Combining anatomical, diffusion, and resting state functional magnetic resonance imaging for individual classification of mild and moderate Alzheimer's disease

AbstractMagnetic resonance imaging (MRI) is sensitive to structural and functional changes in the brain caused by Alzheimer's disease (AD), and can therefore be used to help in diagnosing the disease. Improving classification of AD patients based on MRI scans might help to identify AD earlier in the disease's progress, which may be key in developing treatments for AD. In this study we used an elastic net classifier based on several measures derived from the MRI scans of mild to moderate AD patients (N=77) from the prospective registry on dementia study and controls (N=173) from the Austrian Stroke Prevention Family Study. We based our classification on measures from anatomical MRI, diffusion weighted MRI and resting state functional MRI. Our unimodal classification performance ranged from an area under the curve (AUC) of 0.760 (full correlations between functional networks) to 0.909 (grey matter density). When combining measures from multiple modalities in a stepwise manner, the classification performance improved to an AUC of 0.952. This optimal combination consisted of grey matter density, white matter density, fractional anisotropy, mean diffusivity, and sparse partial correlations between functional networks. Classification performance for mild AD as well as moderate AD also improved when using this multimodal combination. We conclude that different MRI modalities provide complementary information for classifying AD. Moreover, combining multiple modalities can substantially improve classification performance over unimodal classification

Changes in brain electrical activity during extended continuous word recognition

Twenty healthy subjects (10 men, 10 women) participated in an EEG study with an extended continuous recognition memory task, in which each of 30 words was randomly shown 10 times and subjects were required to make old vs. new decisions. Both event-related brain potentials (ERPs) and induced band power (IBP) were investigated. We hypothesized that repeated presentations affect recollection rather than familiarity. For the 300- to 500-ms time window, an 'old/new' ERP effect was found for the first vs. second word presentations. The correct recognition of an 'old' word was associated with a more positive waveform than the correct identification of a new word. The old/new effect was most pronounced at and around the midline parietal electrode position. For the 500- to 800-ms time window, a linear repetition effect was found for multiple word repetitions. Correct recognition after an increasing number of repetitions was associated with increasing positivity. The multiple repetitions effect was most pronounced at the midline central (Cz) and fronto-central (FCz) electrode positions and reflects a graded recollection process: the stronger the memory trace grows, the more positive the ERP in the 500- to 800-ms time window. The ERP results support a dual-processing model, with familiarity being discernable from a more graded recollection state that depends on memory strengths. For IBP, we found 'old/new' effects for the lower-2 alpha, theta, and delta bands, with higher bandpower during 'old' words. The lower-2 alpha 'old/new' effect most probably reflects attentional processes, whereas the theta and delta effects reflect encoding and retrieval processes. Upon repeated word presentations, the magnitude of induced delta power in the 375- to 750-ms time window diminished linearly. Correlation analysis suggests that decreased delta power is moderately associated with faster decision speed and higher accurac

Modelling the cascade of biomarker changes in progranulin‐related frontotemporal dementia

AbstractBackgroundProgranulin related frontotemporal dementia (FTD‐GRN) is a fast progressive disorder, in which pathophysiological changes precede overt clinical symptoms in only a short time period. Modelling the cascade of multimodal biomarker changes aids in understanding the etiology of this disease, enables monitoring of individual mutation carriers, and would give input for disease‐modifying treatments. In this cross‐sectional study, we estimated the temporal cascade of biomarker changes for FTD‐GRN, in a data‐driven way.MethodWe included 56 presymptomatic and 35 symptomatic GRN mutation carriers, and 35 healthy non‐carriers. Of the symptomatic subjects, 17 had behavioural variant FTD (bvFTD), 16 presented as non‐fluent variant primary progressive aphasia (nfvPPA). The selected biomarkers for establishing the cascade of changes were neurofilament light chain, regional grey matter volumes, fractional anisotropy of white matter tracts, and cognitive domains. We used a data‐driven analysis called discriminative event‐based modelling (Venkatraghavan, NeuroImage, 2019) with a novel modification to its Gaussian Mixture Model (GMM) called Siamese GMM, to estimate the cascade of biomarker changes for FTD‐GRN. Using cross‐validation, we estimated disease severities of individual mutation carriers in the test set based on their progression along the biomarker cascade established on the training set.ResultNeurofilament light chain and white matter tracts were the earliest biomarkers to become abnormal in FTD‐GRN mutation carriers. Attention and executive functioning were also affected early on in the disease process. Based on the estimated individual disease severities, presymptomatic mutation carriers could be distinguished from symptomatic mutation carriers with a sensitivity of 95% and specificity of 100% in the cross‐validation experiment. There was a high correlation (r=0.94, p<0.001) between estimated disease severity and years since symptom onset in nfvPPA, but not in bvFTD (r=0.33, p=0.46).ConclusionIn this study, we unravelled the temporal cascade of multimodal biomarker changes for FTD‐GRN. Our results suggest that axonal degeneration is one of the first disease events in FTD‐GRN, which calls for designing disease modifying treatments that strengthens the axons. We also demonstrated a good delineation between symptomatic and presymptomatic carriers using the estimated disease severities, which suggest that our model could enable monitoring of individual mutation carriers

Cholinergic challenge in Alzheimer patients and mild cognitive impairment differentially affects hippocampal activation - A pharmacological fMRI study

Pharmacological functional MRI (phMRI) examines the impact of pharmacologically induced neurochemical changes on brain function at a system level. The current phMRI study directly compared effects of cholinergic stimulation on brain function between patients with Alzheimer's disease and mild cognitive impairment, a disease stage preceding the development of Alzheimer's disease. Brain function during recognition of (un)familiar information was examined for changes after exposure to galantamine, a cholinesterase inhibitor used for treating memory deficits in Alzheimer's disease. Alzheimer patients [n = 18; age 74.5 years ± 8.2; Mini-Mental State Examination (MMSE) 22.5 ± 2.4] and patients with mild cognitive impairment (n = 28; mean age 73.6 ± 7.5; MMSE 27.0 ± 1.2) were scanned during face recognition under three different conditions: at baseline, and after acute (single dose) and prolonged exposure (5 days) to galantamine. Functional data were analysed in an event-related fashion. In both groups, acute exposure produced strong increases in brain activation (Z > 3.1). Prolonged exposure produced less strong effects that mainly involved decreases in activation (Z > 3.1). In mild cognitive impairment, acute exposure increased activation in posterior cingulate, left inferior parietal, and anterior temporal lobe. Prolonged exposure decreased activation in similar posterior cingulate areas, and in bilateral prefrontal areas. Effects were stronger for positive ('familiar') than for negative ('unfamiliar') decisions, indicating that the effect was specific to memory retrieval. In Alzheimer patients, acute exposure increased activation bilaterally in hippocampal areas, whereas prolonged exposure decreased activation in these areas. Effects were more pronounced for negative than for positive decisions, suggesting a preferential effect on memory encoding. Unique profiles of signal reactivity were found in a number of areas, including left inferior parietal lobe and left hippocampus proper. The reactivity of posterior cingulate and hippocampal structures to cholinergic challenge suggests a key role of the cholinergic system in the functional processes that lead to Alzheimer's disease. The differential response to cholinergic challenge in mild cognitive impairment and Alzheimer patients may reflect a difference in the functional status of the cholinergic system between both groups, which is in line with recent results showing a differential clinical response to cholinergic treatment

Unbiased whole-brain analysis of gray matter loss in Alzheimer's disease

In patients with Alzheimer's disease, substantial tissue loss occurs in the medial temporal lobe. In this study, we applied a voxel-based, unbiased whole-brain analysis method to compare magnetic resonance imaging scans of seven patients with Alzheimer's disease and seven healthy elderly controls. Images were transformed to standard coordinate space and tested for gray matter loss in patients. We found symmetrical decreases of gray matter in patients in the hippocampus, and, unexpectedly, also in the head of the caudate nucleus and the insula. The exact role of these two structures in the symptomatology of Alzheimer's disease deserves further attention. Copyright (C) 2000 Elsevier Science Ireland Ltd

Whole brain analysis of T2* weighted baseline FMRI signal in dementia

Brain activation in studies using blood oxygenation level dependent (BOLD) FMRI is associated with an increase in T2* weighted signal between baseline and an active condition. This BOLD technique is often applied to study differences in brain activation between patients and healthy controls. However, the baseline T2* signal itself may also be different between groups, as shown in the hippocampus in Alzheimer's disease using the resting oxygen or ROXY approach (Small et al. [2002]: Ann Neurol 51:290-295). In the current study, we analyzed whole brain, voxel-wise T2* weighted signal of averaged baseline scans of a BOLD FMRI experiment in 41 healthy elderly controls and 46 patients with mild cognitive impairment or Alzheimer's disease. In each subject, T2* weighted images were normalized to the CSF signal of the same image. Additionally, gray matter probability maps of high-resolution structural scans were also compared between groups to assess atrophy. T2* signal was decreased in dementia in the hippocampus, insula/putamen, posterior and middle cingulate cortex, and parietal cortex. Most of these regions also showed decreased gray matter, except insula/putamen. Hippocampal and posterior cingulate gray matter differences were significantly larger than T2* differences. Therefore, decreased T2* signal in most regions are likely to be caused by gray matter atrophy, although decreased metabolism or perhaps iron deposition are also factors that may contribute. We conclude that in FMRI studies of dementia, not only the dynamic BOLD signal (activation and deactivation) but also the average baseline signal is diminished in certain regions. The method we applied may also be used in task-related BOLD FMRI and add to the understanding of the mechanism of task-related group differences

An fMRI study of planning-related brain activity in patients with moderately advanced multiple sclerosis

Introduction: Cognitive impairment occurs in a substantial number of multiple sclerosis (MS) patients and often includes frontal lobe dysfunction. We used functional magnetic resonance imaging (fMRI) to study planning, an executive function, in moderately impaired MS patients. Methods: An fMRI version of the Tower of London (ToL) test was used to study patterns of brain activation in 23 MS patients and 18 healthy controls. The median score on the Expanded Disability Status Scale (EDSS) for the MS patients was 4. fMRI data were analysed using whole brain random effects analysis as well as region of interest (ROI)-based methods to assess group effects. Within the MS group, associations with behavioural data and measures of disease severity (lesion load from structural MRI) were examined. Results: Test performance in MS patients was significantly worse than in controls. Group analysis for the MS patients and the controls showed for both groups globally the same areas of activation, located in the frontal and parietal lobes bilaterally and the cerebellum. Although visual inspection suggested a larger extent of activation in the MS group, no statistically significant differences between groups were found. In the ROI analysis, statistically significant larger extent of activation was only found in the cerebellum. No association between disease severity and brain activity could be determined in the MS group. Conclusion: In MS patients with moderate disability and structural damage, the pattern and extent of brain activation during planning were maintained despite poorer performance. In contrast to other studies showing increased activity, the failure to do so in our group may reflect exhaustion of adaptive mechanisms

A paced visual serial addition test for fMRI

Background and purpose: The Paced Auditory Serial Attention Task (PASAT) is an attention and information processing task used in patients with diffuse brain disorders, like cerebral trauma and multiple sclerosis (MS). Based on the PASAT we used a adapted version of the test to assess several cognitive functions with fMRI. In this study we investigated the activation pattern on a group and individual level and upon parametric stimulation. Methods: Nine young, healthy, right-handed subjects (mean age 24 years) were studied. The test contrasts an adding-and-memory stage with a control stage in a block design, at two different speeds. Group average maps (random effects analysis, p=0.05) were created to identify the brain areas subserving this task. For each area found active in the group map, the percentage of individuals showing activation in that same anatomical area was calculated. Results: Group activation was localized in the superior and inferior parietal lobe bilaterally, the superior frontal gyrus bilaterally, the left medial frontal gyrus, the left inferior frontal gyrus and adjacent part of the insula, the anterior part of the cingulate gyrus and some cerebellar areas. For the main activated areas, 78-100% of the individual subjects showed activation in that same area. Contrasting the low speed with the high speed condition yielded activation with a considerable individual variation. Conclusion: The group mean activated areas were located mainly in the frontal and parietal lobes and those areas were also activated in the majority of the subjects, indicating limited inter-individual variation, rendering this test suitable for clinical applications in a variety of neurological disorders

Early grey matter changes in structural covariance networks in Huntington's disease

Background: Progressive subcortical changes are known to occur in Huntington's disease (HD), a hereditary neurodegenerative disorder. Less is known about the occurrence and cohesion of whole brain grey matter changes in HD. Objectives: We aimed to detect network integrity changes in grey matter structural covariance networks and examined relationships with clinical assessments. Methods: Structural magnetic resonance imaging data of premanifest HD (n = 30), HD patients (n = 30) and controls (n = 30) was used to identify ten structural covariance networks based on a novel technique using the co-variation of grey matter with independent component analysis in FSL. Group differences were studied controlling for age and gender. To explore whether our approach is effective in examining grey matter changes, regional voxel-based analysis was additionally performed. Results: Premanifest HD and HD patients showed decreased network integrity in two networks compared to controls. One network included the caudate nucleus, precuneous and anterior cingulate cortex (in HD p < 0.001, in pre-HD p = 0.003). One other network contained the hippocampus, premotor, sensorimotor, and insular cortices (in HD p < 0.001, in pre-HD p = 0.023). Additionally, in HD patients only, decreased network integrity was observed in a network including the lingual gyrus, intracalcarine, cuneal, and lateral occipital cortices (p = 0.032). Changes in network integrity were significantly associated with scores of motor and neuropsychological assessments. In premanifest HD, voxel-based analyses showed pronounced volume loss in the basal ganglia, but less prominent in cortical regions. Conclusion: Our results suggest that structural covariance might be a sensitive approach to reveal early grey matter changes, especially for premanifest HD

Finding a positive me: Affective and neural insights into the challenges of positive autobiographical memory reliving in borderline personality disorder

Background: This study aimed to investigate whether people with borderline personality disorder (BPD) can benefit from reliving positive autobiographical memories in terms of mood and state self-esteem and elucidate the neural processes supporting optimal memory reliving. Particularly the role of vividness and brain areas involved in autonoetic consciousness were studied, as key factors involved in improving mood and state self-esteem by positive memory reliving. Methods: Women with BPD (N = 25), Healthy Controls (HC, N = 33) and controls with Low Self-Esteem (LSE, N = 22) relived four neutral and four positive autobiographical memories in an MRI scanner. After reliving each memory mood and vividness was rated. State self-esteem was assessed before and after the Reliving Autobiographical Memories (RAM) task. Results: Overall, mood and state self-esteem were lower in participants with BPD compared to HC and LSE, but both the BPD and LSE group improved significantly after positive memory reliving. Moreover, participants with BPD indicated that they relived their memories with less vividness than HC but not LSE, regardless of valence. When reliving (vs reading) memories, participants with BPD showed increased precuneus and lingual gyrus activation compared to HC but not LSE, which was inversely related to vividness. Discussion: Women with BPD seem to experience more challenges in reliving neutral and positive autobiographical memories with lower vividness and less deactivated precuneus potentially indicating altered autonoetic consciousness. Nevertheless, participants with BPD do benefit in mood and self-esteem from reliving positive memories. These findings underline the potential of positive autobiographical memory reliving and suggest that interventions may be further shaped to improve mood and strengthen self-views in people with BPD