MR-guided focused ultrasound (MRgFUS), in combination with intravenous microbubble administration, has been applied for focal temporary BBB opening in patients with neurodegenerative disorders and ...brain tumors. MRgFUS could become a therapeutic tool for drug delivery of putative neurorestorative therapies. Treatment for Parkinson's disease with dementia (PDD) is an important unmet need. We initiated a prospective, single-arm, non-randomized, proof-of-concept, safety and feasibility phase I clinical trial (NCT03608553), which is still in progress. The primary outcomes of the study were to demonstrate the safety, feasibility and reversibility of BBB disruption in PDD, targeting the right parieto-occipito-temporal cortex where cortical pathology is foremost in this clinical state. Changes in β-amyloid burden, brain metabolism after treatments and neuropsychological assessments, were analyzed as exploratory measurements. Five patients were recruited from October 2018 until May 2019, and received two treatment sessions separated by 2-3 weeks. The results are set out in a descriptive manner. Overall, this procedure was feasible and reversible with no serious clinical or radiological side effects. We report BBB opening in the parieto-occipito-temporal junction in 8/10 treatments in 5 patients as demonstrated by gadolinium enhancement. In all cases the procedures were uneventful and no side effects were encountered associated with BBB opening. From pre- to post-treatment, mild cognitive improvement was observed, and no major changes were detected in amyloid or fluorodeoxyglucose PET. MRgFUS-BBB opening in PDD is thus safe, reversible, and can be performed repeatedly. This study provides encouragement for the concept of BBB opening for drug delivery to treat dementia in PD and other neurodegenerative disorders.
The subthalamic nucleus is the preferred neurosurgical target for deep-brain stimulation to treat cardinal motor features of Parkinson's disease. Focused ultrasound is an imaging-guided method for ...creating therapeutic lesions in deep-brain structures, including the subthalamic nucleus.
We randomly assigned, in a 2:1 ratio, patients with markedly asymmetric Parkinson's disease who had motor signs not fully controlled by medication or who were ineligible for deep-brain stimulation surgery to undergo focused ultrasound subthalamotomy on the side opposite their main motor signs or a sham procedure. The primary efficacy outcome was the between-group difference in the change from baseline to 4 months in the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) motor score (i.e., part III) for the more affected body side (range, 0 to 44, with higher scores indicating worse parkinsonism) in the off-medication state. The primary safety outcome (procedure-related complications) was assessed at 4 months.
Among 40 enrolled patients, 27 were assigned to focused ultrasound subthalamotomy (active treatment) and 13 to the sham procedure (control). The mean MDS-UPDRS III score for the more affected side decreased from 19.9 at baseline to 9.9 at 4 months in the active-treatment group (least-squares mean difference, 9.8 points; 95% confidence interval CI, 8.6 to 11.1) and from 18.7 to 17.1 in the control group (least-squares mean difference, 1.7 points; 95% CI, 0.0 to 3.5); the between-group difference was 8.1 points (95% CI, 6.0 to 10.3; P<0.001). Adverse events in the active-treatment group were dyskinesia in the off-medication state in 6 patients and in the on-medication state in 6, which persisted in 3 and 1, respectively, at 4 months; weakness on the treated side in 5 patients, which persisted in 2 at 4 months; speech disturbance in 15 patients, which persisted in 3 at 4 months; facial weakness in 3 patients, which persisted in 1 at 4 months; and gait disturbance in 13 patients, which persisted in 2 at 4 months. In 6 patients in the active-treatment group, some of these deficits were present at 12 months.
Focused ultrasound subthalamotomy in one hemisphere improved motor features of Parkinson's disease in selected patients with asymmetric signs. Adverse events included speech and gait disturbances, weakness on the treated side, and dyskinesia. (Funded by Insightec and others; ClinicalTrials.gov number, NCT03454425.).
The aim of this article is to analyze the influence of the weights when building a tourism competitiveness (TC) synthetic indicator. The most frequently used index is the Travel and Tourism ...Competitiveness Index (TTCI), which is composed of 14 pillars organized into four subindexes. However, this index has been criticized especially regarding the weights. This study measures the weights using statistical methods and analyzes if they affect countries according to their stage of development. Subsequently, we applied these weights to the TTCI and to four TC synthetic indexes calculated by applying multicriteria techniques and we obtained different scenarios. These synthetic indexes enable a more realistic measurement of TC, so we analyze whether the ranking differences caused by variations in the pillar’s weights were equally relevant in the TTCI as in the different indexes proposed. We demonstrate how the choice of these weights benefits some countries while harming others.
Antibodies triggering Fc‐mediated NK cell activity may contribute to protection against disease caused by SARS‐CoV‐2 infection in humans. However, how these Fc‐mediated humoral responses compare ...between individuals displaying hybrid immunity (Vac‐ex) and those fully vaccinated with no history of SARS‐CoV‐2 infection (Vac‐n) and whether they correlate with neutralizing antibody (NtAb) responses remains largely undetermined. In this retrospective study serum samples from 50 individuals (median age, 44.5 years; range, 11–85; 25 males), 25 Vac‐ex and 25 Vac‐n were studied. A flow‐cytometry‐based antibody‐mediated NK‐cell activation assay was used to quantitate effector NK‐cells stimulated to express LAMP1 (lysosomal associated membrane protein 1), MIP1 (Macrophage inflammatory protein 1), and interferon‐γ (IFNγ); NK cells isolated from two donors (D1 and D2) were used. NtAb levels targeting the Spike protein of Wuhan‐Hu‐1 and Omicron BA.1 SARS‐CoV‐2 variants were quantitated using a SARS‐CoV‐2 S pseudotyped neutralization assay. Regardless of the SARS‐CoV‐2 variant S antigen used in the NK‐cell activation assay, the frequency of NK cells stimulated to express LAMP‐1, MIP1β, and IFNγ was higher in Vac‐ex compared with Vac‐n (p values ranging from 0.07 to 0.006) for D1; this was only seen for BA.1 when NK cells from D2 were employed. The frequency of functional NK cells activated by antibody binding to either Wuhan‐Hu‐1 or Omicron BA.1 S protein was not significantly different for both VAC‐ex and VAC‐n. In contrast, NtAb titers against BA.1 were around 10‐fold lower than that against Wuhan‐Hu‐1. Vac‐ex displayed higher NtAb titers against both (sub)variants than Vac‐n. NK‐cell responses correlated poorly with NtAb titers (ρ ≤ 0.30). The data demonstrate higher cross‐reactivity across variants of concern for antibodies triggering Fc‐mediated NK cell than for NtAb. Moreover, Vac‐Ex seemed to display more robust functional antibody responses as compared with Vac‐n.
Abstract
Background and Purpose
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.
Methods
We compared a group of 26 H1/H1 and 20 H1/H2 carriers with late‐onset PD. Participants underwent a comprehensive neuropsychological cognitive evaluation and a 18F‐Fluorodeoxyglucose PET‐MR scan.
Results
MAPT H1/H1 carriers showed worse performance in the digit span forward test of attention compared to MAPT H1/H2 carriers. In the 18F‐Fluorodeoxyglucose PET comparisons, MAPT H1/H1 displayed hypometabolism in the frontal cortex, parahippocampal, and cingulate gyrus, as well as in the caudate and globus pallidus.
Conclusion
PD patients MAPT H1/H1 carriers without dementia exhibit relative hypometabolism in several cortical areas as well as in the basal ganglia, and worse performance in attention than MAPT H1/H2 carriers. Longitudinal studies should assess if lower scores in attention and dysfunction in these areas are predictors of dementia in MAPT H1/H1 homozygotes.
New drugs that target
species, the causative agents of malaria, are needed. The enzyme
-myristoyltransferase (NMT) is an essential protein, which catalyzes the myristoylation of protein substrates, ...often to mediate membrane targeting. We screened ∼1.8 million small molecules for activity against
(
) NMT. Hits were triaged based on potency and physicochemical properties and further tested against
and
(
) NMTs. We assessed the activity of hits against human NMT1 and NMT2 and discarded compounds with low selectivity indices. We identified 23 chemical classes specific for the inhibition of
NMTs over human NMTs, including multiple novel scaffolds. Cocrystallization of
NMT with one compound revealed peptide binding pocket binding. Other compounds show a range of potential modes of action. Our data provide insight into the activity of a collection of selective inhibitors of
NMT and serve as a starting point for subsequent medicinal chemistry efforts.
In Parkinson's disease, striatal dopamine depletion produces profound alterations in the neural activity of the cortico-basal ganglia motor loop, leading to dysfunctional motor output and ...parkinsonism. A key regulator of motor output is the balance between excitation and inhibition in the primary motor cortex, which can be assessed in humans with transcranial magnetic stimulation techniques. Despite decades of research, the functional state of cortical inhibition in Parkinson's disease remains uncertain. Towards resolving this issue, we applied paired-pulse transcranial magnetic stimulation protocols in 166 patients with Parkinson's disease (57 levodopa-naïve, 50 non-dyskinetic, 59 dyskinetic) and 40 healthy controls (age-matched with the levodopa-naïve group). All patients were studied OFF medication. All analyses were performed with fully automatic procedures to avoid confirmation bias, and we systematically considered and excluded several potential confounding factors such as age, gender, resting motor threshold, EMG background activity and amplitude of the motor evoked potential elicited by the single-pulse test stimuli. Our results show that short-interval intracortical inhibition is decreased in Parkinson's disease compared to controls. This reduction of intracortical inhibition was obtained with relatively low-intensity conditioning stimuli (80% of the resting motor threshold) and was not associated with any significant increase in short-interval intracortical facilitation or intracortical facilitation with the same low-intensity conditioning stimuli, supporting the involvement of cortical inhibitory circuits. Short-interval intracortical inhibition was similarly reduced in levodopa-naïve, non-dyskinetic and dyskinetic patients. Importantly, intracortical inhibition was reduced compared to control subjects also on the less affected side (n = 145), even in de novo drug-naïve patients in whom the less affected side was minimally symptomatic (lateralized Unified Parkinson's Disease Rating Scale part III = 0 or 1, n = 23). These results suggest that cortical disinhibition is a very early, possibly prodromal feature of Parkinson's disease.
FLT3 mutation is present in 25-30% of all acute myeloid leukemias (AML), and it is associated with adverse outcome. FLT3 inhibitors have shown improved survival results in AML both as upfront ...treatment and in relapsed/refractory disease. Curiously, a variable proportion of wild-type FLT3 patients also responded to these drugs.
We analyzed 6 different transcriptomic datasets of AML cases. Differential expression between mutated and wild-type FLT3 AMLs was performed with the Wilcoxon-rank sum test. Hierarchical clustering was used to identify FLT3-mutation like AMLs. Finally, enrichment in recurrent mutations was performed with the Fisher's test.
A FLT3 mutation-like gene expression pattern was identified among wild-type FLT3 AMLs. This pattern was highly enriched in NPM1 and DNMT3A mutants, and particularly in combined NPM1/DNMT3A mutants.
We identified a FLT3 mutation-like gene expression pattern in AML which was highly enriched in NPM1 and DNMT3A mutations. Future analysis about the predictive role of this biomarker among wild-type FLT3 patients treated with FLT3 inhibitors is envisaged.
Theory of mind (ToM) is a social cognitive skill that involves the ability to attribute mental states to self and others (what they think (cognitive ToM) and feel (affective ToM)). We aim to provide ...an overview of previous knowledge of ToM in Parkinson’s disease (PD). In the last few years more attention has been paid to the study of this construct as a non-motor manifestation of PD. In advanced stages, both components of ToM (cognitive and affective) are commonly impaired, although in early PD results remain controversial. Executive dysfunction correlates with ToM deficits and other cognitive domains such as language and visuospatial function have also been related to ToM. Recent studies have demonstrated that PD patients with mild cognitive impairment show ToM deficits more frequently in comparison with cognitively normal PD patients. In addition to the heterogeneity of ToM tests administered in different studies, depression and dopaminergic medication may also be acting as confounding factors, but there are still insufficient data to support this. Neuroimaging studies conducted to understand the underlying networks of cognitive and affective ToM deficits in PD are lacking. The study of ToM deficit in PD continues to be important, as this may worsen quality of life and favor social stigma. Future studies should be considered, including assessment of the patients’ cognitive state, associated mood disorders, and the role of dopaminergic deficit.
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