Parkinson’s disease in patients and obligate carriers of Gaucher disease

BackgroundGaucher disease is an autosomal recessive disorder caused by glucocerebrosidase gene mutations. Accumulating evidence from several Parkinson’s disease cohorts of varying ethnicities suggests that glucocerebrosidase mutations even in the heterozygous state (carriers) may be a susceptibility factor for Parkinson’s. Very few studies have analyzed the frequency of Parkinson’s in carriers and individuals with Gaucher disease.ObjectiveTo determine frequency of Parkinson’s in patients with Gaucher disease and obligate carriers of glucocerebrosidase mutations and compare it with a control group.MethodsA questionnaire was completed by 100 Ashkenazi Jewish Gaucher patients followed at our center and 109 ethnicity-matched controls with no personal or family history of Gaucher disease.ResultsFrequency of Parkinson’s was higher in Gaucher patients (8/100) than in controls (0/109; P = 0.0024). Frequency of Parkinson’s in obligate carriers (11/200) was higher than controls (6/218), but the difference was not statistically significant (P = 0.215). Average age of onset of Parkinson’s was earlier in Gaucher patients (57.2) than the general population and in obligate carriers (60) when compared with controls (76.8; P = 0.01). The L444P genotype was more frequent in Gaucher patients who reported a parent with Parkinson’s (36.40%) than those who did not (4.50%).ConclusionOur study suggests that the risk for developing Parkinson’s may be higher in affected versus carriers of glucocerebrosidase mutations and suggests that L444P may pose a higher risk of developing Parkinson’s than other mutations. It also confirms previous findings that the age of onset of Parkinson’s associated with glucocerebrosidase mutations is earlier than in the general population.     

The FRAGAMP study: environmental and genetic factors in Parkinson’s disease, methods and clinical features

The Fattori di Rischio Ambientali e Genetici Associati alla Malattia di Parkinson (FRAGAMP) study is a multicenter case–control study carried out to evaluate the possible role of environmental and genetic factors in Parkinson’s disease (PD). Cases and controls were enrolled from five Movement Disorder centers in Central-Southern Italy. PD was diagnosed according to Gelb’s criteria while the control groups consisted of the spouses of the enrolled patients or of healthy controls matched by age and area of residence. Cases and controls underwent a standardised questionnaire and a blood sample was taken for molecular analyses. At the end of the study 585 cases and 481 control subjects (287 spouse-controls and 194 generic-controls) were enrolled. Patients had a Hoehn–Yahr score of 2.3 ± 0.8; 85% of them took levodopa and 47% had motor complications. The FRAGAMP study represents one of the largest case–control studies carried out in Europe to investigate the possible role of environmental and genetic factors in PD.     

Deep brain stimulation in Parkinson’s disease

Throughout the past decade, there has been a marked increase in surgical therapies, primarily deep brain stimulation (DBS), for the treatment of advanced Parkinson’s disease (PD). DBS of the thalamus has been shown to be effective in reducing parkinsonian tremor; however, it is not the treatment of choice for PD given the progression of other symptoms such as rigidity and bradykinesia. Stimulation of the globus pallidus or the subthalamic nucleus is safe and efficacious in the long-term treatment of all cardinal symptoms of PD, and they are currently the surgeries of choice. Serious adverse events with DBS can occur in 1% to 2% of patients, infection in 5% to 8% of patients, and hardware complications in approximately 25% of patients. Complications associated with DBS are related to the experience of the surgical center. Referring physicians and patients should be aware of the number of surgical procedures and complication rates of any prospective surgical center.     

Clinical problems in late-stage Parkinson’s disease

Advanced Parkinson’s disease patients require for their care the participation of a multidisciplinary team. Particularly in the late stages of the disease, motor complications due both to medication and to progression of the disease, together with non-motor complications, add to the complexity of their management. Increasing age of the population will increase the incidence and the prevalence of the disease, with more patients reaching an advanced age and a more advanced stage of the disease, thus creating a public health problem for which we have to be prepared.

     

Homocysteine levels,genetic background,and cognitive impairment in Parkinson’s disease

Journal of Neurology - Hyperhomocysteinemia is considered an independent risk factor for cognitive impairment. To study the correlation between homocysteine levels and cognitive impairment in...     

Conflict adaptation and related neuronal processing in Parkinson’s disease

Brain Imaging and Behavior - Non-motor symptoms like cognitive impairment are a huge burden for patients with Parkinson’s disease. We examined conflict adaptation by using the congruency...     

Precision medicine in Parkinson’s disease: emerging treatments for genetic Parkinson’s disease

Journal of Neurology - In recent years, numerous clinical trials for disease modification in Parkinson’s disease (PD) have failed, possibly because of a “one-size-fits all”...     

Clinical and demographic correlates of apathy in Parkinson’s disease

Journal of Neurology - To better understand the demographic, neuropsychiatric, cognitive, and motor predictors of apathy in Parkinson’s disease (PD). 112 participants (Mage = 68.53 years;...     

When Parkinson’s disease patients go to sleep: specific sleep disturbances related to Parkinson’s disease

Journal of Neurology -     

New aspects of genetic contributions to Parkinson’s disease

Over the last few years, several genes for rare, monogenically inherited forms of Parkinson’s disease (PD) have been mapped and/or cloned. In dominant families, mutations have been identified in the gene for α-synuclein. Aggregation of this protein in intracellular inclusions (Lewy bodies) may be crucial in the molecular pathogenesis of the disease. Three genes have been identified to cause autosomal-recessive early-onset parkinsonism: parkin, DJ1, and PINK1. These genes are thought to be involved in the proteasomal protein degradation pathway, in the cell’s response to oxidative stress, and in mitochondrial function, respectively. It is therefore concluded that these cellular mechanisms may play an important role in the degenerative process of PD. There is also accumulating evidence that genetic factors play a role in the common sporaidic form of PD, however their precise nature remains unknown.     

Clinical features of Alzheimer’s disease

The preclinical stage of Alzheimer’s disease is inconspicuous and there are – almost by definition – no reliable and valid symptoms and signs which would allow a very early diagnosis before the manifestation of irreversible deficits. For a clinical diagnosis of dementia, cognitive impairment has to be severe enough to compromise the activities of daily living. In the mild dementia stage, difficulties with declarative memory are usually prominent; depressive symptoms are not infrequent, but the patient usually manages to live alone. Supervision is needed in the moderate dementia stage, when other cognitive domains are affected in a more obvious manner and non-cognitive disturbances of thought, perception, affect, and behavior put increasing stress on the caregivers. Complete dependence of the patients, who frequently develop neurological disturbances, is typical of the late stage of illness. The life expectancy of patients with a clinical diagnosis of Alzheimer’s disease is significantly reduced, but to date there is hope that the period of relative well-being and not of suffering can be prolonged with modern symptomatic treatment interventions.     

Deep brain stimulation for camptocormia in dystonia and Parkinson’s disease

Camptocormia, or “bent spine syndrome”, may occur in various movement disorders such as primary dystonia or idiopathic Parkinson’s disease (PD). Although deep brain stimulation (DBS) is an established treatment in refractory primary dystonia and advanced PD, few data are available on the effect of DBS on camptocormia comparing these two conditions. Seven patients (4 with dystonia, 3 with PD; mean age 60.3 years at surgery, range 39–73 years) with camptocormia were included in the study. Five patients underwent bilateral GPi DBS and two patients underwent bilateral STN DBS guided by CT-stereotactic surgery and microelectrode recording. Pre- and postoperative motor assessment included the BFM in the dystonia patients and the UPDRS in the PD patients. Severity of camptocormia was assessed by the BFM subscore for the trunk at the last available follow-up at a mean of 17.3 months (range 9–36 months). There were no surgical complications. In the four patients with dystonia there was a mean improvement of 53% in the BFM motor score (range 41–79%) and of 63% (range 50–67%) in the BFM subscore for the trunk at the last available follow-up (mean 14.3 months, range 9–18 months). In the three patients with camptocormia in PD who underwent bilateral STN DBS (2 patients) or pallidal DBS (1 patient), the PD symptoms improved markedly (mean improvement in the UPDRS motor subscore stimulation on/medication off 55%, range 49–61%), but there was no or only mild improvement of camptocormia in the two patients who underwent STN DBS, and only moderate improvement in the patient with GPi DBS at the last available follow-up (mean 21 months, range 12–36 months). GPi DBS is an effective treatment for camptocormia in dystonia. The response of camptocormia to chronic STN or GPi DBS in PD is more heterogenous. The latter may be due to a variety of causes and needs further clarification.     

Pathological features of cerebral cortical capillaries are doubled in Alzheimer’s disease and Parkinson’s disease

Cerebral capillaries represent a major interface between the general circulation and the central nervous system and are responsible for sufficient and selective nutrient transport to the brain. Structural damage or dysfunctioning carrier systems of such an active barrier leads to compromised nutrient trafficking. Subsequently, a decreased nutrient availability in the neural tissue may contribute to hampered neuronal metabolism, hence to behavioral and cognitive functional deficiencies. Here we focus on the ultrastrucutral abnormalities of cerebral microvessels in Alzheimer’s disease (AD; n = 5) and Parkinson’s diseasse (PD; n = 10). The capillary microanatomy in samples from the cingulate cortex was investigated by electron microscopy and severe damage to the vessel walls was observed. Characteristic pathological changes including capillary basement membrane thickening and collagen accumulation in the basement membrane were enhanced in both AD and PD. The incidence of capillaries with basement membrane deposits was two times higher in AD and PD than in age-matched controls. Degenerative pericytes in all groups appeared at a similar frequency. The data indicate that basement membrane deposists, as opposed to pericytic degeneration, represent an important pathological feature of AD and PD and suggest that capillary dysfunction may play a causal role in the development of these two major neurodegenerative diseases. Received: 21 July 1999 / Revised, accepted: 21 December 1999     

Re-emergent tremor in Parkinson’s disease: Clinical and accelerometric properties

Re-emergent tremor (RET) and the classical parkinsonian rest tremor were considered as two different phenomena of the same central tremor circuit. However, clinical and accelerometric characteristics of these tremors were not previously compared in a single study. We evaluated disease characteristics and accelerometric measurements of two tremor types in 42 patients with Parkinson’s disease. Disease specific features and accelerometric measurements of peak frequency, amplitude at peak frequency and the root mean square (RMS) amplitude of two tremor types were compared. Eighteen patients had RET and the mean latency of the RET was 9.48 (±9.2) s. Groups of only rest tremor and RET did not differ significantly in age of disease onset, disease duration and severity and mean levodopa equivalent dose. Comparison of peak frequency and amplitude at peak frequency were not different between the groups, but RMS amplitude was significantly higher in the RET group (p = 0.03). RMS amplitude of RET was also correlated with disease severity (r = .48, p = 0.04). These results support the previous notion that rest tremor and RET are analogue, both are triggered by the same central ossilator with RET being only the suppression of the rest tremor due to arm repositioning.     

Astrocyte reactivity in related brain regions in a mouse model of MPTP-induced Parkinson’s disease

BACKGROUND： Severe injury to dopaminergic neuronal cell bodies and their axon terminals in the substantia nigra pars compacta （SNC） has been observed in both Parkinson＇s disease （PD） patients or in 1-methy-4-phenyl-1,2,3,6-tetrahydropyrindine（MPTP）-induced PD animal models, but only slight injury occurs in the adjacent ventral tegmentat area （VTA）. The mechanisms underlying this selective injury remain poorly understood. OBJECTIVE： To comparatively observe astrocyte reactivity in the SNC, caudate putamen （CPu）, VTA, and frontal association cortex （FrA）.
DESIGN, TIME AND SETTING： A cellular and molecular biology, randomized, controlled experiment was performed at the Institute of Neurobiology, Department of Human Anatomy, Medical School of Nantong University, between December 2006 and September 2008.
MATERIALS： A total of 80 healthy adult male C57BL/6 mice were included in this study. MPTP was purchased from Sigma, USA.
METHODS： Mice were randomly divided into a model group （n = 64） and a sham-operated group （n = 16）. PD was induced in the mice from the model group by intraperitoneal injection of 20 mg/kg MPTP, once every three hours, for a total of 4 times.
MAIN OUTCOME MEASURES： Tyrosine hydroxylase （TH）-immunoreactive neurons and glial fibrillary acidic protein （GFAP）-immunoreactive astrocytes were examined by dual immunofluorescence labeling. GFAP-immunoreactive astrocytes in the CPu and FrA were determined by immunofluorescent staining. GFAP mRNA expression in the SNC, CPu, VTA, and FrA was detected using real-time polymerase chain reaction. TH protein levels in the TH-immunoreactive axon terminals of the CPu and FrA were detected by Western blotting.
RESULTS： Numbers of TH-immunoreactive neurons in the SNC, and TH protein level in the CPu, markedly decreased （by approximately 68%） 1 day after MPTP injection, and gradually increased at 3 days. Simultaneously, astrocyte reactivity was strengthened, in particular at 7 days. However, after MPTP injection, decreases in the numbers of TH-immunoreactive neurons in the VTA, and TH protein levels in the FrA, were less apparent （approximately 15%）. Also, no obvious astrocyte reactivity was observed.
CONCLUSION： In a mouse model of PD, astrocyte reactivity was apparent in the SNC and CPu, but not the VTA or FrA. In addition, astrocyte reactivity was greater in regions where injury to dopaminergic neurons was more severe.