Michel J. Grothe

Reduction of Basal Forebrain Cholinergic System Parallels Cognitive Impairment in Patients at High Risk of Developing Alzheimer's Disease

Neuropathological studies suggest that the basal forebrain cholinergic system (BFCS) is affected in Alzheimers disease (AD), but there is no in vivo evidence of early damage to this system in subjects at high risk of developing AD. Here, we found that mild cognitive impairment (MCI) patients exhibited significant volume reduction of the nucleus basalis of Meynert (NbM) using recently developed probabilistic maps of the BFCS space. In addition, volumes of different magnocellular compartments varied significantly with regional gray matter atrophy in regions known to be affected by AD and were found to correlate with cognitive decline in MCI patients. Bilateral reductions of the horizontal nucleus of the diagonal band of Broca (Ch3) and frontal lobe (medial frontal, orbital, subcallosal gyrus, anterior cingulate, and middle frontal gyrus) were significantly associated with a global decline in cognitive status, whereas volume reduction of the posterior compartment of Ch4 (NbM) and temporal lobe (including hippocampus, entorhinal cortex, and amygdala) were associated with impaired delayed recall in MCI patients. These findings establish, for the first time, a link between degeneration of specific cholinergic compartments of the BFCS and cognitive-related deficits in subjects at high risk of developing AD.

Atrophy of the cholinergic Basal forebrain over the adult age range and in early stages of Alzheimer's disease.

BACKGROUND The basal forebrain cholinergic system (BFCS) is known to undergo moderate neurodegenerative changes during normal aging as well as severe atrophy in Alzheimers disease (AD). However, there is a controversy regarding how the cholinergic lesion in AD relates to early and incipient stages of the disease. In vivo imaging studies on the structural integrity of the BFCS in normal and pathologic aging are rare. METHODS We applied automated morphometry techniques in combination with high-dimensional image warping and a cytoarchitectonic map of basal forebrain cholinergic nuclei to a large cross-sectional data set of high-resolution magnetic resonance imaging scans, covering the whole adult age range (20-94 years; n = 211) as well as patients with very mild AD (Clinical Dementia Rating = .5; n = 69) and clinically manifest AD (AD; Clinical Dementia Rating = 1; n = 28). For comparison, we investigated hippocampus volume using automated volumetry. RESULTS Volume of the BFCS declined from early adulthood on, and atrophy aggravated in advanced age. Volume reductions in very mild AD were most pronounced in posterior parts of the nucleus basalis of Meynert, whereas in AD, atrophy was more extensive and included the whole BFCS. In clinically manifest AD, the diagnostic accuracy of BFCS volume reached the diagnostic accuracy of hippocampus volume. CONCLUSIONS Our findings indicate that cholinergic degeneration in AD occurs against a background of age-related atrophy and that exacerbated atrophy in AD can be detected at earliest stages of cognitive impairment. Automated in vivo morphometry of the BFCS may become a useful tool to assess BF cholinergic degeneration in normal and pathologic aging.

Relevance of Magnetic Resonance Imaging for Early Detection and Diagnosis of Alzheimer Disease

Hippocampus volumetry currently is the best-established imaging biomarker for AD. However, the effect of multicenter acquisition on measurements of hippocampus volume needs to be explicitly considered when it is applied in large clinical trials, for example by using mixed-effects models to take the clustering of data within centers into account. The marker needs further validation in respect of the underlying neurobiological substrate and potential confounds such as vascular disease, inflammation, hydrocephalus, and alcoholism, and with regard to clinical outcomes such as cognition but also to demographic and socioeconomic outcomes such as mortality and institutionalization. The use of hippocampus volumetry for risk stratification of predementia study samples will further increase with the availability of automated measurement approaches. An important step in this respect will be the development of a standard hippocampus tracing protocol that harmonizes the large range of presently available manual protocols. In the near future, regionally differentiated automated methods will become available together with an appropriate statistical model, such as multivariate analysis of deformation fields, or techniques such as cortical-thickness measurements that yield a meaningful metrics for the detection of treatment effects. More advanced imaging protocols, including DTI, DSI, and functional MRI, are presently being used in monocenter and first multicenter studies. In the future these techniques will be relevant for the risk stratification in phase IIa type studies (small proof-of-concept trials). By contrast, the application of the broader established structural imaging biomarkers, such as hippocampus volume, for risk stratification and as surrogate end point is already today part of many clinical trial protocols. However, clinical care will also be affected by these new technologies. Radiologic expert centers already offer “dementia screening” for well-off middle-aged people who undergo an MRI scan with subsequent automated, typically VBM-based analysis, and determination of z-score deviation from a matched control cohort. Next-generation scanner software will likely include radiologic expert systems for automated segmentation, deformation-based morphometry, and multivariate analysis of anatomic MRI scans for the detection of a typical AD pattern. As these developments will start to change medical practice, first for selected subject groups that can afford this type of screening but later eventually also for other cohorts, clinicians must become aware of the potentials and limitations of these technologies. It is decidedly unclear to date how a middle-aged cognitively intact subject with a seemingly AD-positive MRI scan should be clinically advised. There is no evidence for individual risk prediction and even less for specific treatments. Thus, the development of preclinical diagnostic imaging poses not only technical but also ethical problems that must be critically discussed on the basis of profound knowledge. From a neurobiological point of view, the main determinants of cognitive impairment in AD are the density of synapses and neurons in distributed cortical and subcortical networks. MRI-based measures of regional gray matter volume and associated multivariate analysis techniques of regional interactions of gray matter densities provide insight into the onset and temporal dynamics of cortical atrophy as a close proxy for regional neuronal loss and a basis of functional impairment in specific neuronal networks. From the clinical point of view, clinicians must bear in mind that patients do not suffer from hippocampus atrophy or disconnection but from memory impairment, and that dementia screening in asymptomatic subjects should not be used outside of clinical studies.

The EADC-ADNI Harmonized Protocol for manual hippocampal segmentation on magnetic resonance: Evidence of validity

An international Delphi panel has defined a harmonized protocol (HarP) for the manual segmentation of the hippocampus on MR. The aim of this study is to study the concurrent validity of the HarP toward local protocols, and its major sources of variance.

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

Alzheimers 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 Alzheimers disease pathology in ever increasing temporal and regional detail. Accumulating evidence suggests that distinct types of imaging abnormalities related to Alzheimers 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 Alzheimers 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.

Convergent Findings of Altered Functional and Structural Brain Connectivity in Individuals with High Functioning Autism: A Multimodal MRI Study

Brain tissue changes in autism spectrum disorders seem to be rather subtle and widespread than anatomically distinct. Therefore a multimodal, whole brain imaging technique appears to be an appropriate approach to investigate whether alterations in white and gray matter integrity relate to consistent changes in functional resting state connectivity in individuals with high functioning autism (HFA). We applied diffusion tensor imaging (DTI), voxel-based morphometry (VBM) and resting state functional connectivity magnetic resonance imaging (fcMRI) to assess differences in brain structure and function between 12 individuals with HFA (mean age 35.5, SD 11.4, 9 male) and 12 healthy controls (mean age 33.3, SD 9.0, 8 male). Psychological measures of empathy and emotionality were obtained and correlated with the most significant DTI, VBM and fcMRI findings. We found three regions of convergent structural and functional differences between HFA participants and controls. The right temporo-parietal junction area and the left frontal lobe showed decreased fractional anisotropy (FA) values along with decreased functional connectivity and a trend towards decreased gray matter volume. The bilateral superior temporal gyrus displayed significantly decreased functional connectivity that was accompanied by the strongest trend of gray matter volume decrease in the temporal lobe of HFA individuals. FA decrease in the right temporo-parietal region was correlated with psychological measurements of decreased emotionality. In conclusion, our results indicate common sites of structural and functional alterations in higher order association cortex areas and may therefore provide multimodal imaging support to the long-standing hypothesis of autism as a disorder of impaired higher-order multisensory integration.

The Cholinergic System in Mild Cognitive Impairment and Alzheimer's Disease: An In Vivo MRI and DTI study

Few studies have investigated in vivo changes of the cholinergic basal forebrain in Alzheimers disease (AD) and amnestic mild cognitive impairment (MCI), an at risk stage of AD. Even less is known about alterations of cortical projecting fiber tracts associated with basal forebrain atrophy. In this study, we determined regional atrophy within the basal forebrain in 21 patients with AD and 16 subjects with MCI compared to 20 healthy elderly subjects using deformation‐based morphometry of MRI scans. We assessed effects of basal forebrain atrophy on fiber tracts derived from high‐resolution diffusion tensor imaging (DTI) using tract‐based spatial statistics. We localized significant effects relative to a map of cholinergic nuclei in MRI standard space as determined from a postmortem brain. Patients with AD and MCI subjects showed reduced volumes in basal forebrain areas corresponding to anterior medial and lateral, intermediate and posterior nuclei of the Nucleus basalis of Meynert (NbM) as well as in the diagonal band of Broca nuclei (P < 0.01). Effects in MCI subjects were spatially more restricted than in AD, but occurred at similar locations. The volume of the right antero‐lateral NbM nucleus was correlated with intracortical projecting fiber tract integrity such as the corpus callosum, cingulate, and the superior longitudinal, inferior longitudinal, inferior fronto‐occipital, and uncinate fasciculus (P < 0.05, corrected for multiple comparisons). Our findings suggest that a multimodal MRI‐DTI approach is supportive to determine atrophy of cholinergic nuclei and its effect on intracortical projecting fiber tracts in AD. Hum Brain Mapp, 2010.

Longitudinal measures of cholinergic forebrain atrophy in the transition from healthy aging to Alzheimer's disease.

Recent evidence from cross-sectional in vivo imaging studies suggests that atrophy of the cholinergic basal forebrain (BF) in Alzheimers disease (AD) can be distinguished from normal age-related degeneration even at predementia stages of the disease. Longitudinal study designs are needed to specify the dynamics of BF degeneration in the transition from normal aging to AD. We applied recently developed techniques for in vivo volumetry of the BF to serial magnetic resonance imaging scans of 82 initially healthy elderly individuals (60-93 years) and 50 patients with very mild AD (Clinical Dementia Rating score = 0.5) that were clinically followed over an average of 3 ± 1.5 years. BF atrophy rates were found to be significantly higher than rates of global brain shrinkage even in cognitively stable healthy elderly individuals. Compared with healthy control subjects, very mild AD patients showed reduced BF volumes at baseline and increased volume loss over time. Atrophy of the BF was more pronounced in progressive patients compared with those that remained stable. The cholinergic BF undergoes disproportionate degeneration in the aging process, which is further increased by the presence of AD.

Multimodal analysis of functional and structural disconnection in Alzheimer's disease using multiple kernel SVM

Alzheimers disease (AD) patients exhibit alterations in the functional connectivity between spatially segregated brain regions which may be related to both local gray matter (GM) atrophy as well as a decline in the fiber integrity of the underlying white matter tracts. Machine learning algorithms are able to automatically detect the patterns of the disease in image data, and therefore, constitute a suitable basis for automated image diagnostic systems. The question of which magnetic resonance imaging (MRI) modalities are most useful in a clinical context is as yet unresolved. We examined multimodal MRI data acquired from 28 subjects with clinically probable AD and 25 healthy controls. Specifically, we used fiber tract integrity as measured by diffusion tensor imaging (DTI), GM volume derived from structural MRI, and the graph‐theoretical measures ‘local clustering coefficient’ and ‘shortest path length’ derived from resting‐state functional MRI (rs‐fMRI) to evaluate the utility of the three imaging methods in automated multimodal image diagnostics, to assess their individual performance, and the level of concordance between them. We ran the support vector machine (SVM) algorithm and validated the results using leave‐one‐out cross‐validation. For the single imaging modalities, we obtained an area under the curve (AUC) of 80% for rs‐fMRI, 87% for DTI, and 86% for GM volume. When it came to the multimodal SVM, we obtained an AUC of 82% using all three modalities, and 89% using only DTI measures and GM volume. Combined multimodal imaging data did not significantly improve classification accuracy compared to the best single measures alone. Hum Brain Mapp 36:2118–2131, 2015.

Subregional Basal Forebrain Atrophy in Alzheimer's Disease: A Multicenter Study

Histopathological studies in Alzheimers disease (AD) suggest severe and region-specific neurodegeneration of the basal forebrain cholinergic system (BFCS). Here, we studied the between-center reliability and diagnostic accuracy of MRI-based BFCS volumetry in a large multicenter data set, including participants with prodromal (n = 41) or clinically manifest AD (n = 134) and 148 cognitively healthy controls. Atrophy was determined using voxel-based and region-of-interest based analyses of high-dimensionally normalized MRI scans using a newly created map of the BFCS based on postmortem in cranio MRI and histology. The AD group showed significant volume reductions of all subregions of the BFCS, which were most pronounced in the posterior nucleus basalis Meynert (NbM). The mild cognitive impairment-AD group showed pronounced volume reductions in the posterior NbM, but preserved volumes of anterior-medial regions. Diagnostic accuracy of posterior NbM volume was superior to hippocampus volume in both groups, despite higher multicenter variability of the BFCS measurements. The data of our study suggest that BFCS morphometry may provide an emerging biomarker in AD.