Marie-Catherine Boll

Background/Objectives: Several genetic factors are related to the risk of Alzheimer’s disease (AD) and the response to cholinesterase inhibitors (ChEIs) (donepezil, galantamine, and rivastigmine) or memantine. However, findings have been controversial, and, to the best of our knowledge, admixed populations have not been previously evaluated. We aimed to determine the impact of genetic and non-genetic factors on the risk of AD and the short-term response to ChEIs and memantine in patients with AD from Mexico. Methods: This study included 117 patients from two specialty hospitals in Mexico City, Mexico. We evaluated cognitive performance via clinical evaluations and neuropsychological tests. Nineteen variants in ABCB1, ACHE, APOE, BCHE, CHAT, CYP2D6, CYP3A5, CHRNA7, NR1I2, and POR were assessed through TaqMan assays or PCR. Results: Minor alleles of the ABCB1 rs1045642, ACHE rs17884589, and CHAT rs2177370 and rs3793790 variants were associated with the risk of AD; meanwhile, CHRNA7 rs6494223 and CYP3A5 rs776746 were identified as low-risk variants in AD. BCHE rs1803274 was associated with worse cognitive functioning. None of the genetic and non-genetic factors studied were associated with the response to pharmacological treatment. Conclusions: We identified potential genetic variants related to the risk of AD; meanwhile, no factor was observed to impact the response to pharmacological therapy in patients with AD from Mexico.

Background: Amyotrophic lateral sclerosis (ALS) is a devastating disease that targets motor neurons. Upper motor neurons degeneration is pathologically characterized by brain iron accumulation. Signal attenuation in the shape of a ribbon at the posterior border of the precentral gyrus can be observed on conventional magnetic resonance imaging (MRI) sequences including T2-weighted sequence. Methods: With the aim to know the qualities of this potential marker of ALS, we conducted a prospective study. Patients with definite ALS in the age range of 40–70 years and healthy controls underwent 3T brain MRI using a standardized sequence. A second MRI was performed 18 months later under the same conditions in the patients with ALS. Results: Most of the patients with ALS (91.66%) exhibited a “black ribbon” (BR) with an average area of 79.98 mm3. Signal attenuation discriminated ALS with a mean value of 63.97 arbitrary units (AU) on the left BR (95% CI: 60.67–67.27), a mean value of 59.15 AU (95% CI: 54.78–63.53) on the right BR, and a significant difference with control subjects presenting a mean value of 107.85 AU (p < 0.001). The optimal cut-off point for differentiating patients with ALS from controls (sensitivity, 0.92; specificity, 0.93) was 83 AU. Forced vital capacity and muscle strength in the contralateral upper extremity were significantly correlated with the ribbon intensity in ALS. Patients who underwent a second study exhibited significant changes in the BR related to the rapid evolution of the disease. Conclusions: This marker represents a valuable tool for the selection of candidates and their follow-up in clinical trials. L’hypo-intensité du cortex moteur est-elle une des caractéristiques de la sclérose latérale amyotrophique? Contexte: La sclérose latérale amyotrophique (SLA) est une maladie dévastatrice qui affecte les neurones moteurs. Sur le plan pathologique, la dégénérescence de ces neurones est caractérisée par une accumulation de fer dans le cerveau. L’affaiblissement du potentiel nerveux lié à cette maladie prend la forme d’un ruban situé à la limite postérieure du gyrus précentral. Un tel symptôme peut être observé au moyen de séquences tirées d’examens d’IRM conventionnelle, ce qui inclut la pondération T2. Méthodes: Nous avons mené une étude prospective avec l’objectif de mieux connaître les propriétés de ce marqueur potentiel de la SLA. Ainsi, des patients clairement atteints de SLA et âgés de 40 à 70 ans, de même que des témoins en bonne santé, ont subi une IRM 3T en vertu d’une séquence conventionnelle. Dix-huit mois plus tard, dans les mêmes conditions, une deuxième IRM a été effectuée dans le cas des patients atteints de SLA. Résultats: La plupart de ces patients, soit 91,66 % d’entre eux, ont donné à voir une forme de « ruban noir » dont la superficie moyenne atteignait 79,98 mm3. L’affaiblissement du potentiel nerveux a aussi permis de distinguer la SLA, la valeur moyenne, en unités arbitraires (UA), étant de 63,97 pour la section gauche du « ruban noir » (IC 95 % : 60,67 - 67,27) et de 59,15 (IC 95 % : 54,78 - 63,53) pour la section droite de ce même ruban. Une différence notable a été observée par rapport aux témoins, ces derniers donnant à voir une valeur moyenne de 107,85 (UA) (p < 0,001). Pour distinguer les patients atteints de SLA et les témoins, nous avons aussi déterminé que la limite optimale d’inclusion se situait à 83 (UA) (sensibilité : 0,92 ; spécificité : 0,93). Tant la capacité vitale forcée (CVF) que la force musculaire du membre supérieur controlatéral se sont révélées fortement corrélées à l’intensité du ruban associé à la SLA. Les patients ayant participé à une deuxième étude ont quant à eux présenté des modifications importantes en ce qui a trait à ce ruban en raison de l’évolution accélérée de leur maladie. Conclusions: Ce marqueur représente donc un outil précieux en vue de la sélection et du suivi de candidats devant participer à des essais cliniques.

Background: The serum paraoxonase-1 (PON1) associated to HDL presents two common polymorphisms in the positions 192 and 55. These polymorphisms are considered determinant of the capacity of HDL to protect LDL from their oxidative modification. In this context, the PON1 genotype has been associated with cardiovascular diseases, including stroke. Objective: To determine the allelic and genotypic frequencies of PON1 L55M and Q192R as well as the enzymatic activities of PON1 in subjects with and without atherothrombotic stroke. Methods: There were included 28 people with atherothrombotic stroke and 29 without stroke. The genotyping was carried out by PCR-RFLP and the phenotyping by measurement of the activities of paraoxonase and arylesterase in serum. Results: For the polymorphism Q192R, the allelic frequencies (Q/R) were 0.46/0.54 and 0.48/0.52 (p= 0.843) for the control group and the group with stroke, respectively. While for the polymorphism L55M, the allelic frequencies (L/M) were 0.81/0.19 for the control group, and 0.78/0.22 for the group with stroke (p= 0.610). The activity levels of paraoxonase were not significantly different between the control and stroke groups (450 vs. 348 UI/mL, p= 0.093) While the activity levels of arylesterase were significantly different between the studied groups (90 vs. 70 UI/mL, p= 0.001); however, upon adjustment by multiple linear regression, it was not longer significant. Conclusion: The polymorphisms Q192R and L55M, and the paraoxonase activity of PON1 are not risk factors for atherothrombotic stroke according to the results of this study.

BACKGROUND AND PURPOSE: There is a scarcity of information on the effect of white matter degeneration in patients with spinocerebellar ataxia type 7. Therefore, we investigated the WM integrity in a large group of patients with spinocerebellar ataxia type 7 by using Tract-Based Spatial Statistics. MATERIALS AND METHODS: Thirty-three patients with a molecular diagnosis of spinocerebellar ataxia type 7 and their age- and sex-matched healthy controls participated in this study. The patients' ataxia severity was evaluated with the Scale for the Assessment and Rating of Ataxia. Voxelwise analyses of diffusion metrics, including fractional anisotropy and mean diffusivity, were performed with Tract-Based Spatial Statistics. The correlation between WM abnormalities and ataxia severity was then calculated. RESULTS: Tract-Based Spatial Statistics analysis revealed WM abnormalities in the cerebellum and the cerebellar peduncles, as well as in other major cortical and subcortical pathways. Further analysis between the Scale for the Assessment and Rating of Ataxia score and WM mean diffusivity showed significant associations only in key areas related to motor control and visuospatial processing, including the cerebellar WM, the middle occipital WM, the superior cerebellar peduncle, and bilateral anterior thalamic radiation. No significant associations between fractional anisotropy and the Scale for the Assessment and Rating of Ataxia were found. CONCLUSIONS: These results suggest a significant contribution of local cerebellar and cerebellar-midbrain connections to ataxic impairment in spinocerebellar ataxia type 7. The results also suggest an involvement of cortical WM abnormalities including tracts within the occipital and frontal cortices. These findings contribute to a more comprehensive view of the clinical impact of the white matter degeneration in spinocerebellar ataxia type 7.