7 Tesla MRI in Alzheimer's disease

T2*-weighted (a and b), T2-weighted (c and d), and FLAIR (e and f) images of the medial temporal lobe obtained at 1.5 T (a, c, and e) and 7 T (b, d, and f), illustrating the strikingly improved resolution that high-field MRI offers. Reprinted from Theysohn et al.: The human hippocampus at 7 T-in vivo MRI, Hippocampus 19:1–7, 2009, copyright 2008, Wiley-Liss, Inc.

Five AD hippocampal specimens (A1–A5) and one normal control (N4) are shown. Note the signal voids in AD specimens along the hippocampus compared with the lack of such signal voids in the normal control. The border between field CA1 and the subiculum is indicated by the white line derived from coregistered acetylcholine, myelin, and Nissl staining. The variability in their locations relative to the medial aspect of the hippocampal body illustrates the challenges inherent in in vivo imaging studies of hippocampal subregions. Reprinted from Neurobiology of Aging, vol 36, Zeineh M, Chen Y, Kitzler HH, Hammond R, Vogel H, Rutt BK, “Activated iron-containing microglia in the human hippocampus identified by magnetic resonance imaging in Alzheimer’s disease,” pp 2483–2500, 2015, with permission from Elsevier.

7-T FLAIR MRI in the (left to right) transverse (left), sagittal (center), and coronal (right) views. The arrow is pointing to a microinfarct. Reprinted with permission from van Rooden S, Goos JD, van Opstal AM, Versluis MJ, Webb AG, Blauw GJ, et al: Increased number of microinfarcts in Alzheimer disease at 7-T MR imaging. Radiology 270:205–211, 2014.

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Neuroimaging and Biomarkers: How Early Can We Diagnose Alzheimer's?

Dementia: role of MRI

This review is based on a presentation given by Frederik Barkhof at the Neuroradiology teaching course for the Dutch Radiology Society and was adapted for the Radiology Assistant by Robin Smithuis.
First publication: 1-3-2007.
Updated version: 9-1-2012.

This presentation will focus on the role of MRI in the diagnosis of dementia and related diseases.

We will discuss the following subjects:

• Systematic assessment of MR in dementia
• MR protocol for dementia
• Typical findings in the most common dementia syndromes
  • Alzheimer's disease (AD)
  • Vascular Dementia (VaD)
  • Frontotemporal lobe dementia (FTLD)
• Short overview of neurodegenerative disorders which may be associated with dementia

Preclinical Alzheimer disease: identification of cases at risk among cognitively intact older individuals

Hypothetical model of preclinical Alzheimer's disease (AD). According to the proposed model, the group currently defined as 'preclinical AD' is heterogeneous and comprises two subpopulations. Firstly, there is the group of individuals at different stages of preclinical AD defined by the biomarkers indicated in the lower panel of the figure. All of these individuals will progress to dementia, and we call this phase 'presymptomatic AD'. The second group comprises individuals who are positive for amyloid markers and neuronal injury markers, and fall into one of the stages of preclinical AD, based on the current classification. However, this population has efficient active compensatory mechanisms, and remains resistant to dementia (stable asymptomatic cerebral amyloidosis).

Since the first description of the case of Auguste Deter, presented in Tübingen in 1906 by Alois Alzheimer, there has been an exponential increase in our knowledge of the neuropathological, cellular, and molecular foundation of Alzheimer's disease (AD). The concept of AD pathogenesis has evolved from a static, binary view discriminating cognitive normality from dementia, towards a dynamic view that considers AD pathology as a long-lasting morbid process that takes place progressively over years, or even decades, before the first symptoms become apparent, and thus operating in a continuum between the two aforementioned extreme states. Several biomarkers have been proposed to predict AD-related cognitive decline, initially in cases with mild cognitive impairment, and more recently in cognitively intact individuals. These early markers define at-risk individuals thought to be in the preclinical phase of AD. However, the clinical relevance of this preclinical phase remains controversial. The fate of such individuals, who are cognitively intact, but positive for some early AD biomarkers, is currently uncertain at best. In this report, we advocate the point of view that although most of these preclinical cases will evolve to clinically overt AD, some appear to have efficient compensatory mechanisms and virtually never develop dementia. We critically review the currently available early AD markers, discuss their clinical relevance, and propose a novel classification of preclinical AD, designating these non-progressing cases as 'stable asymptomatic cerebral amyloidosis'.

BMC Medicine 2012, 10:127 doi:10.1186/1741-7015-10-127 © 2012 Lazarczyk et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Fluid-Attenuated Inversion Recovery Hypointensity of the Pulvinar Nucleus of Patients with Alzheimer Disease: Its Possible Association with Iron Accumulation as Evidenced by the T2* Map

Difference of fluid-attenuated inversion recovery signal intensity and T2* values of thalamic pulvinar nuclei in Alzheimer disease subject and control subject. There is no discernable hypointensity (A) and T2* shortening (B) of pulvinar nuclei in age-matched control subject. In contrast, white arrows indicate bilateral hypointense pulvinar nuclei relative to remaining thalami in patient with Alzheimer disease (C). Prominent T2* shortening is noted in this patient (arrows) (D).

Objective We hypothesized that prominent pulvinar hypointensity in brain MRI represents the disease process due to iron accumulation in Alzheimer disease (AD). We aimed to determine whether or not the pulvinar signal intensity (SI) on the fluid-attenuated inversion recovery (FLAIR) sequences at 3.0T MRI differs between AD patients and normal subjects, and also whether the pulvinar SI is correlated with the T2^* map, an imaging marker for tissue iron, and a cognitive scale.

Materials and Methods Twenty one consecutive patients with AD and 21 age-matched control subjects were prospectively included in this study. The pulvinar SI was assessed on the FLAIR image. We measured the relative SI ratio of the pulvinar to the corpus callosum. The T2^* values were calculated from the T2^* relaxometry map. The differences between the two groups were analyzed, by using a Student t test. The correlation between the measurements was assessed by the Pearson's correlation test.

Results As compared to the normal white matter, the FLAIR signal intensity of the pulvinar nucleus was significantly more hypointense in the AD patients than in the control subjects (p < 0.01). The pulvinar T2^* was shorter in the AD patients than in the control subjects (51.5 ± 4.95 ms vs. 56.5 ± 5.49 ms, respectively, p = 0.003). The pulvinar SI ratio was strongly correlated with the pulvinar T2^* (r = 0.745, p < 0.001). When controlling for age, only the pulvinar-to-CC SI ratio was positively correlated with that of the Mini-Mental State Examination (MMSE) score (r = 0.303, p < 0.050). Conversely, the pulvinar T2^* was not correlated with the MMSE score (r = 0.277, p = 0.080).

Conclusion The FLAIR hypointensity of the pulvinar nucleus represents an abnormal iron accumulation in AD and may be used as an adjunctive finding for evaluating AD.

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Biomarkers for Alzheimer’s disease – spinal taps, brain scans, blood tests and the critical role of brain donation

By Professor Simon Lovestone

Professor of Old Age Psychiatry, NIHR Biomedical Research Centre for Mental Health, King's College London, Institute of Psychiatry, De Crespigny Park, London SE5 8AF

Suppose you have memory problems and go to your doctor - what happens next? At best, and the best is not always achieved, then an assessment of memory and other cognitive function is made and, in some cases, a referral is made to a memory clinic where there may be more memory tests and perhaps a brain scan. If the outcomes of these tests are not severe enough to warrant a clear-cut diagnosis then, usually, the cognitive tests are repeated after a year to see if they have got worse. This is unsatisfactory as the wait must seem interminable to patients and their relatives. For professionals too, not being able to make an early diagnosis is frustrating.

When treatments for Alzheimer's disease (AD) go beyond symptomatic treatment to therapies for the illness itself, this wait will be unacceptable since it is in this early phase, before dementia is established, that the drugs are most likely to be effective. This, then, is one of the most important drivers for research into 'biomarkers' of AD. A biomarker is a biological signal that can be detected for diagnosis, ideally very early and before doctors are currently able to diagnose the condition. Biomarkers are also useful as the basis of tests for measuring how a disease is progressing. This latter use of biomarkers would be especially useful in research to find new treatments for dementia. Currently clinical trials rely almost entirely on memory tests which are sometimes less reliable than we would like as measures of disease. A biomarker that reflected the disease progression in the brain would be immensely useful as a measure against which to judge new treatments.

In Big Picture, Familial AD’s Biomarker Data Resemble LOAD

Researchers with eyes peeled toward prodromal Alzheimer’s disease probably see this diagram in their sleep—the one where the field’s five most validated markers trace their poignant path from normal cognition to fully developed AD. Two research groups proposed this theoretical model some years ago (see Perrin et al., 2009; Jack et al., 2010). But is it true? At least in its broad strokes, the answer seems to be yes, according to early data pouring in from biomarker studies in autosomal-dominant AD. By and large, brain amyloid, brain metabolism, atrophy, and functional connectivity data from independent analyses of theDominantly Inherited Alzheimer Network (DIAN) and the Alzheimer’s Prevention Initiative (API) jibe with each other and confirm the sequence of preclinical biomarker changes proposed for late-onset AD. This article highlights DIAN and API neuroimaging results reported 14-19 July 2012 at the Alzheimer’s Association International Conference (AAIC) in Vancouver, Canada.

On the different clinical presentations of AD

AD may have different clinical presentations depending on the area where the neurodegeneration starts first. The more frequent region is the medial temporal lobe, affecting the hippocampus but there are variants starting in the frontal lobe (frontal AD) and parieto-occipital (posterior AD).
Analyses of cortical thickness patterns support the hypothesis that different clinical presentations of AD represent points in a phenotypic spectrum of neuroanatomical variation (Ridway). 
However, serum anti-Aβ IgG1 and IgG3 antibodies differ between distinct forms of AD. Its significance is discussed for possible implications as immune effectors in the specific pathophysiology of AD variants (Dorothée).

Revised Criteria for Mild Cognitive Impairment May Compromise the Diagnosis of Alzheimer Disease Dementia.

OBJECTIVE:

To evaluate the potential impact of revised criteria for mild cognitive impairment (MCI), developed by a work group sponsored by the National Institute on Aging and the Alzheimer's Association, on the diagnosis of very mild and mild Alzheimer disease (AD) dementia.

DESIGN:

Retrospective review of ratings of functional impairment across diagnostic categories.

SETTING:

Alzheimer's Disease Centers and the National Alzheimer's Coordinating Center.

PARTICIPANTS:

Individuals (N = 17 535) with normal cognition, MCI, or AD dementia.

MAIN OUTCOME MEASURES:

The functional ratings of individuals with normal cognition, MCI, or AD dementia who were evaluated at Alzheimer's Disease Centers and submitted to the National Alzheimer's Coordinating Center were assessed in accordance with the definition of "functional independence" allowed by the revised criteria. Pairwise demographic differences between the 3 diagnostic groups were tested using t tests for continuous variables and χ(2) for categorical variables.

RESULTS:

Almost all (99.8%) individuals currently diagnosed with very mild AD dementia and the large majority (92.7%) of those diagnosed with mild AD dementia could be reclassified as having MCI with the revised criteria, based on their level of impairment in the Clinical Dementia Rating domains for performance of instrumental activities of daily living in the community and at home. Large percentages of these individuals with AD dementia also meet the revised "functional independence" criterion for MCI as measured by the Functional Assessment Questionnaire.

CONCLUSIONS:

The categorical distinction between MCI and milder stages of AD dementia has been compromised by the revised criteria. The resulting diagnostic overlap supports the premise that "MCI due to AD" represents the earliest symptomatic stage of AD.

Arch Neurol. 2012 Feb 6. [Epub ahead of print]

Wanted: Better Brain-Process Biomarkers for Drug Trials

Eight years ago, Peter Lansbury decided to become a drug developer. He was a neurology professor at Harvard Medical School with a background in chemistry, and had been doing well-regarded research on the origins of neurodegenerative diseases. Now he had an idea for a blockbuster treatment: a drug that would boost the brain’s ability to dispose of the harmful protein aggregates that seem to cause many of these diseases.
Lansbury and two investors founded a company, Link Medicine, and began screening libraries of chemical compounds for those that would increase autophagy, a natural process that clears away unwanted protein aggregates. Eventually they had a lead autophagy-boosting compound, LNK-754, that worked well in mouse models and appeared safe in human volunteers. In principle, LNK-754 could be useful in treating a number of illnesses including Parkinson’s, Alzheimer’s, and Huntington’s diseases. All that remained, it seemed, was for a large pharmaceutical company to buy the marketing rights and fund the large-scale clinical trials needed to prove LNK-754’s efficacy in humans.
But that hasn’t happened. “It used to be that if you had a drug whose mechanism makes sense, a drug that works in animals and is safe in people, you could immediately go and do a large clinical trial. But for drugs against neurodegenerative diseases, those days are gone,” says Lansbury.
The problem is that for these diseases, the standard measures needed in a conclusive clinical trial—such as cognitive test scores, for Alzheimer’s patients—are expected to show clear evidence of a treatment effect only very gradually, and only in a population of at least hundreds of patients, even for a drug that works. For a would-be disease-modifying drug, that typically means a trial of at least 18 months, costing on the order of $100 million. At the same time, pharmaceutical companies are all too aware that potential neurodegenerative disease treatments have almost always failed in clinical trials, in recent years. “The big pharma companies have become very risk averse,” Lansbury says. “The big issue now is not really the lack of drug strategies, it’s the inability to assess those strategies in short, economical trials.”

Neuropathologic Correlates of Hippocampal Atrophy in the Elderly: A Clinical, Pathologic, Postmortem MRI Study

The volume of the hippocampus measured with structural magnetic resonance imaging (MRI) is increasingly used as a biomarker for Alzheimer's disease (AD). However, the neuropathologic basis of structural MRI changes in the hippocampus in the elderly has not been directly assessed. Postmortem MRI of the aging human brain, combined with histopathology, could be an important tool to address this issue. Therefore, this study combined postmortem MRI and histopathology in 100 elderly subjects from the Rush Memory and Aging Project and the Religious Orders Study. 

A typical three-dimensional region of interest created by manually outlining the hippocampal formation in consecutive T₂-weighted sagittal images of a human cerebral hemisphere.

Shape analysis of (A) hippocampi affected by Alzheimer's disease (AD) and not hippocampal sclerosis (HS) compared to controls, (B) hippocampi most severely affected by AD compared to controls, and (C) hippocampi affected by HS with or without AD compared to controls.The top row of images contains the superior view of the hippocampus, while the bottom row contains the inferior view. Within each comparison, the left side shows a map of the difference in distance between points on the surface mesh of the first group versus the corresponding points on the surface mesh of the second group, projected along a unit vector that is normal to the surface. Thus, red shading shows areas of inward deformation of the first group relative to the second group, and green shading shows areas of outward deformation. The right side of each comparison shows significance maps with color indicating P-value. The significance maps show regions where points on the surface mesh of the first group are significantly displaced from the corresponding points on the surface mesh of the second group in any direction.

First, to validate the information contained in postmortem MRI data, we tested the hypothesis that postmortem hippocampal volume is smaller in subjects with clinically diagnosed Alzheimer's disease compared to subjects with mild or no cognitive impairment, as observed in antemortem imaging studies. Subsequently, the relations of postmortem hippocampal volume to AD pathology, Lewy bodies, amyloid angiopathy, gross infarcts, microscopic infarcts, and hippocampal sclerosis were examined. It was demonstrated that hippocampal volume was smaller in persons with a clinical diagnosis of AD compared to those with no cognitive impairment (P = 2.6×10⁻⁷) or mild cognitive impairment (P = 9.6×10⁻⁷). Additionally, hippocampal volume was related to multiple cognitive abilities assessed proximate to death, with its strongest association with episodic memory. Among all pathologies investigated, the most significant factors related to lower hippocampal volume were shown to be AD pathology (P = 0.0018) and hippocampal sclerosis (P = 4.2×10⁻⁷). Shape analysis allowed for visualization of the hippocampal regions most associated with volume loss for each of these two pathologies. Overall, this investigation confirmed the relation of hippocampal volume measured postmortem to clinical diagnosis of AD and measures of cognition, and concluded that both AD pathology and hippocampal sclerosis affect hippocampal volume in old age, though the impacts of each pathology on the shape of the hippocampus may differ.

Reference: Dawe RJ, Bennett DA, Schneider JA, Arfanakis K, 2011 Neuropathologic Correlates of Hippocampal Atrophy in the Elderly: A Clinical, Pathologic, Postmortem MRI Study. PLoS ONE 6(10): e26286. doi:10.1371/journal.pone.0026286 Free full text

Multiple Indices of Diffusion Identifies White Matter Damage in Mild Cognitive Impairment and Alzheimer’s Disease

The study of multiple indices of diffusion, including axial (DA), radial (DR) and mean diffusion (MD), as well as fractional anisotropy (FA), enables WM damage in Alzheimer’s disease (AD) to be assessed in detail. Here, tract-based spatial statistics (TBSS) were performed on scans of 40 healthy elders, 19 non-amnestic MCI (MCIna) subjects, 14 amnestic MCI (MCIa) subjects and 9 AD patients. Significantly higher DA was found in MCIna subjects compared to healthy elders in the right posterior cingulum/precuneus. Significantly higher DA was also found in MCIa subjects compared to healthy elders in the left prefrontal cortex, particularly in the forceps minor and uncinate fasciculus. In the MCIa versus MCIna comparison, significantly higher DA was found in large areas of the left prefrontal cortex. For AD patients, the overlap of FA and DR changes and the overlap of FA and MD changes were seen in temporal, parietal and frontal lobes, as well as the corpus callosum and fornix. Analysis of differences between the AD versus MCIna, and AD versus MCIa contrasts, highlighted regions that are increasingly compromised in more severe disease stages. Microstructural damage independent of gross tissue loss was widespread in later disease stages. Our findings suggest a scheme where WM damage begins in the core memory network of the temporal lobe, cingulum and prefrontal regions, and spreads beyond these regions in later stages. DA and MD indices were most sensitive at detecting early changes in MCIa.

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Combined imaging markers dissociate Alzheimer’s disease and frontotemporal lobar degeneration – an ALE meta-analysis

To compare and dissociate the neural correlates of Alzheimer’s disease (AD) and frontotemporal lobar degeneration (FTLD), we combine and synthesize here recent comprehensive meta-analyses. Systematic and quantitative meta-analyses were conducted according to the QUOROM statement by calculating anatomical likelihood estimates (ALE). AD (n = 578) and the three subtypes of FTLD, frontotemporal dementia, semantic dementia (SD), and progressive non-fluent aphasia (n = 229), were compared in conjunction analyses, separately for atrophy and reductions in glucose metabolism. Atrophy coincided in the amygdala and hippocampal head in AD and the FTLD subtype SD. The other brain regions did not show any overlap between AD and FTLD subtypes for both atrophy and changes in glucose metabolism. For AD alone (n = 826), another conjunction analysis revealed a regional dissociation between atrophy and hypoperfusion/hypometabolism, whereby hypoperfusion and hypometabolism coincided in the angular/supramarginal gyrus and inferior precuneus/posterior cingulate gyrus. Our data together with other imaging studies suggest a specific dissociation of AD and FTLD if, beside atrophy, additional imaging markers in AD such as abnormally low parietal glucose utilization and perfusion are taken into account. Results support the incorporation of standardized imaging inclusion criteria into future diagnostic systems, which is crucial for early individual diagnosis and treatment in the future (Full text).

Multi-modal MRI analysis with disease-specific spatial filtering: initial testing to predict mild cognitive impairment patients who convert

Background: Alterations of the gray and white matter have been identified in Alzheimer’s disease (AD) by structural magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI). However, whether the combination of these modalities could increase the diagnostic performance is unknown. Methods: Participants included 19 AD patients, 22 amnestic mild cognitive impairment (aMCI) patients, and 22 cognitively normal elderly (NC). The aMCI group was further divided into an “aMCI-converter” group (converted to AD dementia within 3 years), and an “aMCI-stable” group who did not convert in this time period. A T1-weighted image, a T2 map, and a DTI of each participant were normalized, and voxel-based comparisons between AD and NC groups were performed. Regions-of-interest, which defined the areas with significant differences between AD and NC, were created for each modality and named “disease-specific spatial filters” (DSF). Linear discriminant analysis was used to optimize the combination of multiple MRI measurements extracted by DSF to effectively differentiate AD from NC. The resultant DSF and the discriminant function were applied to the aMCI group to investigate the power to differentiate the aMCI-converters from the aMCI-stable patients. Results: The multi-modal approach with AD-specific filters led to a predictive model with an area under the receiver operating characteristic curve (AUC) of 0.93, in differentiating aMCI-converters from aMCI-stable patients. This AUC was better than that of a single-contrast-based approach, such as T1-based morphometry or diffusion anisotropy analysis. Conclusion: The multi-modal approach has the potential to increase the value of MRI in predicting conversion from aMCI to AD (Full text).