Maria M. Shiung

Serial PIB and MRI in normal, mild cognitive impairment and Alzheimer's disease: implications for sequence of pathological events in Alzheimer's disease

The purpose of this study was to use serial imaging to gain insight into the sequence of pathologic events in Alzheimers disease, and the clinical features associated with this sequence. We measured change in amyloid deposition over time using serial 11C Pittsburgh compound B (PIB) positron emission tomography and progression of neurodegeneration using serial structural magnetic resonance imaging. We studied 21 healthy cognitively normal subjects, 32 with amnestic mild cognitive impairment and 8 with Alzheimers disease. Subjects were drawn from two sources—ongoing longitudinal registries at Mayo Clinic, and the Alzheimers disease Neuroimaging Initiative (ADNI). All subjects underwent clinical assessments, MRI and PIB studies at two time points, approximately one year apart. PIB retention was quantified in global cortical to cerebellar ratio units and brain atrophy in units of cm3 by measuring ventricular expansion. The annual change in global PIB retention did not differ by clinical group (P = 0.90), and although small (median 0.042 ratio units/year overall) was greater than zero among all subjects (P < 0.001). Ventricular expansion rates differed by clinical group (P < 0.001) and increased in the following order: cognitively normal (1.3 cm3/year) <  amnestic mild cognitive impairment (2.5 cm3/year) <  Alzheimers disease (7.7 cm3/year). Among all subjects there was no correlation between PIB change and concurrent change on CDR-SB (r = −0.01, P = 0.97) but some evidence of a weak correlation with MMSE (r =−0.22, P = 0.09). In contrast, greater rates of ventricular expansion were clearly correlated with worsening concurrent change on CDR-SB (r = 0.42, P < 0.01) and MMSE (r =−0.52, P < 0.01). Our data are consistent with a model of typical late onset Alzheimers disease that has two main features: (i) dissociation between the rate of amyloid deposition and the rate of neurodegeneration late in life, with amyloid deposition proceeding at a constant slow rate while neurodegeneration accelerates and (ii) clinical symptoms are coupled to neurodegeneration not amyloid deposition. Significant plaque deposition occurs prior to clinical decline. The presence of brain amyloidosis alone is not sufficient to produce cognitive decline, rather, the neurodegenerative component of Alzheimers disease pathology is the direct substrate of cognitive impairment and the rate of cognitive decline is driven by the rate of neurodegeneration. Neurodegeneration (atrophy on MRI) both precedes and parallels cognitive decline. This model implies a complimentary role for MRI and PIB imaging in Alzheimers disease, with each reflecting one of the major pathologies, amyloid dysmetabolism and neurodegeneration.

MRI as a Biomarker of Disease Progression in a Therapeutic Trial of Milameline for AD

Objective: To assess the feasibility of using MRI measurements as a surrogate endpoint for disease progression in a therapeutic trial for AD. Methods: A total of 362 patients with probable AD from 38 different centers participated in the MRI portion of a 52-week randomized placebo-controlled trial of milameline, a muscarinic receptor agonist. The therapeutic trial itself was not completed due to projected lack of efficacy on interim analysis; however, the MRI arm of the study was continued. Of the 362 subjects who underwent a baseline MRI study, 192 subjects underwent a second MRI 1 year later. Hippocampal volume and temporal horn volume were measured from the MRI scans. Results: The annualized percent changes in hippocampal volume (−4.9%) and temporal horn volume (16.1%) in the study patients were consistent with data from prior single-site studies. Correlations between the rate of MRI volumetric change and change in behavioral/cognitive measures were greater for the temporal horn than for the hippocampus. Decline over time was more consistently seen with imaging measures, 99% of the time for the hippocampus, than behavioral/cognitive measures (p < 0.001). Greater consistency in MRI than behavioral/clinical measures resulted in markedly lower estimated sample size requirements for clinical trials. The estimated number of subjects per arm required to detect a 50% reduction in the rate of decline over 1 year are: AD Assessment Scale–cognitive subscale 320; Mini-Mental Status Examination 241; hippocampal volume 21; temporal horn volume 54. Conclusion: The consistency of MRI measurements obtained across sites, and the consistency between the multisite milameline data and that obtained in prior single-site studies, demonstrate the technical feasibility of using structural MRI measures as a surrogate endpoint of disease progression in therapeutic trials. However, validation of imaging as a biomarker of therapeutic efficacy in AD awaits a positive trial.

MRI patterns of atrophy associated with progression to AD in amnestic Mild Cognitive Impairment

Objective: To compare the patterns of gray matter loss in subjects with amnestic mild cognitive impairment (aMCI) who progress to Alzheimer disease (AD) within a fixed clinical follow-up time vs those who remain stable. Methods: Twenty-one subjects with aMCI were identified from the Mayo Clinic Alzheimers research program who remained clinically stable for their entire observed clinical course (aMCI-S), where the minimum required follow-up time from MRI to last follow-up assessment was 3 years. These subjects were age- and gender-matched to 42 aMCI subjects who progressed to AD within 18 months of the MRI (aMCI-P). Each subject was then age- and gender-matched to a control subject. Voxel-based morphometry (VBM) was used to assess patterns of gray matter atrophy in the aMCI-P and aMCI-S groups compared to the control group, and compared to each other. Results: The aMCI-P group showed bilateral loss affecting the medial and inferior temporal lobe, temporoparietal association neocortex, and frontal lobes, compared to controls. The aMCI-S group showed no regions of gray matter loss when compared to controls. When the aMCI-P and aMCI-S groups were compared directly, the aMCI-P group showed greater loss in the medial and inferior temporal lobes, the temporoparietal neocortex, posterior cingulate, precuneus, anterior cingulate, and frontal lobes than the aMCI-S group. Conclusions: The regions of loss observed in subjects with amnestic mild cognitive impairment (aMCI) who progressed to Alzheimer disease (AD) within 18 months of the MRI are typical of subjects with AD. The lack of gray matter loss in subjects with aMCI who remained clinically stable for their entire observed clinical course is consistent with the notion that patterns of atrophy on MRI at baseline map well onto the subsequent clinical course. GLOSSARY: AD = Alzheimer disease; ADNI = Alzheimers Disease Neuroimaging Initiative; ADPR = Alzheimers Disease Patient Registry; ADRC = Mayo Clinic Alzheimers Disease Research Center; aMCI = amnestic mild cognitive impairment; APOE e4 = apolipoprotein epsilon 4; AVLT = Auditory Verbal Learning Test; CDR-SB = CDR sum of boxes; DCT = discrete cosine transformation; FDR = false discovery rate; FWHM = full-width at half-maximum; GM = gray matter; MMSE = Mini-Mental State Examination; MNI = Montreal Neurological Institute; NIA = National Institute on Aging; TIV = total intracranial volume; VBM = voxel-based morphometry; WM = white matter; WMH = white matter hyperintensity.

DWI predicts future progression to Alzheimer disease in amnestic mild cognitive impairment

The authors assessed whether measures of hippocampal water diffusivity at baseline can predict future progression to Alzheimer disease (AD) in amnestic mild cognitive impairment (aMCI). Higher baseline hippocampal diffusivity was associated with a greater risk of progression to AD in aMCI (p = 0.002). Magnetic resonance diffusion-weighted imaging may help identify patients with aMCI who will progress to AD as well as or better than structural MRI measures of hippocampal atrophy.

Distinct anatomical subtypes of the behavioural variant of frontotemporal dementia: a cluster analysis study

The behavioural variant of frontotemporal dementia is a progressive neurodegenerative syndrome characterized by changes in personality and behaviour. It is typically associated with frontal lobe atrophy, although patterns of atrophy are heterogeneous. The objective of this study was to examine case-by-case variability in patterns of grey matter atrophy in subjects with the behavioural variant of frontotemporal dementia and to investigate whether behavioural variant of frontotemporal dementia can be divided into distinct anatomical subtypes. Sixty-six subjects that fulfilled clinical criteria for a diagnosis of the behavioural variant of frontotemporal dementia with a volumetric magnetic resonance imaging scan were identified. Grey matter volumes were obtained for 26 regions of interest, covering frontal, temporal and parietal lobes, striatum, insula and supplemental motor area, using the automated anatomical labelling atlas. Regional volumes were divided by total grey matter volume. A hierarchical agglomerative cluster analysis using Wards clustering linkage method was performed to cluster the behavioural variant of frontotemporal dementia subjects into different anatomical clusters. Voxel-based morphometry was used to assess patterns of grey matter loss in each identified cluster of subjects compared to an age and gender-matched control group at P < 0.05 (family-wise error corrected). We identified four potentially useful clusters with distinct patterns of grey matter loss, which we posit represent anatomical subtypes of the behavioural variant of frontotemporal dementia. Two of these subtypes were associated with temporal lobe volume loss, with one subtype showing loss restricted to temporal lobe regions (temporal-dominant subtype) and the other showing grey matter loss in the temporal lobes as well as frontal and parietal lobes (temporofrontoparietal subtype). Another two subtypes were characterized by a large amount of frontal lobe volume loss, with one subtype showing grey matter loss in the frontal lobes as well as loss of the temporal lobes (frontotemporal subtype) and the other subtype showing loss relatively restricted to the frontal lobes (frontal-dominant subtype). These four subtypes differed on clinical measures of executive function, episodic memory and confrontation naming. There were also associations between the four subtypes and genetic or pathological diagnoses which were obtained in 48% of the cohort. The clusters did not differ in behavioural severity as measured by the Neuropsychiatric Inventory; supporting the original classification of the behavioural variant of frontotemporal dementia in these subjects. Our findings suggest behavioural variant of frontotemporal dementia can therefore be subdivided into four different anatomical subtypes.

β-amyloid burden is not associated with rates of brain atrophy

To test the hypothesis that β‐amyloid (Aβ) burden is associated with rates of brain atrophy.

Comparison of different methodological implementations of voxel-based morphometry in neurodegenerative disease.

Voxel-based morphometry (VBM) is a popular method for probing inter-group differences in brain morphology. Variation in the detailed implementation of the algorithm, however, will affect the apparent results of VBM analyses and in turn the inferences drawn about the anatomic expression of specific disease states. We qualitatively assessed group comparisons of 43 normal elderly control subjects and 51 patients with probable Alzheimers disease, using five different VBM variations. Based on the known pathologic expression of the disease, we evaluated the biological plausibility of each. The use of a custom template and custom tissue class prior probability images (priors) produced inter-group comparison maps with greater biological plausibility than the use of the Montreal Neurological Institute (MNI) template and priors. We present a method for initializing the normalization to a custom template, and conclude that, when incorporated into the VBM processing chain, it yields the most biologically plausible inter-group differences of the five methods presented.

Comparative Diagnostic Utility of Different MR Modalities in Mild Cognitive Impairment and Alzheimer’s Disease

This study compares the diagnostic accuracy of magnetic resonance (MR)-based hippocampal volumetry, single voxel 1H MR spectroscopy (1H MRS) and MR diffusion-weighted imaging (DWI) measurements in discriminating patients with amnestic mild cognitive impairment (MCI), Alzheimer’s disease (AD) and normally aging elderly. Sixty-one normally aging elderly, 24 MCI and 22 AD patients underwent MR-based hippocampal volumetry, 1H MRS and DWI. 1H MRS voxels were placed over both of the posterior cingulate gyri, and N-acetyl aspartate (NAA)/creatine (Cr), myoinositol (MI)/Cr and NAA/MI ratios were obtained. Apparent diffusion coefficient (ADC) maps were derived from DWI, and hippocampal borders were traced to measure hippocampal ADC. At 80% specificity, the most sensitive single measurement to discriminate MCI (79%) and AD (86%) from controls was hippocampal volumes. The most sensitive single measurement to discriminate AD from MCI was posterior cingulate gyrus NAA/Cr (67%). At high specificity (>85–90%), combinations of MR measures had superior diagnostic sensitivity compared with any single MR measurement for the AD vs. control and control vs. MCI comparisons. The MR measures that best discriminate more from less affected individuals along the cognitive continuum from normal to AD vary with disease severity. Selection of imaging measures used for clinical assessment or monitoring efficiency of therapeutic intervention should be tailored to the clinical stage of the disease.

Atrophy rates accelerate in amnestic mild cognitive impairment

Background: We tested if rates of brain atrophy accelerate in individuals with amnestic mild cognitive impairment (aMCI) as they progress to typical late onset Alzheimer disease (AD). We included comparisons to subjects with aMCI who did not progress (labeled aMCI-S) and also to cognitively normal elderly subjects (CN). Methods: We studied 46 subjects with aMCI who progressed to AD (labeled aMCI-P), 46 CN, and 23 aMCI-S. All subjects must have had three or more serial MRI scans. Rates of brain shrinkage and ventricular expansion were measured across all available serial MRI scans in each subject. Change in volumes relative to the point at which subjects progressed to a clinical diagnosis of AD (the index date) was modeled in aMCI-P. Change in volumes relative to age was modeled in all three clinical groups. Results: In aMCI-P the change in pre to post index rate (i.e., acceleration) of ventricular expansion was 1.7 cm3/year, and acceleration in brain shrinkage was 5.3 cm3/year. Brain volume declined and ventricular volume increased in all three groups with age. Volume changes decelerated with increasing age in aMCI-P, and to a lesser extent in aMCI-S, but were linear in the matched CN. Among all subjects with aMCI, rates of atrophy were greater in apolipoprotein E ε4 carriers than noncarriers. Conclusions: Rates of atrophy accelerate as individuals progress from amnestic mild cognitive impairment (aMCI) to typical late onset Alzheimer disease (AD). Rates of atrophy are greater in younger than older subjects with aMCI who progressed to AD and subjects with aMCI who did not progress. We did not find that atrophy rates varied with age in 70- to 90-year-old cognitively normal subjects.

FLAIR Histogram Segmentation for Measurement of Leukoaraiosis Volume

The purposes of this study were to develop a method to measure brain and white matter hyperintensity (leukoaraiosis) volume that is based on the segmentation of the intensity histogram of fluid‐attenuated inversion recovery (FLAIR) images and to assess the accuracy and reproducibility of the method. Whole‐head synthetic image phantoms with manually introduced leukoaraiosis lesions of varying severity were constructed. These synthetic image phantom sets incorporated image contrast and anatomic features that mimicked leukoaraiosis found in real life. One set of synthetic image phantoms was used to develop the segmentation algorithm (FLAIR‐histoseg). A second set was used to measure its accuracy. Test retest reproducibility was assessed in 10 elderly volunteers who were imaged twice. The mean absolute error of the FLAIR‐histoseg method was 6.6% for measurement of leukoaraiosis volume and 1.4% for brain volume. The mean test retest coefficient of variation was 1.4% for leukoaraiosis volume and 0.3% for brain volume. We conclude that the FLAIR‐histoseg method is an accurate and reproducible method for measuring leukoaraiosis and whole‐brain volume in elderly subjects. J. Magn. Reson. Imaging 2001;14:668–676.