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Impulse control disorders and their consequences display variability among individuals, indicating potential involvement of environmental and genetic factors. In this retrospective study, we analyzed a cohort of Parkinson's disease patients treated with dopamine agonists and investigated the influence of the dopamine D4 receptor gene polymorphism, DRD4 7R+, which is linked to psychiatric disorders, impulsive traits, and addictive behaviors. We found that DRD4 7R+ is a significant genetic risk factor associated with the severity of ICD.
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Wasteosomes (or corpora amylacea) are polyglucosan bodies that appear in the human brain with aging and in some neurodegenerative diseases, and have been suggested to have a potential role in a nervous system cleaning mechanism. Despite previous studies in several neurodegenerative disorders, their status in frontotemporal lobar degeneration (FTLD) remains unexplored. Our study aims to characterize wasteosomes in the three primary FTLD proteinopathies, assessing frequency, distribution, protein detection, and association with aging or disease duration. Wasteosome scores were obtained in various brain regions from 124 post-mortem diagnosed sporadic FTLD patients, including 75 participants with tau (FTLD-tau), 42 with TAR DNA-binding protein 43 (FTLD-TDP), and 7 with Fused in Sarcoma (FTLD-FUS) proteinopathies, along with 29 control subjects. The wasteosome amount in each brain region for the different FLTD patients was assessed with a permutation test with age at death and sex as covariables, and multiple regressions explored associations with age at death and disease duration. Double immunofluorescence studies examined altered proteins linked to FTLD in wasteosomes. FTLD patients showed a higher accumulation of wasteosomes than control subjects, especially those with FTLD-FUS. Unlike FTLD-TDP and control subjects, wasteosome accumulation did not increase with age in FTLD-tau and FTLD-FUS. Cases with shorter disease duration in FTLD-tau and FTLD-FUS seemed to exhibit higher wasteosome quantities, whereas FTLD-TDP appeared to show an increase with disease progression. Immunofluorescence studies revealed the presence of tau and phosphorylated-TDP-43 in the periphery of isolated wasteosomes in some patients with FTLD-tau and FTLD-TDP, respectively. Central inclusions of FUS were observed in a higher number of wasteosomes in FTLD-FUS patients. These findings suggest a role of wasteosomes in FTLD, especially in the more aggressive forms of FLTD-FUS. Detecting these proteins, particularly FUS, in wasteosomes from cerebrospinal fluid could be a potential biomarker for FTLD.
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Proteínas de Ligação a DNA , Degeneração Lobar Frontotemporal , Proteína FUS de Ligação a RNA , Proteínas tau , Humanos , Degeneração Lobar Frontotemporal/patologia , Degeneração Lobar Frontotemporal/metabolismo , Feminino , Masculino , Proteína FUS de Ligação a RNA/metabolismo , Idoso , Proteínas tau/metabolismo , Pessoa de Meia-Idade , Idoso de 80 Anos ou mais , Proteínas de Ligação a DNA/metabolismo , Encéfalo/patologia , Encéfalo/metabolismoRESUMO
BACKGROUND: Multiple system atrophy is a neurodegenerative disease with α-synuclein aggregation in glial cytoplasmic inclusions, leading to dysautonomia, parkinsonism, and cerebellar ataxia. OBJECTIVE: The aim of this study was to validate the accuracy of the International Parkinson and Movement Disorder Society Multiple System Atrophy clinical diagnostic criteria, particularly considering the impact of the newly introduced brain magnetic resonance imaging (MRI) markers. METHODS: Diagnostic accuracy of the clinical diagnostic criteria for multiple system atrophy was estimated retrospectively in autopsy-confirmed patients with multiple system atrophy, Parkinson's disease, progressive supranuclear palsy, and corticobasal degeneration. RESULTS: We identified a total of 240 patients. Sensitivity of the clinically probable criteria was moderate at symptom onset but improved with disease duration (year 1: 9%, year 3: 39%, final ante mortem record: 77%), whereas their specificity remained consistently high (99%-100% throughout). Sensitivity of the clinically established criteria was low during the first 3 years (1%-9%), with mild improvement at the final ante mortem record (22%), whereas specificity remained high (99%-100% throughout). When MRI features were excluded from the clinically established criteria, their sensitivity increased considerably (year 1: 3%, year 3: 22%, final ante mortem record: 48%), and their specificity was not compromised (99%-100% throughout). CONCLUSIONS: The International Parkinson and Movement Disorder Society multiple system atrophy diagnostic criteria showed consistently high specificity and low to moderate sensitivity throughout the disease course. The MRI markers for the clinically established criteria reduced their sensitivity without improving specificity. Combining clinically probable and clinically established criteria, but disregarding MRI features, yielded the best sensitivity with excellent specificity and may be most appropriate to select patients for therapeutic trials. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Idiopathic Parkinson's disease (iPD) is believed to have a heterogeneous pathophysiology, but molecular disease subtypes have not been identified. Here, we show that iPD can be stratified according to the severity of neuronal respiratory complex I (CI) deficiency, and identify two emerging disease subtypes with distinct molecular and clinical profiles. The CI deficient (CI-PD) subtype accounts for approximately a fourth of all cases, and is characterized by anatomically widespread neuronal CI deficiency, a distinct cell type-specific gene expression profile, increased load of neuronal mtDNA deletions, and a predilection for non-tremor dominant motor phenotypes. In contrast, the non-CI deficient (nCI-PD) subtype exhibits no evidence of mitochondrial impairment outside the dopaminergic substantia nigra and has a predilection for a tremor dominant phenotype. These findings constitute a step towards resolving the biological heterogeneity of iPD with implications for both mechanistic understanding and treatment strategies.
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DNA Mitocondrial , Complexo I de Transporte de Elétrons , Complexo I de Transporte de Elétrons/deficiência , Mitocôndrias , Doenças Mitocondriais , Doença de Parkinson , Doença de Parkinson/genética , Doença de Parkinson/metabolismo , Humanos , Complexo I de Transporte de Elétrons/genética , Complexo I de Transporte de Elétrons/metabolismo , Doenças Mitocondriais/genética , Doenças Mitocondriais/metabolismo , Masculino , DNA Mitocondrial/genética , Feminino , Mitocôndrias/metabolismo , Mitocôndrias/genética , Idoso , Substância Negra/metabolismo , Substância Negra/patologia , Pessoa de Meia-Idade , Fenótipo , Neurônios/metabolismoRESUMO
The hypothesis that neurodegenerative diseases are proteinopathies due to toxic effect of different underlying proteins, such as amyloid-beta and 3+4R-tau in Alzheimer's disease (AD) and alpha-synuclein in Parkinson's disease (PD), while still controversial is supported by several studies in the literature. This has led to conduct clinical trials attempting to reduce the load of these allegedly toxic proteins by immunotherapy, mostly but not solely based on antibodies against these proteins. Already completed clinical trials have ranged from initially negative results to recently partial positive outcomes, specifically for anti-amyloid antibodies in AD but also albeit to lesser degree for anti-synuclein antibodies in PD. Currently, there are several ongoing clinical trials in degenerative parkinsonisms with anti-synuclein approaches in PD and multiple system atrophy (MSA), as well as with anti-tau antibodies in 4R-tauopathies such as progressive supranuclear palsy (PSP). While it can be argued that expectations that part of these clinical trials will be positive can be hope or hype, it is reasonable to consider the future possibility of "cocktail" combination of different antibodies after the available experimental evidence of cross-talk between these proteins and neuropathological evidence of coexistence of these proteinopathies more frequently than expected by chance. Moreover, such "cocktail" approaches are widespread and accepted common practice in other fields such as oncology, and the complexity of neurodegenerative parkinsonisms makes reasonable the option for testing and eventually applying such combined approaches, should these prove useful separately, in the setting of patients with evidence of underlying concomitant proteinopathies, for example through biomarkers.
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Imunoterapia , alfa-Sinucleína , Proteínas tau , Humanos , alfa-Sinucleína/imunologia , Imunoterapia/métodos , Proteínas tau/imunologia , Animais , Doença de Parkinson/terapia , Doença de Parkinson/imunologia , Doença de Parkinson/tratamento farmacológicoRESUMO
BACKGROUND: Evidence regarding cortical atrophy patterns in Parkinson's disease (PD) with probable rapid eye movement sleep behavior disorder (RBD) (PD-pRBD) remains scarce. Cortical mean diffusivity (cMD), as a novel imaging biomarker highly sensitive to detecting cortical microstructural changes in different neurodegenerative diseases, has not been investigated in PD-pRBD yet. OBJECTIVES: The aim was to investigate cMD as a sensitive measure to identify subtle cortical microstructural changes in PD-pRBD and its relationship with cortical thickness (CTh). METHODS: Twenty-two PD-pRBD, 31 PD without probable RBD (PD-nonpRBD), and 28 healthy controls (HC) were assessed using 3D T1-weighted and diffusion-weighted magnetic resonance imaging on a 3-T scanner and neuropsychological testing. Measures of cortical brain changes were obtained through cMD and CTh. Two-class group comparisons of a general linear model were performed (P < 0.05). Cohen's d effect size for both approaches was computed. RESULTS: PD-pRBD patients showed higher cMD than PD-nonpRBD patients in the left superior temporal, superior frontal, and precentral gyri, precuneus cortex, as well as in the right middle frontal and postcentral gyri and paracentral lobule (d > 0.8), whereas CTh did not detect significant differences. PD-pRBD patients also showed increased bilateral posterior cMD in comparison with HCs (d > 0.8). These results partially overlapped with CTh results (0.5 < d < 0.8). PD-nonpRBD patients showed no differences in cMD when compared with HCs but showed cortical thinning in the left fusiform gyrus and lateral occipital cortex bilaterally (d > 0.5). CONCLUSIONS: cMD may be more sensitive than CTh displaying significant cortico-structural differences between PD subgroups, indicating this imaging biomarker's utility in studying early cortical changes in PD. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Córtex Cerebral , Doença de Parkinson , Transtorno do Comportamento do Sono REM , Humanos , Doença de Parkinson/diagnóstico por imagem , Doença de Parkinson/patologia , Doença de Parkinson/complicações , Doença de Parkinson/fisiopatologia , Transtorno do Comportamento do Sono REM/diagnóstico por imagem , Transtorno do Comportamento do Sono REM/patologia , Masculino , Feminino , Idoso , Pessoa de Meia-Idade , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/patologia , Imageamento por Ressonância Magnética , Imagem de Difusão por Ressonância Magnética/métodos , Atrofia/patologia , Testes NeuropsicológicosRESUMO
Previous studies have suggested a relationship between the number of CAG triplet repeats in the HTT gene and neurodegenerative diseases not related to Huntington's disease (HD). This study seeks to investigate whether the number of CAG repeats of HTT is associated with the risk of developing certain tauopathies and its influence as a modulator of the clinical and neuropathological phenotype. Additionally, it aims to evaluate the potential of polyglutamine staining as a neuropathological screening. We genotyped the HTT gene CAG repeat number and APOE-â° isoforms in a cohort of patients with neuropathological diagnoses of tauopathies (n=588), including 34 corticobasal degeneration (CBD), 98 progressive supranuclear palsy (PSP) and 456 Alzheimer's disease (AD). Furthermore, we genotyped a control group of 1070 patients, of whom 44 were neuropathologic controls. We identified significant differences in the number of patients with pathological HTT expansions in the CBD group (2.7%) and PSP group (3.2%) compared to control subjects (0.2%). A significant increase in the size of the HTT CAG repeats was found in the AD compared to the control group, influenced by the presence of the Apoliprotein E (APOE)-â°4 isoform. Post-mortem assessments uncovered tauopathy pathology with positive polyglutamine aggregates, with a slight predominance in the neostriatum for PSP and CBD cases and somewhat greater limbic involvement in the AD case. Our results indicated a link between HTT CAG repeat expansion with other non-HD pathology, suggesting they could share common neurodegenerative pathways. These findings support that genetic or histological screening for HTT repeat expansions should be considered in tauopathies.
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Proteína Huntingtina , Tauopatias , Humanos , Masculino , Feminino , Idoso , Tauopatias/genética , Tauopatias/patologia , Pessoa de Meia-Idade , Proteína Huntingtina/genética , Idoso de 80 Anos ou mais , Paralisia Supranuclear Progressiva/genética , Paralisia Supranuclear Progressiva/patologia , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Repetições de Trinucleotídeos/genética , Encéfalo/patologia , Expansão das Repetições de Trinucleotídeos/genética , Genótipo , Degeneração Corticobasal/genética , Degeneração Corticobasal/patologia , PeptídeosRESUMO
Over the last two decades there have been meaningful developments on biomarkers of neurodegenerative diseases, extensively (but not solely) focusing on their proteinopathic nature. Accordingly, in Alzheimer's disease determination of levels of total and phosphorylated tau (τ and p-τ, usually p-τ181) along with amyloid-beta1-42 (Aß1-42) by immunodetection in cerebrospinal fluid (CSF) and currently even in peripheral blood, have been widely accepted and introduced to routine diagnosis. In the case of Parkinson's disease, α-synuclein as a potential biomarker (both for diagnosis and progression tracking) has proved more elusive under the immunodetection approach. In recent years, the emergence of the so-called seed amplification assays is proving to be a game-changer, with mounting evidence under different technical approaches and using a variety of biofluids or tissues, yielding promising diagnostic accuracies. Currently the least invasive but at once more reliable source of biosamples and techniques are being sought. Here we overview these advances.
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Doença de Alzheimer , Doença de Parkinson , Humanos , Doença de Parkinson/diagnóstico , Doença de Parkinson/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidiano , alfa-Sinucleína/líquido cefalorraquidiano , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , Peptídeos beta-Amiloides/líquido cefalorraquidianoRESUMO
Deep brain stimulation (DBS) is an effective treatment for patients with Parkinson's disease (PD). However, some patients may not respond optimally to clinical programming adjustments. Advances in DBS technology have led to more complex and time-consuming programming. Image-guided programming (IGP) could optimize and improve programming leading to better clinical outcomes in patients for whom DBS programming is not ideal due to sub-optimal response. We conducted a prospective single-center study including 31 PD patients with subthalamic nucleus (STN) DBS and suboptimal responses refractory to clinical programming. Programming settings were adjusted according to the volumetric reconstruction of the stimulation field using commercial postoperative imaging software. Clinical outcomes were assessed at baseline and at 3-month follow-up after IGP, using motor and quality of life (QoL) scales. Additionally, between these two assessment points, follow-up visits for fine-tuning amplitude intensity and medication were conducted at weeks 2, 4, 6, and 9. After IGP, twenty-six patients (83.9%) experienced motor and QoL improvements, with 25.8% feeling much better and 38.7% feeling moderately better according to the patient global impression scale. Five patients (16.1%) had no clinical or QoL changes after IGP. The MDS-UPDRS III motor scale showed a 21.9% improvement and the DBS-IS global score improved by 41.5%. IGP optimizes STN-DBS therapy for PD patients who are experiencing suboptimal clinical outcomes. These findings support using IGP as a standard tool in clinical practice, which could save programming time and improve patients' QoL.
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Clinical and cognitive progression in alpha-synucleinopathies is highly heterogeneous. While some patients remain stable over long periods of time, other suffer early dementia or fast motor deterioration. Sleep disturbances and nocturnal blood pressure abnormalities have been identified as independent risk factors for clinical progression but a mechanistic explanation linking both aspects is lacking. We hypothesize that impaired glymphatic system might play a key role on clinical progression. Glymphatic system clears brain waste during specific sleep stages, being blood pressure the motive force that propels the interstitial fluid through brain tissue to remove protein waste. Thus, the combination of severe sleep alterations, such as REM sleep behavioral disorder, and lack of the physiological nocturnal decrease of blood pressure due to severe dysautonomia may constitute the perfect storm for glymphatic failure, causing increased abnormal protein aggregation and spreading. In Lewy body disorders (Parkinson's disease and dementia with Lewy bodies) the increment of intraneuronal alpha-synuclein and extracellular amyloid-ß would lead to cognitive deterioration, while in multisystemic atrophy, increased pathology in oligodendroglia would relate to the faster and malignant motor progression. We present a research model that may help in developing studies aiming to elucidate the role of glymphatic function and associated factors mainly in alpha-synucleinopathies, but that could be relevant also for other protein accumulation-related neurodegenerative diseases. If the model is proven to be useful could open new lines for treatments targeting glymphatic function (for example through control of nocturnal blood pressure) with the objective to ameliorate cognitive and motor progression in alpha-synucleinopathies.
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Doença de Parkinson , Açúcares , Humanos , Dieta Saudável , Alimentos , Ácidos Graxos Insaturados , DietaRESUMO
Neurological disorders (ND) are diseases that affect the brain and the central and autonomic nervous systems, such as neurodevelopmental disorders, cerebellar ataxias, Parkinson's disease, or epilepsies. Nowadays, recommendations of the American College of Medical Genetics and Genomics strongly recommend applying next generation sequencing (NGS) as a first-line test in patients with these disorders. Whole exome sequencing (WES) is widely regarded as the current technology of choice for diagnosing monogenic ND. The introduction of NGS allows for rapid and inexpensive large-scale genomic analysis and has led to enormous progress in deciphering monogenic forms of various genetic diseases. The simultaneous analysis of several potentially mutated genes improves the diagnostic process, making it faster and more efficient. The main aim of this report is to discuss the impact and advantages of the implementation of WES into the clinical diagnosis and management of ND. Therefore, we have performed a retrospective evaluation of WES application in 209 cases referred to the Department of Biochemistry and Molecular Genetics of the Hospital Clinic of Barcelona for WES sequencing derived from neurologists or clinical geneticists. In addition, we have further discussed some important facts regarding classification criteria for pathogenicity of rare variants, variants of unknown significance, deleterious variants, different clinical phenotypes, or frequency of actionable secondary findings. Different studies have shown that WES implementation establish diagnostic rate around 32% in ND and the continuous molecular diagnosis is essential to solve the remaining cases.
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Epilepsia , Exoma , Humanos , Sequenciamento do Exoma , Estudos Retrospectivos , Exoma/genética , Fenótipo , Epilepsia/diagnóstico , Epilepsia/genéticaRESUMO
BACKGROUND: Iron content is increased in the substantia nigra of persons with Parkinson's disease and may contribute to the pathophysiology of the disorder. Early research suggests that the iron chelator deferiprone can reduce nigrostriatal iron content in persons with Parkinson's disease, but its effects on disease progression are unclear. METHODS: We conducted a multicenter, phase 2, randomized, double-blind trial involving participants with newly diagnosed Parkinson's disease who had never received levodopa. Participants were assigned (in a 1:1 ratio) to receive oral deferiprone at a dose of 15 mg per kilogram of body weight twice daily or matched placebo for 36 weeks. Dopaminergic therapy was withheld unless deemed necessary for symptom control. The primary outcome was the change in the total score on the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS; range, 0 to 260, with higher scores indicating more severe impairment) at 36 weeks. Secondary and exploratory clinical outcomes at up to 40 weeks included measures of motor and nonmotor disability. Brain iron content measured with the use of magnetic resonance imaging was also an exploratory outcome. RESULTS: A total of 372 participants were enrolled; 186 were assigned to receive deferiprone and 186 to receive placebo. Progression of symptoms led to the initiation of dopaminergic therapy in 22.0% of the participants in the deferiprone group and 2.7% of those in the placebo group. The mean MDS-UPDRS total score at baseline was 34.3 in the deferiprone group and 33.2 in the placebo group and increased (worsened) by 15.6 points and 6.3 points, respectively (difference, 9.3 points; 95% confidence interval, 6.3 to 12.2; P<0.001). Nigrostriatal iron content decreased more in the deferiprone group than in the placebo group. The main serious adverse events with deferiprone were agranulocytosis in 2 participants and neutropenia in 3 participants. CONCLUSIONS: In participants with early Parkinson's disease who had never received levodopa and in whom treatment with dopaminergic medications was not planned, deferiprone was associated with worse scores in measures of parkinsonism than those with placebo over a period of 36 weeks. (Funded by the European Union Horizon 2020 program; FAIRPARK-II ClinicalTrials.gov number, NCT02655315.).
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Antiparkinsonianos , Deferiprona , Quelantes de Ferro , Ferro , Doença de Parkinson , Substância Negra , Humanos , Deferiprona/administração & dosagem , Deferiprona/efeitos adversos , Deferiprona/farmacologia , Deferiprona/uso terapêutico , Ferro/análise , Ferro/metabolismo , Levodopa/uso terapêutico , Neutropenia/induzido quimicamente , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo , Doença de Parkinson/fisiopatologia , Quelantes de Ferro/administração & dosagem , Quelantes de Ferro/efeitos adversos , Quelantes de Ferro/farmacologia , Quelantes de Ferro/uso terapêutico , Substância Negra/química , Substância Negra/diagnóstico por imagem , Substância Negra/efeitos dos fármacos , Substância Negra/metabolismo , Progressão da Doença , Método Duplo-Cego , Administração Oral , Encéfalo/diagnóstico por imagem , Química Encefálica , Dopaminérgicos/administração & dosagem , Dopaminérgicos/efeitos adversos , Dopaminérgicos/farmacologia , Dopaminérgicos/uso terapêutico , Antiparkinsonianos/administração & dosagem , Antiparkinsonianos/efeitos adversos , Antiparkinsonianos/farmacologia , Antiparkinsonianos/uso terapêuticoRESUMO
BACKGROUND: Impulse control disorders (ICDs) are commonly developed among patients who take dopamine agonist drugs as a treatment for Parkinson disease (PD). Gambling disorder and hypersexuality are more frequent in male patients with PD, with a prevalence over 4% in dopamine agonists users. Although impulsive-compulsive behaviors are related to antiparkinsonian medication, and even though ICD symptomatology, such as hypersexuality, often subsides when the dopaminergic dose is reduced, sometimes ICD persists in spite of drug adjustment. Consequently, a multidisciplinary approach should be considered to address these comorbidities and to explore new forms of complementary interventions, such as serious games or therapies adapted to PD. OBJECTIVE: The aim of this study is to present the case of a patient with ICD (ie, hypersexuality) triggered by dopaminergic medication for PD. A combined intervention was carried out using cognitive behavioral therapy (CBT) for ICD adapted to PD, plus an intervention using a serious game-e-Estesia-whose objective is to improve emotion regulation and impulsivity. The aim of the combination of these interventions was to reduce the harm of the disease. METHODS: After 20 CBT sessions, the patient received the e-Estesia intervention over 15 sessions. Repeated measures, before and after the combined intervention, were administered to assess emotion regulation, general psychopathology, and emotional distress and impulsivity. RESULTS: After the intervention with CBT techniques and e-Estesia, the patient presented fewer difficulties to regulate emotion, less emotional distress, and lower levels of impulsivity in comparison to before the treatment. Moreover, the frequency and severity of the relapses also decreased. CONCLUSIONS: The combined intervention-CBT and a serious game-showed positive results in terms of treatment outcomes.
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BACKGROUND: Negative (vacuum) pressure therapy promotes wound healing. However, commercially available devices are unaffordable to most potential users in low- and middle-income countries (LMICs), limiting access to many patients who could benefit from this treatment. This study aimed to design and test a cheap and easy-to-build negative pressure device and provide its detailed open-source description, thereby enabling free replication. METHODS: the negative pressure device was built using off-the-shelf materials available via e-commerce and was based on a small pump, a pressure transducer, and the simplest Arduino controller with a digital display (total retail cost ≤ 75 US$). The device allows the user to set any therapeutic range of intermittent negative pressure and has two independent safety mechanisms. The performance of the low-cost device was carefully tested on the bench using a phantom wound, producing a realistic exudate flow rate. RESULTS: the device generates the pressure patterns set by the user (25-175 mmHg of vacuum pressure, 0-60 min periods) and can drain exudate flows within the clinical range (up to 1 L/h). CONCLUSIONS: a novel, low-cost, easy-to-build negative pressure device for wound healing displays excellent technical performance. The open-source hardware description provided here, which allows for free replication and use in LMICs, will facilitate the application and wider utilization of this therapy to patients.