Focused ultrasound for opening blood-brain barrier and drug delivery monitored with positron emission tomography

Focused ultrasound (FUS) is a minimally-invasive technology used for treatment of many diseases, including diseases related to the colon, uterus, prostate, and brain. Although it has been mainly used for ablative procedures, the ability of FUS to open the blood-brain barrier (BBB) presents a promising new application. However, the mechanism of BBB opening by FUS remains unclear. This review focuses on the use of FUS to open the BBB for enhancing drug delivery and investigating how Positron Emission Tomography (PET) provides insight into the underlying mechanism

Investigating Voice as a Biomarker for Leucine-Rich Repeat Kinase 2-Associated Parkinson's Disease

We investigate the potential association between leucine-rich repeat kinase 2 (LRRK2) mutations and voice. Sustained phonations ('aaah' sounds) were recorded from 7 individuals with LRRK2-associated Parkinson's disease (PD), 17 participants with idiopathic PD (iPD), 20 non-manifesting LRRK2-mutation carriers, 25 related non-carriers, and 26 controls. In distinguishing LRRK2-associated PD and iPD, the mean sensitivity was 95.4% (SD 17.8%) and mean specificity was 89.6% (SD 26.5%). Voice features for non-manifesting carriers, related non-carriers, and controls were much less discriminatory. Vocal deficits in LRRK2-associated PD may be different than those in iPD. These preliminary results warrant longitudinal analyses and replication in larger cohorts

Propuesta metodológica para la toma de decisiones entre rehabilitación y clausura de sitios de disposición final

Ponència presentada al IX Simposio Iberoamericano de Ingeniería de Residuos, Panamá, del 20 al 24 de setembre de 2021En México, los residuos sólidos urbanos (RSU) generados se deposita preferentemente en rellenos sanitarios (RESA); sin embargo, en número, solo el 13% de los sitios de disposición final (SDF) son RESA y el 87% son sitios no controlados (SNC). Los SNC implican riesgos para la salud y al ambiente. La SEMARNAT ha buscado que los SDF del país cumplan con la NOM-083-SEMARNAT-2003; y para ello ha elaborado con otras instituciones, manuales y guías; sin embargo, aplicar estos documentos, representa un gran gasto para los municipios que tienen SNC. El objetivo de este trabajo fue proponer una metodología para evaluar a nivel preliminar SNC, que con menores costos y tiempo, apoye en la toma de decisión entre clausura o rehabilitación. Para ello, la propuesta comprende: ubicación de SDF y análisis histórico del área afectada mediante Mapa Digital de INEGI, Google Mapas y Google Earth Pro; análisis del cumplimiento de la NOM-083-SEMARNAT-2003 con el Sistema de Información Geográfica para el Manejo de RSU (SIGMIRSU) y la aplicación de una Tabla de Verificación a responsables del SDF; así como la elaboración de recomendaciones. Se eligieron como casos de estudio el SDF de Xalatlaco, Estado de México y el SDF de Tlalpujahua, Michoacán. La aplicación de la metodología para la evaluación a nivel preliminar, evidenció que el SDF de Xalatlaco requiere de atención urgente y debe ser revisado de cerca con la Secretaría del Medio Ambiente; y que el SDF de Tlalpujahua, tiene posibilidades de ser rehabilitado para operar conforme a la NOM-083-SEMARNAT-2003.In Mexico, the municipal solid waste (MSW) generated is preferably deposited in sanitary landfills (SL); however, in number, only 13% of the final disposal sites (FDS) are SL and 87% are uncontrolled sites (UNS). The UNS pose risks to health and the environment. SEMARNAT has sought that the country's SDF comply with NOM-083-SEMARNAT-2003; and for this it has prepared with other institutions, manuals and guides; However, applying these documents represents a great expense for municipalities that have UNS. The objective of this work was to propose a methodology to evaluate UNS at a preliminary level, which with lower costs and time, supports decision-making between closure or rehabilitation. For this, the proposal includes: FDS location and historical analysis of the affected area using INEGI's Digital Map, Google Maps and Google Earth Pro; analysis of compliance of NOM-083-SEMARNAT-2003 with the Geographic Information System for MSW Management (SIGMIRSU) and the application of a Verification Table to those responsible for the SDF; as well as that the development of recommendations. The FDS of Xalatlaco, State of Mexico and the SDF of Tlalpujahua, Michoacán were chosen as case studies. The application of the methodology for the evaluation at a preliminary level, showed that the SDF of Xalatlaco requires urgent attention and should be closely reviewed with the Ministry of the Environment; and the SDF of Tlalpujahua, has the possibility of being reactivated to operate according to NOM-083-SEMARNAT2003

Cognitive Reserve in Parkinson's Disease without Dementia: β-Amyloid and Metabolic Assessment

[Background] Cognitive reserve (CR) is the mismatch between preserved cognition and neuropathological damage. Amyloidopathy in Parkinson's disease (PD) could be associated with faster progression to dementia, but the putative protective effect of CR is unknown.[Objectives] To evaluate the effect of CR on β-amyloid burden and brain metabolism in non-demented PD subjects.[Methods] Participants with PD (n = 53) underwent a clinical evaluation, [18F]-fluorodeoxyglucose and [18F]-flutemetamol positron emission tomography magnetic resonances, and were classified according to CR. The metabolic pattern of 16 controls was compared to PD subjects.[Results] The PD subjects showed hypometabolism mainly in the bilateral posterior cortex. Superior-CR subjects (n = 22) exhibited better cognitive performance, increased amyloid burden, and higher metabolism in several right hemisphere areas compared to low-medium-CR subjects (n = 31).[Conclusions] Higher CR in non-demented PD is associated with better cognitive performance, which might reduce vulnerability to the effect of β-amyloid. Whether superior CR leads to protection against metabolic deterioration, and predominantly right hemisphere involvement, deserves further exploration.PET-magnetic resonance studies were funded by the collaboration agreement between General Electric, Siemens Health-care S.L.U., HM Hospitales 1989 S.A., and Fundación de Investigación HM Hospitales.Peer reviewe

BBB opening with focused ultrasound in nonhuman primates and Parkinson’s disease patients: Targeted AAV vector delivery and PET imaging

血液脳関門開放術による遺伝子治療法の開発 --身体を傷つけない脳疾患の治療を目指して--. 京都大学プレスリリース. 2023-04-20.Intracerebral vector delivery in nonhuman primates has been a major challenge. We report successful blood-brain barrier opening and focal delivery of adeno-associated virus serotype 9 vectors into brain regions involved in Parkinson’s disease using low-intensity focus ultrasound in adult macaque monkeys. Openings were well tolerated with generally no associated abnormal magnetic resonance imaging signals. Neuronal green fluorescent protein expression was observed specifically in regions with confirmed blood-brain barrier opening. Similar blood-brain barrier openings were safely demonstrated in three patients with Parkinson’s disease. In these patients and in one monkey, blood-brain barrier opening was followed by 18F-Choline uptake in the putamen and midbrain regions based on positron emission tomography. This indicates focal and cellular binding of molecules that otherwise would not enter the brain parenchyma. The less-invasive nature of this methodology could facilitate focal viral vector delivery for gene therapy and might allow early and repeated interventions to treat neurodegenerative disorders

Focused ultrasound subthalamotomy in patients with asymmetric Parkinson's disease: a pilot study

Ablative neurosurgery has been used to treat Parkinson's disease for many decades. MRI-guided focused ultrasound allows focal lesions to be made in deep brain structures without skull incision. We investigated the safety and preliminary efficacy of unilateral subthalamotomy by focused ultrasound in Parkinson's disease.Fundación de investigación HM Hospitales and Insightec.Peer reviewe

Prospective Long-term Follow-up of Focused Ultrasound Unilateral Subthalamotomy for Parkinson Disease

Unilateral magnetic resonance-guided focused ultrasound subthalamotomy (FUS-STN) has been shown to improve the cardinal motor features of Parkinson disease (PD). Whether this effect is sustained is not known. This study aims to report the long-term outcome of patients with PD treated with unilateral FUS-STN.Peer reviewe

Unilateral focused ultrasound subthalamotomy in early Parkinson's disease: a pilot study

[Background] Unilateral focused ultrasound subthalamotomy (FUS-STN) improves motor features of Parkinson’s disease (PD) in moderately advanced patients. The less invasive nature of FUS makes its early application in PD feasible. We aim to assess the safety and efficacy of unilateral FUS-STN in patients with PD of less than 5 years from diagnosis (early PD).[Methods] Prospective, open-label study. Eligible patients with early PD had highly asymmetrical cardinal features. The primary outcome was safety, defined as treatment-related adverse events at 6 months. Secondary outcomes included efficacy, assessed as motor improvement in the Movement Disorders Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS), motor fluctuations, non-motor symptoms, daily living activities, quality of life, medication and patients’ impression of change.[Results] Twelve patients with PD (median age 52.0 (IQR 49.8–55.3) years, median time from diagnosis 3.0 (2.1–3.9) years) underwent unilateral FUS-STN. Within 2 weeks after treatment, five patients developed dyskinesia on the treated side, all resolved after levodopa dose adjustment. One patient developed mild contralateral motor weakness which fully resolved in 4 weeks. One patient developed dystonic foot and another hand and foot dystonia. The latter impaired gait and became functionally disabling initially. Both cases were well controlled with botulinum toxin injections. The off-medication motor MDS-UPDRS score for the treated side improved at 12 months by 68.7% (from 14.5 to 4.0, p=0.002), and the total motor MDS-UPDRS improved by 49.0% (from 26.5 to 13.0, p=0.002). Eleven patients (92%) reported global improvement 12 months after treatment.[Conclusion] Unilateral FUS-STN may be safe and effective to treat motor manifestations in patients with early PD. A larger confirmatory trial is warranted.[Trial registration number] NCT04692116.This study was supported by Fundación de Investigación HM Hospitales and Fundación MAPFRE. ENV was supported in 2021 for this specific project by a fellowship from the Movement Disorders Group of the Spanish Neurology Society (Sociedad Española de Neurología, SEN) granted by Zambon.Peer reviewe

Cognitive safety after unilateral magnetic resonance-guided focused ultrasound thalamotomy for essential tremor

Essential tremor (ET) is the most common movement disorder, affecting 1% of the population worldwide. There is sound evidence that medically refractory tremor improves with thalamotomy and deep brain stimulation (DBS) targeting the thalamic ventralis intermedius nucleus (VIM). In the last few years, the incisionless technique of magnetic resonance- guided focused ultrasound (MRgFUS) has been demonstrated to be an effective procedure for unilateral thalamotomy,1 with a positive profile with regard to side effects. The thalamus is involved in cognitive functions such as attention/executive control, memory and language. Focal ablation of the thalamus, even when targeting a sensorimotor region as the VIM, raises question about potential cognitive side effects. After unilateral VIM-DBS in 40 patients with ET, Fields et al2 showed statistically significant improvements in visuoperceptual function and verbal memory. There was no significant decline in any measure, but four patients with preoperative low verbal fluency showed a further decline. Most studies have shown reduced verbal fluency under active VIM-DBS.2–4 Since focused ultrasound thalamotomy is a less invasive procedure, we hypothesised that the risk of procedure-related cognitive decline is further reduced.Peer reviewe

Brain hypometabolism in non-demented microtubule-associated protein tau H1 carriers with Parkinson's disease

The microtubule-associated protein tau (MAPT) H1 homozygosity (H1/H1 haplotype) is a genetic risk factor for neurodegenerative diseases, such as Parkinson's disease (PD). MAPT H1 homozygosity has been associated with conversion to PD; however, results are conflicting since some studies did not find a strong influence. Cortical hypometabolism is associated with cognitive impairment in PD. In this study, we aimed to evaluate the metabolic pattern in nondemented PD patients MAPT H1/H1 carriers in comparison with MAPT H1/H2 haplotype. In addition, we evaluated domain-specific cognitive differences according to MAPT haplotype.PET-MR studies were funded by the collaboration agreement between Siemens Healthcare S.L.U., HM Hospitales 1989 S.A., and Fundación de Investigación HM Hospitales.Peer reviewe