergic as well as dopaminergic neurons. Sleep disturbances is common and could be overlooked as an expression of depression.     

The second brain in Parkinson’s disease: fact or fantasy?

Parkinson’s disease(PD)is a movement disorder characterized by reduced dopamine levels due to degeneration of the substantia nigra.The clinical presentation is underlined by bradykinesia,postural instability,and tremors.PD is the second most common neurodegenerative disease worldwide,with a huge monetary burden.In the United States alone,it is estimated that in 2017,the total economic cost was$51.9 billion,and projected to surpass$79 billion by 2037.Extensive research has been conducted into the pathophysiology and clinical implications of the disease.Within neurodegenerative disorder itself,the entity involving the brain-gut axis has been a fundamental model in understanding the disease process.More so than ever in PD,the association between gut health and neurological disease is gaining momentum,with the fascinating idea of influencing neurological health by treating the gut.     

Distinct differences in tachykinin gene expression in ulcerative colitis,Crohn’s disease and diverticular disease: a role for hemokinin‐1?

Background In the intestine, the tachykinins substance P (SP) and neurokinin A (NKA) are found in neurons and have key roles in motility, secretion, and immune functions. A new tachykinin, hemokinin (HK‐1), has been identified in non‐neuronal cells in recent years and its role in intestinal inflammation is unclear. We aimed to examine the expression of genes encoding tachykinin peptides and receptors in colon from patients with ulcerative colitis (UC), Crohn’s disease (CD), and acute diverticular disease (DD). Methods Human colon segments were dissected into mucosa and muscle, and evaluated for tachykinin and tachykinin receptor gene expression by real‐time PCR. Key Results In UC mucosa, the TAC4 gene (encoding HK‐1) was 10‐fold more abundant than in control mucosa (P < 0.01). Similarly, TAC1 (encoding SP and NKA) and TACR1 (encoding NK1 receptor) displayed 6‐fold and 12‐fold upregulation, respectively, in UC mucosa, but no change occurred in UC muscle. In contrast to UC, no difference was observed for any tachykinin genes in CD mucosa. In CD muscle, expression of TAC1 (P < 0.01), TAC4 and TACR1 (both P < 0.05) were moderately upregulated. In DD, there was a decrease in TACR1 (P < 0.05), and TACR2 (encoding NK2 receptor, P < 0.0001) in muscle compared with control. Histological staining showed increased collagen fibers between muscle bundles in DD smooth muscle. Conclusions & Inferences We provide evidence for the first time that HK‐1, like SP, may be involved in the pathophysiology of inflammatory bowel disease. Distinctly different expression patterns of tachykinin‐related genes occur in UC, CD and DD.     

Psychiatry: mindless or brainless, both or neither?

After a period marked by one-sided emphasis on psychodynamics and social issues, or what could be called "brainless" psychiatry on account of its relative neglect of cerebral processes, we are witnessing an opposite trend towards extreme biologism or "mindless" psychiatry. The pendulum has swung periodically from one to the other of these reductionistic positions throughout the history of psychiatry. The author argues that neither brainless nor mindless psychiatry can do justice to the complexity of mental illness and to the treatment of patients. Psychiatry's distinguishing feature as a clinical discipline is its equal concern with subjective experience, or the mind, and with the body, including brain function, which together constitute a person, a psychiatrist's proper focus of inquiry and intervention. Moreover, a person, viewed as a mindbody complex, is in constant interaction with the environment. It follows that both study of mental illness and clinical practice need to take into account the psychological, the biological and the social aspects. These three aspects are not mutually reducible and are indispensable for the understanding and treatment of the individual patient. Such a comprehensive, biopsychosocial approach provides an antithesis to the reductionistic viewpoints and, in the writer's opinion, is both practically and theoretically most satisfying.