Degeneration of the Mid-Cingulate Cortex in Amyotrophic Lateral Sclerosis Detected In Vivo with MR Spectroscopy

Sudharshan, N.; Hanstock, Chris; Hui, Benjamin; Pyra, Timothy; Johnston, Wendy; Kalra, Sanjay

doi:10.3174/ajnr.a2289

Cited by 26 publications

(23 citation statements)

References 49 publications

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“…Furthermore, a decrease in tNA was associated with a decrease in forced vital capacity, another measure of disease progression. A number of studies have also explored correlations between tNA and clinical scales, and have reported significant associations among tNA levels and ALSFRS-R scores [12, 17, 41], UMNB burden scores [16, 17, 41], and rate of disease progression [42]. Thus, our study confirms the importance of NAA as reliable biomarker for neuronal injury and disease progression.…”

Section: Resultssupporting

confidence: 83%

Ultra high-field (7tesla) magnetic resonance spectroscopy in Amyotrophic Lateral Sclerosis

Atassi

Triantafyllou

et al. 2017

PLoS ONE

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The main objective of this study was to utilize high field (7T) in vivo proton magnetic resonance imaging to increase the ability to detect metabolite changes in people with ALS, specifically, to quantify levels of glutamine and glutamine separately. The second objective of this study was to correlate metabolic markers with clinical outcomes of disease progression. 13 ALS participants and 12 age-matched healthy controls (HC) underwent 7 Tesla MRI and MRS. Single voxel MR spectra were acquired from the left precentral gyrus using a very short echo time (TE = 5 ms) STEAM sequence. MRS data was quantified using LCModel and correlated to clinical outcome markers. N-acetylaspartate (NAA) and total NAA (tNA, NAA + NAAG) were decreased by 17% in people with ALS compared to HC (P = 0.004 and P = 0.005, respectively) indicating neuronal injury and/or loss in the precentral gyrus. tNA correlated with disease progression as measured by forced vital capacity (FVC) (P = 0.014; Rρ = 0.66) and tNA/tCr correlated with overall functional decline as measured by worsening of the ALS Functional Rating Scale-Revised (ALSFRS-R) (P = 0.004; Rρ = -0.74). These findings underscore the importance of NAA as a reliable biomarker for neuronal injury and disease progression in ALS. Glutamate (Glu) was 15% decreased in people with ALS compared to HC (P = 0.02) while glutamine (Gln) concentrations were similar between the two groups. Furthermore, the decrease in Glu correlated with the decrease in FVC (P = 0.013; Rρ = 0.66), a clinical marker of disease progression. The decrease in Glu is most likely driven by intracellular Glu loss due to neuronal loss and degeneration. Neither choline containing components (Cho), a marker for cell membrane turnover, nor myo-Inositol (mI), a suspected marker for neuroinflammation, showed significant differences between the two groups. However, mI/tNA was correlated with upper motor neuron burden (P = 0.004, Rρ = 0.74), which may reflect a relative increase of activated microglia around motor neurons. In summary, 7T 1H MRS is a powerful non-invasive imaging technique to study molecular changes related to neuronal injury and/or loss in people with ALS.

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Section: Resultssupporting

confidence: 83%

Ultra high-field (7tesla) magnetic resonance spectroscopy in Amyotrophic Lateral Sclerosis

Atassi

Triantafyllou

et al. 2017

PLoS ONE

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“…39 A number of studies have also explored correlations between NAA and clinical scales, and have reported significant associations between NAA levels and revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) scores, 37,38,47,51 UMN disease burden, 37,44,52 Norris Scale scores, 36,42 finger-tapping rate, 38 hand strength, 38 disease duration, 47 and rate of disease progression. 34 Taken together, these results point to a reduction in neuronal integrity in the motor cortex in ALS.…”

Section: Advanced Neuroimaging In Alsmentioning

confidence: 81%

“…34–46 Evidence is conflicting as to whether these changes occur early in clinically evident disease: one study reported decreases in NAA:Cr ratios at a mean disease duration of 6.5 months, 47 whereas another study reported no significant differences in NAA levels in patients diagnosed with ALS within the past year. 48 …”

Section: Advanced Neuroimaging In Alsmentioning

confidence: 99%

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25 years of neuroimaging in amyotrophic lateral sclerosis

2013

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Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease for which a precise cause has not yet been identified. Standard CT or MRI evaluation does not demonstrate gross structural nervous system changes in ALS, so conventional neuroimaging techniques have provided little insight into the pathophysiology of this disease. Advanced neuroimaging techniques—such as structural MRI, diffusion tensor imaging and proton magnetic resonance spectroscopy—allow evaluation of alterations of the nervous system in ALS. These alterations include focal loss of grey and white matter and reductions in white matter tract integrity, as well as changes in neural networks and in the chemistry, metabolism and receptor distribution in the brain. Given their potential for investigation of both brain structure and function, advanced neuroimaging methods offer important opportunities to improve diagnosis, guide prognosis, and direct future treatment strategies in ALS. In this article, we review the contributions made by various advanced neuroimaging techniques to our understanding of the impact of ALS on different brain regions, and the potential role of such measures in biomarker development.

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“…This notion is consistent with previous studies using advance brain imaging techniques that showed decreased activity in various brain regions, including the thalamus in ALS patients. [29][30][31][32][33][34] Considering that a number of thalamic nuclei project their axons to motor cortical areas, 35 alteration of thalamic network activity caused by ALS-associated mutations may alter the electrical input received by motor neuronal structures, which may eventually cause an alteration of motor movement control. Alteration in T-type channel resulting in a loss of function can also alter the balance between excitatory and inhibitory neuronal networks.…”

Section: Discussionmentioning

confidence: 99%

CACNA1Hmissense mutations associated with amyotrophic lateral sclerosis alter Ca_v3.2 T-type calcium channel activity and reticular thalamic neuron firing

et al. 2016

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Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects nerve cells in the brain and the spinal cord. In a recent study by Steinberg and colleagues, 2 recessive missense mutations were identified in the Ca v 3.2 T-type calcium channel gene (CACNA1H), in a family with an affected proband (early onset, long duration ALS) and 2 unaffected parents. We have introduced and functionally characterized these mutations using transiently expressed human Ca v 3.2 channels in tsA-201 cells. Both of these mutations produced mild but significant changes on T-type channel activity that are consistent with a loss of channel function. Computer modeling in thalamic reticular neurons suggested that these mutations result in decreased neuronal excitability of thalamic structures. Taken together, these findings implicate CACNA1H as a susceptibility gene in amyotrophic lateral sclerosis.

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Degeneration of the Mid-Cingulate Cortex in Amyotrophic Lateral Sclerosis Detected In Vivo with MR Spectroscopy

Abstract: BACKGROUND AND PURPOSE:Various lines of evidence implicate cerebral involvement beyond the motor cortex in ALS, including the cingulate gyrus and the thalamus. The purpose of this study was to assess neurodegeneration in these regions in vivo by using MRSI.

Cited by 26 publications

References 49 publications

Ultra high-field (7tesla) magnetic resonance spectroscopy in Amyotrophic Lateral Sclerosis

Ultra high-field (7tesla) magnetic resonance spectroscopy in Amyotrophic Lateral Sclerosis

25 years of neuroimaging in amyotrophic lateral sclerosis

CACNA1Hmissense mutations associated with amyotrophic lateral sclerosis alter Ca_v3.2 T-type calcium channel activity and reticular thalamic neuron firing

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Degeneration of the Mid-Cingulate Cortex in Amyotrophic Lateral Sclerosis Detected In Vivo with MR Spectroscopy

Abstract: BACKGROUND AND PURPOSE:Various lines of evidence implicate cerebral involvement beyond the motor cortex in ALS, including the cingulate gyrus and the thalamus. The purpose of this study was to assess neurodegeneration in these regions in vivo by using MRSI.

Cited by 26 publications

References 49 publications

Ultra high-field (7tesla) magnetic resonance spectroscopy in Amyotrophic Lateral Sclerosis

Ultra high-field (7tesla) magnetic resonance spectroscopy in Amyotrophic Lateral Sclerosis

25 years of neuroimaging in amyotrophic lateral sclerosis

CACNA1Hmissense mutations associated with amyotrophic lateral sclerosis alter Cav3.2 T-type calcium channel activity and reticular thalamic neuron firing

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CACNA1Hmissense mutations associated with amyotrophic lateral sclerosis alter Ca_v3.2 T-type calcium channel activity and reticular thalamic neuron firing