Early Alzheimer's Disease Neuropathology Detected by Proton MR Spectroscopy

Murray, Melissa E.; Przybelski, Scott A.; Lesnick, Timothy G.; Liesinger, Amanda M.; Spychalla, Anthony J.; Zhang, Bing; Gunter, Jeffrey L.; Parisi, Joseph E.; Boeve, Bradley F.; Knopman, David S.; Petersen, Ronald C.; Jack, Clifford R.; Dickson, Dennis W.; Kantarci, Kejal

doi:10.1523/jneurosci.2027-14.2014

Cited by 112 publications

(128 citation statements)

References 51 publications

(28 reference statements)

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“…3). In particular, the tNAA/mIns ratio was significantly lower in these areas in affected subjects compared to healthy controls and suggests neurodegenerative changes [8,51]. Importantly, we also observed that the levels of NAA, mIns, and Glu depend on diagnostic categories as defined by El Escorial criteria (Fig.…”

Section: Discussionsupporting

confidence: 53%

Ultra-High Field Proton MR Spectroscopy in Early-Stage Amyotrophic Lateral Sclerosis

et al. 2017

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A major hurdle in the development of effective treatments for amyotrophic lateral sclerosis (ALS) has been the lack of robust biomarkers for use as clinical trial endpoints. Neurochemical profiles obtained in vivo by high field proton magnetic resonance spectroscopy (1H-MRS) can potentially provide biomarkers of cerebral pathology in ALS. However, previous 1H-MRS studies in ALS have produced conflicting findings regarding alterations in the levels of neurochemical markers such as glutamate (Glu) and myo-inositol (mIns). Furthermore, very few studies have investigated the neurochemical abnormalities associated with ALS early in its course. In this study, we measured neurochemical profiles using single-voxel 1H-MRS at 7 tesla (T) and glutathione (GSH) levels using edited MRS at 3 T in 19 subjects with ALS who had relatively high functional status (ALS Functional Rating Scale-Revised mean ± SD = 39.8 ± 5.6) and 17 healthy controls. We observed significantly lower total N-acetylaspartate over mIns (tNAA/mIns) ratio in the motor cortex and pons of subjects with ALS versus healthy controls. No group differences were detected in GSH at 3 and 7 T. In subjects with ALS, the levels of tNAA, mIns, and Glu in the motor cortex were dependent on the extent of disease represented by El Escorial diagnostic subcategories. Specifically, combined probable/definite ALS had lower tNAA than possible ALS and controls (both p = 0.03), higher mIns than controls (p < 0.01), and lower Glu than possible ALS (p < 0.01). The effect of disease stage on MRS-measured metabolite levels may account for dissimilar findings among previous 1H-MRS studies in ALS.

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Section: Discussionsupporting

confidence: 53%

Ultra-High Field Proton MR Spectroscopy in Early-Stage Amyotrophic Lateral Sclerosis

et al. 2017

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“…By contrast, SUVr in the striatum and thalamus of Tg mice was significantly elevated at age 3.5 mo and progressively elevated thereafter. These findings are consistent with previous functional MRI studies of brain regions vulnerable to AD [17,18,19] and imply that the entorhinal cortex and hippocampus can be target sites for AD detection via glucose metabolism.…”

Section: Discussionsupporting

confidence: 92%

“…The hippocampus was selected because it is closely related with learning and memory formation and its damage is thought to vitally involve the AD process. Also, studies have shown that the hippocampus is an initial site of Aβ accumulation and neuronal damage [19,34], offering a pathologic basis for AD-related cognitive deficits. Once hippocampal damage reaches a certain level, resulting learning and memory deficits can be evaluated by the MWM in mice.…”

Section: Discussionmentioning

confidence: 99%

Age- and Brain Region-Specific Changes of Glucose Metabolic Disorder, Learning, and Memory Dysfunction in Early Alzheimer’s Disease Assessed in APP/PS1 Transgenic Mice Using 18F-FDG-PET

Men

Zhu

et al. 2016

IJMS

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Alzheimer’s disease (AD) is a leading cause of dementia worldwide, associated with cognitive deficits and brain glucose metabolic alteration. However, the associations of glucose metabolic changes with cognitive dysfunction are less detailed. Here, we examined the brains of APP/presenilin 1 (PS1) transgenic (Tg) mice aged 2, 3.5, 5 and 8 months using 18F-labed fluorodeoxyglucose (18F-FDG) microPET to assess age- and brain region-specific changes of glucose metabolism. FDG uptake was calculated as a relative standardized uptake value (SUVr). Morris water maze (MWM) was used to evaluate learning and memory dysfunction. We showed a glucose utilization increase in multiple brain regions of Tg mice at 2 and 3.5 months but not at 5 and 8 months. Comparisons of SUVrs within brains showed higher glucose utilization than controls in the entorhinal cortex, hippocampus, and frontal cortex of Tg mice at 2 and 3.5 months but in the thalamus and striatum at 3.5, 5 and 8 months. By comparing SUVrs in the entorhinal cortex and hippocampus, Tg mice were distinguished from controls at 2 and 3.5 months. In MWM, Tg mice aged 2 months shared a similar performance to the controls (prodromal-AD). By contrast, Tg mice failed training tests at 3.5 months but failed all MWM tests at 5 and 8 months, suggestive of partial or complete cognitive deficits (symptomatic-AD). Correlation analyses showed that hippocampal SUVrs were significantly correlated with MWM parameters in the symptomatic-AD stage. These data suggest that glucose metabolic disorder occurs before onset of AD signs in APP/PS1 mice with the entorhinal cortex and hippocampus affected first, and that regional FDG uptake increase can be an early biomarker for AD. Furthermore, hippocampal FDG uptake is a possible indicator for progression of Alzheimer’s cognition after cognitive decline, at least in animals.

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“…Results were comparable in models that did not include fCSF volume as a covariate. NAA is typically diminished in AD,17, 18 and this pattern held for this study ( F [2,75] = 7.231, P = 0.001; NAA was lower in the AD than in the younger CN ( P = 0.0003) and older CN groups ( P = 0.022). Metabolite ratios in the normal groups were consistent with those reported earlier in ProFit literature 24.…”

Section: Resultssupporting

confidence: 76%

“…Proton Magnetic Resonance Spectroscopy ( 1 H‐MRS) provides accurate noninvasive in vivo measures of a limited set of brain metabolites, and aspects of AD neuropathology have long been associated with consistent changes in certain metabolites within its sensitivity. Specifically, reductions in the neuronal marker N‐Acetyl Aspartate (NAA) have long been associated with neurodegeneration, and elevations in myo‐inositol (mI), have been associated with reactive astrocytosis 14, 17, 18. Despite its immediate relevance to metabolic dysfunction, glucose has rarely been mentioned in earlier MRS studies.…”

Section: Introductionmentioning

confidence: 99%

Magnetic resonance spectroscopy reveals abnormalities of glucose metabolism in the Alzheimer's brain

Mullins

Reiter

Kapogiannis

2018

Ann Clin Transl Neurol

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ObjectiveBrain glucose hypometabolism is a prominent feature of Alzheimer's disease (AD), and in this case–control study we used Magnetic Resonance Spectroscopy (MRS) to assess AD‐related differences in the posterior cingulate/precuneal ratio of glucose, lactate, and other metabolites.MethodsJ‐modulated Point‐Resolved Spectroscopy (J‐PRESS) and Prior‐Knowledge Fitting (ProFit) software was used to measure glucose and other metabolites in the posterior cingulate/precuneus of 25 AD, 27 older controls, and 27 younger control participants. Clinical assessments for AD participants included cognitive performance measures, insulin resistance metrics and CSF biomarkers.Results AD participants showed substantially elevated glucose, lactate, and ascorbate levels compared to older (and younger) controls. In addition, the precuneal glucose elevation discriminated well between AD participants and older controls. Myo‐inositol correlated with CSF p‐Tau181P, total Tau, and the Clinical Dementia Rating (CDR) sum‐of‐boxes score within the AD group.InterpretationHigher glucose to creatine ratios in the AD brain likely reflect lower glucose utilization. Our findings reveal pronounced metabolic abnormalities in the AD brain and strongly suggest that brain glucose merits further investigation as a candidate AD biomarker.

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Early Alzheimer's Disease Neuropathology Detected by Proton MR Spectroscopy

Abstract: Proton magnetic resonance spectroscopy ( 1 H-MRS) is sensitive to early neurodegenerative processes associated with Alzheimer's disease (AD).

Cited by 112 publications

References 51 publications

Ultra-High Field Proton MR Spectroscopy in Early-Stage Amyotrophic Lateral Sclerosis

Ultra-High Field Proton MR Spectroscopy in Early-Stage Amyotrophic Lateral Sclerosis

Age- and Brain Region-Specific Changes of Glucose Metabolic Disorder, Learning, and Memory Dysfunction in Early Alzheimer’s Disease Assessed in APP/PS1 Transgenic Mice Using 18F-FDG-PET

Magnetic resonance spectroscopy reveals abnormalities of glucose metabolism in the Alzheimer's brain

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