Revistas
Revista:
ACS CHEMICAL NEUROSCIENCE
ISSN:
1948-7193
Año:
2023
Vol.:
14
N°:
11
Págs.:
2074 - 2088
c-Jun N-terminal kinases (JNKs) are a family of proteinkinasesactivated by a myriad of stimuli consequently modulating a vast rangeof biological processes. In human postmortem brain samples affectedwith Alzheimer ' s disease (AD), JNK overactivation has beendescribed; however, its role in AD onset and progression is stillunder debate. One of the earliest affected areas in the pathologyis the entorhinal cortex (EC). Noteworthy, the deterioration of theprojection from EC to hippocampus (Hp) point toward the idea thatthe connection between EC and Hp is lost in AD. Thus, the main objectiveof the present work is to address if JNK3 overexpression in the ECcould impact on the hippocampus, inducing cognitive deficits. Dataobtained in the present work suggest that JNK3 overexpression in theEC influences the Hp leading to cognitive impairment. Moreover, proinflammatorycytokine expression and Tau immunoreactivity were increased both inthe EC and in the Hp. Therefore, activation of inflammatory signalingand induction of Tau aberrant misfolding caused by JNK3 could be responsiblefor the observed cognitive impairment. Altogether, JNK3 overexpressionin the EC may impact on the Hp inducing cognitive dysfunction andunderlie the alterations observed in AD.
Revista:
NEUROBIOLOGY OF DISEASE
ISSN:
0969-9961
Año:
2023
Vol.:
183
Págs.:
106166
Synucleinopathies are a group of neurodegenerative diseases without effective treatment characterized by the abnormal aggregation of alpha-synuclein (aSyn) protein. Changes in levels or in the amino acid sequence of aSyn (by duplication/triplication of the aSyn gene or point mutations in the encoding region) cause familial cases of synucleinopathies. However, the specific molecular mechanisms of aSyn-dependent toxicity remain unclear. Increased aSyn protein levels or pathological mutations may favor abnormal protein-protein interactions (PPIs) that could either promote neuronal death or belong to a coping response program against neurotoxicity. Therefore, the identification and modulation of aSyn-dependent PPIs can provide new therapeutic targets for these diseases. To identify aSyn-dependent PPIs we performed a proximity biotinylation assay based on the promiscuous biotinylase BioID2. When expressed as a fusion protein, BioID2 biotinylates by proximity stable and transient interacting partners, allowing their identification by streptavidin affinity purification and mass spectrometry. The aSyn interactome was analyzed using BioID2-tagged wild-type (WT) and pathological mutant E46K aSyn versions in HEK293 cells. We found the 14-3-3 epsilon isoform as a common protein interactor for WT and E46K aSyn. 14-3-3 epsilon correlates with aSyn protein levels in brain regions of a transgenic mouse model overexpressing WT human aSyn. Using a neuronal model in which aSyn cell-autonomous toxicity is quantitatively scored by longitudinal survival analysis, we found that stabilization of 14-3-3 protein-proteins interactions with Fusicoccin-A (FC-A) decreases aSyn-dependent toxicity. Furthermore, FC-A treatment protects dopaminergic neuronal somas in the substantia nigra of a Parkinson's disease mouse model. Based on these results, we propose that the stabilization of 14-3-3 epsilon interaction with aSyn might reduce aSyn toxicity, and highlight FC-A as a potential therapeutic compound for synucleinopathies.
Autores:
Santos-Garcia, D. (Autor de correspondencia); de Deus Fonticoba, T.; Cores Bartolome, C.; et al.
Revista:
JOURNAL OF PARKINSON'S DISEASE
ISSN:
1877-7171
Año:
2023
Vol.:
13
N°:
3
Págs.:
379 - 402
Background: Recently, a novel simple classification called MNCD, based on 4 axes (Motor; Non-motor; Cognition; Dependency) and 5 stages, has been proposed to classify Parkinson's disease (PD). Objective: Our aim was to apply the MNCD classification in a cohort of PD patients for the first time and also to analyze the correlation with quality of life (QoL) and disease severity. Methods: Data from the baseline visit of PD patients recruited from 35 centers in Spain from the COPPADIS cohort from January 2016 to November 2017 were used to apply the MNCD classification. Three instruments were used to assess QoL: 1) the 39-item Parkinson's disease Questionnaire [PDQ-39]); PQ-10; the EUROHIS-QOL 8-item index (EUROHIS-QOL8). Results: Four hundred and thirty-nine PD patients (62.05 +/- 7.84 years old; 59% males) were included. MNCD stage was: stage 1, 8.4% (N = 37); stage 2, 62% (N = 272); stage 3, 28.2% (N = 124); stage 4-5, 1.4% (N = 6). A more advanced MNCD stage was associated with a higher score on the PDQ39SI (p < 0.0001) and a lower score on the PQ-10 (p < 0.0001) and EUROHIS-QOL8 (p < 0.0001). In many other aspects of the disease, such as disease duration, levodopa equivalent daily dose, motor symptoms, non-motor symptoms, and autonomy for activities of daily living, an association between the stage and severity was observed, with data indicating a progressive worsening related to disease progression throughout the proposed stages. Conclusion: Staging PD according to the MNCD classification correlated with QoL and disease severity. The MNCD could be a proper tool to monitor the progression of PD.
Revista:
ARQUIVOS DE NEURO-PSIQUIATRIA
ISSN:
0004-282X
Año:
2022
Vol.:
80
N°:
2
Págs.:
145 - 152
Background: Parkinson's disease (PD) is a chronic disease that presents a multitude of symptoms, with symptoms of both motor and nonmotor nature. The Delphi method is widely used to create consensuses among experts in a field of knowledge. Objective: In order to reach a consensus on the values that should be assigned to the different motor and nonmotor manifestations of Parkinson's disease, a linear evaluation index (LEI) was created. Subsequently, the metric properties of this index were studied. Methods: 120 consecutive patients with a Parkinson's diagnosis were chosen in accordance with the UKPDSBB criteria. The Delphi method was used to reach a consensus among experts regarding the values of each of the manifestations included. Subsequently, the following attributes were analyzed: quality and acceptability of the data; reliability, in terms of internal consistency, reliability index, Cronbach's alpha and standard error of measurement; and validity, in terms of convergent validity and validity for known groups. Results: Twenty-five experts participated. The importance factor did not differ between the first round and the second round (chi-square test). We analyzed the responses that assigned percentage values to the 10 dimensions of the LEI. Both in the first and in the second round, the values of the scattering coefficient Vr were always close to 0. The homogeneity index was 0.36; the corrected-item total correlation values ranged from 0.02 to 0.7; Cronbach's alpha was 0.69; and the SEM was 4.23 (55.1%). Conclusions: The LEI was obtained through rigorous recommended methodology. The results showed adequate metric properties.
Autores:
Martínez-Valbuena, I.; Visanji, N. P.; Kim, A.; et al.
Revista:
TRANSLATIONAL NEURODEGENERATION
ISSN:
2047-9158
Año:
2022
Vol.:
11
N°:
1
Págs.:
7
Background: Multiple system atrophy (MSA) is a neurodegenerative condition characterized by variable combinations of parkinsonism, autonomic failure, cerebellar ataxia and pyramidal features. Although the distribution of synucleinopathy correlates with the predominant clinical features, the burden of pathology does not fully explain observed differences in clinical presentation and rate of disease progression. We hypothesized that the clinical heterogeneity in MSA is a consequence of variability in the seeding activity of alpha-synuclein both between different patients and between different brain regions. Methods: The reliable detection of alpha-synuclein seeding activity derived from MSA using cell-free amplification assays remains challenging. Therefore, we conducted a systematic evaluation of 168 different reaction buffers, using an array of pH and salts, seeded with fully characterized brain homogenates from one MSA and one PD patient. We then validated the two conditions that conferred the optimal ability to discriminate between PD- and MSA-derived samples in a larger cohort of 40 neuropathologically confirmed cases, including 15 MSA. Finally, in a subset of brains, we conducted the first multi-region analysis of seeding behaviour in MSA. Results: Using our novel buffer conditions, we show that the physicochemical factors that govern the in vitro amplification of alpha-synuclein can be tailored to generate strain-specific reaction buffers that can be used to reliably study the seeding capacity from MSA-derived alpha-synuclein. Using this novel approach, we were able to sub-categorize the 15 MSA brains into 3 groups: high, intermediate and low seeders. To further demonstrate heterogeneity in alpha-synuclein seeding in MSA, we conducted a comprehensive multi-regional evaluation of alpha-synuclein seeding in 13 different regions from 2 high seeders, 2 intermediate seeders and 2 low seeders. Conclusions: We have identified unexpected differences in seed-competent alpha-synuclein across a cohort of neuropathologically comparable MSA brains. Furthermore, our work has revealed a substantial heterogeneity in seeding activity, driven by the PBS-soluble alpha-synuclein, between different brain regions of a given individual that goes beyond immunohistochemical observations. Our observations pave the way for future subclassification of MSA, which exceeds conventional clinical and neuropathological phenotyping and considers the structural and biochemical heterogeneity of alpha-synuclein present. Finally, our methods provide an experimental framework for the development of vitally needed, rapid and sensitive diagnostic assays for MSA.
Revista:
BIOMACROMOLECULES
ISSN:
1525-7797
Año:
2022
Vol.:
23
N°:
11
Págs.:
4629 - 4644
The co-administration of glial cell line-derived neurotrophic factor (GDNF) and mesenchymal stem cells (MSCs) in hydrogels (HGs) has emerged as a powerful strategy to enhance the efficient integration of transplanted cells in Parkinson's disease (PD). This strategy could be improved by controlling the cellular microenvironment and biomolecule release and better mimicking the complex properties of the brain tissue. Here, we develop and characterize a drug delivery system for brain repair where MSCs and GDNF are included in a nanoparticle-modified supramolecular guest-host HA HG. In this system, the nanoparticles act as both carriers for the GDNF and active physical crosslinkers of the HG. The multifunctional HG is mechanically compatible with brain tissue and easily injectable. It also protects GDNF from degradation and achieves its controlled release over time. The cytocompatibility studies show that the developed biomaterial provides a friendly environment for MSCs and presents good compatibility with PC12 cells. Finally, using RNA-sequencing (RNA-seq), we investigated how the three-dimensional (3D) environment, provided by the nanostructured HG, impacted the encapsulated cells. The transcriptome analysis supports the beneficial effect of including MSCs in the nanoreinforced HG. An enhancement in the anti-inflammatory effect of MSCs was observed, as well as a differentiation of the MSCs toward a neuron-like cell type. In summary, the suitable strength, excellent self healing properties, good biocompatibility, and ability to boost MSC regenerative potential make this nanoreinforced HG a good candidate for drug and cell administration to the brain.
Autores:
Santos García, D. (Autor de correspondencia); Álvarez Sauco, M.; Calopa, M.; et al.
Revista:
DIAGNOSTICS
ISSN:
2075-4418
Año:
2022
Vol.:
12
N°:
1
Págs.:
55
Background and objective: Parkinson's disease (PD) is a clinically heterogeneous disorder in which the symptoms and prognosis can be very different among patients. We propose a new simple classification to identify key symptoms and staging in PD. Patients and Methods: Sixteen movement disorders specialists from Spain participated in this project. The classification was consensually approved after a discussion and review process from June to October 2021. The TNM classification and the National Institutes of Health Stroke Scale (NIHSS) were considered as models in the design. Results: The classification was named MNCD and included 4 major axes: (1) motor symptoms; (2) non-motor symptoms; (3) cognition; (4) dependency for activities of daily living (ADL). Motor axis included 4 sub-axes: (1) motor fluctuations; (2) dyskinesia; (3) axial symptoms; (4) tremor. Four other sub-axes were included in the non-motor axis: (1) neuropsychiatric symptoms; (2) autonomic dysfunction; (3) sleep disturbances and fatigue; (4) pain and sensory disorders. According to the MNCD, 5 stages were considered, from stage 1 (no disabling motor or non-motor symptoms with normal cognition and independency for ADL) to 5 (dementia and dependency for basic ADL). Conclusions: A new simple classification of PD is proposed. The MNCD classification includes 4 major axes and 5 stages to identify key symptoms and monitor the evolution of the disease in patients with PD. It is necessary to apply this proof of concept in a properly designed study.
Revista:
FRONTIERS IN NEUROLOGY
ISSN:
1664-2295
Año:
2022
Vol.:
13
Págs.:
938686
Revista:
BRAIN SCIENCES
ISSN:
2076-3425
Año:
2021
Vol.:
11
N°:
3
Págs.:
385
Background: Both cerebral vascular disorders and cognitive decline increase in incidence with age. The role of cerebral vascular disease and hemodynamic changes in the development of cognitive deficits is controversial. The objective of this study was to assess the cardiovascular response during cardiac stress testing in neurologically asymptomatic individuals who developed cognitive impairment several years after previous cardiac stress testing. (2) Methods: This was a retrospective cohort study of patients who underwent cardiac stress testing between January 2001 and December 2010. Patients were followed up until May 2015, and we selected those who developed cognitive dysfunction including dementia, mild cognitive impairment, and subjective cognitive decline, after the stress test. Heart rate and blood pressure both at rest and at peak exercise, and the mean R-R interval at rest were recorded. For each patient who developed cognitive impairment, we selected one matched control who did not show cognitive decline by the end of the follow-up period. (3) Results: From the cohort of 7224 patients, 371 developed cognitive impairment; of these, 186 (124 men) met the inclusion criteria, and 186 of the other patients were selected as matched controls. During follow-up, cognitive impairment appeared 6.2 +/- 4.7 years after the cardiac stress test. These patients who had subsequently developed cognitive impairment had significantly lower at-rest systolic, diastolic, and mean blood...
Revista:
CEPHALALGIA
ISSN:
0333-1024
Año:
2021
Vol.:
41
N°:
5
Págs.:
604 - 612
Background Recently, amylin and its receptors were found in different structures involved in migraine pathophysiology. Here, we evaluate interictal concentrations of amylin and calcitonin gene-related peptide in peripheral blood as biomarkers for chronic migraine. Methods We prospectively recruited patients with episodic migraine, chronic migraine and healthy controls. Interictal amylin and calcitonin gene-related peptide levels were assessed in blood samples using enzyme linked immunosorbent assay. Results We assessed plasma samples from 58 patients with episodic migraine (mean age 37.71 +/- 10.47, 87.9% female), 191 with chronic migraine (mean age 46.03 +/- 11.93, 95% female), and on 68 healthy controls (mean age 43.58 +/- 11.08 years, 86% female). Body mass index was 25.94 +/- 4.53 kg/m(2) for migraine patients and 25.13 +/- 4.92 kg/m(2) for healthy controls (p = 0.0683). Interictal plasma amylin levels were higher in chronic migraine patients (47.1 pg/mL) than in the episodic migraine patients (28.84 pg/mL, p < 0.0001) and healthy controls (24.74 pg/mL, p < 0.0001). Plasma calcitonin gene-related peptide levels were increased (20.01 pg/mL) in chronic migraine patients when compared to healthy controls (11.37 pg/mL, p = 0.0016), but not to episodic migraine patients (18.89 pg/mL, p = 0.4369). Applying a cut-off concentration of 39.68 pg/mL plasma amylin, the sensitivity to differentiate chronic migraine from healthy controls was 57.6% and the specificity was 88.2%. Variables such as age, analgesic overuse, depression, allodynia, use of preventive medication or a history of aura did not influence the plasma concentrations of amylin or calcitonin gene-related peptide. Conclusion Interictal plasma amylin levels are higher in patients with chronic migraine and may serve as a diagnostic biomarker for chronic migraine.
Revista:
NEUROLOGICAL SCIENCES
ISSN:
1590-1874
Año:
2021
Vol.:
42
N°:
4
Págs.:
1473 - 1482
The olfactory bulb (OB) seems to be the first affected structure in neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and Lewy body dementia (LBD). Deposits of protein aggregates, increased dopaminergic neurons, and decreased cholinergic inputs have all been described in the OB of these diseases. We investigated here the contribution of the activated microglial cells to the increased deposits of protein aggregates. We quantified the number of activated microglial cells and astrocytes in the OB of patients with histological diagnosis of PD (n= 5), AD (n= 13), and LBD (n= 7) and aged-matched controls (n= 8). Specific consensus diagnostic criteria were applied for AD, LBD, and PD. Protein aggregates were scored in the OB as grade 0, none; grade 1, mild; grade 2, moderate; and grade 3, severe. OB sections from the 33 subjects were stained with specific antibodies markers for reactive astrocytes (GFAP) and microglial cells (Iba1 and HLA-DR). The total number of Iba1-ir (Iba-immunoreactive) and HLAD-DR cells was estimated by stereological analysis, while quantification of astrocytes was performed by GFAP optical density. Statistical analysis was done using the Stata 12.0 software. The number of microglia and activated microglia cells (HLA-RD-ir) was increased in patients with neurodegenerative diseases (p< 0.05). Moreover, the density of GFAP-ir cells was higher in the OB of patients. Neither the number of microglia cells nor the density of astrocytes correlated with the number of b-amyloid and alpha-synuclein deposits, but the density of Iba1-ir cells correlated with the number of p-Tau aggregates. Activated microglial cells and reactive astrocytes are present in the OB of patients with neurodegenerative diseases. The lack of correlation between the number of activated microglia cells and protein deposits indicate that they might independently contribute to the degenerative process. The presence of microglia is related to phosphorylated Tau deposits in neurodegenerative diseases.
Revista:
ACTA NEUROPATHOLOGICA COMMUNICATIONS
ISSN:
2051-5960
Año:
2021
Vol.:
9
N°:
1
Págs.:
64
Protein misfolding diseases refer to a variety of disorders that develop as a consequence of the misfolding of proteins in various organs. The etiologies of Parkinson's and Alzheimer's disease remain unclear, but it seems that type two diabetes and other prediabetic states could contribute to the appearance of the sporadic forms of these diseases. In addition to amylin deposition, other amyloidogenic proteins implicated in the pathophysiology of neurodegenerative diseases could have important roles in the pathogenesis of this disease. As we have previously demonstrated the presence of alpha-synuclein deposits in the pancreas of patients with synucleinopathies, as well as tau and A beta deposits in the pancreatic tissue of Alzheimer's disease patients, we studied the immunoreactivity of amylin, tau and alpha-synuclein in the pancreas of 138 subjects with neurodegenerative diseases or type two diabetes and assessed whether the pancreatic beta-cells of these subjects present cooccurrence of misfolded proteins. Furthermore, we also assessed the pancreatic expression of prion protein (PrP) in these subjects and its interaction, both in the pancreas and brain, with alpha-synuclein, tau, A beta and amylin. Our study shows, for the first time, that along with amylin, pancreatic alpha-synuclein, A beta, PrP and tau may contribute together to the complex pathophysiology of type two diabetes and in the appearance of insulin resistance in Alzheimer's and Parkinson's disease. Furthermore, we show that the same mixed pathologies that are observed in the brains of patients with neurodegenerative diseases are also present outside the nervous system. Finally, we provide the first histological evidence of an interaction between PrP and A beta, alpha-synuclein, amylin or tau in the pancreas and locus coeruleus. These findings will shed more light on the common pathological pathways shared by neurodegenerative diseases and type two diabetes, benefiting the exploration of common therapeutic strategies to prevent or treat these devastating amyloid diseases.
Autores:
Santos García, D. (Autor de correspondencia); Blázquez-Estrada, M.; Calopa, M.; et al.
Revista:
BRAIN SCIENCES
ISSN:
2076-3425
Año:
2021
Vol.:
11
N°:
8
Págs.:
1027
Parkinson's disease (PD) is a chronic progressive and irreversible disease and the second most common neurodegenerative disease worldwide. In Spain, it affects around 120.000-150.000 individuals, and its prevalence is estimated to increase in the future. PD has a great impact on patients' and caregivers' lives and also entails a substantial socioeconomic burden. The aim of the present study was to examine the current situation and the 10-year PD forecast for Spain in order to optimize and design future management strategies. This study was performed using the modified Delphi method to try to obtain a consensus among a panel of movement disorders experts. According to the panel, future PD management will improve diagnostic capacity and follow-up, it will include multidisciplinary teams, and innovative treatments will be developed. The expansion of new technologies and studies on biomarkers will have an impact on future PD management, leading to more accurate diagnoses, prognoses, and individualized therapies. However, the socio-economic impact of the disease will continue to be significant by 2030, especially for patients in advanced stages. This study highlighted the unmet needs in diagnosis and treatment and how crucial it is to establish recommendations for future diagnostic and therapeutic management of PD.
Autores:
Martínez-Castrillo, J. C. (Autor de correspondencia); Martínez-Martin, P.; Burgos, A.; et al.
Revista:
BRAIN SCIENCES
ISSN:
2076-3425
Año:
2021
Vol.:
11
N°:
12
Background: Advanced Parkinson's disease (APD) has been recently defined as a stage in which certain symptoms and complications are present, with a detrimental influence on the overall patient's health conditions and with a poor response to conventional treatments. However, historically, the term APD has been controversial, thus consequently, APD prevalence has not been previously studied. Objectives: The main objective was to determine the prevalence of APD in patients diagnosed with idiopathic PD in hospitals of the Spanish National Healthcare System. Secondary objectives were the prevalence and incidence of PD and the clinical and sociodemographic characteristics and quality of life of patients with APD or non-APD. Methods: This was a non-interventional, cross-sectional, multicenter, national study in the hospital setting. Results: The study population included 929 patients with PD (mean age 71.8 +/- 10.1 years; 53.8% male) and a mean time since diagnosis of 6.6 +/- 5.4 years. At the time of diagnosis, 613 patients (66.06%) reported having had premotor symptoms. The Hoehn and Yahr stage was 1 in 15.7% of the patients, 2 in 42.8%, 3 in 30.1%, 4 in 9.9%, and 5 in 1.4%; 46.9% of the patients had comorbidities (mean age-adjusted Charlson comorbidity index 3.5 +/- 1.7; median 10-year survival 77%) and the mean 8-item Parkinson's Disease Quality of Life Questionnaire was 27.8 +/- 20.5. We found an APD prevalence of 38.21% (95%CI: 35.08-41.42%), a PD prevalence of 118.4 (95%CI: 117.3-119.6), and a PD incidence of 9.4 (95%CI: 5.42-13.4) all per 100,000 population. Among the APD population, a 15.2% were receiving some form of therapy for advanced stages of the disease (deep brain stimulation, levodopa/carbidopa intestinal gel, or apomorphine subcutaneous infusion). Conclusions: The percentage of patients with APD in the hospitals of the Spanish National Healthcare System was 38.2%.
Revista:
FRONTIERS IN MOLECULAR NEUROSCIENCE
ISSN:
1662-5099
Parkinson's disease is characterized by motor and nonmotor symptoms that gradually appear as a consequence of the selective loss of dopaminergic neurons in the substantia nigra pars compacta. Currently, no treatment can slow Parkinson's disease progression. Inasmuch, there is a need to develop animal models that can be used to understand the pathophysiological mechanisms underlying dopaminergic neuron death. The initial goal of this study was to determine if canine adenovirus type 2 (CAV-2) vectors are effective gene transfer tools in the monkey brain. A second objective was to explore the possibility of developing a large nonhuman primate that expresses one of the most common genetic mutations causing Parkinson's disease. Our studies demonstrate the neuronal tropism, retrograde transport, biodistribution, and efficacy of CAV-2 vectors expressing GFP and leucine-rich repeat kinase 2 (LRRK2(G2019S)) in the Macaca fascicularis brain. Our data also suggest that following optimization CAV-2-mediated LRRK2(G2019S) expression could help us model the neurodegenerative processes of this genetic subtype of Parkinson's disease in monkeys.
Autores:
Pagonabarraga, J. (Autor de correspondencia); Arbelo, J. M.; Grandas, F. ; et al.
Revista:
BRAIN SCIENCES
ISSN:
2076-3425
Año:
2020
Vol.:
10
N°:
5
Págs.:
313
Revista:
JOURNAL OF HEADACHE AND PAIN
ISSN:
1129-2369
Año:
2020
Vol.:
21
N°:
1
Págs.:
9
Objective To investigate the specific relationship between cutaneous allodynia (CA) and the percentages of body fat (BF) and abdominal fat in migraineurs. Additionally, we compared serum levels of inflammatory biomarkers in patients with and without CA. Background Excess abdominal fat might facilitate progressive changes in nociceptive thresholds causing central sensitization, clinically reflected as CA, which could drive migraine progression. Methods This prospective cohort study included 80 patients with migraine (mean age 39 years, 81.2% female) and 39 non-migraine controls. We analysed each participant's height, body weight, and body mass index (BMI). The amount and distribution of BF was also assessed by air displacement plethysmography (ADP) and ViScan, respectively. We analysed serum levels of markers of inflammation, during interictal periods. Results We studied 52 patients with episodic migraine (EM) and 28 with chronic migraine (CM). Of the 80 patients, 53 (53.8%) had CA. Migraineurs with CA had a higher proportion of abdominal fat values than patients without CA (p = 0.04). The independent risk factors for CA were the use of migraine prophylaxis (OR 3.26, 95% CI [1.14 to 9.32]; p = 0.03), proportion of abdominal fat (OR 1.13, 95% CI [1.01 to 1.27]; p = 0.04), and presence of sleep disorders (OR 1.13, 95% CI [00.01 to 1.27]; p = 0.04). The concordance correlation coefficient between the ADP and BMI measurements was 0.51 (0.3681 to 0.6247). CA was not correlated with the mean plasma levels of inflammatory biomarkers. Conclusions There is a relation between excess abdominal fat and CA. Abdominal obesity might contribute to the development of central sensitization in migraineurs, leading to migraine chronification.
Revista:
MOVEMENT DISORDERS
ISSN:
0885-3185
Año:
2020
Vol.:
35
N°:
11
Págs.:
2009 - 2018
It remains unclear whether the supportive imaging features described in the diagnostic criteria for progressive supranuclear palsy (PSP) are suitable for the full clinical spectrum. The aim of the current study was to define and cross-validate the pattern of glucose metabolism in the brain associated with a diagnosis of different PSP variants. A retrospective multicenter cohort study performed on 73 PSP patients who were referred for a fluorodeoxyglucose positron emission tomography PET scan: PSP-Richardson's syndrome, n = 47; PSP-parkinsonian variant, n = 18; and progressive gait freezing, n = 8. In addition, we included 55 healthy controls and 58 Parkinson's disease (PD) patients. Scans were normalized by global mean activity. We analyzed the regional differences in metabolism between the groups. Moreover, we applied a multivariate analysis to obtain a PSP-related pattern that was cross-validated in independent populations at the individual level. Group analysis showed relative hypometabolism in the midbrain, basal ganglia, thalamus, and frontoinsular cortices and hypermetabolism in the cerebellum and sensorimotor cortices in PSP patients compared with healthy controls and PD patients, the latter with more severe involvement in the basal ganglia and occipital cortices. The PSP-related pattern obtained confirmed the regions described above. At the individual level, the PSP-related pattern showed optimal diagnostic accuracy to distinguish between PSP and healthy controls (sensitivity, 80.4%; specificity, 96.9%) and between PSP and PD (sensitivity, 80.4%; specificity, 90.7%). Moreover, PSP-Richardson's syndrome and PSP-parkinsonian variant patients showed significantly more PSP-related pattern expression than PD patients and healthy controls. The glucose metabolism assessed by fluorodeoxyglucose PET is a useful and reproducible supportive diagnostic tool for PSP-Richardson's syndrome and PSP-parkinsonian variant.
Revista:
NEUROLOGY RESEARCH INTERNATIONAL
ISSN:
2090-1852
Año:
2020
Vol.:
2020
Págs.:
8871870
Objective. This study has been designed with the aim of using optimal scaling to perform the allocation of scores and to be able to construct an indicator of the Parkinson's Disease Gravity Index. Scores were assigned to interrelated dimensions that share information about the patient's situation, to have an objective, holistic tool which integrates scores so that doctors can have a comprehensive idea of the patient's situation. Patients and Methods. 120 consecutive patients with Parkinson's diagnosis were chosen according to the United Kingdom Parkinson's Disease Society Brain Bank criteria. Subsequently, all the chosen dimensions were transformed into interval variables for which the formula proposed by Sturges was used. Once the dimensions were transformed into interval variables, optimal scaling was carried out. Subsequently, the following attributes were analyzed: quality and acceptability of the data; reliability: internal consistency, reliability index, Cronbach's alpha, and standard error of measurement; finally, validity: convergent validity and validity for known groups. Results. There were no missing data. An appropriate Cronbach's alpha value of 0.71 was gathered, and all items were found to be pertinent to the scale. The item homogeneity index was 0.36. Precision evaluated with the standard error of measurement was 7.8. The Parkinson's Disease Gravity Index discriminant validity (validity for known groups), assessed among the different stages of Hoehn and Yahr scale by the Kruskal-Wallis test, showed major significance (X-2 = 32.7, p <= 0.001). Conclusions. The Parkinson's Disease Gravity Index has shown adequate metric properties.
Revista:
ANNALS OF NEUROLOGY
ISSN:
0364-5134
Año:
2019
Vol.:
86
N°:
4
Págs.:
539 - 551
Objective Alzheimer disease (AD) is the leading cause of dementia, and although its etiology remains unclear, it seems that type 2 diabetes mellitus (T2DM) and other prediabetic states of insulin resistance could contribute to the appearance of sporadic AD. As such, we have assessed whether tau and beta-amyloid (A beta) deposits might be present in pancreatic tissue of subjects with AD, and whether amylin, an amyloidogenic protein deposited in the pancreas of T2DM patients, might accumulate in the brain of AD patients. Methods We studied pancreatic and brain tissue from 48 individuals with no neuropathological alterations and from 87 subjects diagnosed with AD. We examined A beta and tau accumulation in the pancreas as well as that of amylin in the brain. Moreover, we performed proximity ligation assays to ascertain whether tau and/or A beta interact with amylin in either the pancreas or brain of these subjects. Results Cytoplasmic tau and A beta protein deposits were detected in pancreatic beta cells of subjects with AD as well as in subjects with a normal neuropathological examination but with a history of T2DM and in a small cohort of control subjects without T2DM. Furthermore, we found amylin deposits in the brain of these subjects, providing histological evidence that amylin can interact with A beta and tau in both the pancreas and hippocampus. Interpretation The presence of both tau and A beta inclusions in pancreatic beta cells, and of amylin deposits in the brain, provides new evidence of a potential overlap in the mechanisms underlying the pathogenesis of T2DM and AD. ANN NEUROL 2019
Revista:
CLINICAL AUTONOMIC RESEARCH
ISSN:
0959-9851
Año:
2019
Vol.:
29
N°:
4
Págs.:
415 - 425
Purpose Systemic administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induces degeneration of dopaminergic neurons and reproduces the motor features of Parkinson disease (PD); however, the effect of MPTP on extranigral structures has been poorly studied. The aim of this research was to study the cardiac sympathetic innervation of control and MPTP-treated monkeys in order to describe the influence of MPTP toxicity on cardiac tissue. Methods Eight monkeys were included in the study and divided into two groups, four monkeys serving as controls and four forming the MPTP group. Sections from the anterior left ventricle were immunohistochemically examined to characterize the sympathetic fibers of cardiac tissue. The intensity of immunoreactivity in the nerve fibers was quantitatively analyzed using ImageJ software. Results As occurs in PD, the sympathetic peripheral nervous system is affected in MPTP-treated monkeys. The percentage of tyrosine hydroxylase immunoreactive fibers in the entire fascicle area was markedly lower in the MPTP group (24.23%) than the control group (35.27%) (p < 0.05), with preservation of neurofilament immunoreactive fibers in the epicardium of MPTP-treated monkeys. Alpha-synuclein deposits were observed in sections of the anterior left ventricle of MPTP-treated monkeys but not in control animals, whereas phosphorylated synuclein aggregates were not observed in either controls or MPTP-treated monkeys. Conclusion The peripheral autonomic system can also be affected by neurotoxins that specifically inhibit mitochondrial complex I.
Autores:
Erro, M. E. (Autor de correspondencia); Zelayaz, M. V.; Mendioroz, M.; et al.
Revista:
JOURNAL OF NEUROLOGY
ISSN:
0340-5354
Año:
2019
Vol.:
266
N°:
10
Págs.:
2396 - 2405
Objective To describe the clinical, biochemical, and neuropathological findings of an autosomal dominant globular glial tauopathy caused by the P301T mutation at the MAPT gene. Methods Five patients from two unrelated pedigrees underwent clinical evaluation. Genetic analysis, brain pathological examination, and biochemical analysis of tau were performed. Results The patients studied were 3 men and 2 women with a mean age at onset of 52.2 years and mean disease duration of 5.2 years. Three patients presented a corticobasal syndrome, one patient an asymmetric pyramidal syndrome compatible with primary lateral sclerosis, and one patient a frontotemporal dementia. In both pedigrees (4 patients) Sanger sequencing showed the p.P301T mutation in exon 10 of the MAPT gene. Neuropathological findings consisted of atrophy of frontal and temporal lobes with marked spongiosis and astrogliosis, and abundant phosphorylated tau protein deposits in the frontal and temporal cortex, limbic area, basal ganglia, and brain stem. The most striking finding was the presence of oligodendroglial 4R phospho-tau globular positive inclusions in the white matter and cortex. Globose-type neurofibrillary neuronal tangles, and in particular astrocytic globular inclusions and coarse tufts, were present in the grey matter. Biochemical analysis of sarkosyl-insoluble fractions revealed two tau bands of 64 and 68 kDa and case-dependent bands of lower molecular weight. Conclusion This is the first pathological and biochemical study of the MAPT p.P301T mutation showing variable clinical manifestation and neuropathological phenotype of globular glial tauopathy not only among different families but also within families.
Revista:
BRAIN SCIENCES
ISSN:
2076-3425
Año:
2019
Vol.:
9
N°:
10
Págs.:
272
Background: Safinamide is an approved drug for the treatment of motor fluctuations of Parkinson's Disease (PD) patients with a potential benefit on non-motor symptoms (NMS). Methods: A retrospective multicenter cohort study was conducted, in which the clinical effect of safinamide on both motor and NMS was assessed by the Clinical Global Impression of Change scale. Furthermore, we assessed the appearance of adverse events (AEs) and its effect on dyskinesia, that were also recorded in non-fluctuating PD patients and in those previously treated with rasagiline. Results: We included 213 PD patients who received safinamide in addition to their regular levodopa therapy. Thirty-five withdrew prematurely from safinamide, mainly because of AEs. Out of 178, clinical improvement on motor and NMS was found in 76.4% and 26.2%, respectively. A total of 44 reported AEs of mild intensity. We did not find a difference concerning the clinical benefit or AEs when comparing either patients who had or had not been taking Monoamine Oxidase B Inhibitor (MAOB-I) previously or between patients with and without motor complications. Conclusions: Safinamide is an effective and safe add-on to levodopa drug for PD patients. Moreover, safinamide could elicit an additional clinical improvement in PD patients previously treated with other MAOB-I and in non- fluctuating patients with suboptimal motor control.
Autores:
Carmona-Abellan, M.; Gabilondo, I.; Murueta-Goyena, A.; et al.
Revista:
PARKINSONISM AND RELATED DISORDERS
ISSN:
1353-8020
Año:
2019
Vol.:
65
Págs.:
139 - 145
Background and objective: In 2004 we described the E46K mutation in alpha-synuclein gene (E46K-SNCA), a rare point mutation causing an aggressive Lewy body disease with early prominent non-motor features and small fiber denervation of myocardium. Considering the potential interest of the skin as a target for the development of biomarkers in Parkinson's Disease (PD), in this work we aimed to evaluate structural and functional integrity of small autonomic nerve fibers and phosphorylated alpha-synuclein (p-synuclein) deposition in the skin of E46K-SNCA carriers as compared to those observed in parkin gene mutation (PARK2) carriers and healthy controls. Patients and methods: We studied 7 E46K-SNCA carriers (3 dementia with Lewy bodies, 2 pure autonomic failure, 1 PD and 1 asymptomatic), 2 PARK2 carriers and 2 healthy controls to quantify intraepidermal nerve fiber density and p-synuclein deposition with cervical skin punch biopsies (immunohistochemistry against anti PGP9.5/UCHL-1, TH and p-synuclein) and sudomotor function with electrochemical skin conductance (ESC) (SudoScan). Results: All E46K-SNCA carriers had moderate to severe p-synuclein deposits and small fiber neurodegeneration in different epidermal and dermal structures including nerve fascicles and glands, especially in carriers with Pure Autonomic Failure, while p-synuclein aggregates where absent in healthy controls and in one of two PARK2 carriers. The severity of the latter skin abnormalities in E46K-SNCA were correlated with sudomotor dysfunction (lower ESC) in hands (p = 0.035). Interpretation: These results together with our previous findings support the relevance of E46K-SNCA mutation as a suitable model to study small fiber neuropathy in Lewy body diseases.
Autores:
Garcia-Ruiz, P. J.; Sanz-Cartagena, P. (Autor de correspondencia); Martinez-Castrillo, J. C.; et al.
Revista:
REVISTA DE NEUROLOGIA
ISSN:
0210-0010
Año:
2018
Vol.:
66
N°:
5
Págs.:
163 - 172
Introduction. Botulinum toxin type A (BTA) is a bacterial endotoxin, whose therapeutic use has had a dramatic impact on different neurological disorders, such as dystonia and spasticity. Aim. To analyze and summarize different questions about the use of BTA in our clinical practice. Development. A group of experts in neurology developed a list of topics related with the use of BTA. Two groups were considered: neuropharmacology and dystonia. A literature search at PubMed, mainly for English language articles published up to June 2016 was performed. The manuscript was structured as a questionnaire that includes those questions that, according to the panel opinion, could generate more controversy or doubt. The initial draft was reviewed by the expert panel members to allow modifications, and after subsequent revisions for achieving the highest degree of consensus, the final text was then validated. Different questions about diverse aspects of neuropharmacology, such as mechanism of action, bioequivalence of the different preparations, immunogenicity, etc. were included. Regarding dystonia, the document included questions about methods of evaluation, cervical dystonia, blepharospasm, etc. Conclusion. This review does not pretend to be a guide, but rather a tool for continuous training of residents and specialists in neurology, about different specific areas of the management of BTA.
Revista:
NEUROBIOLOGY OF DISEASE
ISSN:
0969-9961
Año:
2018
Vol.:
118
Págs.:
64 - 75
Management of levodopa-induced dyskinesias (LID) is one of the main challenges in the treatment of Parkinson's disease patients. Mechanisms involved in the appearance of these involuntary movements are not well known but modifications in the activity of different neurotransmitter pathways seem to play an important role. The objective of this study was to determine differences in the expression levels of the endocannabinoid system (ECS) elements that would support a role in LID. The basal ganglia nuclei, putamen, external segment of the globus pallidus (GPe), internal segment of the globus pallidus (GPi), subthalamic nucleus (STN) and substantia nigra (SN) were dissected out from cryostat sections obtained from two groups of parkinsonian monkeys treated with levodopa to induce dyskinesias. One group of dyskinetic animals was sacrificed under the effect of levodopa, during the active phase of LID, and the other group 24 h after the last levodopa dose (OFF levodopa). Biochemical analysis by real-time PCR for ECS elements was performed. CBI receptor expression was upregulated in the putamen, GPe and STN during the active phase of dyskinesia and downregulated in the same nuclei and in the SN when dyskinetic animals were OFF levodopa. Changes in the 2-arachidonoyl glycerol (2-AG) synthesizing/degrading enzymes affecting the pallidal-subthalamic projections in dyskinetic animals OFF levodopa would suggest that 2-AG may play a role in LID. Anandamide (AEA) synthesizing/degrading enzymes were altered specifically in the GPe of untreated parkinsonian monkeys, suggesting that increased AEA levels may be a compensatory mechanism. These results indicate that the expression of the ECS elements is influenced by alterations in dopaminergic neurotransmission. On one hand, changes in CBI, receptor expression and in the 2-AG synthesizing/degrading enzymes suggest that they could be a therapeutic target for the active phase of LID. On the other hand, AEA metabolism could provide a non-dopaminergic target for symptomatic relief. However, further research is needed to unravel the mechanism of action of the ECS and how they could be modulated for a therapeutic purpose.
Autores:
Martinez-Martin, P. (Autor de correspondencia); Kulisevsky, J. ; Mir, P. ; et al.
Revista:
NPJ PARKINSON'S DISEASE
ISSN:
2373-8057
Early clinical diagnosis of advanced Parkinson's disease (APD) may be difficult. This study aimed to validate a simple screening tool, the CDEPA questionnaire ("Cuestionario De Enfermedad de Parkinson Avanzada" [Questionnaire for Advanced Parkinson's Disease]), for the identification of APD in daily practice. The study included 173 consecutively selected patients with PD (40% were women, mean age was 68.4 +/- 10.5 years), stratified according to the Hoehn and Yahr (HY) scale. The CDEPA questionnaire defined APD as the presence of severe disability requiring help for activities of daily living (ADL), motor fluctuations with limitation or inability to perform ADL, severe dysphagia, recurrent falls, or dementia. The diagnostic performance of the questionnaire was assessed against the gold standard criterion based on clinical judgment. PD was categorized as advanced in 65 (38%) patients when using the gold standard and in 109 (63%) patients when the CDEPA questionnaire was used. The CDEPA questionnaire and the gold standard agreed moderately (kappa statistic of 0.48, P < 0.001). The CDEPA classified APD with a sensitivity of 97%; specificity of 57%; total accuracy of 72.3%; and area under the curve (for a binary classifier) of 77.2%. Significant differences were found between the groups created by the CDEPA in several usual PD evaluations (HY Scale, SCOPA Motor Scale, Non-motor Symptoms Scale for PD, Clinical Impression of Severity Index for PD, Clinical Global Impression-Severity Scale, and Patient Global Impression-Severity Scale). CDEPA showed satisfactory inter-rater agreement (kappa = 0.88) and test-retest concordance (kappa 0.83). In conclusion, the CDEPA questionnaire is a valid, reliable, and useful instrument for easily screening APD.
Revista:
BIOMATERIALS
ISSN:
0142-9612
Año:
2016
Vol.:
110
Págs.:
11-23
Glial cell line-derived neurotrophic factor (GDNF) remains the most potent neurotrophic factor for dopamine neurons. Despite its potential as treatment for Parkinson's disease (PD), its clinical application has been hampered by safety and efficacy concerns associated with GDNF's short in vivo half-life and with significant brain delivery obstacles. Drug formulation systems such as microparticles (MPs) may overcome these issues providing protein protection from degradation and sustained drug release over time. We therefore sought to evaluate the efficacy and safety of GDNF delivered via injectable biodegradable MPs in a clinically relevant model of PD and to investigate the mechanism contributing to their beneficial effects. MPs were injected unilaterally into the putamen of parkinsonian monkeys with severe nigrostriatal degeneration. Notably, a single administration of the microencapsulated neurotrophic factor achieved sustained GDNF levels in the brain, providing motor improvement and dopaminergic function restoration. This was reflected by a bilateral increase in the density of striatal dopaminergic neurons 9 months after treatment. Moreover, GDNF was retrogradely transported to the substantia nigra increasing bilaterally the number of dopaminergic and total neurons, regardless of the severe degeneration. GDNF-MP injection within the putamen elicited no adverse effects such as immunogenicity, cerebellar degeneration or weight loss. MPs are therefore a safe, efficient vehicle for sustained protein delivery to the brain, supporting the therapeutic benefit of GDNF when encapsulated within MPs for brain repair. Overall, these findings constitute important groundwork for GDNF-MP clinical development.
Revista:
EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING
ISSN:
1619-7070
Año:
2015
Vol.:
42
N°:
10
Págs.:
1522-9
Patients with a prion disease exhibit a characteristic pattern of brain metabolism presentation in FDG PET imaging. Consequently, in patients with rapidly progressive cognitive impairment, the detection of these patterns in the FDG PET study could orient the diagnosis to a prion disease.
Revista:
ANALES DEL SISTEMA SANITARIO DE NAVARRA
ISSN:
1137-6627
Año:
2015
Vol.:
38
N°:
1
Págs.:
79 - 92
La degeneración lobar frontotemporal engloba tres síndromes diferentes, que comparten características clínicas y patológicas comunes, dificultando así su diagnóstico en estadios iniciales. Se incluyen en este grupo las tres variantes de la demencia frontotemporal, el síndrome corticobasal y el síndrome de parálisis supranuclear progresiva. Se ha llevado a cabo una revisión del perfil neuropsicológico de cada uno de los síndromes, que permita clarificar las características fundamentales que los definen y ayudar a diferenciarlos de otras demencias.Se ha hecho una revisión de los diferentes trabajos publicados en la literatura al respecto, describiendo las características clínicas, patológicas y los hallazgos de imagen fundamentales de cada entidad para describir de manera exhaustiva los hallazgos en los diferentes dominios neuropsicológicos y su progresión. Aunque existe un solapamiento entre los síndromes que conforman la degeneración lobar frontotemporal, la comparación del perfil neuropsicológico de las mismas entre sí y frente a otras demencias permite establecer características propias de su perfil neuropsicológico para llevar a cabo un diagnóstico diferencial.
Revista:
NEUROLOGÍA (BARCELONA. ED. IMPRESA)
ISSN:
0213-4853
Año:
2014
Vol.:
30
N°:
3
Págs.:
144 - 152
Introducción
Las prionopatías representan hasta el 62% de los casos de demencia rápidamente progresiva (DRP) en los que se alcanza un diagnóstico definitivo. La variabilidad de los síntomas y signos iniciales y las diferencias en su evolución dificultan el diagnóstico precoz.
Métodos
Estudio retrospectivo en el que se incluye a pacientes con prionopatía probable o definitiva, que acudieron a la consulta de Neurología de nuestro centro durante el periodo 1999-2012. Se describen las características clínicas y los resultados de las exploraciones complementarias (proteína 14-3-3, EEG, RM, PET-FDG y análisis genético), con la finalidad de identificar qué marcadores permiten un diagnóstico precoz.
Resultados
Se describe a 14 pacientes: 6 con enfermedad de Creutzfeldt-Jakob esporádica (ECJe) definitiva, 3 con ECJe probable, 4 con insomnio familiar fatal y uno con la nueva variante de la enfermedad de Creutzfeldt-Jakob. La mediana de edad al diagnóstico fue de 54 años y la mediana de supervivencia de 9,5 meses. El trastorno del ánimo fue el síntoma inicial más frecuente, seguido de inestabilidad de la marcha y deterioro cognitivo. La proteína 14-3-3 fue positiva en el líquido cefalorraquídeo en 7 de 11 pacientes y el EEG mostró signos típicos en 2 de 12 pacientes explorados. El estudio de neuroimagen mostró alteraciones en 13 de los 14 pacientes.
Conclusiones
Además de la DRP, el trastorno conductual y de la marcha son síntomas iniciales frecuentes en las prionopatías. En nuestra serie, las pruebas complementarias más útiles para apoyar el diagnóstico fueron la RM y la PET-FDG.
Revista:
REVISTA DE NEUROLOGIA
ISSN:
0210-0010
Año:
2014
Vol.:
58
N°:
6
Págs.:
241 - 246
Objetivo. Identificar las características clínicas que predicen una respuesta favorable al tratamiento con onabotulinumtoxina A (OnabotA) en pacientes con migraña refractaria.
Pacientes y métodos. Estudio retrospectivo de pacientes con migraña refractaria que recibieron al menos dos infiltraciones de OnabotA entre los años 2008 y 2012. Los pacientes fueron divididos en respondedores y no respondedores a OnabotA y se compararon entre ambos grupos, y de forma retrospectiva, una serie de características clínicas consideradas predictoras de respuesta en estudios previos: localización unilateral de la cefalea, presencia de tensión muscular pericraneal, tipo de dolor (implosivo, explosivo u ocular), tiempo de evolución de la migraña (menor o mayor de 10 años) y abuso de medicación analgésica.
Resultados. Se incluyeron 39 pacientes (35 mujeres) con una edad media de 46 años. En 18 pacientes (46,2%) se observó una reducción mayor del 50% en el número de días de cefalea/mes (pacientes respondedores). Al analizar las diferentes características de la migraña, se observó que todas ellas fueron igualmente prevalentes en los pacientes respondedores y en los no respondedores (p > 0,05): localización unilateral (66,7% frente a 66,6%, respectivamente), dolor implosivo (27,8% frente a 38,1%), presencia de tensión muscular pericraneal (33,3% frente a 38,1%), tiempo de evolución de la migraña mayor de 10 años (77,8% frente a 69,2%) y presencia de abuso de medicación analgésica (50% frente a 81%), Conclusión. En esta serie de pacientes no se ha identificado ningún rasgo clínico que permita predecir en pacientes con migraña refractaria una respuesta favorable al tratamiento con OnabotA.
Revista:
NEUROBIOLOGY OF DISEASE
ISSN:
0969-9961
Año:
2014
Vol.:
62
Págs.:
250-259
Much controversy exists concerning the effect of levodopa on striatal dopaminergic markers in Parkinson's disease (PD) and its influence on functional neuroimaging. To deal with this issue we studied the impact of neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and chronic levodopa administration on striatal (18)F-DOPA uptake (Ki) in an animal model of PD. The levels of several striatal dopaminergic markers and the number of surviving dopaminergic neurons in the substantia nigra (SN) were also assessed. Eleven Macaca fascicularis were included in the study. Eight animals received weekly intravenous injections of MPTP for 7weeks and 3 intact animals served as controls. MPTP-monkeys were divided in two groups. Group I was treated with placebo while Group II received levodopa. Both treatments were maintained for 11months and then followed by a washout period of 6months. (18)F-DOPA positron emission tomography (PET) scans were performed at baseline, after MPTP intoxication, following 11months of treatment, and after a washout period of 1, 3 and 6months. Monkeys were sacrificed 6months after concluding either placebo or levodopa treatment and immediately after the last (18)F-DOPA PET study. Striatal dopamine transporter (DAT) content, tyrosine hydroxylase (TH) content and aromatic l-amino acid decarboxylase (AADC) content were assessed. In Group II (18)F-DOPA PET studies performed at 3 and 6months after interrupting levodopa showed a significantly increased Ki in the anterior putamen as compared to Group I. Levodopa and placebo treated animals exhibited a similar number of surviving dopaminergic cells in the SN. Striatal DAT content was equally reduced in both groups of animals. Animals in Group I exhibited a significant decrease in TH protein content in all the striatal regions assessed. However, in Group II, TH levels were significantly reduced only in the anterior and posterior putamen. Surprisingly, in the levodopa-treated animals the TH levels in the posterior putamen were significantly lower than those in the placebo group. AADC levels in MPTP groups were similar to those of control animals in all striatal areas analyzed. This study shows that chronic levodopa administration to monkeys with partial nigrostriatal degeneration followed by a washout period induces modifications in the functional activity of the dopaminergic nigrostriatal pathway.
Revista:
MOLECULAR NEUROBIOLOGY
ISSN:
0893-7648
Año:
2014
Vol.:
50
N°:
3
Págs.:
1131 - 1141
Department of Industry of the Basque Government [S-PE12UN030]; Spanish Health Ministry [FIS PI08/1866, FIS PI13/01250]
Revista:
NEUROLOGIA
ISSN:
0213-4853
Año:
2013
Vol.:
28
N°:
5
Págs.:
299-308
Revista:
ACTA NEUROPATHOLOGICA
ISSN:
0001-6322
Año:
2013
Vol.:
126
N°:
3
Págs.:
411 - 425
UTE-project/Foundation for Applied Medical Research (FIMA)
Revista:
REVISTA DE NEUROLOGIA
ISSN:
0210-0010
Año:
2012
Vol.:
54
N°:
12
Págs.:
705-11
Aim. To analyse our experience in the treatment of refractory chronic migraine, episodic frequent refractory migraine (>= 10 days/month), with onabotulinumtoxin A (OnabotA). Patients and methods. Retrospective analysis of patients with refractory migraine who underwent, at least two sessions of OnabotA pericranial injections following the PREEMPT protocol between 2008 and 2012. The efficacy of OnabotA was evaluated comparing the basal situation with 12-16 weeks after the second session. We analysed the subjective improvement of the patients, number of days with headache, preventive and abortive drugs consumption, and adverse effects. Results. Forty-one patients (37 women, 4 male) were identified. 65.8% patients experienced subjective improvement after OnabotA treatment. 36.58% responded (reduction of > 50% in headache days). Differences between days with headache before the first session (24.5 +/- 7.3), and 12-16 weeks after the second session (17.4 +/- 11.6), as well as the differences between the number of abortive drugs taken before the first session (26.8 +/- 23.1) and 12-16 weeks after the second session (16.7 +/- 19.3), were statistically significant (p < 0.001). Subgroups analysis showed that all differences were significant, except for the reduction of the number of days with headache in patients with episodic frequent refractory migraine. Conclusion. Our work shows that treatment with OnabotA is safe and useful in patients with episodic and chronic refractory migraine, including those patients with medication overuse headache.
Revista:
MOVEMENT DISORDERS
ISSN:
0885-3185
Año:
2012
Vol.:
27
N°:
1
Págs.:
146 - 151
Background and objective. Mutations in the Leucine-Rich Repeat Kinase 2 (LRRK2) gene at chromosome 12q12 are the most common genetic cause of sporadic and familial late-onset Parkinson's disease. Our aim was to identify novel LRRK2 mutations in late-onset Parkinson's disease families.
Design. We analyzed chromosome 12p11.2-q13.1 haplotypes in 14 late-onset Parkinson's disease families without known LRRK2 mutations.
Results. Haplotype analysis identified 12 families in which the affected subjects shared chromosome 12p11.2-q13.1 haplotypes. LRRK2 sequencing revealed a novel co-segregating missense mutation in exon 36 (c.5281A > C; p.S1761R) located within a highly conserved region of the COR [C-terminal of ROC (Ras of complex proteins)] domain wherein it could deregulate LRRK2 kinase activity by modifying ROC-COR dimer stability. p.S1761R was present in a late-onset Parkinson's disease family and in 2 unrelated Parkinson's disease subjects, but not in 2491 healthy controls. LRRK2 p.S1761R carriers developed levodopa-responsive asymmetrical parkinsonism, with variable age at onset (range: 37-72 years) suggesting age-dependent penetrance. These findings indicate that mutations interfering with LRRK2 ROC-COR domain dimerization lead to typical Parkinson's disease.
Revista:
SOCIEDAD ESPAÑOLA DE ENFERMERIA NEUROLOGICA. REVISTA CIENTIFICA
ISSN:
2013-5246
Año:
2012
Vol.:
36
N°:
1
Págs.:
31 - 38
ICS Introducción: En la bibliografía hay un vacío relacionado con la perspectiva holística del proceso de integración de la enfermedad de Parkinson en las vidas de pacientes y familiares.
Objetivo: Explorar el proceso de convivencia con la enfermedad de Parkinson de pacientes y familiares, así como los factores y los mecanismos que lo favorecen o inhiben.
Método: El proyecto ReNACE es un proyecto con metodología combinada, multicéntrico y multidisciplinario, de 3 años de duración, que consta de 2 fases (cualitativa y cuantitativa), realizado en la Clínica Universidad de Navarra, un centro de Salud del Servicio Navarro de Salud-Osasunbidea y la Asociación Navarra de Parkinson. Se presentan resultados preliminares de la Fase I Cualitativa. Se han recogido datos con entrevistas semiestructuradas, hojas sociodemográficas y escalas (estadio Parkinson). Se ha realizado un análisis de contenido comparativo (programa NVivo9) y un análisis estadístico (SPSS 15.0).
Resultados: Participaron 15 pacientes con enfermedad de Parkinson y 16 familiares. Su mediana y rango intercuartil de edad eran de 73 (65¿76,25) y 65 (59,5¿74) años, respectivamente. En el proceso de adaptación al Parkinson, se destacan dos etapas dinámicas: 1) etapa extraordinaria, y 2) etapa de normalidad. Los principales factores y mecanismos que influían en la convivencia con el Parkinson eran: las estrategias de afrontamiento, el apoyo familiar, las redes personales y sociales, los recursos disponibles, así como la educ
Revista:
JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY
ISSN:
0022-3050
Año:
2012
Vol.:
83
N°:
2
Págs.:
235 - 236
Revista:
Brain Research
ISSN:
0006-8993
Año:
2011
Vol.:
1375
Págs.:
120 -127
Striatal carotid body cell aggregates (CBCA) grafts improve parkinsonism in animals and patients with Parkinson's disease. As CB cells contain trophic factors, we investigated the long-term effect of striatal CBCA grafts on nigrostriatal dopaminergic cells in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys receiving unilateral (UL-grafted group, n=4) or bilateral (BL-grafted group, n=3) CBCA autotransplant. Two MPTP monkeys were sham-operated receiving only Tyrode. For histological analysis, we also included 3 MPTP-untreated and 3 intact animals. Brain [18]F-luorodopa ((18)F-DOPA)-positron emission tomography (PET) scans were performed to assess dopaminergic function in vivo at baseline, 6 and 12months after surgery. The number of nigral dopaminergic cells was assessed in UL-grafted animals, and the number of dopaminergic cells expressing glial cell line-derived neurotrophic factor (GDNF) in all groups. After 1 year, animals showed a significant recovery of the parkinsonism (San Sebastian et al., 2007) and PET studies revealed a larger striatal (18)F-DOPA uptake in the CBCA-grafted striatum compared to that receiving Tyrode. No differences were found in the number of surviving dopaminergic cells when comparing both subtantia nigra of UL-grafted animals. However, both UL- and BL-grafted animals showed a bilaterally increased number of TH-GDNF immunoreactive nigral neurons compared to intact and MPTP-untreated monkeys, indicating that in addition to the proven long-term motor benefit, CBCA autograft might exert a neuroprotective effect on the surviving dopaminergic cells.
Revista:
ACTA NEUROPATHOL
ISSN:
0001-6322
Año:
2011
Vol.:
122
N°:
1
Págs.:
61 -74
Using stereological techniques we found an increased number of dopaminergic periglomerular neurons in the OB of AD, PD and FTD patients when compared with age-matched controls. Moreover, volumetric measurements of OBs showed a significant decrease only in AD patients, while the OB volume was similar to control in PD or FTD cases. The increased dopaminergic tone created in the OBs of these patients could reflect a compensatory mechanism created by the early degeneration of other neurotransmitter systems and might contribute to the olfactory dysfunction exhibited by patients with neurodegenerative disorders
Revista:
EUROPEAN JOURNAL OF NEUROLOGY
ISSN:
1351-5101
Año:
2010
Vol.:
17
N°:
2
Págs.:
321 - 325