Citations

Background and purposeThe aim of our study was to determine the utility of longitudinal magnetic resonance imaging (MRI) measurements as potential biomarkers in the main genetic variants of frontotemporal dementia (FTD), including microtubule‐associated protein tau (MAPT) and progranulin (GRN) mutations and C9ORF72 repeat expansions, as well as sporadic FTD.MethodsIn this longitudinal study, 58 subjects were identified who had at least two MRI and MAPT mutations (n = 21), GRN mutations (n = 11), C9ORF72 repeat expansions (n = 11) or sporadic FTD (n = 15). A total of 198 serial MRI measurements were analyzed. Rates of whole brain atrophy were calculated using the boundary shift integral. Regional rates of atrophy were calculated using tensor‐based morphometry. Sample size estimates were calculated.ResultsProgressive brain atrophy was observed in all groups, with fastest rates of whole brain atrophy in GRN, followed by sporadic FTD, C9ORF72 and MAPT. All variants showed greatest rates in the frontal and temporal lobes, with parietal lobes also strikingly affected in GRN. Regional rates of atrophy across all lobes were greater in GRN compared to the other groups. C9ORF72 showed greater rates of atrophy in the left cerebellum and right occipital lobe than MAPT, and sporadic FTD showed greater rates in the anterior cingulate than C9ORF72 and MAPT. Sample size estimates were lowest using temporal lobe rates in GRN, ventricular rates in MAPT and C9ORF72, and whole brain rates in sporadic FTD.ConclusionThese data support the utility of using rates of atrophy as outcome measures in future drug trials in FTD and show that different imaging biomarkers may offer advantages in the different variants of FTD.

AbstractObjectiveThe pathologic validation of European Alzheimer's Disease Consortium Alzheimer’s Disease Neuroimaging Initiative Center Harmonized Hippocampal Segmentation Protocol (HarP).MethodsTemporal lobes of nine Alzheimer's disease (AD) and seven cognitively normal subjects were scanned post‐mortem at 7 Tesla. Hippocampal volumes were obtained with HarP. Six‐micrometer‐thick hippocampal slices were stained for amyloid beta (Aβ), tau, and cresyl violet. Hippocampal subfields were manually traced. Neuronal counts, Aβ, and tau burden for each hippocampal subfield were obtained.ResultsWe found significant correlations between hippocampal volume and Braak and Braak staging (ρ = −0.75, P = .001), tau (ρ = −0.53, P = .034), Aβ burden (ρ = −0.61, P = .012), and neuronal count (ρ = 0.77, P < .001). Exploratory subfield‐wise significant associations were found for Aβ in Cornu Ammonis (CA)1 (ρ = −0.58, P = .019) and subiculum (ρ = −0.75, P = .001), tau in CA2 (ρ = −0.59, P = .016), and CA3 (ρ = −0.5, P = .047), and neuronal count in CA1 (ρ = 0.55, P = .028), CA3 (ρ = 0.65, P = .006), and CA4 (ρ = 0.76, P = .001).ConclusionsThe observed associations provide pathological confirmation of hippocampal morphometry as a valid biomarker for AD and pathologic validation of HarP.

AbstractBackgroundThe European Alzheimer's Disease Consortium and Alzheimer's Disease Neuroimaging Initiative (ADNI) Harmonized Protocol (HarP) is a Delphi definition of manual hippocampal segmentation from magnetic resonance imaging (MRI) that can be used as the standard of truth to train new tracers, and to validate automated segmentation algorithms. Training requires large and representative data sets of segmented hippocampi. This work aims to produce a set of HarP labels for the proper training and certification of tracers and algorithms.MethodsSixty‐eight 1.5 T and 67 3 T volumetric structural ADNI scans from different subjects, balanced by age, medial temporal atrophy, and scanner manufacturer, were segmented by five qualified HarP tracers whose absolute interrater intraclass correlation coefficients were 0.953 and 0.975 (left and right). Labels were validated as HarP compliant through centralized quality check and correction.ResultsHippocampal volumes (mm3) were as follows: controls: left = 3060 (standard deviation [SD], 502), right = 3120 (SD, 897); mild cognitive impairment (MCI): left = 2596 (SD, 447), right = 2686 (SD, 473); and Alzheimer’s disease (AD): left = 2301 (SD, 492), right = 2445 (SD, 525). Volumes significantly correlated with atrophy severity at Scheltens' scale (Spearman's ρ = <−0.468, P = <.0005).Cerebrospinal fluid spaces (mm3) were as follows: controls: left = 23 (32), right = 25 (25); MCI: left = 15 (13), right = 22 (16); and AD: left = 11 (13), right = 20 (25). Five subjects (3.7%) presented with unusual anatomy.ConclusionsThis work provides reference hippocampal labels for the training and certification of automated segmentation algorithms. The publicly released labels will allow the widespread implementation of the standard segmentation protocol.

Background and Purpose— The relationships between cerebrovascular lesions visible on imaging and cognition are complex. We explored the possibility that the cerebral cortical volume mediated these relationships. Methods— Total of 1906 nondemented participants (59% women; 25% African–American; mean age, 76.6 years) in the Atherosclerosis Risk in Communities (ARIC) study underwent cognitive assessments, risk factor assessments, and quantitative MRI for white matter hyperintensities (WMH) and infarcts. The Freesurfer imaging analysis pipeline was used to determine regional cerebral volumes. We examined the associations of cognitive domain outcomes with cerebral volumes (hippocampus and separate groups of posterior and frontal cortical regions of interest) and cerebrovascular imaging features (presence of large or small cortical/subcortical infarcts and WMH volume). We performed mediation pathway analyses to assess the hypothesis that hippocampal and cortical volumes mediated the associations between cerebrovascular imaging features and cognition. Results— In unmediated analyses, WMH and infarcts were both associated with worse psychomotor speed/executive function. In mediation analyses, WMH and infarct associations on psychomotor speed/executive function were significantly attenuated, but not abolished, by the inclusion of the posterior cortical regions of interest volume in the models, and the infarcts on psychomotor speed/executive function association were attenuated, but not abolished, by inclusion of the frontal cortical regions of interest volume. Conclusions— Both WMH and infarcts were associated with cortical volume, and both lesions were also associated with cognitive performance, implying shared pathophysiological mechanisms. Although cross-sectional, our findings suggest that WMH and infarcts could be proxies for clinically covert processes that directly damage cortical regions. Microinfarcts are 1 candidate for such a clinically covert process.

We used whole‐exome sequencing to identify variants other than APOE associated with the rate of hippocampal atrophy in amnestic mild cognitive impairment. An in‐silico predicted missense variant in REST (rs3796529) was found exclusively in subjects with slow hippocampal volume loss and validated using unbiased whole‐brain analysis and meta‐analysis across 5 independent cohorts. REST is a master regulator of neurogenesis and neuronal differentiation that has not been previously implicated in Alzheimer's disease. These findings nominate REST and its functional pathways as protective and illustrate the potential of combining next‐generation sequencing with neuroimaging to discover novel disease mechanisms and potential therapeutic targets. Ann Neurol 2015;77:547–552

AbstractIntroductionAlzheimer's disease (AD) is characterized by the accumulation of β‐amyloid (Aβ) associated with brain atrophy and cognitive decline. The functional form to model the association between Aβ and regional brain atrophy has not been well defined. To determine the relationship between Aβ and atrophy, we compared the performance of the usual dichotomization of cerebrospinal fluid (CSF) Aβ to identify subjects as Aβ+ and Aβ− with a trilinear spline model of CSF Aβ.MethodsOne hundred and eighty‐three subjects with mild cognitive impairment and 108 cognitively normal controls with baseline CSF Aβ and up to 4 years of longitudinal magnetic resonance imaging data from the Alzheimer's Disease Neuroimaging Initiative were analyzed using mixed‐effects regression. Piecewise‐linear splines were used to evaluate the nonlinear nature of the association between CSF Aβ and regional atrophy and to identify points of acceleration of atrophy with respect to Aβ. Several parameterizations of CSF Aβ were compared using likelihood ratio tests and the Akaike information criterion. Periods of acceleration of atrophy in which subjects transition from CSF Aβ negativity to CSF Aβ positivity were estimated from the spline models and tested for significance.ResultsSpline models resulted in better fits for many temporal and parietal regions compared with the dichotomous models. The trilinear model showed that periods of acceleration of atrophy varied greatly by region with early changes seen in the insula, amygdala, precuneus, hippocampus, and other temporal regions, occurring before the clinical threshold for CSF Aβ positivity.DiscussionThe use of piecewise‐linear splines provides an improved model of the nonlinear association between CSF Aβ and regional atrophy in regions implicated in the progression of AD. The important biological finding of this work is that some brain regions show periods of accelerated volume loss well before the CSF Aβ42 threshold. This implies that signs of brain atrophy develop before the current conventional definition of “preclinical AD”.

AbstractBackgroundInexpensive, non‐invasive tools for assessing Alzheimer‐type pathophysiologies are needed. Computerized cognitive assessments are prime candidates.MethodsCognitively normal participants, aged 51–71, with magnetic resonance imaging, fluorodeoxyglucose‐positron emission tomography (FDG‐PET), amyloid PET, CogState computerized cognitive assessment, and standard neuropsychological tests were included. We first examined the association between the CogState battery and neuroimaging measures. We then compared that association to the one between standard neuropsychological z‐scores and neuroimaging.ResultsSlower reaction times for CogState Identification and One Back, and lower memory and attention z‐scores, were associated (P < .05) with FDG‐PET hypometabolism. Slower time on the Groton Maze Learning Task and worse One Card Learning accuracy were associated (P < .05) with smaller hippocampal volumes. There were no associations with amyloid PET. Associations of CogState and neuropsychological Z‐scores with neuroimaging were small and of a similar magnitude.ConclusionsCogState subtests were cross‐sectionally comparable to standard neuropsychological tests in their relatively weak associations with neurodegeneration imaging markers.