ObjectiveInterindividual variations in responsiveness to zonisamide in patients with Parkinson’s disease (PD) have been observed in clinical settings. To decipher the molecular mechanisms determining ...the efficacy of zonisamide, we conducted whole transcriptome sequencing analysis of patients with PD.MethodsWe selected 23 super-responders (SRs) and 25 non-responders (NRs) to zonisamide from patients with PD who had participated in a previous clinical trial for the approval of zonisamide for the treatment of ‘wearing-off’. Whole transcriptome analysis of peripheral blood was conducted on samples taken before and 12 weeks after zonisamide treatment. We performed differential gene expression analysis to compare between the SRs and NRs at each time point.ResultsDifferentially expressed genes in the pre-treatment samples were significantly enriched for glutamatergic synapses and insulin-like growth factor binding (P adj=7.8 × 10−3 and 0.029, respectively). The gene sets associated with these functions changed more dynamically by treatment in SRs than NRs (p=7.2 × 10−3 and 8.2 × 10−3, respectively).ConclusionsOur results suggest that the efficacy of zonisamide in PD patients is associated with glutamate-related synaptic modulation and p53-mediated dopaminergic neural loss. Their transcriptomic differences could be captured before treatment, which would lead to the realisation of future personalised treatment.
In this paper, we consider a resolvent problem arising in the study of a Korteweg-type model of isothermal compressible viscous fluids derived by Dunn and Serrin (1985), and we prove resolvent ...estimates in bounded and exterior domains. The Korteweg-type model is employed to describe fluid capillarity effects or a liquid-vapor two-phase flow with phase transition as diffuse interface model. Our resolvent problem is obtained from a linearized system of the Korteweg-type model around the steady state
(
ρ
,
u
)
=
(
1
,
0
)
, where
ρ
is the fluid density and
u
is the fluid velocity. For bounded domains, we treat variable coefficients and prove that the resolvent set contains
C
+
¯
=
{
z
∈
C
:
ℜ
z
≥
0
}
under the condition that the pressure function
P
(
ρ
)
satisfies not only
P
′
(
1
)
≥
0
but also
P
′
(
1
)
<
0
, where
P
′
(
1
)
=
(
d
P
/
d
ρ
)
(
1
)
. We follow the idea of Kotschote (2014) to handle
P
′
(
1
)
<
0
. For exterior domains, we treat constant coefficients and prove that the resolvent set contains
{
z
∈
C
+
¯
:
|
z
|
≥
δ
}
for any
δ
>
0
when
P
′
(
1
)
≥
0
. Furthermore, we introduce a global solvability result for the nonlinear problem in a bounded domain as an application of the resolvent estimate.
We report a 38-year-old woman who presented with mild proximal dominant muscle weakness and fatigability that fluctuated during menstruation and treatment with ephedrine-containing medication. The ...patient had been diagnosed with “congenital myopathy with tubular aggregates” by muscle biopsy at age 19. Her revised diagnosis was congenital myasthenic syndrome (CMS) caused by a mutation in GFPT1 (2p13.3 MIM 610542, c.722_723insG homozygote, CMS-GFPT1) based on a screening gene analysis. Muscle CT revealed diffuse atrophy of proximal and axial muscles focused on the vastus lateralis, hamstrings, medial gastrocnemius and soleus muscles. Oral administration of pyridostigmine bromide clearly ameliorated weakness and fatigability. This is the first reported case of CMS-GFPT1 in Japan. Since CMS symptoms are reactive to treatment, it is important for clinicians to make an accurate diagnosis at an early stage to improve patient QOL. Tubular aggregates in muscle biopsy and day-to-day fluctuations are important features of the disorder. Quantitative muscle strength measurement was effective for evaluating treatment efficacy.
Huntington's disease (HD) is an autosomal dominant inheritable neurodegenerative disorder currently without effective treatment. It is caused by an expanded polyglutamine (poly Q) tract in the ...corresponding protein, huntingtin (htt), and therefore suppressing the huntingtin expression in brain neurons is expected to delay the onset and mitigate the severity of the disease. Here, we have used small interfering RNAs (siRNAs) directed against the huntingtin gene to repress the transgenic mutant huntingtin expression in an HD mouse model, R6/2. Results showed that intraventricular injection of siRNAs at an early postnatal period inhibited transgenic huntingtin expression in brain neurons and induced a decrease in the numbers and sizes of intranuclear inclusions in striatal neurons. Treatments using this siRNA significantly prolonged model mice longevity, improved motor function and slowed down the loss of body weight. This work suggests that siRNA-based therapy is promising as a future treatment for HD.
Objective
Dementia with Lewy bodies (DLB) is often cited as the second most common dementia after Alzheimer’s disease (AD). It is clinically important to distinguish DLB from AD because specific side ...effects of antipsychotic drugs are limited to DLB. The relative preservation of cingulate glucose metabolism in the posterior cingulate gyri versus that in the precuni, known as the cingulate island sign (CIS), in patients with DLB compared with AD is supposed to be highly specific for diagnosing DLB. In a previous study, using brain perfusion SPECT, the largest value (0.873) for the area under the receiver operating characteristic (ROC) curve (AUC) for differentiating DLB from AD was obtained with the ratio of the posterior cingulate gyri from an early Alzheimer’s disease-specific hypoperfusion volume of interest (VOI) versus the medial occipital lobe. Two purposes of this study are as follows: one is optimization of VOI setting for calculating CIS values and the other is to evaluate their accuracy and simultaneously to retest the method described in our previous paper.
Methods
We conducted a retest of this SPECT method with another cohort of 13 patients with DLB and 13 patients with AD. Furthermore, we optimized VOIs using contrast images obtained from group comparisons of DLB and normal controls; the same 18 patients with DLB and 18 normal controls examined in our previous study. We obtained DLB-specific VOIs from areas where brain perfusion was significantly decreased in DLB. As the numerators of these ratios, early Alzheimer’s disease-specific VOIs were used after subtracting DLB-specific VOIs. The DLB-specific VOIs were used as the denominator.
Results
In retest, the obtained AUC was 0.858 and the accuracy, sensitivity, and specificity were 84.6, 84.6, and 84.6%, respectively. The ROC curve analysis with these optimized VOIs yielded a higher AUC of 0.882; and the accuracy, sensitivity, and specificity of these new CIS ratios were 84.6, 92.3, and 76.9%, respectively, with a threshold value of 0.281.
Conclusion
Optimized CISs using brain perfusion SPECT are clinically useful for differentiating DLB from AD.
In Parkinson's disease (PD) patients, magnetic resonance (MR) imaging studies using phase difference enhanced imaging (PADRE) and susceptibility-weighted imaging (SWI) showed the obscuration of the ...boundary between the crural fibers and substantia nigra, and the absence of dorsolateral nigral hyperintensity, respectively. PADRE images have not been evaluated in other types of neurodegenerative parkinsonism, and PADRE and SWI images have not been compared. Here we evaluated PADRE and SWI images in patients with progressive supranuclear palsy (PSP), multiple system atrophy (MSA), or PD and controls, and we compared the diagnostic values.
PADRE and SWI-like MR images were visually assessed focusing on the substantia nigra in 39 PD patients, eight with PSP, 13 with MSA, and 34 normal controls.
The obscuration of the boundary between the crural fibers and substantia nigra on PADRE was observed in: the PD group, 62%; PSP, 100%; MSA, 60%, and controls, 19%. The overall collect classification for neurodegenerative parkinsonism was 74%. The absence of dorsolateral nigral hyperintensity on SWI-like images was present in: PD, 97%; PSP, 100%; MSA, 67%; and controls, 6%, resulting in the overall correct classification of 96%.
The MR feature on PADRE was observed not only in PD but also in other neurodegenerative parkinsonism, especially in PSP with high sensitivity. The finding in substantia nigra on SWI had greater discrimination power than that of PADRE in neurodegenerative parkinsonism, especially in PD.
•Nigral finding on PADRE was found in neurodegenerative parkinsonism as well as PD.•Nigral finding on SWI had a greater discriminative power than PADRE in PD.•Both findings on PARE and SWI had an equivalent discriminative power in PSP.
Oligomer formation and accumulation of pathogenic proteins are key events in the pathomechanisms of many neurodegenerative diseases, such as Alzheimer disease, ALS, and the polyglutamine (polyQ) ...diseases. The autophagy-lysosome degradation system may have therapeutic potential against these diseases because it can degrade even large oligomers. Although p62/sequestosome 1 plays a physiological role in selective autophagy of ubiquitinated proteins, whether p62 recognizes and degrades pathogenic proteins in neurodegenerative diseases has remained unclear. In this study, to elucidate the role of p62 in such pathogenic conditions in vivo, we used Drosophila models of neurodegenerative diseases. We found that p62 predominantly co-localizes with cytoplasmic polyQ protein aggregates in the MJDtr-Q78 polyQ disease model flies. Loss of p62 function resulted in significant exacerbation of eye degeneration in these flies. Immunohistochemical analyses revealed enhanced accumulation of cytoplasmic aggregates by p62 knockdown in the MJDtr-Q78 flies, similarly to knockdown of autophagy-related genes (Atgs). Knockdown of both p62 and Atgs did not show any additive effects in the MJDtr-Q78 flies, implying that p62 function is mediated by autophagy. Biochemical analyses showed that loss of p62 function delays the degradation of the MJDtr-Q78 protein, especially its oligomeric species. We also found that loss of p62 function exacerbates eye degeneration in another polyQ disease fly model as well as in ALS model flies. We therefore conclude that p62 plays a protective role against polyQ-induced neurodegeneration, by the autophagic degradation of polyQ protein oligomers in vivo, indicating its therapeutic potential for the polyQ diseases and possibly for other neurodegenerative diseases.Oligomers of pathogenic proteins are implicated in the pathomechanisms of neurodegenerative diseases.
Depletion of p62 delays the degradation of polyglutamine protein oligomers via autophagy and exacerbates neurodegeneration in polyglutamine disease model flies.
p62 plays a protective role via autophagic degradation of polyglutamine protein oligomers.
p62 should be a therapeutic target for the polyglutamine diseases.
Neuromyelitis optica (NMO) is an inflammatory disease characterized by recurrent attacks of optic neuritis and myelitis. It is generally accepted that autoantibodies against aquaporin 4 water channel ...protein play a pathogenic role in neuromyelitis optica. We have recently reported that plasmablasts are increased in the peripheral blood of this autoimmune disease, and are capable of producing autoantibodies against aquaporin 4. Here, we demonstrate that CD138(+)HLA-DR(+) plasmablasts, a subset of IgG-producing cells, are increased in the peripheral blood and are enriched among the cerebrospinal fluid (CSF) lymphocytes during the relapse of neuromyelitis optica. Notably, these CD138(+)HLA-DR(+) plasmablasts overexpress CXCR3, whose ligands are present in the cerebrospinal fluid during the relapse of neuromyelitis optica. These results led us to speculate that plasmablasts producing anti-aquaporin 4 autoantibodies might traffic toward the central nervous system (CNS). Furthermore, we performed single-cell sorting of plasmablasts from peripheral blood and CSF samples from NMO and sequenced the complementarity-determining regions (CDRs) of the IgG heavy chain expressed by the sorted plasmablast clones. There were high frequencies of mutations in the CDRs compared with framework regions, indicating that these plasmablast clones would represent a post-germinal center B-cell lineage. Consistent with the preceding results, the plasmablast clones from the peripheral blood shared the same CDR sequences with the clones from the CSF. These results indicate that IgG-producing plasmablasts, which are guided by helper T-cells, may migrate from the peripheral blood preferentially to the CSF. Since migratory plasmablasts could be involved in the inflammatory pathology of NMO, the B-cell subset and their migration might be an attractive therapeutic target.
Camptocormia is characterized by a pathological forward flexion of the trunk, which is reversible when lying and worsened by standing and walking. So far there is no consensus on how to measure the ...angle of flexion, and studies therefore give differing results. Harmonization is needed for both research and clinical practice. Orthopedic measures are not useful for this purpose.
Two expert raters independently analyzed the photographs of 39 Parkinson patients with camptocormia while standing. They used four different methods to determine the camptocormia angle. The results were compared statistically. An international Consensus Group reviewed the results and drafted recommendations.
The four methods yielded camptocormia angles that differed by up to 50% in the same patient. Inter-rater reliability and test-retest reliability also differed, but were satisfactory to excellent.
This Consensus Group concluded that two of the methods qualified as reliable measures of the trunk angles in standing patients based on their clinimetric properties. They propose that the ‘total camptocomia angle’ be the angle between the line from the lateral malleolus to the L5 spinous process and the line between the L5 spinous process and the spinous process of C7. They also propose that the ‘upper camptocormia angle’ be the angle of the lines between the vertebral fulcrum to the spinous processes of L5 and C7, respectively. An app is provided on the web for these measurements (http://www.neurologie.uni-kiel.de/de/axial-posturale-stoerungen/camptoapp).
•There is no agreement on how to measure the camptocormia angle. Therefore studies on camptocormia are not comparable.•In this paper four different methods of angle assessment were empirically evaluated regarding reliability and face validity.•A consensus could be reached to measure a total camptocormia angle and an upper camptocormia angle.•Apps are available to measure these angles (http://www.neurologie.uni-kiel.de/de/axial-posturale-stoerungen/camptoapp).
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