scholarly journals Neurochemical correlates of functional decline in amyotrophic lateral sclerosis

2018 ◽  
Vol 90 (3) ◽  
pp. 294-301 ◽  
Author(s):  
Ian Cheong ◽  
Dinesh K Deelchand ◽  
Lynn E Eberly ◽  
Małgorzata Marjańska ◽  
Georgios Manousakis ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Cortex ◽  
Disease Progression ◽  
Upper Limb ◽  
Functional Decline ◽  
Body Regions ◽  
Neurochemical Changes ◽  
Lateral Sclerosis ◽  
Over Time

ObjectiveTo determine whether proton magnetic resonance spectroscopy (1H-MRS) can detect neurochemical changes in amyotrophic lateral sclerosis (ALS) associated with heterogeneous functional decline.MethodsNineteen participants with early-stage ALS and 18 age-matched and sex ratio-matched controls underwent ultra-high field 1H-MRS scans of the upper limb motor cortex and pons, ALS Functional Rating Scale-Revised (ALSFRS-R total, upper limb and bulbar) and upper motor neuron burden assessments in a longitudinal observational study design with follow-up assessments at 6 and 12 months. Slopes of neurochemical levels over time were compared between patient subgroups classified by the rate of upper limb or bulbar functional decline. 1H-MRS and clinical ratings at baseline were assessed for ability to predict study withdrawal due to disease progression.ResultsMotor cortex total N-acetylaspartate to myo-inositol ratio (tNAA:mIns) significantly declined in patients who worsened in upper limb function over the follow-up period (n=9, p=0.002). Pons glutamate + glutamine significantly increased in patients who worsened in bulbar function (n=6, p<0.0001). Neurochemical levels did not change in patients with stable function (n=5–6) or in healthy controls (n=14–16) over time. Motor cortex tNAA:mIns and ALSFRS-R at baseline were significantly lower in patients who withdrew from follow-up due to disease progression (n=6) compared with patients who completed the 12-month scan (n=10) (p<0.001 for tNAA:mIns; p<0.01 for ALSFRS-R), with a substantially larger overlap in ALSFRS-R between groups.ConclusionNeurochemical changes in motor areas of the brain are associated with functional decline in corresponding body regions. 1H-MRS was a better predictor of study withdrawal due to ALS progression than ALSFRS-R.

Progressive Neurochemical Abnormalities in Cognitive and Motor Subgroups of Amyotrophic Lateral Sclerosis: A Prospective Multicenter Study

Neurology ◽  
2021 ◽  
pp. 10.1212/WNL.0000000000012367
Author(s):  
Daniel Ta ◽  
Abdullah Ishaque ◽  
Ojas Srivastava ◽  
Chris Hanstock ◽  
Peter Seres ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Prefrontal Cortex ◽  
Motor Cortex ◽  
Disease Progression ◽  
Multicenter Study ◽  
Rapid Disease Progression ◽  
Prospective Longitudinal ◽  
Lateral Sclerosis ◽  
Over Time ◽  
Cerebral Degeneration

OBJECTIVE:To evaluate progressive cerebral degeneration in amyotrophic lateral sclerosis (ALS) by assessing alterations in N-acetylaspartate (NAA) ratios in the motor and prefrontal cortex within clinical subgroups of ALS.METHODS:Seventy-six ALS patients and 59 healthy controls were enrolled in a prospective, longitudinal, multicenter study in the Canadian ALS Neuroimaging Consortium (CALSNIC). Participants underwent serial clinical evaluations and MR spectroscopy at baseline, 4 and 8 months using a harmonized protocol across 5 centers. NAA ratios were quantified in the motor cortex and prefrontal cortex. Patients were stratified into subgroups based on disease progression rate, upper motor neuron (UMN) signs, and cognitive status. Linear mixed models were used for baseline and longitudinal comparisons of NAA metabolite ratios.RESULTS:Patients with ALS had reduced NAA ratios in the motor cortex at baseline (P < 0.001). Ratios were lower in those with more rapid disease progression and greater UMN signs (P < 0.05). A longitudinal decline in NAA ratios was observed in the motor cortex in the rapid progressing (P < 0.01) and high UMN burden (P < 0.01) cohorts. The severity of UMN signs did not change significantly over time. NAA ratios were reduced in the prefrontal cortex only in cognitively impaired patients (P < 0.05); prefrontal cortex metabolites did not change over time.CONCLUSIONS:Progressive degeneration of the motor cortex in ALS is associated with more aggressive clinical presentations These findings provide biological evidence of variable spatial and temporal cerebral degeneration linked to the disease heterogeneity of ALS. The use of standardized imaging protocols may have a role to play in clinical trials for patient selection or subgrouping.CLASSIFICATION OF EVIDENCE:This study provides Class II evidence that MRS NAA metabolite ratios of the motor cortex are associated with more rapid disease progression and greater UMN signs in patients with ALS.

scholarly journals IL6 receptor358Ala variant and trans-signaling are disease modifiers in amyotrophic lateral sclerosis

2019 ◽  
Vol 6 (6) ◽  
pp. e631 ◽  
Author(s):  
Marlena Wosiski-Kuhn ◽  
Mac Robinson ◽  
Jane Strupe ◽  
Phonepasong Arounleut ◽  
Matthew Martin ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Disease Progression ◽  
Interleukin 6 ◽  
Serum Levels ◽  
Interleukin 6 Receptor ◽  
The Common ◽  
Paired Serum ◽  
Control Study ◽  
Lateral Sclerosis

ObjectiveTo test the hypothesis that patients with amyotrophic lateral sclerosis (ALS) inheriting the common interleukin 6 receptor (IL6R) coding variant (Asp358Ala, rs2228145, C allele) have associated increases in interleukin 6 (IL6) and IL6R levels in serum and CSF and faster disease progression than noncarriers.MethodsAn observational, case-control study of paired serum and CSF of 47 patients with ALS, 46 healthy, and 23 neurologic disease controls from the Northeastern ALS Consortium Biofluid Repository (cohort 1) was performed to determine serum levels of IL6, sIL6R, and soluble glycoprotein 130 and compared across groups and IL6R genotype. Clinical data regarding disease progression from a separate cohort of 35 patients with ALS from the Wake Forest ALS Center (cohort 2) were used to determine change in ALSFRS-R scores by genotype.ResultsPatients with ALS had increased CSF IL6 levels compared with healthy (p < 0.001) and neurologic (p = 0.021) controls. Patients with ALS also had increased serum IL6 compared with healthy (p = 0.040) but not neurologic controls. Additive allelic increases in serum IL6R were observed in all groups (average increase of 52% with the presence of the IL6R C allele; p < 0.001). However, only subjects with ALS had significantly increased CSF sIL6R levels compared with controls (p < 0.001). When compared across genotypes, only patients with ALS inheriting the IL6R C allele exhibit increased CSF IL6. ALSFRS-R scores decreased more in patients with ALS with the IL6R C allele than in those without (p = 0.019).ConclusionsTheses results suggest that for individuals inheriting the IL6R C allele, the cytokine exerts a disease- and location-specific role in ALS. Follow-up, prospective studies are necessary, as this subgroup of patients may be identified as ideally responsive to IL6 receptor–blocking therapies.

scholarly journals Longitudinal Study of Cognitive and Emotional Alterations in Amyotrophic Lateral Sclerosis: Clinical and Imaging Data

2021 ◽  
Vol 12 ◽  
Author(s):  
Soumia Benbrika ◽  
Franck Doidy ◽  
Laurence Carluer ◽  
Audrey Mondou ◽  
Alice Pélerin ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Executive Functions ◽  
Inferior Frontal Gyrus ◽  
Disease Onset ◽  
Psychological State ◽  
Imaging Data ◽  
Cortical Thinning ◽  
Lateral Sclerosis ◽  
Over Time

Objectives: Extra-motor manifestations occur in 50% of patients with amyotrophic lateral sclerosis (ALS). These mainly concern cognition, emotional processing and behavior. Depression and anxiety are less frequent. Little is known about how these manifestations change as the disease progresses. Similarly, although cortical thinning has been well-documented at disease onset, there are scant data about cortical thinning over time and how this correlates with extra-motor manifestations. The present study therefore assessed cognitive, emotional and psychological state and cortical thinning in a group of patients with ALS at baseline and after a follow-up period.Methods: We assessed executive functions, facial emotion recognition, depressive and anxious symptoms, and cortical thinning in 43 patients with ALS at baseline, comparing them with 28 healthy controls, and 21 of them 9 months later. We looked for links among the extra-motor manifestations and correlations with cortical thickness.Results: At baseline, patients had poor executive function and recognition of complex emotions from the eyes, and more anxious and depressive symptoms than controls. At follow-up, only inhibition abilities had worsened. Cortical thinning was observed in bilateral pre-central regions and other parts of the cerebral cortex at baseline. Over time, it worsened in motor and extra-motor areas. Executive functions correlated with thinning in the middle and inferior frontal gyrus and orbitofrontal cortex.Conclusions: During follow-up, there was little deterioration in extra-motor manifestations and psychological state, despite continuing cortical thinning. Patients with affective Theory of Mind (ToM) changes seemed less depressed than the others. Impaired mental flexibility was subtended by prefrontal regions with cortical thinning.

scholarly journals Cerebral degeneration in amyotrophic lateral sclerosis

2019 ◽  
Vol 9 (5) ◽  
pp. 400-407 ◽  
Author(s):  
Ojas Srivastava ◽  
Chris Hanstock ◽  
Sneha Chenji ◽  
Dennell Mah ◽  
Dean Eurich ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Prefrontal Cortex ◽  
Motor Cortex ◽  
Disease Progression ◽  
Progression Rate ◽  
Healthy Controls ◽  
Potential Biomarker ◽  
Disease Progression Rate ◽  
Lateral Sclerosis ◽  
Cerebral Degeneration

BackgroundWe investigated cerebral degeneration and neurochemistry in patients with amyotrophic lateral sclerosis (ALS) using magnetic resonance spectroscopy (MRS).MethodsWe prospectively studied 65 patients and 43 age-matched healthy controls. Participants were recruited from 4 centers as part of a study in the Canadian ALS Neuroimaging Consortium. All participants underwent single-voxel proton MRS using a protocol standardized across all sites. Metabolites reflecting neuronal integrity (total N-acetyl aspartyl moieties [tNAA]) and gliosis (myo-inositol [Ino]), as well as creatine (Cr) and choline (Cho), were quantified in the midline motor cortex and midline prefrontal cortex. Comparisons were made between patients with ALS and healthy controls. Metabolites were correlated with clinical measures of upper motor neuron dysfunction, disease progression rate, and cognitive performance.ResultsIn the motor cortex, tNAA/Cr, tNAA/Cho, and tNAA/Ino ratios were reduced in the ALS group compared with controls. Group differences in tNAA/Cr and tNAA/Cho in the prefrontal cortex displayed reduced ratios in ALS patients; however, these were not statistically significant. Reduced motor cortex ratios were associated with slower foot tapping rate, whereas only motor tNAA/Ino was associated with finger tapping rate. Disease progression rate was associated with motor tNAA/Cho. Verbal fluency, semantic fluency, and digit span forwards and backwards were associated with prefrontal tNAA/Cr.ConclusionsThis study demonstrates that cerebral degeneration in ALS is more pronounced in the motor than prefrontal cortex, that multicenter MRS studies are feasible, and that motor tNAA/Ino shows promise as a potential biomarker.

scholarly journals Longitudinal Quantitative MRI Evaluation of Muscle Involvement in Amyotrophic Lateral Sclerosis

2021 ◽  
Vol 12 ◽  
Author(s):  
Matteo Paoletti ◽  
Luca Diamanti ◽  
Shaun I. Muzic ◽  
Elena Ballante ◽  
Francesca Solazzo ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Disease Progression ◽  
Rating Scale ◽  
Quantitative Mri ◽  
Triceps Surae ◽  
Muscle Mri ◽  
Muscle Involvement ◽  
Leg Muscles ◽  
Lateral Sclerosis ◽  
Over Time

Background: Biomarkers of disease progression and outcome measures are still lacking for patients with amyotrophic lateral sclerosis (ALS). Muscle MRI can be a promising candidate to track longitudinal changes and to predict response to the therapy in clinical trials.Objective: Our aim is to apply quantitative muscle MRI in the evaluation of disease progression, focusing on thigh and leg muscles of patients with ALS, and to explore the correlation between radiological and clinical scores.Methods: We enrolled newly diagnosed patients with ALS, longitudinally scored using the ALS Functional Rating Scale-Revised (ALSFRS-R), who underwent a 3T muscle MRI protocol including a 6-point Dixon gradient-echo sequence and multi-echo turbo spin echo (TSE) T2-weighted sequence for quantification of fat fraction (FF), cross-sectional area (CSA), and water T2 (wT2). A total of 12 muscles of the thigh and six muscles of the leg were assessed by the manual drawing of 18 regions of interest (ROIs), for each side. A group of 11 age-matched healthy controls (HCs) was enrolled for comparison.Results: 15 patients (M/F 8/7; mean age 62.2 years old, range 29–79) diagnosed with possible (n = 2), probable (n = 12), or definite (n = 1) ALS were enrolled. Eleven patients presented spinal onset, whereas four of them had initial bulbar involvement. All patients performed MRI at T0, nine of them at T1, and seven of them at T2. At baseline, wT2 was significantly elevated in ALS subjects compared to HCs for several muscles of the thigh and mainly for leg muscles. By contrast, FF was elevated in few muscles, and mainly at the level of the thigh. The applied mixed effects model showed that FF increased significantly in the leg muscles over time (mainly in the triceps surae) and that wT2 decreased significantly in line with worsening in the leg subscore of ALSFRS-R, mainly at the leg level and in the anterior and medial compartment of the thigh.Conclusions: Quantitative MRI represents a non-invasive tool that is able to outline the trajectory of pathogenic modifications at the muscle level in ALS. In particular, wT2 was found to be increased early in the clinical history of ALS and also tended to decrease over time, also showing a positive correlation with leg subscore of ALSFRS-R.

Reduction of disease progression in a patient with amyotrophic lateral sclerosis after several years of epidural motor cortex stimulation

2017 ◽  
Vol 10 (2) ◽  
pp. 324-325 ◽  
Author(s):  
Vincenzo Di Lazzaro ◽  
Giovanni Pellegrino ◽  
Fioravante Capone ◽  
Lucia Florio ◽  
Michele Dileone ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Cortex ◽  
Disease Progression ◽  
Motor Cortex Stimulation ◽  
Lateral Sclerosis

Changes in motor cortex inhibition over time in patients with amyotrophic lateral sclerosis

2002 ◽  
Vol 249 (12) ◽  
pp. 1723-1728 ◽  
Author(s):  
Giampietro Zanette ◽  
Stefano Tamburin ◽  
Paolo Manganotti ◽  
Nicola Refatti ◽  
Antonio Forgione ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Cortex ◽  
Lateral Sclerosis ◽  
Over Time

scholarly journals Dominant Heterogeneity of Upper and Lower Motor Neuron Degeneration to Motor Manifestation of Involved Region in Amyotrophic Lateral Sclerosis

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Jiaoting Jin ◽  
Fangfang Hu ◽  
Qiuli Zhang ◽  
Qiaoyi Chen ◽  
Haining Li ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neuron ◽  
Cortical Thickness ◽  
Upper Limb ◽  
Lower Motor Neuron ◽  
Body Region ◽  
Control Group ◽  
Body Regions ◽  
Onset Group ◽  
Lateral Sclerosis

AbstractThe aim of this study was to localize the anatomic distribution of upper motor neuron (UMN) loss through examining cortical thickness at the clinical onset of amyotrophic lateral sclerosis (ALS) and explore motor manifestation in functionally impaired body region attribute to impairment of lower motor neuron (LMN) or UMN or mixed LMN and UMN? The clinical features, cortical thickness of corresponding areas from different body regions in MRI and electromyography (EMG) data were collected from 108 classical ALS patients. The cortical thickness was thinner in ALS group than control group in bilateral head-face and upper-limb areas (p < 0.05). In head-face area, the cortical thickness of bulbar-onset group was significantly lower than that of control groups (p < 0.05). In upper-limb areas, the cortical thickness of cervical-onset group was significantly thinner than that of control group. Notably, the bulbar ALSFRS-R subscore was correlated with cortical thickness in bilateral head-face areas (p < 0.05). The bulbar ALSFRS-R subscore of the positive LMN damage group was lower compared to that of the negative LMN damage group (P < 0.001). The limb ALSFRS-R subscore correlated with compound muscle action potential (CMAP) amplitudes of median, ulnar, peroneal, and tibial nerves (P < 0.001), but was not related to cortical thickness. In conclusion, the UMN degeneration in ALS was derived from focal initiation, bulbar- and cervical-onset may date from head-face and upper-limb areas in motor homunculus cortex, respectively. The bulbar dysfunction was resulted from the mixed UMN and LMN impairment, while limb dysfunction derived mostly from LMN loss.

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