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

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.

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Neurochemical correlates of functional decline in amyotrophic lateral sclerosis

Journal of Neurology Neurosurgery & Psychiatry ◽

10.1136/jnnp-2018-318795 ◽

2018 ◽

Vol 90 (3) ◽

pp. 294-301 ◽

Cited By ~ 6

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.

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Stem-cell transplantation into the frontal motor cortex in amyotrophic lateral sclerosis patients

Cytotherapy ◽

10.1080/14653240802644651 ◽

2009 ◽

Vol 11 (1) ◽

pp. 26-34 ◽

Cited By ~ 89

Author(s):

Hector R. Martinez ◽

Maria T. Gonzalez-Garza ◽

Jorge E. Moreno-Cuevas ◽

Enrique Caro ◽

Eugenio Gutierrez-Jimenez ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Stem Cell ◽

Motor Cortex ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Lateral Sclerosis

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Changes Over Time in Dysarthric Patients with Amyotrophic Lateral Sclerosis(ALS). II. A Study of Changes in Speaking Rate and Maximum Repetition Rate(MRR).

The Japan Journal of Logopedics and Phoniatrics ◽

10.5112/jjlp.40.8 ◽

1999 ◽

Vol 40 (1) ◽

pp. 8-16

Author(s):

Masaki Nishio ◽

Seiji Niimi

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Repetition Rate ◽

Speaking Rate ◽

Changes Over Time ◽

Lateral Sclerosis ◽

Over Time

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Long-term survival in amyotrophic lateral sclerosis after stem cell transplantation into the frontal motor cortex

Cytotherapy ◽

10.1016/j.jcyt.2016.03.294 ◽

2016 ◽

Vol 18 (6) ◽

pp. 806-808 ◽

Cited By ~ 3

Author(s):

Héctor R. Martínez ◽

María Teresa González-Garza ◽

Jorge Moreno-Cuevas ◽

César E. Escamilla-Ocañas ◽

Juan Miguel Tenorio-Pedraza ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Stem Cell ◽

Motor Cortex ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Term Survival ◽

Long Term Survival ◽

Lateral Sclerosis

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Patterns of Non-Invasive Ventilation in Amyotrophic Lateral Sclerosis

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques ◽

10.1017/cjn.2018.25 ◽

2018 ◽

Vol 45 (4) ◽

pp. 445-450

Author(s):

Nevena Markovic ◽

Marcus Povitz ◽

Joanne Smith ◽

David Leasa ◽

Christen Shoesmith ◽

...

Keyword(s):

Decision Making ◽

Amyotrophic Lateral Sclerosis ◽

End Of Life ◽

Invasive Ventilation ◽

Non Invasive ◽

Non Invasive Ventilation ◽

End Of Life Decision ◽

Life Decision ◽

Lateral Sclerosis ◽

Over Time

AbstractBackground: Non-invasive ventilation (NIV) improves quality of life and survival in patients with amyotrophic lateral sclerosis (ALS) and respiratory symptoms. Little is known about the patterns of NIV use over time and the impact of NIV on end-of-life decision-making in ALS. Objective: This study assessed the pattern of NIV use over the course of the disease and the timing of end-of-life discussions in people living with ALS. Method: A retrospective single-center cohort study was performed at London Health Sciences Centre. Daily NIV duration of use was evaluated at 3-month intervals. The timing of diagnosis, NIV initiation, discussions relating to do-not-attempt-resuscitation (DNAR) and death were examined. Results: In total, 48 patients were included in the analysis. Duration of NIV use increased over time, and tolerance to NIV was observed to be better than expected in patients with bulbar-onset ALS. There was a high degree of variability in the timing of end-of-life discussions in patients with ALS (356±451 days from diagnosis). In this cohort, there was a strong association between the timing of discussions regarding code status and establishment of a DNAR order (r2=0.93). Conclusion: This retrospective cohort study suggests that the use of NIV in ALS increases over time and that there remains a great deal of variability in the timing of end-of-life discussions in people living with ALS. Future prospective studies exploring the use NIV over the disease trajectory and how NIV affects end-of-life decision-making in people with ALS are needed.

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Serial assessment of iron in the motor cortex in limb-onset amyotrophic lateral sclerosis using quantitative susceptibility mapping

Quantitative Imaging in Medicine and Surgery ◽

10.21037/qims-20-187 ◽

2020 ◽

Vol 10 (7) ◽

pp. 1465-1476

Author(s):

Anjan Bhattarai ◽

Zhaolin Chen ◽

Phillip G. D. Ward ◽

Paul Talman ◽

Susan Mathers ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Motor Cortex ◽

Susceptibility Mapping ◽

Quantitative Susceptibility Mapping ◽

Lateral Sclerosis ◽

Limb Onset

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First-in-human trial of blood–brain barrier opening in amyotrophic lateral sclerosis using MR-guided focused ultrasound

Nature Communications ◽

10.1038/s41467-019-12426-9 ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 51

Author(s):

Agessandro Abrahao ◽

Ying Meng ◽

Maheleth Llinas ◽

Yuexi Huang ◽

Clement Hamani ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Motor Cortex ◽

Blood Brain Barrier ◽

Focused Ultrasound ◽

Primary Motor Cortex ◽

Brain Barrier ◽

Human Trial ◽

Blood Brain ◽

Lateral Sclerosis ◽

Bbb Opening

Abstract MR-guided focused ultrasound (MRgFUS) is an emerging technology that can accurately and transiently permeabilize the blood-brain barrier (BBB) for targeted drug delivery to the central nervous system. We conducted a single-arm, first-in-human trial to investigate the safety and feasibility of MRgFUS-induced BBB opening in eloquent primary motor cortex in four volunteers with amyotrophic lateral sclerosis (ALS). Here, we show successful BBB opening using MRgFUS as demonstrated by gadolinium leakage at the target site immediately after sonication in all subjects, which normalized 24 hours later. The procedure was well-tolerated with no serious clinical, radiologic or electroencephalographic adverse events. This study demonstrates that non-invasive BBB permeabilization over the motor cortex using MRgFUS is safe, feasible, and reversible in ALS subjects. In future, MRgFUS can be coupled with promising therapeutics providing a targeted delivery platform in ALS.

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