The Pathophysiology of Essential Tremor and Parkinson’s Tremor

Varicella zoster virus (VZV) is an exclusively human neurotropic alphaherpesvirus. Primary infection causes varicella (chickenpox), after which the virus becomes latent in ganglionic neurons along the entire neuraxis. With advancing age or immunosuppression, cell-mediated immunity to VZV declines, and the virus reactivates to cause zoster (shingles), dermatomal distribution, pain, and rash. Zoster is often followed by chronic pain (postherpetic neuralgia), cranial nerve palsies, zoster paresis, vasculopathy, meningoencephalitis, and multiple ocular disorders. This review covers clinical, laboratory, and pathological features of neurological complications of VZV reactivation, including diagnostic testing to verify active VZV infection in the nervous system. Additional perspectives are provided by discussions of VZV latency, animal models to study varicella pathogenesis and immunity, and of the value of vaccination of elderly individuals to boost cell-mediated immunity to VZV and prevent VZV reactivation.     

Olfactory Dysfunction as an Early Biomarker in Parkinson’s Disease

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

Neuroimaging as a Window into Gait Disturbances and Freezing of Gait in Patients with Parkinson’s Disease

Neuroimaging has been applied to better understand the neural mechanisms underlying gait disturbances in Parkinson’s disease (PD). In the present paper, we review studies that used neuroimaging methods to investigate mobility, walking and freezing of gait (FOG) in PD, focusing on the recent literature. Examination of these studies suggests that gait changes in PD are due to widespread alterations in the structure and function of the brain that go beyond the basal ganglia. For example, cortical structures including the frontal and parietal lobes, the mesencephalic locomotor region and specifically, the pedunculopontine nucleus, all apparently play important roles in the control of gait in PD. Nonetheless, there are some significant inconsistencies across the different studies and many questions remain regarding the precise pathological processes that contribute to gait disturbances, in general, and to FOG, more specifically. A discussion of new insights into the neural mechanisms underlying gait disturbances are presented along with a summary of the disadvantages and limitations of the existing techniques and suggestions for future directions.     

Memory Similarities Between Essential Tremor and Parkinson’s Disease: A Final Common Pathway?

Objective: A growing body of literature supports the view that essential tremor (ET) involves alteration of cerebellar–thalamo–cortical networks which can result in working memory and executive deficits. In this study, we tested the hypothesis that individuals with ET would exhibit worse performance on memory tasks requiring more intrinsic organization and structuring (i.e., word lists) relative to those with fewer ‘executive’ demands (i.e., stories), similar to that previously observed in individuals with Parkinson’s disease (PD). Method: Participants included a convenience sample of 68 ET patients and 68 idiopathic PD patients, retrospectively matched based on age, education, and sex. All patients underwent routine neuropsychological evaluation assessing recent memory, auditory attention/working memory, language, and executive function. Memory measures included the Hopkins Verbal Learning Test-R and WMS-III Logical Memory. Results: Both ET and PD patients performed significantly worse on word list than story memory recall tasks. The magnitude of the difference between these two memory tasks was similar for ET and PD patients. In both patient groups, performance on measures of executive function and auditory attention/working memory was not distinctly correlated with word list vs. story recall. Conclusions: These findings suggest that frontal-executive dysfunction in both ET and PD may negatively influence performance on memory tests that are not inherently organized. Although the pathophysiology of these two ‘movement disorders’ are quite distinct, both have downstream effects on thalamo–frontal circuitry which may provide a common pathway for a similar memory phenotype. Findings are discussed in terms of neuroimaging evidence, conceptual models, and best practice.     

Validation of the Turkish Version of the Montreal Cognitive Assessment Scale (MoCA-TR) in Patients With Parkinson’s Disease

The study aimed to examine the reliability and validity of the Turkish version of the Montreal Cognitive Assessment Scale (MoCA-TR) as a screening tool for cognitive dysfunction in Parkinson’s disease (PD). A total of 50 patients with PD and 50 healthy controls were included. The screening instruments—MoCA-TR followed by the Mini-Mental Status Examination (MMSE-TR) and MoCA-TR retest within 1 month—and detailed neuropsychological testing were administered to the PD patients. MoCA-TR and MMSE-TR were also administered to controls. The discriminant validities of the MoCA-TR and MMSE-TR as screening and diagnostic instruments were ascertained. The concurrent and criterion validity, test–retest reliability, and internal consistency of the MoCA-TR and MMSE-TR were examined. The Cronbach’s alpha of the MoCA-TR as an index of internal consistency was 0.664, and the test–retest reliability of MoCA-TR was 0.742. With a cut-off score of < 21 points, the MoCA-TR showed sensitivity of 59% and specificity of 89% in the detection of cognitive dysfunction in PD. The area under the receiver-operating characteristics curve (95% confidence interval) for MoCA-TR was 0.794 (0.670–0.918), p?<?.001. The present results indicated that the MoCA-TR has acceptable psychometric properties and it should be used to assess mild cognitive impairment and early dementia in PD patients, whereas the MMSE-TR should remain the instrument of choice to assess cognitive impairment in PD dementia.     

Behavioral Ratings of Executive Functioning Explain Instrumental Activities of Daily Living beyond Test Scores in Parkinson’s Disease

Objective: Executive dysfunction is common in Parkinson’s disease (PD), yet the relationship between executive functioning (EF) and instrumental activities of daily living (IADLs) is inconsistent. This inconsistency may be due to the limited relationship between EF test scores and behaviors. Rating scales provide a potential way to supplement test scores in predicting patient’s ability to complete IADLs by capturing a wide range of EF behaviors in their everyday environment. We hypothesized that informant-rated EF would provide incremental validity in predicting IADLs above and beyond EF test scores. Methods: Eighty-five patients were selected from a clinical neuropsychological database of PD patients evaluated for deep brain stimulation surgery at The Johns Hopkins Hospital between September 2006 and January 2015. Hierarchical regression was completed to determine the relationship between an EF behavioral rating scale (i.e., FrSBe), EF test scores, and IADLs. Results: The EF behavioral rating scale added incremental validity to neuropsychological test scores in predicting IADLs. Conclusions: Behavioral ratings of EF may provide additional information about how PD patients’ EF is influencing their everyday life.     

Peripheral Lymphocyte Subsets as a Marker of Parkinson’s Disease in a Chinese Population

In this study, we conducted a clinical analysis of lymphocyte subtypes in 268 patients with Parkinson's disease(PD) to assess their clinical impact as a potential marker of advanced PD in Chinese patients. The participants comprised 268 sporadic PD patients and 268 healthy controls. The numbers of natural killer(NK) cells and CD3+, CD3+CD4+, CD3+CD8+, and CD19+ lymphocytes from peripheral blood were determined by immunostaining and flow cytometric analysis and the percentages of these CD+ T cells were calculated. The ratio of regulatory T(Treg)/helper T 17(Th17) lymphocytes from 64 PD patients and 46 controls was determined by flow cytometric analysis.The results showed that the percentage of NK cells was higher in advanced PD patients than in controls(22.92% ±10.08% versus 19.76% ± 10.09%, P = 0.006), while CD3+ T cells are decreased(62.93% ± 9.27% versus65.75% ± 9.13%, P = 0.005). The percentage of CD19+B cells in male patients was lower(P = 0.021) than in female patients, whereas NK cells were increased(P \ 0.0001). The scores on the Unified Parkinson's Disease Rating Scale(UPDRS) and the Non-Motor Symptoms Scale in late-onset PD patients were significantly higher than those in earlyonset patients(P = 0.024 and P = 0.007, respectively). The percentage of CD19+ B cells in patients with UPDRS scores[24 was lower than in those with scores \24(10.17% ±4.19% versus 12.22% ± 5.39%, P = 0.009). In addition, the Treg/Th17 ratio in female patients was higher than that in female controls(13.88 ± 6.32 versus 9.94 ± 4.06, P =0.042). These results suggest that the percentages of NK cells,CD3+ T cells, and CD19+ B cells along with the Treg/Th17 ratio in peripheral blood may be used to predict the risk of PD in Chinese individuals and provide fresh avenues for novel diagnostic biomarkers and therapeutic designs.     

Temporal Preparation Strategy may Inflate RT Deficit in Patients With Parkinson’s Disease

Twelve patients with Parkinson’s disease (PD) and 12 age-matched controls completed a visual reaction time (RT) task to assess the effect of temporal parameters on response preparation. Simple and choice RT conditions were presented in separate blocks. In both conditions, preparatory intervals of various durations (1, 3 and 5 s) were introduced between an auditory warning signal and the visual target. Within a block of trials, intervals varied randomly. The results indicated that PD patients responded slower than controls in both task conditions. Also, there was evidence for preparation in both groups, as RT decreased with increasing intervals. A three-way interaction indicated that PD patients’ RT was longer than that of controls at the shortest interval in simple RT. This suggests that PD patients show a different pattern of temporal response preparation and that this may contribute to their deficit on RT tasks.     

Nonsynonymous Polymorphisms of Histamine-Metabolising Enzymes in Patients with Parkinson’s Disease

Objective To analyze genetically based impairment in histamine-metabolising enzymes in patients with Parkinson’s disease (PD). Methods Leukocytary DNA from 214 PD patients and a control group of 295 unrelated healthy individuals was studied for nonsynonymous histamine N-methyltransferase (HNMT) and diamine oxidase (ABP1) polymorphisms by using amplification–restriction analyses. Results An association of the HNMT Thr105Ile polymorphism, but not of the ABP1 His645Asp polymorphism, with PD was observed. Patients with PD showed a higher frequency of homozygous HNMT genotypes leading to high activity with a gene-dose effect (P < 0.001), as compared to healthy subjects. These findings were independent of gender, but the association with the HNMT polymorphism is higher among patients with late-onset PD (P < 0.0001). Conclusion These results, combined with previous findings indicating alterations in histamine levels in patients with PD, suggest that alterations of histamine homeostasis in the SNC are associated with the risk for PD.     

Disturbances of Sleep and Alertness in Parkinson’s Disease

Purpose of Review

Parkinson’s disease (PD) is the second most common neurodegenerative disorder. Sleep dysfunction is one of the most common non-motor manifestations of PD that has gained significant interest over the past two decades due to its impact on the daily lives of PD patients, poorly understood mechanisms, and limited treatment options. In this review, we discuss the most common sleep disorders in PD and present recent investigations that have broadened our understanding of the epidemiology, clinical manifestations, diagnosis, and treatment of disturbed sleep and alertness in PD.

Resent Findings

The etiology of impaired sleep-wake cycles in PD is multifactorial. Sleep dysfunction in PD encompasses insomnia, REM sleep behavior disorder, sleep-disordered breathing, restless legs syndrome, and circadian dysregulation. Despite the high prevalence of sleep dysfunction in PD, evidence supporting the efficacy of treatment strategies is limited.

Summary

We are at the opportune time to advance our understanding of sleep dysfunction in PD, which will hopefully lead to mechanisms-driven interventions for better sleep and allow us to approach sleep as a modifiable therapeutic target for other non-motor and motor manifestations in PD.

     

The Frontal Assessment Battery (FAB) in Parkinson’s disease and correlations with formal measures of executive functioning

BACKGROUND: The Frontal Assessment Battery (FAB) is a short tool for the assessment of executive functions consisting of six subtests that explore different abilities related to the frontal lobes. Several studies have indicated that executive dysfunction is the main neuropsychological feature in Parkinson's disease (PD). GOALS: To evaluate the clinical usefulness of the FAB in identifying executive dysfunction in PD; to determine if FAB scores in PD are correlated with formal measures of executive functions; and to provide normative data for the Portuguese version of the FAB. METHODS: The study involved 122 healthy participants and 50 idiopathic PD patients. We compared FAB scores in normal controls and in PD patients matched for age, education and Mini-Mental State Examination (MMSE) score. In PD patients, FAB results were compared to the performance on tests of executive functioning. RESULTS: In the healthy subjects, FAB scores varied as a function of age, education and MMSE. In PD, FAB scores were significantly decreased compared to normal controls, and correlated with measures of executive functions such as phonemic and semantic verbal fluency tests, Wisconsin Card Sorting Test and Trail Making Test Part A and Part B. CONCLUSION: The FAB is a useful tool for the screening of executive dysfunction in PD, showing good discriminant and concurrent validities. Normative data provided for the Portuguese version of this test improve the accuracy and confidence in the clinical use of the FAB.     

Investigation of Supervisory Attentional System Functions in Patients With Parkinson’s Disease Using the Hayling Task

The study explored executive dysfunction in Parkinson’s disease (PD) by using the Hayling test (Burgess & Shallice, 1996) and verbal fluency tasks (VFTs). PD patients showed longer response latencies than controls in both parts of the Hayling test (Section A/automatic and Section B/inhibition). Patients and controls did not differ in the proportion of errors or number of responses that revealed the use of strategies. PD patients also showed verbal fluency deficits in semantic, phonemic, and alternating fluency tasks. These impairments on tests known to be sensitive to frontal lobe dysfunction confirm executive or Supervisory Attentional System (Norman & Shallice, 1986) deficits and further indicate suppression skills impairments in PD.     

Mitochondrial Dysfunction in Parkinson’s Disease: New Mechanistic Insights and Therapeutic Perspectives

Purpose of Review

Parkinson’s disease (PD) is a complex neurodegenerative disorder, the aetiology of which is still largely unknown. Overwhelming evidence indicates that mitochondrial dysfunction is a central factor in PD pathophysiology. Here we review recent developments around mitochondrial dysfunction in familial and sporadic PD, with a brief overview of emerging therapies targeting mitochondrial dysfunction.

Recent Findings

Increasing evidence supports the critical role for mitochondrial dysfunction in the development of sporadic PD, while the involvement of familial PD-related genes in the regulation of mitochondrial biology has been expanded by the discovery of new mitochondria-associated disease loci and the identification of their novel functions.

Summary

Recent research has expanded knowledge on the mechanistic details underlying mitochondrial dysfunction in PD, with the discovery of new therapeutic targets providing invaluable insights into the essential role of mitochondria in PD pathogenesis and unique opportunities for drug development.

     

Quality of Life and Motor Outcomes in Patients With Parkinson’s Disease 12 Months After Deep Brain Stimulation in China

BackgroundLong-term levodopa use is frequently associated with fluctuations in motor response and can have a serious adverse effect on the quality of life (QoL) of patients with Parkinson’s disease (PD). Deep brain stimulation (DBS) is effective in improving symptoms of diminished levodopa responsiveness. QoL improvements with DBS have been shown in several randomized control trials, mostly in Europe and the United States; however, there is a need for evidence from regions around the world.ObjectiveThe study aimed to demonstrate improvement in PD-related QoL in patients undergoing DBS in a prospective, multicenter study conducted in China.Materials and MethodsTo evaluate the effect of neurostimulation on the QoL of patients with PD, a Parkinson’s Disease Questionnaire (PDQ-8); Unified Parkinson’s Disease Rating Scale (UPDRS) I, II, III, and IV; and EuroQol 5-dimension questionnaire (EQ-5D) were administered at baseline and 12 months after DBS implantation. The mean change and percent change from baseline were reported for these clinical outcomes.ResultsAssessments were completed for 85 of the 89 implanted patients. DBS substantially improved patients’ QoL and function. Implanted patients showed statistically significant mean improvement in PDQ-8 and UPDRS III (on stimulation/off medication). In the patients who completed the 12-month follow-up visit, the percent change was ?22.2% for PDQ-8 and ?51.6% for UPDRS III (on stimulation/off medication). Percent change from baseline to 12 months for UPDRS I, II, III, and IV and EQ-5D were ?16.8%, ?39.4%, ?18.5%, and ?50.0% and 22.7%, respectively. The overall rate of incidence for adverse events was low at 15.7%. Favorable outcomes were also reported based on patient opinion; 95.3% were satisfied with DBS results.ConclusionsThese data were comparable to other studies around the world and showed alignment with the ability of DBS to meaningfully improve the QoL of patients with PD. More studies investigating DBS therapy for patients with PD are necessary to accurately characterize clinical outcomes for the global PD population.Clinical Trial RegistrationThe ClinicalTrials.gov registration number for this study is NCT02937688.     

Histaminergic Activity in a Rodent Model of Parkinson’s Disease

Rats lesioned shortly after birth with 6-OHDA have been proposed to be a near-ideal model of severe Parkinson’s disease, because of non-lethality of the procedure, near-total destruction of nigrostriatal dopaminergic fibers, and near-total dopamine (DA) denervation of striatum. There are scarce data that in Parkinson’s disease, activity of the central histaminergic system is increased. Therefore, the aim of this study was to determine histamine content in the brain and the effect of histamine receptor antagonists on behavior of adult rats. At 3 days after birth, Wistar rats were pretreated with desipramine (20.0 mg/kg ip) 1 h before bilateral icv administration of the catecholaminergic neurotoxin 6-OHDA (67 μg base, on each side) or saline-ascorbic acid (0.1%) vehicle (control). At 8 weeks levels of DA and its metabolites l-3,4-dihydroxyphenylalanine (DOPAC) and homovanillic acid (HVA) were estimated in the striatum and frontal cortex by HPCL/ED technique. In the hypothalamus, hippocampus, frontal cortex, and medulla oblongata, the level of histamine was analyzed by immunoenzymatic method. Behavioral observations (locomotion, exploratory-, oral-, and stereotyped-activity) were additionally made on control and 6-OHDA neonatally lesioned rats. Effects of DA receptor agonists (SKF 38393, apomorphine) and histamine receptor antagonists (e.g., S(+)chlorpheniramine, H₁; cimetidine, H₂; thioperamide, H₃ agonist) were determined. We confirmed that 6-OHDA significantly reduced contents of DA and its metabolites in the brain in adulthood. Histamine content was significantly increased in the hypothalamus, hipocampus, and medulla oblongata. Moreover, in 6-OHDA-lesioned rats behavioral response was altered mainly by thioperamide (H₃ antagonist). These findings indicate that histamine and the central histaminergic system are altered in the brain of rats lesioned to model Parkinson’s disease, and that histaminergic neurons exert a modulating role in Parkinsonian 6-OHDA-lesioned rats.     

Clinical Trials of Dementia With Lewy Bodies and Parkinson’s Disease Dementia

Despite the frequency and importance of dementia associated with Parkinson's disease (PDD) and dementia with Lewy bodies (DLB), there is relatively little evidence on which to base treatment. Evidence from meta-analysis suggests that rivastigmine can improve cognition and functioning in PDD and also reduce risk of falling. There is also evidence supporting its use in DLB. Recent evidence suggests that memantine may also be effective, particularly for PDD, although evidence is more conflicting. Memantine may also improve parkinsonism and dyskinesias. Few clinical trials of cognition in PD without dementia exist, but there is preliminary evidence for atomoxetine, memantine, and piribedil. There is a lack of systematic evidence for the treatment of visual hallucinations and depression in PDD and DLB. In addition, there is a need for studies of whether potentially disease-modifying agents can prevent or delay the progression to dementia in PD.     

Role of Apolipoproteins and α-Synuclein in Parkinson’s Disease

Parkinson’s disease (PD) is a progressive brain disorder that interferes with activities of normal life. The main pathological feature of this disease is the loss of more than 80% of dopamine-producing neurons in the substantia nigra (SN). Dopaminergic neuronal cell death occurs when intraneuronal, insoluble, aggregated proteins start to form Lewy bodies (LBs), the most important component of which is a protein called α-synuclein (α-syn). α-Syn structurally contains hexameric repeats of 11 amino acids, which are characteristic of apolipoproteins and thus α-syn can also be considered an apolipoprotein. Moreover, apolipoproteins seem to be involved in the incidence and development of PD. Some apolipoproteins such as ApoD have a neuroprotective role in the brain. In PD, apoD levels increase in glial cells surrounding dopaminergic cells. However, elevated levels of some other apolipoproteins such as ApaA1 and ApoE are reported as a vulnerability factor of PD. At present, when a clinical diagnosis of PD is made, based on symptoms such as shaking, stiff muscles and slow movement, serious damage has already been done to nerve cells of the SN. The diagnosis of PD in its earlier stages, before this irreversible damage, would be of enormous benefit for future treatment strategies designed to slow or halt the progression of PD. This review presents the roles of apolipoproteins and α-syn in PD and how some of them could potentially be used as biomarkers for PD.     

Naming in Patients With Alzheimer’s Disease: Influence of Age of Acquisition and Categorical Effects

The role of age of acquisition (AoA) and other variables classically supposed to influence lexical semantic tasks is explored in Alzheimer’s disease (AD) patients. A naming test that included living and nonliving items was given to patients and controls. Measures of AoA of the test items were obtained from normal subjects. Living items were acquired earlier than nonliving items. Semipartial correlation analyses were performed to determine the independent contribution of each variable to naming. The “category” (living vs. nonliving items) was included as an independent factor. It emerged that AoA, name agreement and category (with living category predicting lower scores) were the main predictors of naming in AD patients. Only factor agreement reached significance in control groups. The hypothesis is discussed that the category dissociation may be produced by the different nature of the semantic correlation network that makes the categories differentially demanding of processing resources.