MRS shows abnormalities before symptoms in familial Alzheimer disease

Dementia Research Centre, Institute of Neurology, University College of London, London, UK.
Neurology (Impact Factor: 8.29). 04/2006; 66(5):718-22. DOI: 10.1212/01.wnl.0000201237.05869.df
Source: PubMed


Pathologic change in Alzheimer disease (AD) begins some years before symptoms. MRS has the potential to detect metabolic abnormalities reflecting this early pathologic change. Presenilin 1 (PS1) and amyloid precursor protein (APP) mutation carriers have a nearly 100% risk of developing AD and may be studied prior to symptom onset.
Short echo time proton MR spectra were acquired from a midline posterior cingulate voxel in presymptomatic carriers of PS1 or APP mutations ("presymptomatic mutation carriers" [PMCs]; n = 7) and age- and sex-matched control subjects (n = 6). Ratios of N-acetyl aspartate (NAA), myo-inositol (MI), and choline-containing compounds (Cho) to creatine (Cr) were measured and NAA/MI calculated. Regression analyses and t tests were performed after log transformation.
PMC and control subjects were matched for age and sex. PMC subjects were 1.7 to 21.6 years (mean 9.8 years) before expected symptom onset, predicted from family-specific mean age at onset. Age did not significantly affect metabolite ratios. Geometric mean ratios in control subjects were as follows: NAA/Cr = 1.75, MI/Cr = 0.59, and NAA/MI = 2.95. NAA/Cr and NAA/MI were significantly reduced in PMC relative to controls (NAA/Cr mean decrease 10% [95% CI 2 to 18%]; NAA/MI mean decrease 25% [95% CI 3 to 44%]). MI/Cr was increased in PMC, but the differences did not achieve significance (19% increase [95% CI 1% decrease to 41% increase]; p = 0.07)). In PMCs, reduction in NAA/MI (p = 0.001) and MI/Cr (p = 0.002) were related to proximity of expected age at onset.
Metabolic changes are detectable in presymptomatic mutation carriers years before expected onset of Alzheimer disease. Their magnitude is related to proximity of expected age at onset.

9 Reads
  • Source
    • "The metabolite formula changes in preclinical familial AD families with amyloid precursor protein, presenilin 1 or 2 mutations. Asymptomatic mutation carriers demonstrated elevated mI/Cr and decreased NAA/Cr with reduction in NAA/mI correlating with nearness to age of onset.92 In addition to serving as a marker of preclinical disease, MRS has utility in monitoring disease progression. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Aging is the primary risk factor for dementia. With increasing life expectancy and aging populations worldwide, dementia is becoming one of the significant public health problems of the century. The most common pathology underlying dementia in older adults is Alzheimer's disease. Proton magnetic resonance spectroscopy (MRS) may provide a window into the biochemical changes associated with the loss of neuronal integrity and other neurodegenerative pathology that involve the brain before the manifestations of cognitive impairment in patients who are at risk for Alzheimer's disease. This review focuses on proton MRS studies in normal aging, mild cognitive impairment, and dementia, and how proton MRS metabolite levels may be potential biomarkers for early diagnosis of dementia-related pathologic changes in the brain.
    Neuropsychiatric Disease and Treatment 05/2013; 9:687-96. DOI:10.2147/NDT.S35440 · 1.74 Impact Factor
  • Source
    • "Clinically defined normal, MCI, and AD patients (MMSE normal = 28–30, MCI = 23–27, AD < 23) was accompanied by reduction in NAA/mI (−36% ± 0.05; P = 0.01) as previously described.5 "
    [Show abstract] [Hide abstract]
    ABSTRACT: We applied (13)C magnetic resonance spectroscopy (MRS), a nonradioactive, noninvasive brain imaging technique, to quantify the oxidation of [1-(13)C] acetate in a conventional clinical magnetic resonance imaging (MRI) scanner in five consecutive elderly subjects at various clinical stages of Alzheimer's disease (AD) progression. [1-(13)C] acetate entered the brain and was metabolized to [5-(13)C] glutamate and glutamine, as well as [1-(13)C] glutamate and glutamine, and the final glial oxidation product, (13)C bicarbonate, at a linear rate. Calculation of the initial slope was similar in a single subject, examined twice, 1 month apart (test-re-test 8%). Mean rate of cerebral bicarbonate production in this elderly group was 0.040 ± 0.01 (n = 5). Assuming that the rate of conversion of acetate to bicarbonate is a reflection of glial metabolic rate and that glial metabolic rate is a surrogate marker for 'neuroinflammation', our preliminary results suggest that [1-(13)C] MRS may provide biomarkers for diseases, believed to involve microglia and other cells of the astrocyte series. Among these is AD, for which novel drugs which ameliorate the damaging effects of neuroinflammation before symptoms of dementia appear, are in advanced development. The value of (13)C MRS as an early, noninvasive biomarker may lie in the conduct of cost-effective clinical trials.
    Neuropsychiatric Disease and Treatment 08/2011; 7(1):495-9. DOI:10.2147/NDT.S23721 · 1.74 Impact Factor
  • Source
    • "Prior studies have shown that levels of the neuronal integrity markers N-acetylaspartate (NAA) and NAA/Cr, as assessed by 1 H MRS, are lower in AD patients compared to healthy elderly individuals, and that decreased NAA/Cr levels can predict future conversion from MCI to AD (Chao et al., 2005; Metastasio et al., 2006). Previous studies have investigated 1 H MRS imaging of specific regions of the brain in patients with AD (Godbolt et al., 2006; Jessen et al., 2009). In one study, decreased NAA levels were found in the cortical gray matter of individuals with AD, relative to control subjects (Adalsteinsson et al., 2000). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Single-volume proton magnetic resonance spectroscopy (1H MRS) has considerable diagnostic potential for Alzheimer's disease (AD). This study investigated 1H MRS in specific regions of the brain, the posterior cingulate gyri (PCG) and the hippocampus, in patients with AD, amnestic mild cognitive impairment (aMCI), and in normal control subjects. 1H MRS analysis was carried out on 47 patients with AD, 32 patients with aMCI and 56 normal control subjects (NC group). Volumes of the PCG and hippocampus were assessed, and the metabolic signals of N-acetylaspartate (NAA), choline compounds (Cho), myo-inositol (mI), and creatine (Cr) were quantified. In the PCG, differences between the test groups were found in NAA/Cr, Cho/Cr, mI/Cr and NAA/mI ratios. Group differences were also found in mI/Cr and NAA/mI ratios in the left hippocampus, and in mI/Cr and NAA/mI ratios in the right hippocampus. NAA/Cr ratios increased in the PCG between AD and aMCI patients, and between aMCI and NC patients. Conversely, mI/Cr ratios in the PCG and left hippocampus decreased across AD, aMCI, and NC subjects. In discriminate and ROC (Receiver Operating Characteristic) analyses, a NAA/Cr ratio of ≤ 1.50 in the PCG indicated optimal potential for discriminating between aMCI patients and normal control subjects. Discriminating potential was also found to be high for a NAA/mI ratio in the PCG of ≤ 2.72. Despite significant differences between NC and aMCI patients in the mI/Cr ratio in the PCG and in the NAA/mI ratio in the left hippocampus, their sensitivity and specificity were all lower than 75%. Proton MRS of the PCG using the NAA/Cr ratio as a metabolic marker indicates considerable potential for distinguishing between aMCI and NC subjects.
    International Psychogeriatrics 06/2011; 24(1):19-27. DOI:10.1017/S1041610211000962 · 1.93 Impact Factor
Show more