Adam D. Waldman

MRS shows abnormalities before symptoms in familial Alzheimer disease

Background: 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. Methods: 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. Results: 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. Conclusions: 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.

The relationship between cognitive impairment and in vivo metabolite ratios in patients with clinical Alzheimer's disease and vascular dementia: a proton magnetic resonance spectroscopy study.

Previous magnetic resonance spectroscopy (MRS) studies have shown increased myo-inositol (MI) and decreased N-acetyl aspartate (NAA) levels in the parieto-occipital lobes of patients with Alzheimers disease (AD) compared to those with other dementias and normal subjects. This study aimed to establish the quantitative relationship between metabolite ratios and degree of cognitive impairment in patients with mild to moderate AD and sub-cortical ischaemic vascular dementia (SIVD). Forty-four older people with clinical dementia were recruited from a memory clinic and followed up for 2.0–3.5 years; 20 cases were finally classified as probable AD, 18 as SIVD and 6 as mixed type. Mini Mental State Examination (MMSE) and short echo time single voxel automated MRS from the mesial parieto-occipital lobes were performed at the time of initial referral. Spearman rank correlation coefficients were calculated for MMSE scores and measured metabolite ratios MI/Cr, NAA/Cr, Cho/Cr and NAA/MI. The AD group showed a significant correlation between MMSE and NAA/MI (r=0.54, P=0.014) and NAA/Cr (r=0.48, P=0.033), and a negative, non-significant association with MI/Cr (r=−0.41, P=0.072). MI/Cr was negatively correlated with NAA/Cr (r=−0.51, P=0.021). Neither Cho/Cr ratios nor age correlated with cognitive function. The SIVD group showed no correlation between any of the measured metabolite ratios and MMSE score. This study reinforces the specific association between reduced NAA and increased MI levels in the parieto-occipital region and cognitive impairment in AD. MRS may have a role in evaluating disease progression and therapeutic monitoring in AD, as new treatments become available.

Quantitative Analysis of Whole-Tumor Gd Enhancement Histograms Predicts Malignant Transformation in Low-Grade Gliomas

To quantify subtle gadolinium (Gd) enhancement (signal increase) in whole‐tumor histograms and optimize their ability to predict subsequent malignant transformation in low‐grade gliomas (LGGs).

Inclusion or exclusion of intratumoral vessels in relative cerebral blood volume characterization in low-grade gliomas: does it make a difference?

SUMMARY: We assessed the influence of inclusion (method 1) and exclusion (method 2) of intratumoral vessels when determining maximum relative cerebral blood volume (rCBVmax) in 3 types of low-grade gliomas (LGGs): astrocytomas, oligoastrocytomas, and oligodendrogliomas. Method 1 yielded significantly higher mean rCBVmax than method 2. However, only method 2 demonstrated a significant (P = .026) association between rCBVmax and membership of a differently ranked histologic category. Exclusion of intratumoral vessels appears, therefore, preferable when determining rCBVmax in LGGs.

Regional brain metabolite abnormalities in inherited prion disease and asymptomatic gene carriers demonstrated in vivo by quantitative proton magnetic resonance spectroscopy

IntroductionInherited prion diseases are caused by mutations in the gene which codes for prion protein (PrP), leading to proliferation of abnormal PrP isomers in the brain and neurodegeneration; they include Gerstmann–Sträussler–Scheinker disease (GSS), fatal familial insomnia (FFI) and familial Creutzfeldt–Jakob disease (fCJD).MethodsWe studied two patients with symptomatic inherited prion disease (P102L) and two pre-symptomatic P102L gene carriers using quantitative magnetic resonance spectroscopy (MRS). Short echo time spectra were acquired from the thalamus, caudate region and frontal white matter, metabolite levels and ratios were measured and z-scores calculated for individual patients relative to age-matched normal controls. MRS data were compared with structural magnetic resonance imaging.ResultsOne fCJD case had generalised atrophy and showed increased levels of myo-inositol (MI) in the thalamus (z=3.7). The other had decreased levels of N-acetylaspartate (z=4) and diffuse signal abnormality in the frontal white matter. Both asymptomatic gene carriers had normal imaging, but increased frontal white matter MI (z=4.3, 4.1), and one also had increased MI in the caudate (z=5.3).ConclusionIsolated MI abnormalities in asymptomatic gene carriers are a novel finding and may reflect early glial proliferation, prior to significant neuronal damage. MRS provides potential non-invasive surrogate markers of early disease and progression in inherited prion disease.

Short TE Quantitative Proton Magnetic Resonance Spectroscopy in Variant Creutzfeldt-Jakob Disease

Variant Creutzfeldt-Jakob disease (vCJD) is a fatal neurodegerative disorder. Clinical diagnosis is difficult in the early stages as the disease often presents with non-specific psychiatric and neurological symptoms. To investigate the diagnostic potential of quantitative short TE in vivo MRS, and the nature and anatomical distribution of biochemical abnormalities in vCJD, localised single-voxel spectra (TE/TR 30xa0ms/2,000xa0ms) were acquired from three brain regions: thalami, caudate nuclei and frontal white matter. Metabolite concentrations and ratios from three patients with definite or probable vCJD were compared with eight normal age-matched controls. Abnormal signal on T2-weighted MRI was apparent in the pulvinar region in all vCJD patients; this region also showed greatly increased myo-inositol [MI] (mean 2.5-fold, P=0.01) and decreased N-acetyl-aspartate (NAA; mean 2-fold, P=0.01). Two patients also showed increased [MI] (z=17, 11; one with decreased NAA, z=-12) in normal-appearing caudate nuclei. The magnitude of metabolite abnormalities in the thalami in moderately advanced vCJD suggests a potential role in earlier diagnosis. Short TE protocols allow the measurement of MI, which adds discriminant power to the MRS examination.

Rapid echoplanar diffusion imaging in a case of variant Creutzfeldt-Jakob disease; where speed is of the essence

Neuroimaging with magnetic resonance imaging (MRI) is important in the diagnosis of Creutzfeldt-Jakob disease (CJD), but is frequently frustrated by patient movement. Diffusion-weighted imaging (DWI) has previously shown markedly restricted diffusion in grey matter structures of patients with CJD, and may add to diagnostic sensitivity. Echoplanar imaging (EPI) sequences, which are usually used for DWI, are also very rapid, and typically allow imaging of the whole brain in less than 1xa0min. A case of histologically proven variant CJD (vCJD) in which conventional MRI was difficult to interpret confidently owing to motion artefact, but EPI was diagnostic, emphasises the utility of rapid imaging in agitated patients. Comparison of the regional quantitative apparent diffusion coefficient (ADC) with a control group (n=5) showed restricted diffusion in the caudate (vCJD: 0.63×10−3xa0mm2/s; controls: mean 0.722×10−3 mm2/s, SD 0.017) and lentiform (vCJD: 0.65×10−3xa0mm2/s; controls: mean 0.707×10−3xa0mm2/s, SD 0.011) nuclei. T2 effects dominated the signal abnormality on DWI in the pulvinar; ADC was increased (vCJD: 0.87–0.95×10−3xa0mm2/s; controls: mean 0.773×10−3xa0mm2/s, SD 0.038). Our data emphasise variation in diffusion patterns in vCJD, and illustrate the value in using all the components available from the DWI examination for maximum diagnostic information. EPI-DWI provides both rapid T2- and diffusion-dependent information, and is recommended for those patients in whom confusion and agitation is likely to confound standard MRI protocols.