In Italy, medical grade cannabis (MGC) can be prescribed for different medical conditions, including drug-resistant epilepsy (DRE), once standard and approved therapies have failed, or caused ...non-tolerable side effects. Here, we present a retrospective case series report of five patients with DRE who started therapy with MGC. Authorized ISO 9001:2008 pharmacies prepared MGC according to Italian laws. Olive oil extracts (OOEs) were prepared following standard extraction protocols, and cannabinoids were measured on each OOE to check for successful extraction.After treatment with MGC, all patients reported a reduction in seizure frequency and severity, and some reported improved mood, sleep quality, and general well-being without relevant side effects. Despite the small sample size and open-label nature of the data, we show that MGC may be successfully used to treat DRE. This is especially true when considering that no valid therapeutic option exists for these patients and that MGC was extremely well tolerated.
Friedreich's Ataxia (FA) is an inherited neurodegenerative disorder resulting from decreased expression of the mitochondrial protein frataxin, for which there is no approved therapy. High throughput ...screening of clinically used drugs identified Dimethyl fumarate (DMF) as protective in FA patient cells. Here we demonstrate that DMF significantly increases frataxin gene (FXN) expression in FA cell model, FA mouse model and in DMF treated humans. DMF also rescues mitochondrial biogenesis deficiency in FA-patient derived cell model. We further examined the mechanism of DMF's frataxin induction in FA patient cells. It has been shown that transcription-inhibitory R-loops form at GAA expansion mutations, thus decreasing FXN expression. In FA patient cells, we demonstrate that DMF significantly increases transcription initiation. As a potential consequence, we observe significant reduction in both R-loop formation and transcriptional pausing thereby significantly increasing FXN expression. Lastly, DMF dosed Multiple Sclerosis (MS) patients showed significant increase in FXN expression by ~85%. Since inherited deficiency in FXN is the primary cause of FA, and DMF is demonstrated to increase FXN expression in humans, DMF could be considered for Friedreich's therapy.
Background
Recent studies have suggested the presence of a significant atrophy affecting the cerebellar cortex in Friedreich ataxia (FRDA) patients, an area of the brain long considered to be ...relatively spared by neurodegenerative phenomena. Cognitive deficits, which occur in FRDA patients, have been associated with cerebellar volume loss in other conditions. The aim of this study was to investigate the correlation between cerebellar volume and cognition in FRDA.
Methods
Nineteen FRDA patients and 20 healthy controls (HC) were included in this study and evaluated via a neuropsychological examination. Cerebellar global and lobular volumes were computed using the Spatially Unbiased Infratentorial Toolbox (SUIT). Furthermore, a cerebellar voxel-based morphometry (VBM) analysis was also carried out. Correlations between MRI metrics and clinical data were tested via partial correlation analysis.
Results
FRDA patients showed a significant reduction of the total cerebellar volume (
p
= 0.004), significantly affecting the Lobule IX (
p
= 0.001). At the VBM analysis, we found a cluster of significant reduced GM density encompassing the entire lobule IX (
p
= 0.003). When correlations were probed, we found a direct correlation between Lobule IX volume and impaired visuo-spatial functions (
r
= 0.58,
p
= 0.02), with a similar correlation that was found between the same altered function and results obtained at the VBM (
r
= 0.52;
p
= 0.03).
Conclusions
With two different image analysis techniques, we confirmed the presence of cerebellar volume loss in FRDA, mainly affecting the posterior lobe. In particular, Lobule IX atrophy correlated with worse visuo-spatial abilities, further expanding our knowledge about the physiopathology of cognitive impairment in FRDA.
Purpose
Cerebellar ataxias are a large and heterogeneous group of disorders. The evaluation of brain parenchyma via MRI plays a central role in the diagnostic assessment of these conditions, being ...mandatory to exclude the presence of other underlying causes in determining the clinical phenotype. Once these possible causes are ruled out, the diagnosis is usually researched in the wide range of hereditary or sporadic ataxias.
Methods
We here propose a review of the main clinical and conventional imaging findings of the most common hereditary degenerative ataxias, to help neuroradiologists in the evaluation of these patients.
Results
Hereditary degenerative ataxias are all usually characterized from a neuroimaging standpoint by the presence, in almost all cases, of cerebellar atrophy. Nevertheless, a proper assessment of imaging data, extending beyond the mere evaluation of cerebellar atrophy, evaluating also the pattern of volume loss as well as concomitant MRI signs, is crucial to achieve a proper diagnosis.
Conclusion
The integration of typical neuroradiological characteristics, along with patient’s clinical history and laboratory data, could allow the neuroradiologist to identify some conditions and exclude others, addressing the neurologist to the more appropriate genetic testing.
Introduction
Psychosis in Parkinson’s disease (PD) is common and consists of hallucinations, illusions, and delusions. Among the latter, delusional jealousy, also named Othello syndrome (OS), might ...impair the quality of life of both patients and their partners. We aimed to perform a systematic review and report a series of PD patients presenting with OS.
Methods
A systematic review research was performed in PubMed database, excluding non-English articles, single case reports, reviews and neuropathology articles, comments, and articles concerning OS associated with deep brain stimulation (DBS) and levodopa-carbidopa intestinal gel infusion. We also described eleven PD patients (9 M and 2 F) with OS, identified in a cohort of consecutive 153 patients, comparing them with eleven matched no OS (nOS) PD subjects taken from the same cohort.
Results
We included eight articles (four case series and four cross-sectional studies). OS resulted more common among males than females. We did not find higher levodopa dose and levodopa equivalent dose for dopamine agonists and for all anti-parkinsonian drugs in our OS group. In our case series, OS patients showed visual hallucinations (
p
=0.001) and a trend to have depression (
p
=0.080) more frequently than nOS ones.
Conclusions
OS is not a rare disorder in PD, probably due not only to abnormal dopaminergic stimulation but also to serotonergic dysfunction in biologically predisposed subjects. Visual hallucinations and other concomitant psychiatric diseases, in particular depression, might represent a risk factor for the OS development.
Introduction
Friedreich Ataxia (FRDA) is an autosomal recessive neurodegenerative disorder that causes gait and limb ataxia, dysarthria, and impaired vibratory sense, with cardiomyopathy being the ...predominant cause of death. There is no approved therapy, which results in the use of symptomatic treatments and the chronic support of physiotherapy. Dimethyl fumarate (DMF) is a fumaric acid ester used for the treatment of psoriasis and Multiple Sclerosis (MS). It induces Nrf2
in vitro
and
in vivo
, and it increases frataxin in FRDA patient lymphoblasts, in mouse models, and in MS treated patients.
Methods
The aim of our study is to investigate if DMF can increase the expression of the
FXN
gene and frataxin protein and ameliorate
in-vivo
detectable measures of mitochondrial dysfunction in FRDA. The study is composed of a screening visit and two sequential 12-week phases: a core phase and an extension phase. During the first phase (core), patients will be randomly assigned to either the DMF or a placebo group in a 1:1 ratio. During the first week, patients will receive a total daily dose of 240 mg of DMF or placebo; from the second week of treatment, the dose will be increased to two 120 mg tablets BID for a total daily dose of 480 mg. During the second phase (extension), all patients will be treated with DMF. EudraCT number 2021-006274-23.
Endpoints
The primary endpoint will be a change in
FXN
gene expression level after 12 weeks of treatment. Secondary endpoints will be frataxin protein level,
c
ardiopulmonary exercise test outputs, echocardiographic measures, Nrf2 pathway and mitochondrial biogenesis gene expression, safety, clinical scales, and quality of life scales.
Conclusions
This is the first study aimed at exploring the ability of DMF, an already available treatment for MS and psoriasis, to correct the biological deficits of FRDA and potentially improve mitochondrial respiration
in-vivo
.
Objective
Timed neuropsychological tests do not take into account physical impairment during scoring procedures. Dysarthria and upper limb impairment can be easily measured with the PATA rate test ...(PRT) and the nine-hole pegboard test (9HPT). We recently validated a normalization method for timed neuropsychological tests using the PRT and 9HPT (p9NORM). We now validate the p9NORM in Parkinson’s disease (Yarnall et al. Neurology 82(4):308–316;
2014
) and multiple system atrophy (MSA).
Methods
We enrolled twenty-six patients with PD, eighteen patients with MSA, and fifteen healthy controls (HC). p9NORM was applied to patients with abnormal PRT and/or 9HPT. All subjects were tested with a comprehensive neuropsychological battery.
Results
No differences emerged in demographics across groups: (PD: mean age ± SD 66 ± 8; education 9 ± 4 years; MSA: age 60 ± 8; education 10 ± 4 years; HC: age 61 ± 12; education 9 ± 4 years). In MSA patients, the scores on the trail making test (TMT-A
p
= 0.003; TMT-B
p
= 0.018), attentional matrices (AM;
p
= 0.042), and symbol digit modalities test (SDMT
p
= 0.027) significantly differed following application of p9NORM. In PD patients, the TMT-A (
p
< 0.001), TMT-B (
p
= 0.001), and AM (
p
= 0.001) differed after correction. PD and MSA showed cognitive impairment relative to HC performance. When comparing MSA with PD, the SDMT, AM, and fluencies were similar. TMT-A and -B raw scores were different between groups (
p
= 0.006;
p
= 0.034), but these differences lost significance after p9NORM corrections (
p
= 0.100;
p
= 0.186).
Conclusions
We confirm that the p9NORM can be successfully used in both PD and MSA patients, as it mitigates the impact of disability on timed tests, resulting in a more accurate analysis of cognitive domains.
Polyglutamine disorders are neurodegenerative diseases that share a CAG repeat expansion in the coding region, resulting in aggregated proteins that can be only degraded through aggrephagy. We ...measured the expression of autophagy genes in peripheral blood mononuclear cells of 20 patients with Huntington’s disease (HD), 20 with spinocerebellar ataxia type 2 (SCA2), and 20 healthy individuals. HD patients showed increased expression of
MAP1LC3B
(+ 43%;
p
= 0.048),
SQSTM1
(+ 49%;
p
= 0.002), and
WDFY3
(+ 89%;
p
< 0.001). SCA2 patients had increased expression of
WDFY3
(+ 69%;
p
< 0.001). We show that peripheral markers of autophagy are elevated in polyQ diseases, and this is particularly evident in HD.
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