PhD student, University of Cambridge/ Radiology
Level of brain metabolites in MRS have distinct relationship with amyloid and hypometabolism in AD
Alzheimer’s disease (AD) is the most common type of dementia affecting more than 850,000 people in the UK in 2015 and costing NHS around £26 billion. Diagnosis of Alzheimer at an early stage, particularly in day to day clinical practice, is challenging. Available imaging techniques such as routine MRI or CT are not sensitive enough for the diagnosis. On the other hand, more advanced methods like Positron Emission Tomography (PET) are very expensive and need specialised facilities. Therefore, they cannot be offered in the routine clinical practice. The aim of this study is to determine if MR spectroscopy can improve early diagnosis of AD in clinical practice. MRS is a non-invasive, available and relatively cheap technique used for measuring the level of different brain chemicals. We hypothesized that the level of these chemicals is a good representative of underlying pathological changes. To test this hypothesis, we correlated the levels of of these MRS derived chemicals with findings of two types of PET scans. These PET scans are the current gold standard for measuring brain activity and levels of the main abnormal protein that accumulates in AD (amyloid). To our knowledge this study is the first of its kind. Our study showed that the changes in the level of brain chemicals measured by MRS are strongly correlated with PET results. We found that level of Myoinositol (one of the measured chemicals) is highly associated with the level of Amyloid. Another chemical called N-acetylaspartate was significantly associated with brain activity that goes down in Alzheimer’s disease. Based on our findings MRS, an available and cheap technique, has the potential of improving the accuracy of AD diagnosis in daily clinical practice and outside specialized centers.
Abstract: To determine the relationship between proton magnetic resonance spectroscopy ((1)H MRS) metabolites and β-amyloid (Aβ) load and the effects of Aβ load on the association between (1)H MRS metabolites and cognitive function in cognitively normal older adults.We studied 311 cognitively normal older adults who participated in the population-based Mayo Clinic Study of Aging from January 2009 through September 2010. Participants underwent (11)C-Pittsburgh compound B (PiB) PET, (1)H MRS from the posterior cingulate gyri, and neuropsychometric testing to assess memory, attention/executive, language, and visual-spatial domain functions within 6 months. Partial Spearman rank order correlations were adjusted for age, sex, and education.Higher PiB retention was associated with abnormal elevations in myoinositol (mI)/creatine (Cr) (partial r(s) = 0.17; p = 0.003) and choline (Cho)/Cr (partial r(s) = 0.13; p = 0.022) ratios. Higher Cho/Cr was associated with worse performance on Auditory Verbal Learning Test Delayed Recall (partial r(s) = -0.12; p = 0.04), Trail Making Test Part B (partial r(s) = 0.12; p = 0.04), Wechsler Adult Intelligence Scale-Revised (WAIS-R) Digit Symbol (partial r(s) = -0.18; p < 0.01), and WAIS-R Block Design (partial r(s) = -0.12; p = 0.03). Associations between (1)H MRS metabolites and cognitive function were not different among participants with high vs low PiB retention.In cognitively normal older adults, the (1)H MRS metabolite ratios mI/Cr and Cho/Cr are associated with the preclinical pathologic processes in the Alzheimer disease cascade. Higher Cho/Cr is associated with worse performance on domain-specific cognitive tests independent of Aβ load, suggesting that Cho/Cr elevation may also be dependent on other preclinical dementia pathologies characterized by Cho/Cr elevation such as Lewy body or ischemic vascular disease in addition to Aβ load.
Pub.: 26 Aug '11, Pinned: 28 Jun '17
Abstract: We aimed to test whether in vivo levels of magnetic resonance spectroscopy (MRS) metabolites myo-inositol (mI), N-acetylaspartate (NAA), and choline are abnormal already during preclinical Alzheimer disease (AD), relating these changes to amyloid or tau pathology, and functional connectivity.In this cross-sectional multicenter study (a subset of the prospective Swedish BioFINDER study), we included 4 groups, representing the different stages of predementia AD: (1) cognitively healthy elderly with normal CSF β-amyloid 42 (Aβ42), (2) cognitively healthy elderly with abnormal CSF Aβ42, (3) patients with subjective cognitive decline and abnormal CSF Aβ42, (4) patients with mild cognitive decline and abnormal CSF Aβ42 (Ntotal = 352). Spectroscopic markers measured in the posterior cingulate/precuneus were considered alongside known disease biomarkers: CSF Aβ42, phosphorylated tau, total tau, [(18)F]-flutemetamol PET, f-MRI, and the genetic risk factor APOE.Amyloid-positive cognitively healthy participants showed a significant increase in mI/creatine and mI/NAA levels compared to amyloid-negative healthy elderly (p < 0.05). In amyloid-positive healthy elderly, mI/creatine and mI/NAA correlated with cortical retention of [(18)F] flutemetamol tracer ([Formula: see text] = 0.44, p = 0.02 and [Formula: see text] = 0.51, p = 0.01, respectively). Healthy elderly APOE ε4 carriers with normal CSF Aβ42 levels had significantly higher mI/creatine levels (p < 0.001) than ε4 noncarriers. Finally, elevated mI/creatine was associated with decreased functional connectivity within the default mode network (rpearson = -0.16, p = 0.02), independently of amyloid pathology.mI levels are elevated already at asymptomatic stages of AD. Moreover, mI/creatine concentrations were increased in healthy APOE ε4 carriers with normal CSF Aβ42 levels, suggesting that mI levels may reveal regional brain consequences of APOE ε4 before detectable amyloid pathology.
Pub.: 11 May '16, Pinned: 28 Jun '17
Abstract: Proton magnetic resonance spectroscopy ((1)H-MRS) is sensitive to early neurodegenerative processes associated with Alzheimer's disease (AD). Although (1)H-MRS metabolite ratios of N-acetyl aspartate (NAA)/creatine (Cr), NAA/myoinositol (mI), and mI/Cr measured in the posterior cingulate gyrus reveal evidence of disease progression in AD, pathologic underpinnings of the (1)H-MRS metabolite changes in AD are unknown. Pathologically diagnosed human cases ranging from no likelihood to high likelihood AD (n = 41, 16 females and 25 males) who underwent antemortem (1)H-MRS of the posterior cingulate gyrus at 3 tesla were included in this study. Immunohistochemical evaluation was performed on the posterior cingulate gyrus using antibodies to synaptic vesicles, hyperphosphorylated tau (pTau), neurofibrillary tangle conformational-epitope (cNFT), amyloid-β, astrocytes, and microglia. The slides were digitally analyzed using Aperio software, which allows neuropathologic quantification in the posterior cingulate gray matter. MRS and pathology associations were adjusted for time from scan to death. Significant associations across AD and control subjects were found between reduced synaptic immunoreactivity and both NAA/Cr and NAA/mI in the posterior cingulate gyrus. Higher pTau burden was associated with lower NAA/Cr and NAA/mI. Higher amyloid-β burden was associated with elevated mI/Cr and lower NAA/mI ratios, but not with NAA/Cr. (1)H-MRS metabolite levels reveal early neurodegenerative changes associated with AD pathology. Our findings support the hypothesis that a decrease in NAA/Cr is associated with loss of synapses and early pTau pathology, but not with amyloid-β or later accumulation of cNFT pathology in the posterior cingulate gyrus. In addition, elevation of mI/Cr is associated with the occurrence of amyloid-β plaques in AD.
Pub.: 05 Dec '14, Pinned: 28 Jun '17
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