The Parkinson's progression markers initiative (PPMI) - establishing a PD biomarker cohort.

OBJECTIVE: The Parkinson's Progression Markers Initiative (PPMI) is an observational, international study designed to establish biomarker-defined cohorts and identify clinical, imaging, genetic, and biospecimen Parkinson's disease (PD) progression markers to accelerate disease-modifying therapeutic trials. METHODS: A total of 423 untreated PD, 196 Healthy Control (HC) and 64 SWEDD (scans without evidence of dopaminergic deficit) subjects were enrolled at 24 sites. To enroll PD subjects as early as possible following diagnosis, subjects were eligible with only asymmetric bradykinesia or tremor plus a dopamine transporter (DAT) binding deficit on SPECT imaging. Acquisition of data was standardized as detailed at www.ppmi-info.org. RESULTS: Approximately 9% of enrolled subjects had a single PD sign at baseline. DAT imaging excluded 16% of potential PD subjects with SWEDD. The total MDS-UPDRS for PD was 32.4 compared to 4.6 for HC and 28.2 for SWEDD. On average, PD subjects demonstrated 45% and 68% reduction in mean striatal and contralateral putamen Specific Binding Ratios (SBR), respectively. Cerebrospinal fluid (CSF) was acquired from >97% of all subjects. CSF (PD/HC/SWEDD pg/mL) α-synuclein (1845/2204/2141) was reduced in PD vs HC or SWEDD (P < 0.03). Similarly, t-tau (45/53) and p-tau (16/18) were reduced in PD versus HC (P < 0.01). INTERPRETATION: PPMI has detailed the biomarker signature for an early PD cohort defined by clinical features and imaging biomarkers. This strategy provides the framework to establish biomarker cohorts and to define longitudinal progression biomarkers to support future PD treatment trials.

Longitudinal Change of Clinical and Biological Measures in Early Parkinson's Disease: Parkinson's Progression Markers Initiative Cohort.

OBJECTIVE: The objective of this study was to assess longitudinal change in clinical and dopamine transporter imaging outcomes in early, untreated PD. METHODS: We describe 5-year longitudinal change of the MDS-UPDRS and other clinical measures using results from the Parkinson's Progression Markers Initiative, a longitudinal cohort study of early Parkinson's disease (PD) participants untreated at baseline. We also provide data on the longitudinal change in dopamine transporter 123-I Ioflupane striatal binding and correlation between the 2 measures. RESULTS: A total of 423 PD participants were recruited, and 358 remain in the study at year 5. Baseline MDS-UPDRS total score was 32.4 (standard deviation 13.1), and the average annual change (assessed medications OFF for the treated participants) was 7.45 (11.6), 3.11 (11.7), 4(11.9), 4.7 (11.1), and 1.74(11.9) for years 1, 2, 3, 4, and 5, respectively (P < .0001 for the change over time), with a steeper change in year 1. Dopaminergic therapy had a significant effect on the change of MDS-UPDRS. There was a significant longitudinal change in dopamine transporter binding in all striatal regions (P < .001). There was a significant but weak correlation between MDS-UPDRS and dopamine transporter binding at baseline and years 1, 2, and 4, but no correlation between the rate of change of the 2 variables. CONCLUSIONS: We present 5-year longitudinal data on the change of the MDS-UPDRS and other clinical and dopamine transporter imaging outcome measures in early PD. These data can be used for sample size estimates for interventional studies in the de novo PD population. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Data-driven regions of interest for longitudinal change in three variants of frontotemporal lobar degeneration.

INTRODUCTION: Longitudinal imaging of neurodegenerative disorders is a potentially powerful biomarker for use in clinical trials. In Alzheimer's disease, studies have demonstrated that empirically derived regions of interest (ROIs) can provide more reliable measurement of disease progression compared with anatomically defined ROIs. METHODS: We set out to derive ROIs with optimal effect size for quantifying longitudinal change in a hypothetical clinical trial by comparing atrophy rates in 44 patients with behavioral variant of frontotemporal dementia (bvFTD), 30 with the semantic variant primary progressive aphasia (svPPA), and 26 with the nonfluent variant PPA (nfvPPA) to atrophy in 97 cognitively healthy controls. RESULTS: The regions identified for each variant were generally what would be expected from prior studies of frontotemporal lobar degeneration (FTLD). Sample size estimates for detecting a 40% reduction in annual rate of ROI atrophy varied substantially across groups, being 103 per arm in bvFTD, 31 in nfvPPA, and 10 in svPPA, but in all groups were less than those estimated for a priori ROIs and clinical measures. The variability in location of peak regions of atrophy across individuals was highest in bvFTD and lowest in svPPA, likely relating to the differences in effect size. CONCLUSIONS: These findings suggest that, while cross-validated maps of change can improve sensitivity to change in FTLD compared with a priori regions, the reliability of these maps differs considerably across syndromes. Future studies can utilize these maps to design clinical trials, and should try to identify factors accounting for the variability in patterns of atrophy across individuals, particularly those with bvFTD.

Progression of Regional Microstructural Degeneration in Parkinson's Disease: A Multicenter Diffusion Tensor Imaging Study.

This study aimed to identify the utility of diffusion tensor imaging (DTI) in measuring the regional distribution of abnormal microstructural progression in patients with Parkinson's disease who were enrolled in the Parkinson's progression marker initiative (PPMI). One hundred and twenty two de-novo PD patients (age = 60.5±9) and 50 healthy controls (age = 60.6±11) had DTI scans at baseline and 12.6±1 months later. Automated image processing included an intra-subject registration of all time points and an inter-subjects registration to a brain atlas. Annualized rates of DTI variations including fractional anisotropy (FA), radial (rD) and axial (aD) diffusivity were estimated in a total of 118 white matter and subcortical regions of interest. A mixed effects model framework was used to determine the degree to which DTI changes differed in PD relative to changes in healthy subjects. Significant DTI changes were also tested for correlations with changes in clinical measures, dopaminergic imaging and CSF biomarkers in PD patients. Compared to normal aging, PD was associated with higher rates of FA reduction, rD and aD increases predominantly in the substantia nigra, midbrain and thalamus. The highest rates of FA reduction involved the substantia nigra (3.6±1.4%/year from baseline, whereas the highest rates of increased diffusivity involved the thalamus (rD: 8.0±2.9%/year, aD: 4.0±1.5%/year). In PD patients, high DTI changes in the substantia nigra correlated with increasing dopaminergic deficits as well as with declining α-synuclein and total tau protein concentrations in cerebrospinal fluid. Increased DTI rates in the thalamus correlated with progressive decline in global cognition in PD. The results suggest that higher rates of regional microstructural degeneration are potential markers of PD progression.

Progression of brain atrophy in PSP and CBS over 6 months and 1 year.

OBJECTIVE: To examine the utility and reliability of volumetric MRI in measuring disease progression in the 4 repeat tauopathies, progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS), to support clinical development of new tau-directed therapeutic agents. METHODS: Six- and 12-month changes in regional MRI volumes and PSP Rating Scale scores were examined in 55 patients with PSP and 33 patients with CBS (78% amyloid PET negative) compared to 30 normal controls from a multicenter natural history study. Longitudinal voxel-based morphometric analyses identified patterns of volume loss, and region-of-interest analyses examined rates of volume loss in brainstem (midbrain, pons, superior cerebellar peduncle), cortical, and subcortical regions based on previously validated atlases. Results were compared to those in a replication cohort of 226 patients with PSP with MRI data from the AL-108-231 clinical trial. RESULTS: Patients with CBS exhibited greater baseline atrophy and greater longitudinal atrophy rates in cortical and basal ganglia regions than patients with PSP; however, midbrain and pontine atrophy rates were similar. Voxel-wise analyses showed distinct patterns of regional longitudinal atrophy in each group as compared to normal controls. The midbrain/pons volumetric ratio differed between diagnoses but remained stable over time. In both patient groups, brainstem atrophy rates were correlated with disease progression measured using the PSP Rating Scale. CONCLUSIONS: Volume loss is quantifiable over a period of 6 months in CBS and PSP. Future clinical trials may be able to combine CBS and PSP to measure therapeutic effects.

Diagnostic utility of ASL-MRI and FDG-PET in the behavioral variant of FTD and AD.

OBJECTIVE: To compare the values of arterial spin-labeled (ASL) MRI and fluorodeoxyglucose (FDG) PET in the diagnosis of behavioral variant of frontotemporal dementia (bvFTD) and Alzheimer's disease (AD). METHODS: Partial least squares logistic regression was used to identify voxels with diagnostic value in cerebral blood flow (CBF) and cerebral metabolic rate of glucose (CMRgl) maps from patients with bvFTD (n = 32) and AD (n = 28), who were compared with each other and with cognitively normal controls (CN, n = 15). Diagnostic values of these maps were compared with each other. RESULTS: Regions that differentiated each disorder from controls were similar for CBF and CMRgl. For differentiating AD from CN, the areas under the curve (AUC) for CBF (0.89) and CMRgl (0.91) were similar, with similar sensitivity (CBF: 86%, CMRgl: 78%) and specificity (CBF: 92%, CMRgl: 100%). Likewise, for differentiating bvFTD from CN performances of CBF (AUC = 0.83) and CMRgl (AUC = 0.85) were equivalent, with similar sensitivity (CBF: 78%, CMRgl: 79%) and specificity (CBF: 92%, CMRgl: 100%). In differentiating bvFTD from AD, classification was again similar for CBF (AUC = 0.87) and CMRgl (AUC = 0.79), as were sensitivity (CBF: 83%, CMRgl: 89%) and specificity (CBF: 93%, CMRgl: 78%). None of the differences in any performance measure were statistically significant. INTERPRETATION: ASL-MRI has similar diagnostic utility as FDG-PET in the diagnosis of AD and bvFTD. Continued development of ASL-MRI as a diagnostic tool for neurodegenerative dementias is warranted.

Data-driven regions of interest for longitudinal change in frontotemporal lobar degeneration.

Current research is investigating the potential utility of longitudinal measurement of brain structure as a marker of drug effect in clinical trials for neurodegenerative disease. Recent studies in Alzheimer's disease (AD) have shown that measurement of change in empirically derived regions of interest (ROIs) allows more reliable measurement of change over time compared with regions chosen a-priori based on known effects of AD on brain anatomy. Frontotemporal lobar degeneration (FTLD) is a devastating neurodegenerative disorder for which there are no approved treatments. The goal of this study was to identify an empirical ROI that maximizes the effect size for the annual rate of brain atrophy in FTLD compared with healthy age matched controls, and to estimate the effect size and associated power estimates for a theoretical study that would use change within this ROI as an outcome measure. Eighty six patients with FTLD were studied, including 43 who were imaged twice at 1.5 T and 43 at 3 T, along with 105 controls (37 imaged at 1.5 T and 67 at 3 T). Empirically-derived maps of change were generated separately for each field strength and included the bilateral insula, dorsolateral, medial and orbital frontal, basal ganglia and lateral and inferior temporal regions. The extent of regions included in the 3 T map was larger than that in the 1.5 T map. At both field strengths, the effect sizes for imaging were larger than for any clinical measures. At 3 T, the effect size for longitudinal change measured within the empirically derived ROI was larger than the effect sizes derived from frontal lobe, temporal lobe or whole brain ROIs. The effect size derived from the data-driven 1.5 T map was smaller than at 3 T, and was not larger than the effect size derived from a-priori ROIs. It was estimated that measurement of longitudinal change using 1.5 T MR systems requires approximately a 3-fold increase in sample size to obtain effect sizes equivalent to those seen at 3 T. While the results should be confirmed in additional datasets, these results indicate that empirically derived ROIs can reduce the number of subjects needed for a longitudinal study of drug effects in FTLD compared with a-priori ROIs. Field strength may have a significant impact on the utility of imaging for measuring longitudinal change.

Progression of Microstructural Degeneration in Progressive Supranuclear Palsy and Corticobasal Syndrome: A Longitudinal Diffusion Tensor Imaging Study.

Progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS) are both 4 microtubule binding repeat tauopathy related disorders. Clinical trials need new biomarkers to assess the effectiveness of tau-directed therapies. This study investigated the regional distribution of longitudinal diffusion tensor imaging changes, measured by fractional anisotropy, radial and axial diffusivity over 6 months median interval, in 23 normal control subjects, 35 patients with PSP, and 25 patients with CBS. A mixed-effects framework was used to test longitudinal changes within and between groups. Correlations between changes in diffusion variables and clinical progression were also tested. The study found that over a 6 month period and compared to controls, the most prominent changes in PSP were up to 3±1% higher rates of FA reduction predominantly in superior cerebellar peduncles, and up to 18±6% higher rates of diffusivity increases in caudate nuclei. The most prominent changes in CBS compared to controls were up to 4±1% higher rates of anisotropy reduction and 18±6% higher rates of diffusivity increase in basal ganglia and widespread white matter regions. Compared to PSP, CBS was mainly associated with up to 3±1% greater rates of anisotropy reduction around the central sulci, and 11±3% greater rates of diffusivity increase in superior fronto-occipital fascicules. Rates of diffusivity increases in the superior cerebellar peduncle correlated with rates of ocular motor decline in PSP patients. This study demonstrated that longitudinal diffusion tensor imaging measurement is a promising surrogate marker of disease progression in PSP and CBS over a relatively short period.

Discriminative Power of Arterial Spin Labeling Magnetic Resonance Imaging and 18F-Fluorodeoxyglucose Positron Emission Tomography Changes for Amyloid-ß-Positive Subjects in the Alzheimer's Disease Continuum.

BACKGROUND: Recent studies have demonstrated that arterial spin labeling magnetic resonance imaging (ASL-MRI) and fluorodeoxyglucose positron emission tomography (FDG-PET) identify similar regional abnormalities and have comparable diagnostic accuracy in Alzheimer's disease (AD). The agreement between these modalities in the AD continuum, which is an important concept for early detection and disease monitoring, is yet unclear. OBJECTIVE: We aimed to assess the ability of the cerebral blood flow (CBF) measures from ASL-MRI and cerebral metabolic rate for glucose (CMRgl) measures from FDG-PET to distinguish amyloid-ß-positive (Aß+) subjects in the AD continuum from healthy controls. METHODS: The study included asymptomatic, cognitively normal (CN) controls and patients with early mild cognitive impairment (MCI), late MCI, and AD, all with significant levels of cortical Aß based on their florbetapir PET scans to restrict the study to patients truly in the AD continuum. The discrimination power of each modality was based on the whole-brain patterns of CBF and CMRgl changes identified by partial least squares logistic regression, a multivariate analysis technique. RESULTS: While CBF changes in the posterior inferior aspects of the brain and a pattern of CMRgl changes in the superior aspects of the brain including frontal and parietal regions best discriminated the Aß+ subjects in the early disease stages from the Aß- CN subjects, there was a greater agreement in the whole-brain patterns of CBF and CMRgl changes that best discriminated the Aß+ subjects from the Aß- CN subjects in the later disease stages. Despite the differences in the whole-brain patterns of CBF and CMRgl changes, the discriminative powers of both modalities were similar with statistically nonsignificant performance differences in sensitivity and specificity. CONCLUSION: The results comparing measurements of CBF to CMRgl add to previous reports that MRI-measured CBF has a similar diagnostic ability to detect AD as has FDG-PET. Our findings that CBF and CMRgl changes occur in different brain regions in Aß+ subjects across the AD continuum compared with Aß- CN subjects may be the result of methodological differences. Alternatively, these findings may signal alterations in neurovascular coupling which alter relationships between brain perfusion and glucose metabolism in the AD continuum.

A fast algorithm for denoising magnitude diffusion-weighted images with rank and edge constraints.

PURPOSE: To accelerate denoising of magnitude diffusion-weighted images subject to joint rank and edge constraints. METHODS: We extend a previously proposed majorize-minimize method for statistical estimation that involves noncentral χ distributions to incorporate joint rank and edge constraints. A new algorithm is derived which decomposes the constrained noncentral χ denoising problem into a series of constrained Gaussian denoising problems each of which is then solved using an efficient alternating minimization scheme. RESULTS: The performance of the proposed algorithm has been evaluated using both simulated and experimental data. Results from simulations based on ex vivo data show that the new algorithm achieves about a factor of 10 speed up over the original Quasi-Newton-based algorithm. This improvement in computational efficiency enabled denoising of large datasets containing many diffusion-encoding directions. The denoising performance of the new efficient algorithm is found to be comparable to or even better than that of the original slow algorithm. For an in vivo high-resolution Q-ball acquisition, comparison of fiber tracking results around hippocampus region before and after denoising will also be shown to demonstrate the denoising effects of the new algorithm. CONCLUSION: The optimization problem associated with denoising noncentral χ distributed diffusion-weighted images subject to joint rank and edge constraints can be solved efficiently using a majorize-minimize-based algorithm.

Amyloid in dementia associated with familial FTLD: not an innocent bystander.

Patients with frontotemporal lobar degeneration (FTLD) can show superimposed amyloid pathology, though the impact of amyloid on the clinical presentation of FTLD is not well characterized. This cross-sectional case-control study compared clinical features, fluorodeoxyglucose-positron emission tomography metabolism and gray matter volume loss in 30 patients with familial FTLD in whom amyloid status was confirmed with autopsy or Pittsburgh compound B-PET. Compared to the amyloid-negative patients, the amyloid-positive patients performed significantly worse on several cognitive tests and showed hypometabolism and volume loss in more temporoparietal regions. Our results suggest that in FTLD amyloid positivity is associated with a more Alzheimer's disease-like pattern of neurodegeneration.

Quantitative framework for prospective motion correction evaluation.

PURPOSE: Establishing a framework to evaluate performances of prospective motion correction (PMC) MRI considering motion variability between MRI scans. METHODS: A framework was developed to obtain quantitative comparisons between different motion correction setups, considering that varying intrinsic motion patterns between acquisitions can induce bias. Intrinsic motion was considered by replaying in a phantom experiment the recorded motion trajectories from subjects. T1-weighted MRI on five volunteers and two different marker fixations (mouth guard and nose bridge fixations) were used to test the framework. Two metrics were investigated to quantify the improvement of the image quality with PMC. RESULTS: Motion patterns vary between subjects as well as between repeated scans within a subject. This variability can be approximated by replaying the motion in a distinct phantom experiment and used as a covariate in models comparing motion corrections. We show that considering the intrinsic motion alters the statistical significance in comparing marker fixations. As an example, two marker fixations, a mouth guard and a nose bridge, were evaluated in terms of their effectiveness for PMC. A mouth guard achieved better PMC performance. CONCLUSION: Intrinsic motion patterns can bias comparisons between PMC configurations and must be considered for robust evaluations. A framework for evaluating intrinsic motion patterns in PMC is presented.

Diffusion imaging of nigral alterations in early Parkinson's disease with dopaminergic deficits.

BACKGROUND: This study reports the baseline characteristics of diffusion tensor imaging data in Parkinson's disease (PD) patients and healthy control subjects from the Parkinson's Progression Markers Initiative. The main goals were to replicate previous findings of abnormal diffusion imaging values from the substantia nigra. in a large multicenter cohort and determine whether nigral diffusion alterations are associated with dopamine deficits. METHODS: Two hundred twenty subjects (PD = 153; control = 67) from 10 imaging sites were included. All subjects had a full neurological exam, a ((123) I)ioflupane dopamine transporter (DAT) single-photon emission computer tomography scan, and diffusion tensor imaging. Fractional anisotropy as well as radial and axial diffusivity was computed within multiple regions across the substantia nigra. RESULTS: A repeated-measures analysis of variance found a marginally nonsignificant interaction between regional fractional anisotropy of the substantia nigra and disease status (P = 0.08), conflicting with an earlier study. However, a linear mixed model that included control regions in addition to the nigral regions revealed a significant interaction between regions and disease status (P = 0.002), implying a characteristic distribution of reduced fractional anisotropy across the substantia nigra in PD. Reduced fractional anisotropy in PD was also associated with diminished DAT binding ratios. Both axial and radial diffusivity were also abnormal in PD. CONCLUSIONS: Although routine nigral measurements of fractional anisotropy are clinically not helpful, the findings in this study suggest that more-sophisticated diffusion imaging protocols should be used when exploring the clinical utility of this imaging modality.

Multimodal imaging in Alzheimer's disease: validity and usefulness for early detection.

Alzheimer's disease is a progressive neurodegenerative disease that typically manifests clinically as an isolated amnestic deficit that progresses to a characteristic dementia syndrome. Advances in neuroimaging research have enabled mapping of diverse molecular, functional, and structural aspects of Alzheimer's disease pathology in ever increasing temporal and regional detail. Accumulating evidence suggests that distinct types of imaging abnormalities related to Alzheimer's disease follow a consistent trajectory during pathogenesis of the disease, and that the first changes can be detected years before the disease manifests clinically. These findings have fuelled clinical interest in the use of specific imaging markers for Alzheimer's disease to predict future development of dementia in patients who are at risk. The potential clinical usefulness of single or multimodal imaging markers is being investigated in selected patient samples from clinical expert centres, but additional research is needed before these promising imaging markers can be successfully translated from research into clinical practice in routine care.

Magnetic resonance imaging in Alzheimer's Disease Neuroimaging Initiative 2.

INTRODUCTION: Alzheimer's Disease Neuroimaging Initiative (ADNI) is now in its 10th year. The primary objective of the magnetic resonance imaging (MRI) core of ADNI has been to improve methods for clinical trials in Alzheimer's disease (AD) and related disorders. METHODS: We review the contributions of the MRI core from present and past cycles of ADNI (ADNI-1, -Grand Opportunity and -2). We also review plans for the future-ADNI-3. RESULTS: Contributions of the MRI core include creating standardized acquisition protocols and quality control methods; examining the effect of technical features of image acquisition and analysis on outcome metrics; deriving sample size estimates for future trials based on those outcomes; and piloting the potential utility of MR perfusion, diffusion, and functional connectivity measures in multicenter clinical trials. DISCUSSION: Over the past decade the MRI core of ADNI has fulfilled its mandate of improving methods for clinical trials in AD and will continue to do so in the future.

Directed network motifs in Alzheimer's disease and mild cognitive impairment.

Directed network motifs are the building blocks of complex networks, such as human brain networks, and capture deep connectivity information that is not contained in standard network measures. In this paper we present the first application of directed network motifs in vivo to human brain networks, utilizing recently developed directed progression networks which are built upon rates of cortical thickness changes between brain regions. This is in contrast to previous studies which have relied on simulations and in vitro analysis of non-human brains. We show that frequencies of specific directed network motifs can be used to distinguish between patients with Alzheimer's disease (AD) and normal control (NC) subjects. Especially interesting from a clinical standpoint, these motif frequencies can also distinguish between subjects with mild cognitive impairment who remained stable over three years (MCI) and those who converted to AD (CONV). Furthermore, we find that the entropy of the distribution of directed network motifs increased from MCI to CONV to AD, implying that the distribution of pathology is more structured in MCI but becomes less so as it progresses to CONV and further to AD. Thus, directed network motifs frequencies and distributional properties provide new insights into the progression of Alzheimer's disease as well as new imaging markers for distinguishing between normal controls, stable mild cognitive impairment, MCI converters and Alzheimer's disease.

Diffusion tensor imaging of the nigrostriatal fibers in Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is histopathologically characterized by the loss of dopamine neurons in the substantia nigra pars compacta. The depletion of these neurons is thought to reduce the dopaminergic function of the nigrostriatal pathway, as well as the neural fibers that link the substantia nigra to the striatum (putamen and caudate), causing a dysregulation in striatal activity that ultimately leads to lack of movement control. Based on diffusion tensor imaging, visualizing this pathway and measuring alterations of the fiber integrity remain challenging. The objectives were to 1) develop a diffusion tensor tractography protocol for reliably tracking the nigrostriatal fibers on multicenter data; 2) test whether the integrities measured by diffusion tensor imaging of the nigrostriatal fibers are abnormal in PD; and 3) test whether abnormal integrities of the nigrostriatal fibers in PD patients are associated with the severity of motor disability and putaminal dopamine binding ratios. METHODS: Diffusion tensor tractography was performed on 50 drug-naïve PD patients and 27 healthy control subjects from the international multicenter Parkinson's Progression Marker Initiative. RESULTS: Tractography consistently detected the nigrostriatal fibers, yielding reliable diffusion measures. Fractional anisotropy, along with radial and axial diffusivity of the nigrostriatal tract, showed systematic abnormalities in patients. In addition, variations in fractional anisotropy and radial diffusivity of the nigrostriatal tract were associated with the degree of motor deficits in PD patients. CONCLUSION: Taken together, the findings imply that the diffusion tensor imaging characteristic of the nigrostriatal tract is potentially an index for detecting and staging of early PD.

Bayesian segmentation of brainstem structures in MRI.

In this paper we present a method to segment four brainstem structures (midbrain, pons, medulla oblongata and superior cerebellar peduncle) from 3D brain MRI scans. The segmentation method relies on a probabilistic atlas of the brainstem and its neighboring brain structures. To build the atlas, we combined a dataset of 39 scans with already existing manual delineations of the whole brainstem and a dataset of 10 scans in which the brainstem structures were manually labeled with a protocol that was specifically designed for this study. The resulting atlas can be used in a Bayesian framework to segment the brainstem structures in novel scans. Thanks to the generative nature of the scheme, the segmentation method is robust to changes in MRI contrast or acquisition hardware. Using cross validation, we show that the algorithm can segment the structures in previously unseen T1 and FLAIR scans with great accuracy (mean error under 1mm) and robustness (no failures in 383 scans including 168 AD cases). We also indirectly evaluate the algorithm with a experiment in which we study the atrophy of the brainstem in aging. The results show that, when used simultaneously, the volumes of the midbrain, pons and medulla are significantly more predictive of age than the volume of the entire brainstem, estimated as their sum. The results also demonstrate that the method can detect atrophy patterns in the brainstem structures that have been previously described in the literature. Finally, we demonstrate that the proposed algorithm is able to detect differential effects of AD on the brainstem structures. The method will be implemented as part of the popular neuroimaging package FreeSurfer.

Variables associated with hippocampal atrophy rate in normal aging and mild cognitive impairment.

The goal of this study was to identify factors contributing to hippocampal atrophy rate (HAR) in clinically normal older adults (NC) and participants with mild cognitive impairment (MCI). Longitudinal HAR was measured on T1-weighted magnetic resonance imaging, and the contribution of age, gender, apolipoprotein E (ApoE) ε4 status, intracranial volume, white matter lesions, and ß-amyloid (Aß) levels to HAR was determined using linear regression. Age-related effects of HAR were compared in Aß positive (Aß+) and Aß negative (Aß-) participants. Age and Aß levels had independent effects on HAR in NC, whereas gender, ApoE ε4 status, and Aß levels were associated with HAR in MCI. In multivariable models, Aß levels were associated with HAR in NC; ApoE ε4 and Aß levels were associated with HAR in MCI. In MCI, age was a stronger predictor of HAR in Aß- versus Aß+ participants. HAR was higher in Aß+ participants, but most of the HAR was because of factors other than Aß status. Age-related effects on HAR did not differ between NC versus MCI participants with the same Aß status. Therefore, we conclude that even when accounting for other covariates, Aß status, and not age, is a significant predictor of HAR; and that most of the HAR is not accounted for by Aß status in either NC or MCI.

Sensitive measures of executive dysfunction in non-demented Parkinson's disease.

BACKGROUND: We examined the sensitivity of different executive function measures for detecting deficits in Parkinson's disease patients without dementia. METHODS: Twenty-one non-demented PD subjects and 21 neurologically healthy controls were administered widely used clinical executive functioning measures as well as the NIH EXAMINER battery, which produces Cognitive Control, Working Memory, and Verbal Fluency scores, along with an overall Executive Composite score, using psychometrically matched scales. RESULTS: No significant differences between groups were observed on widely used clinical measures. The PD patients scored lower than controls on the EXAMINER Executive Composite, Cognitive Control, and Working Memory Scores. CONCLUSIONS: The NIH EXAMINER Executive Composite and Cognitive Control Scores are sensitive measures of executive dysfunction in non-demented PD, and may be more sensitive than several widely used measures. Results highlight the importance of careful test selection when evaluating for mild cognitive impairment in PD.