Secondary prevention trials in subjects with preclinical Alzheimer disease may require documentation of brain amyloidosis. The identification of inexpensive and noninvasive screening variables that can identify individuals who have significant amyloid accumulation would reduce screening costs.
A total of 483 cognitively normal (CN) individuals, aged 70–92 years, from the population-based Mayo Clinic Study of Aging, underwent Pittsburgh compound B (PiB)–PET imaging. Logistic regression determined whether age, sex, APOE genotype, family history, or cognitive performance was associated with odds of a PiB retention ratio >1.4 and >1.5. Area under the receiver operating characteristic curve (AUROC) evaluated the discrimination between PiB-positive and -negative subjects. For each characteristic, we determined the number needed to screen in each age group (70–79 and 80–89) to identify 100 participants with PiB >1.4 or >1.5.
A total of 211 (44%) individuals had PiB >1.4 and 151 (31%) >1.5. In univariate and multivariate models, discrimination was modest (AUROC ∼0.6–0.7). Multivariately, age and APOE best predicted odds of PiB >1.4 and >1.5. Subjective memory complaints were similar to cognitive test performance in predicting PiB >1.5. Indicators of PiB positivity varied with age. Screening APOE ε4 carriers alone reduced the number needed to screen to enroll 100 subjects with PIB >1.5 by 48% in persons aged 70–79 and 33% in those aged 80–89.
Age and APOE genotype are useful predictors of the likelihood of significant amyloid accumulation, but discrimination is modest. Nonetheless, these results suggest that inexpensive and noninvasive measures could significantly reduce the number of CN individuals needed to screen to enroll a given number of amyloid-positive subjects.
To determine the association between the focal atrophy measures on antemortem MRI and postmortem neuropathologic classification of dementia with Lewy bodies (DLB) using the Third Report of the DLB Consortium criteria.
We retrospectively identified 56 subjects who underwent antemortem MRI and had Lewy body (LB) pathology at autopsy. Subjects were pathologically classified as high (n = 25), intermediate (n = 22), and low likelihood DLB (n = 9) according to the Third Report of the DLB Consortium criteria. We included 2 additional pathologic comparison groups without LBs: one with low likelihood Alzheimer disease (AD) (control; n = 27) and one with high likelihood AD (n = 33). The associations between MRI-based volumetric measurements and the pathologic classification of DLB were tested with analysis of covariance by adjusting for age, sex, and MRI-to-death interval.
Antemortem hippocampal and amygdalar volumes increased from low to intermediate to high likelihood DLB (p < 0.001, trend test). Smaller hippocampal and amygdalar volumes were associated with higher Braak neurofibrillary tangle stage (p < 0.001). Antemortem dorsal mesopontine gray matter (GM) atrophy was found in those with high likelihood DLB compared with normal control subjects (p = 0.004) and those with AD (p = 0.01). Dorsal mesopontine GM volume decreased from low to intermediate to high likelihood DLB (p = 0.01, trend test).
Antemortem hippocampal and amygdalar volumes increase and dorsal mesopontine GM volumes decrease in patients with low to high likelihood DLB according to the Third Report of the DLB Consortium criteria. Patients with high likelihood DLB typically have normal hippocampal volumes but have atrophy in the dorsal mesopontine GM nuclei.
Acetylcholinesterase inhibitors are commonly used to treat patients with dementia with Lewy bodies. Hippocampal atrophy on magnetic resonance imaging and amyloid-β load on positron emission tomography are associated with the Alzheimer’s disease-related pathology in patients with dementia with Lewy bodies. To date, few studies have investigated imaging markers that predict treatment response in patients with dementia with Lewy bodies. Our objective was to determine whether imaging markers of Alzheimer’s disease-related pathology such as hippocampal volume, brain amyloid-β load on 11C Pittsburgh compound B positron emission tomography predict treatment response to acetylcholinesterase inhibitors in patients with dementia with Lewy bodies. We performed a retrospective analysis on consecutive treatment-naive patients with dementia with Lewy bodies (n = 54) from the Mayo Clinic Alzheimer’s Disease Research Centre who subsequently received acetylcholinesterase inhibitors and underwent magnetic resonance imaging with hippocampal volumetry. Baseline and follow-up assessments were obtained with the Mattis Dementia Rating Scale. Subjects were divided into three groups (reliable improvement, stable or reliable decline) using Dementia Rating Scale reliable change indices determined previously. Associations between hippocampal volumes and treatment response were tested with analysis of covariance adjusting for baseline Dementia Rating Scale, age, gender, magnetic resonance field strength and Dementia Rating Scale interval. Seven subjects underwent 11C Pittsburgh compound B imaging within 12 weeks of magnetic resonance imaging. Global cortical 11C Pittsburgh compound B retention (scaled to cerebellar retention) was calculated in these patients. Using a conservative psychometric method of assessing treatment response, there were 12 patients with reliable decline, 29 stable cases and 13 patients with reliable improvement. The improvers had significantly larger hippocampi than those that declined (P = 0.02) and the stable (P = 0.04) group. An exploratory analysis demonstrated larger grey matter volumes in the temporal and parietal lobes in improvers compared with those who declined (P < 0.05). The two patients who had a positive 11C Pittsburgh compound B positron emission tomography scan declined and those who had a negative 11C Pittsburgh compound B positron emission tomography scan improved or were stable after treatment. Patients with dementia with Lewy bodies who do not have the imaging features of coexistent Alzheimer’s disease-related pathology are more likely to cognitively improve with acetylcholinesterase inhibitor treatment.
dementia with Lewy bodies; acetylcholinesterase inhibitors; MRI; PiB; PET; amyloid
The hexanucleotide repeat in the chromosome 9 open reading frame 72 (C9ORF72) gene was recently discovered as the pathogenic mechanism underlying many families with frontotemporal dementia (FTD) and/or amyotrophic lateral sclerosis (ALS) linked to chromosome 9 (c9FTD/ALS). We report the clinical, neuropsychological, and neuroimaging findings of a family with the C9ORF72 mutation and clinical diagnoses bridging the FTD, parkinsonism and ALS spectrum.
To characterize the antemortem characteristics of a family with c9FTD/ALS associated with the GGGGCC repeat expansion in C9ORF72
Tertiary care academic medical center.
The members of the family affected by the mutation with features of FTD and/or ALS.
Main Outcome Measures
Clinical, neuropsychological, and neuroimaging assessments.
All three examined subjects had the hexanucleotide expansion detected in C9ORF72. All had personality/behavioral changes early in the course of the disease. One case had levodopa-unresponsive parkinsonism, and one had ALS. MRI showed symmetric bilateral frontal, temporal, insular and cingulate atrophy.
This report highlights the clinical and neuroimaging characteristics of a family with c9FTD/ALS. Further studies are needed to better understand the phenotypical variability and the clinico-neuroimaging-neuropathologic correlations.
To characterize the shape of the trajectories of Alzheimer’s Disease (AD) biomarkers as a function of MMSE.
Longitudinal registries from the Mayo Clinic and the Alzheimer’s Disease Neuroimaging Initiative (ADNI).
Two different samples (n=343 and n=598) were created that spanned the cognitive spectrum from normal to AD dementia. Subgroup analyses were performed in members of both cohorts (n=243 and n=328) who were amyloid positive at baseline.
Main Outcome Measures
The shape of biomarker trajectories as a function of MMSE, adjusted for age, was modeled and described as baseline (cross-sectional) and within-subject longitudinal effects. Biomarkers evaluated were cerebro spinal fluid (CSF) Aβ42 and tau; amyloid and fluoro deoxyglucose position emission tomography (PET) imaging, and structural magnetic resonance imaging (MRI).
Baseline biomarker values generally worsened (i.e., non-zero slope) with lower baseline MMSE. Baseline hippocampal volume, amyloid PET and FDG PET values plateaued (i.e., non-linear slope) with lower MMSE in one or more analyses. Longitudinally, within-subject rates of biomarker change were associated with worsening MMSE. Non-constant within-subject rates (deceleration) of biomarker change were found in only one model.
Biomarker trajectory shapes by MMSE were complex and were affected by interactions with age and APOE status. Non-linearity was found in several baseline effects models. Non-constant within-subject rates of biomarker change were found in only one model, likely due to limited within-subject longitudinal follow up. Creating reliable models that describe the full trajectories of AD biomarkers will require significant additional longitudinal data in individual participants.
Alzheimer’s disease biomarkers; Magnetic Resonance Imaging; cerebro spinal fluid; amyloid PET imaging; FDG PET imaging
A workgroup commissioned by the Alzheimer’s Association (AA) and the National Institute on Aging (NIA) recently published research criteria for preclinical Alzheimer’s disease (AD). We performed a preliminary assessment of these guidelines.
We employed Pittsburgh compound B positron emission tomography (PET) imaging as our biomarker of cerebral amyloidosis and 18fluorodeoxyglucose PET imaging and hippocampal volume as biomarkers of neurodegeneration. A group of 42 clinically diagnosed AD subjects was used to create imaging biomarker cut-points. A group of 450 cognitively normal (CN) subjects from a population based sample was used to develop cognitive cut-points and to assess population frequencies of the different preclinical AD stages using different cut-point criteria.
The new criteria subdivide the preclinical phase of AD into stages 1–3. To classify our CN subjects, two additional categories were needed. Stage 0 denotes subjects with normal AD biomarkers and no evidence of subtle cognitive impairment. Suspected Non-AD Pathophysiology (SNAP) denotes subjects with normal amyloid PET imaging, but abnormal neurodegeneration biomarker studies. At fixed cut-points corresponding to 90% sensitivity for diagnosing AD and the 10th percentile of CN cognitive scores, 43% of our sample was classified as stage 0; 16% stage 1; 12 % stage 2; 3% stage 3; and 23% SNAP.
This cross-sectional evaluation of the NIA-AA criteria for preclinical AD indicates that the 1–3 staging criteria coupled with stage 0 and SNAP categories classify 97% of CN subjects from a population-based sample, leaving just 3% unclassified. Future longitudinal validation of the criteria will be important.
Fully automated classification algorithms have been successfully applied to diagnose a wide range of neurological and psychiatric diseases. They are sufficiently robust to handle data from different scanners for many applications and in specific cases outperform radiologists. This article provides an overview of current applications taking structural imaging in Alzheimer's Disease and schizophrenia as well as functional imaging to diagnose depression as examples. In this context, we also report studies aiming to predict the future course of the disease and the response to treatment for the individual. This has obvious clinical relevance but is also important for the design of treatment studies that may aim to include a cohort with a predicted fast disease progression to be more sensitive to detect treatment effects.
In the second part, we present our own opinions on i) the role these classification methods can play in the clinical setting; ii) where their limitations are at the moment and iii) how those can be overcome. Specifically, we discuss strategies to deal with disease heterogeneity, diagnostic uncertainties, a probabilistic framework for classification and multi-class classification approaches.
Automated diagnosing; MRI; SVM; Dementia; Depression; Schizophrenia
Fully automated machine learning methods based on structural magnetic resonance imaging (MRI) data can assist radiologists in the diagnosis of Alzheimer’s disease (AD). These algorithms require large data sets to learn the separation of subjects with and without AD. Training and test data may come from heterogeneous hardware settings, which can potentially affect the performance of disease classification.
A total of 518 MRI sessions from 226 healthy controls and 191 individuals with probable AD from the multicenter Alzheimer’s Disease Neuroimaging Initiative (ADNI) were used to investigate whether grouping data by acquisition hardware (i.e. vendor, field strength, coil system) is beneficial for the performance of a support vector machine (SVM) classifier, compared to the case where data from different hardware is mixed. We compared the change of the SVM decision value resulting from (a) changes in hardware against the effect of disease and (b) changes resulting simply from rescanning the same subject on the same machine.
Maximum accuracy of 87% was obtained with a training set of all 417 subjects. Classifiers trained with 95 subjects in each diagnostic group and acquired with heterogeneous scanner settings had an empirical detection accuracy of 84.2±2.4% when tested on an independent set of the same size. These results mirror the accuracy reported in recent studies. Encouragingly, classifiers trained on images acquired with homogenous and heterogeneous hardware settings had equivalent cross-validation performances. Two scans of the same subject acquired on the same machine had very similar decision values and were generally classified into the same group. Higher variation was introduced when two acquisitions of the same subject were performed on two scanners with different field strengths. The variation was unbiased and similar for both diagnostic groups. The findings of the study encourage the pooling of data from different sites to increase the number of training samples and thereby improving performance of disease classifiers. Although small, a change in hardware could lead to a change of the decision value and thus diagnostic grouping. The findings of this study provide estimators for diagnostic accuracy of an automated disease diagnosis method involving scans acquired with different sets of hardware. Furthermore, we show that the level of confidence in the performance estimation significantly depends on the size of the training sample, and hence should be taken into account in a clinical setting.
Magnetic resonance imaging; MRI; Support vector machines (SVM); Alzheimer’s disease; Multi-site study
Progressive supranuclear palsy (PSP) is associated with pathological changes along the dentatorubrothalamic tract and in premotor cortex. We aimed to assess whether functional neural connectivity is disrupted along this pathway in PSP, and to determine how functional changes relate to changes in structure and diffusion. Eighteen probable PSP subjects and 18 controls had resting-state (task-free) fMRI, diffusion tensor imaging and structural MRI. Functional connectivity was assessed between thalamus and the rest of the brain, and within the basal ganglia, salience and default mode networks (DMN). Patterns of atrophy were assessed using voxel-based morphometry, and patterns of white matter tract degeneration were assessed using tract-based spatial statistics. Reduced in-phase functional connectivity was observed between the thalamus and premotor cortex including supplemental motor area (SMA), striatum, thalamus and cerebellum in PSP. Reduced connectivity in premotor cortex, striatum and thalamus were observed in the basal ganglia network and DMN, with subcortical salience network reductions. Tract degeneration was observed between cerebellum and thalamus and in superior longitudinal fasciculus, with grey matter loss in frontal lobe, premotor cortex, SMA and caudate. SMA functional connectivity correlated with SMA volume and measures of cognitive and motor dysfunction, while thalamic connectivity correlated with degeneration of superior cerebellar peduncles. PSP is therefore associated with disrupted thalamocortical connectivity that is associated with degeneration of the dentatorubrothalamic tract and the presence of cortical atrophy.
Resting state fMRI; functional connectivity; white matter tracts; atrophy; dentatorubrothalamic tract
To examine default mode and salience network functional connectivity as a function of APOE ε4 status in a group of cognitively normal age, gender and education-matched older adults.
Fifty-six cognitively normal APOE ε4 carriers and 56 age, gender and education-matched cognitively normal APOE ε4 non-carriers.
Main Outcome Measure
Alterations in in-phase default mode and salience network connectivity in APOE ε4 carriers compared to APOE ε4 non-carriers ranging from 63 to 91 years of age.
A posterior cingulate seed revealed decreased in-phase connectivity in regions of the posterior default mode network that included the left inferior parietal lobe, left middle temporal gyrus, and bilateral anterior temporal lobes in the ε4 carriers relative to APOE ε4 non-carriers. An anterior cingulate seed showed greater in-phase connectivity in the salience network, including the cingulate gyrus, medial prefrontal cortex, bilateral insular cortex, striatum, and thalamus in APOE ε4 carriers vs. non-carriers. There were no group-wise differences in brain anatomy.
We found reductions in posterior default mode network connectivity but increased salience network connectivity in elderly cognitively normal APOE ε4 carriers relative to APOE ε4 non-carriers at rest. The observation of functional alterations in connectivity in the absence of structural changes between APOE e4 carriers and non-carriers suggests that alterations in connectivity may have the potential to serve as an early biomarker.
Resting-state functional magnetic resonance imaging (fMRI) is emerging as an interesting biomarker for measuring connectivity of the brain in patients with Alzheimer's disease (AD). In this review, we discuss the origins of resting-state fMRI, common methodologies used to extract information from these four-dimensional fMRI scans, and important considerations for the analysis of these scans. Then we present the current state of knowledge in this area by summarizing various AD resting-state fMRI studies presented in the first section and end with a discussion of future developments and open questions in the field.
To empirically assess the concept that Alzheimer’s disease (AD) biomarkers significantly depart from normality in a temporally ordered manner.
Multi-site, referral centers
We studied 401 elderly cognitively normal (CN), Mild Cognitive Impairment (MCI) and AD dementia subjects from the Alzheimer’s Disease Neuroimaging Initiative. We compared the proportions of three AD biomarkers – CSF Aβ42, CSF total tau (t-tau), and hippocampal volume adjusted by intra-cranial volume (HVa) - that were abnormal as cognitive impairment worsened. Cut-points demarcating normal vs. abnormal for each biomarker were established by maximizing diagnostic accuracy in independent autopsy samples.
Main Outcome measures
Within each clinical group in the entire sample (n=401) CSF Aβ42 was abnormal more often than t-tau or HVa. Among the 298 subjects with both baseline and 12 month data, the proportion of subjects with abnormal Aβ42 did not change from baseline to 12 months in any group. The proportion of subjects with abnormal t-tau increased from baseline to 12 months in CN (p=0.05) but not in MCI or dementia. In 209 subjects with abnormal CSF AB42 at baseline, the percent abnormal HVa, but not t-tau, increased from baseline to 12 months in MCI.
Reduction in CSF Aβ42 denotes a pathophysiological process that significantly departs from normality (i.e., becomes dynamic) early, while t-tau and HVa are biomarkers of downstream pathophysiological processes. T-tau becomes dynamic before HVa, but HVa is more dynamic in the clinically symptomatic MCI and dementia phases of the disease than t-tau.
Alzheimer’s disease biomarkers; Magnetic Resonance Imaging; CSF tau; CSF Abeta; Alzheimer’s disease staging
Task-free functional magnetic resonance imaging (TF-fMRI) has great potential for advancing the understanding and treatment of neurologic illness. However, as with all measures of neural activity, variability is a hallmark of intrinsic connectivity networks (ICNs) identified by TF-fMRI. This variability has hampered efforts to define a robust metric of connectivity suitable as a biomarker for neurologic illness. We hypothesized that some of this variability rather than representing noise in the measurement process, is related to a fundamental feature of connectivity within ICNs, which is their non-stationary nature. To test this hypothesis, we used a large (n = 892) population-based sample of older subjects to construct a well characterized atlas of 68 functional regions, which were categorized based on independent component analysis network of origin, anatomical locations, and a functional meta-analysis. These regions were then used to construct dynamic graphical representations of brain connectivity within a sliding time window for each subject. This allowed us to demonstrate the non-stationary nature of the brain’s modular organization and assign each region to a “meta-modular” group. Using this grouping, we then compared dwell time in strong sub-network configurations of the default mode network (DMN) between 28 subjects with Alzheimer’s dementia and 56 cognitively normal elderly subjects matched 1∶2 on age, gender, and education. We found that differences in connectivity we and others have previously observed in Alzheimer’s disease can be explained by differences in dwell time in DMN sub-network configurations, rather than steady state connectivity magnitude. DMN dwell time in specific modular configurations may also underlie the TF-fMRI findings that have been described in mild cognitive impairment and cognitively normal subjects who are at risk for Alzheimer’s dementia.
The common neurodegenerative pathologies underlying dementia are Alzheimer’s disease (AD), Lewy body disease (LBD) and Frontotemporal lobar degeneration (FTLD). Our aim was to identify patterns of atrophy unique to each of these diseases using antemortem structural-MRI scans of pathologically-confirmed dementia cases and build an MRI-based differential diagnosis system. Our approach of creating atrophy maps using structural-MRI and applying them for classification of new incoming patients is labeled Differential-STAND (Differential-diagnosis based on STructural Abnormality in NeuroDegeneration). Pathologically-confirmed subjects with a single dementing pathologic diagnosis who had an MRI at the time of clinical diagnosis of dementia were identified: 48 AD, 20 LBD, 47 FTLD-TDP (pathology-confirmed FTLD with TDP-43). Gray matter density in 91 regions-of-interest was measured in each subject and adjusted for head-size and age using a database of 120 cognitively normal elderly. The atrophy patterns in each dementia type when compared to pathologically-confirmed controls mirrored known disease-specific anatomic patterns: AD-temporoparietal association cortices and medial temporal lobe; FTLD-TDP-frontal and temporal lobes and LBD-bilateral amygdalae, dorsal midbrain and inferior temporal lobes. Differential-STAND based classification of each case was done based on a mixture model generated using bisecting k-means clustering of the information from the MRI scans. Leave-one-out classification showed reasonable performance compared to the autopsy gold-standard and clinical diagnosis: AD (sensitivity:90.7%; specificity:84 %), LBD (sensitivity:78.6%; specificity:98.8%) and FTLD-TDP (sensitivity:84.4%; specificity:93.8%). The proposed approach establishes a direct a priori relationship between specific topographic patterns on MRI and “gold standard” of pathology which can then be used to predict underlying dementia pathology in new incoming patients.
MRI; Alzheimer’s disease; Lewy body disease; Frontotemporal lobar degeneration
PIB PET and CSF Aβ42 demonstrate a highly significant inverse correlation. Both are presumed to measure brain Aβ amyloid load. Our objectives were to develop a method to transform CSF Aβ42 measures into calculated PIB measures (PIBcalc) of Aβ amyloid load, and to partially validate the method in an independent sample of subjects.
Forty-one ADNI subjects underwent PIB PET imaging and lumbar puncture (LP) at the same time. This sample, referred to as the “training” sample (9 cognitively normal (CN), 22 MCI, and 10 AD), was used to develop a regression model by which CSF Aβ42 (with APOE ε4 genotype as a covariate) was transformed into units of PIB PET (PIBcalc). An independent “supporting” sample of 362 (105 CN, 164 MCI, 93AD) ADNI subjects who underwent LP but not PIB PET imaging had their CSF Aβ42 values converted to PIBcalc. These values were compared to the overall PIB PET distribution found in the ADNI subjects (n = 102).
A linear regression model demonstrates good prediction of actual PIB PET from CSF Aβ42 measures obtained in the training sample (R2 = 0.77, P<0.001). PIBcalc data (derived from CSF Aβ42) in the supporting sample of 362 ADNI subjects who underwent LP but not PIB PET imaging demonstrates group-wise distributions that are highly consistent with the larger ADNI PIB PET distribution and with published PIB PET imaging studies.
Although the precise parameters of this model are specific for the ADNI sample, we conclude that CSF Aβ42 can be transformed into calculated PIB (PIBcalc) measures of Aβ amyloid load. Brain Aβ amyloid load can be ascertained at baseline in therapeutic or observational studies by either CSF or amyloid PET imaging and the data can be pooled using well-established multiple imputation techniques that account for the uncertainty in a CSF-based calculated PIB value.
Alzheimer's disease; Pittsburgh Compound B; amyloid imaging; Aβ amyloid; cerebrospinal fluid; Alzheimer's disease biomarkers
Numerous kindreds with familial frontotemporal dementia and/or amyotrophic lateral sclerosis have been linked to chromosome 9, and an expansion of the GGGGCC hexanucleotide repeat in the non-coding region of chromosome 9 open reading frame 72 has recently been identified as the pathogenic mechanism. We describe the key characteristics in the probands and their affected relatives who have been evaluated at Mayo Clinic Rochester or Mayo Clinic Florida in whom the hexanucleotide repeat expansion were found. Forty-three probands and 10 of their affected relatives with DNA available (total 53 subjects) were shown to carry the hexanucleotide repeat expansion. Thirty-six (84%) of the 43 probands had a familial disorder, whereas seven (16%) appeared to be sporadic. Among examined subjects from the 43 families (n = 63), the age of onset ranged from 33 to 72 years (median 52 years) and survival ranged from 1 to 17 years, with the age of onset <40 years in six (10%) and >60 in 19 (30%). Clinical diagnoses among examined subjects included behavioural variant frontotemporal dementia with or without parkinsonism (n = 30), amyotrophic lateral sclerosis (n = 18), frontotemporal dementia/amyotrophic lateral sclerosis with or without parkinsonism (n = 12), and other various syndromes (n = 3). Parkinsonism was present in 35% of examined subjects, all of whom had behavioural variant frontotemporal dementia or frontotemporal dementia/amyotrophic lateral sclerosis as the dominant clinical phenotype. No subject with a diagnosis of primary progressive aphasia was identified with this mutation. Incomplete penetrance was suggested in two kindreds, and the youngest generation had significantly earlier age of onset (>10 years) compared with the next oldest generation in 11 kindreds. Neuropsychological testing showed a profile of slowed processing speed, complex attention/executive dysfunction, and impairment in rapid word retrieval. Neuroimaging studies showed bilateral frontal abnormalities most consistently, with more variable degrees of parietal with or without temporal changes; no case had strikingly focal or asymmetric findings. Neuropathological examination of 14 patients revealed a range of transactive response DNA binding protein molecular weight 43 pathology (10 type A and four type B), as well as ubiquitin-positive cerebellar granular neuron inclusions in all but one case. Motor neuron degeneration was detected in nine patients, including five patients without ante-mortem signs of motor neuron disease. While variability exists, most cases with this mutation have a characteristic spectrum of demographic, clinical, neuropsychological, neuroimaging and especially neuropathological findings.
frontotemporal dementia; amyotrophic lateral sclerosis; motor neuron disease; TDP-43; neurogenetics; chromosome 9
When using imaging to predict time to progression from mild cognitive impairment (MCI) to Alzheimer's disease (AD), time-to-event statistical methods account for varying lengths of follow-up times among subjects whereas two-sample t-tests in voxel-based morphometry (VBM) do not. Our objectives were to apply a time-to-event voxel-based analytic method to identify regions on MRI where atrophy is associated with significantly increased risk of future progression to AD in subjects with MCI and to compare it to traditional voxel-level patterns obtained by applying two-sample methods. We also compared the power required to detect an association using time-to-event methods versus two-sample approaches.
Subjects with MCI at baseline were followed prospectively. The event of interest was clinical diagnosis of AD. Cox proportional hazards models adjusted for age, sex, and education were used to estimate the relative hazard of progression from MCI to AD based on rank-transformed voxel-level gray matter density (GMD) estimates.
The greatest risk of progression to AD was associated with atrophy of the medial temporal lobes. Patients ranked at the 25th percentile of GMD in these regions had more than a doubling of risk of progression to AD at a given time-point compared to patients at the 75th percentile. Power calculations showed the time-to-event approach to be more efficient than the traditional two-sample approach.
We present a new voxel-based analytic method that incorporates time-to-event statistical methods. In the context of a progressive disease like AD, time-to-event VBM seems more appropriate and powerful than traditional two-sample methods.
Alzheimer Disease; mild cognitive impairment; magnetic resonance imaging; Cox proportional hazards model
Atrophy measured on structural magnetic resonance imaging (sMRI) is a powerful biomarker of the stage and intensity of the neurodegenerative aspect of Alzheimer's disease (AD) pathology. In this review, we will discuss the role of sMRI as an AD biomarker by summarizing (a) the most commonly used methods to extract information from sMRI images, (b) the different roles in which sMRI can be used as an AD biomarker, and (c) comparisons of sMRI with other major AD biomarkers.
The clinical diagnosis of Alzheimer Disease (AD) does not exactly match the pathological findings at autopsy in every subject. Therefore, in-vivo imaging measures, such as Magnetic Resonance Imaging (MRI) that measure anatomical variations in each brain due to atrophy, would be clinically useful independent supplementary measures of pathology. We have developed an algorithm that extracts atrophy information from individual patient’s 3D MRI scans and assigns a STructural Abnormality iNDex (STAND)-score to the scan based on the degree of atrophy in comparison to patterns extracted from a large library of clinically well characterized AD and CN (cognitively normal) subject’s MRI scans. STAND-scores can be adjusted for demographics to give adjusted-STAND (aSTAND)-scores which are typically > 0 for subjects with abnormal brains. Since histopathological findings are considered to represent the “ground truth”, our objective was to assess the sensitivity of aSTAND-scores to pathological AD staging. This was done by comparing antemortem MRI based aSTAND-scores with post mortem grading of disease severity in 101 subjects who had both antemortem MRI and postmortem Braak neurofibrillary tangle (NFT) staging. We found a rank correlation of 0.62 (p<0.0001) between Braak NFT stage and aSTAND-scores. The results show that optimally extracted information from MRI scans such as STAND-scores accurately capture disease severity and can be used as an independent approximate surrogate marker for in-vivo pathological staging as well as for early identification of AD in individual subjects.
Alzheimer Disease; neurofibrillary tangles; amnestic mild cognitive impairment; Braak NFT stage; magnetic resonance imaging
The objective of this study was to investigate how a measure of educational and occupational attainment, a component of cognitive reserve, modifies the relationship between biomarkers of pathology and cognition in Alzheimer's disease. The biomarkers evaluated quantified neurodegeneration via atrophy on magnetic resonance images, neuronal injury via cerebral spinal fluid t-tau, brain amyloid-β load via cerebral spinal fluid amyloid-β1–42 and vascular disease via white matter hyperintensities on T2/proton density magnetic resonance images. We included 109 cognitively normal subjects, 192 amnestic patients with mild cognitive impairment and 98 patients with Alzheimer's disease, from the Alzheimer's Disease Neuroimaging Initiative study, who had undergone baseline lumbar puncture and magnetic resonance imaging. We combined patients with mild cognitive impairment and Alzheimer's disease in a group labelled ‘cognitively impaired’ subjects. Structural Abnormality Index scores, which reflect the degree of Alzheimer's disease-like anatomic features on magnetic resonance images, were computed for each subject. We assessed Alzheimer's Disease Assessment Scale (cognitive behaviour section) and mini-mental state examination scores as measures of general cognition and Auditory–Verbal Learning Test delayed recall, Boston naming and Trails B scores as measures of specific domains in both groups of subjects. The number of errors on the American National Adult Reading Test was used as a measure of environmental enrichment provided by educational and occupational attainment, a component of cognitive reserve. We found that in cognitively normal subjects, none of the biomarkers correlated with the measures of cognition, whereas American National Adult Reading Test scores were significantly correlated with Boston naming and mini-mental state examination results. In cognitively impaired subjects, the American National Adult Reading Test and all biomarkers of neuronal pathology and amyloid load were independently correlated with all cognitive measures. Exceptions to this general conclusion were absence of correlation between cerebral spinal fluid amyloid-β1–42 and Boston naming and Trails B. In contrast, white matter hyperintensities were only correlated with Boston naming and Trails B results in the cognitively impaired. When all subjects were included in a flexible ordinal regression model that allowed for non-linear effects and interactions, we found that the American National Adult Reading Test had an independent additive association such that better performance was associated with better cognitive performance across the biomarker distribution. Our main conclusions included: (i) that in cognitively normal subjects, the variability in cognitive performance is explained partly by the American National Adult Reading Test and not by biomarkers of Alzheimer's disease pathology; (ii) in cognitively impaired subjects, the American National Adult Reading Test, biomarkers of neuronal pathology (structural magnetic resonance imaging and cerebral spinal fluid t-tau) and amyloid load (cerebral spinal fluid amyloid-β1–42) all independently explain variability in general cognitive performance; and (iii) that the association between cognition and the American National Adult Reading Test was found to be additive rather than to interact with biomarkers of Alzheimer's disease pathology.
Alzheimer's disease; mild cognitive impairment; CSF biomarkers; MRI; cognitive reserve
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 Ward's 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.
behavioural variant frontotemporal dementia; atrophy; cluster analysis; voxel-based morphometry
Biomarkers of brain Aβ amyloid deposition can be measured either by cerebrospinal fluid Aβ42 or Pittsburgh compound B positron emission tomography imaging. Our objective was to evaluate the ability of Aβ load and neurodegenerative atrophy on magnetic resonance imaging to predict shorter time-to-progression from mild cognitive impairment to Alzheimer’s dementia and to characterize the effect of these biomarkers on the risk of progression as they become increasingly abnormal. A total of 218 subjects with mild cognitive impairment were identified from the Alzheimer’s Disease Neuroimaging Initiative. The primary outcome was time-to-progression to Alzheimer’s dementia. Hippocampal volumes were measured and adjusted for intracranial volume. We used a new method of pooling cerebrospinal fluid Aβ42 and Pittsburgh compound B positron emission tomography measures to produce equivalent measures of brain Aβ load from either source and analysed the results using multiple imputation methods. We performed our analyses in two phases. First, we grouped our subjects into those who were ‘amyloid positive’ (n = 165, with the assumption that Alzheimer's pathology is dominant in this group) and those who were ‘amyloid negative’ (n = 53). In the second phase, we included all 218 subjects with mild cognitive impairment to evaluate the biomarkers in a sample that we assumed to contain a full spectrum of expected pathologies. In a Kaplan–Meier analysis, amyloid positive subjects with mild cognitive impairment were much more likely to progress to dementia within 2 years than amyloid negative subjects with mild cognitive impairment (50 versus 19%). Among amyloid positive subjects with mild cognitive impairment only, hippocampal atrophy predicted shorter time-to-progression (P < 0.001) while Aβ load did not (P = 0.44). In contrast, when all 218 subjects with mild cognitive impairment were combined (amyloid positive and negative), hippocampal atrophy and Aβ load predicted shorter time-to-progression with comparable power (hazard ratio for an inter-quartile difference of 2.6 for both); however, the risk profile was linear throughout the range of hippocampal atrophy values but reached a ceiling at higher values of brain Aβ load. Our results are consistent with a model of Alzheimer’s disease in which Aβ deposition initiates the pathological cascade but is not the direct cause of cognitive impairment as evidenced by the fact that Aβ load severity is decoupled from risk of progression at high levels. In contrast, hippocampal atrophy indicates how far along the neurodegenerative path one is, and hence how close to progressing to dementia. Possible explanations for our finding that many subjects with mild cognitive impairment have intermediate levels of Aβ load include: (i) individual subjects may reach an Aβ load plateau at varying absolute levels; (ii) some subjects may be more biologically susceptible to Aβ than others; and (iii) subjects with mild cognitive impairment with intermediate levels of Aβ may represent individuals with Alzheimer’s disease co-existent with other pathologies.
mild cognitive impairment; amyloid imaging; magnetic resonance imaging; cerebrospinal fluid; Alzheimer’s disease biomarkers
To study the effect of apolipoprotein E ε4 status on biomarkers of neurodegeneration (atrophy on magnetic resonance imaging [MRI]), neuronal injury (cerebrospinal fluid [CSF] t-tau), and brain Aβ amyloid load (CSF Aβ1–42) in cognitively normal subjects (CN), amnestic subjects with mild cognitive impairment (aMCI), and patients with Alzheimer disease (AD).
We included all 399 subjects (109 CN, 192 aMCI, 98 AD) from the Alzheimer's Disease Neuroimaging Initiative study with baseline CSF and MRI scans. Structural Abnormality Index (STAND) scores, which reflect the degree of AD-like anatomic features on MRI, were computed for each subject.
A clear ε4 allele dose effect was seen on CSF Aβ1–42 levels within each clinical group. In addition, the proportion of the variability in Aβ1–42 levels explained by APOE ε4 dose was significantly greater than the proportion of the variability explained by clinical diagnosis. On the other hand, the proportion of the variability in CSF t-tau and MRI atrophy explained by clinical diagnosis was greater than the proportion of the variability explained by APOE ε4 dose; however, this effect was only significant for STAND scores.
Low CSF Aβ1–42 (surrogate for Aβ amyloid load) is more closely linked to the presence of APOE ε4 than to clinical status. In contrast, MRI atrophy (surrogate for neurodegeneration) is closely linked with cognitive impairment, whereas its association with APOE ε4 is weaker. The data in this paper support a model of AD in which CSF Aβ1–42 is the earliest of the 3 biomarkers examined to become abnormal in both APOE carriers and noncarriers.
To develop and validate a tool for Alzheimer's disease (AD) diagnosis in individual subjects using support vector machine (SVM) based classification of structural MR (sMR) images.
Libraries of sMR scans of clinically well characterized subjects can be harnessed for the purpose of diagnosing new incoming subjects.
190 patients with probable AD were age- and gender-matched with 190 cognitively normal (CN) subjects. Three different classification models were implemented: Model I uses tissue densities obtained from sMR scans to give STructural Abnormality iNDex (STAND)-score; and Models II and III use tissue densities as well as covariates (demographics and Apolipoprotein E genotype) to give adjusted-STAND (aSTAND)-score. Data from 140 AD and 140 CN were used for training. The SVM parameter optimization and training was done by four-fold cross validation. The remaining independent sample of 50 AD and 50 CN were used to obtain a minimally biased estimate of the generalization error of the algorithm.
The CV accuracy of Model II and Model III aSTAND-scores was 88.5% and 89.3% respectively and the developed models generalized well on the independent test datasets. Anatomic patterns best differentiating the groups were consistent with the known distribution of neurofibrillary AD pathology.
This paper presents preliminary evidence that application of SVM-based classification of an individual sMR scan relative to a library of scans can provide useful information in individual subjects for diagnosis of AD. Including demographic and genetic information in the classification algorithm slightly improves diagnostic accuracy.
support vector machines; classification; diagnosis; Alzheimer's