Magnetic resonance imaging and spectroscopy in at-risk populations and preclinical Alzheimer's disease

Alzheimer’s disease (AD) is the most common form of dementia. One of the earliest and most distinct features of AD is memory loss, followed by difficulties in learning and a decline in cognitive abilities. People afflicted with AD usually develop symptoms in their late seventies, but we know today that the very first signs of pathology can be detected decades before symptom onset. A considerable part of AD research today is focused on the detailed characterization of this asymptomatic “silent” phase of AD. The main pathological hallmarks of AD are amyloid plaques – abnormal extracellular deposits of the amyloid-β (Aβ) protein and intracellular neurofibrillary tangles (NFTs) – aggregates of the phosphorylated tau protein. AD is also characterized by progressive neurodegeneration – a deterioration of the structure and function of neurons, which leads to loss of brain tissue. Atrophy first takes place the medial temporal lobe (the entorhinal cortex and the hippocampus) and subsequently propagates to other areas of the brain. Magnetic resonance imaging (MRI) is a powerful method used to assess the extent of atrophy of the whole brain or specific structures. Another useful tool for studying AD pathology is magnetic resonance spectroscopy (MRS). This method allows quantification of certain brain metabolites in vivo. The most relevant MRS metabolites in the context of AD are myo-inositol – an organic osmolyte and N-acetyl-aspartate – a marker of neuronal integrity. The overall aim of this thesis is to further characterize structural and metabolic changes associated with incipient AD pathology. Study I assesses a common methodological issue of volumetric MRI studies related to inter-individual differences in intracranial volume (ICV). In a study setting where regional brain volumes are analyzed, it is often of interest to compare groups, e.g. control vs patient, in order to quantify atrophy due to pathology. This type of group comparison is confounded by the fact that people with larger ICV usually have larger brain structures, making it difficult to isolate disease-related atrophy. This work examines multiple procedures that can be used to compensate for ICV in volumetric studies, highlighting that the choice of ICV normalization approach may have profound effects on the interpretation of study results. Study II examines brain morphology from a network perspective. Here, the brain is represented as a graph – a set of nodes interconnected by edges – where the nodes are based on anatomical regions and the edges are measures of the “connection” (i.e. structural co-variance) between these regions. We examine global and local network properties in cognitively healthy elderly with evidence of amyloid pathology. Study II reveals that the changes in cerebral network topology in asymptomatic individuals at risk for AD occur before to any detectable cortical thinning. Studies III and IV explored whether brain metabolites measured with MRS may be useful biomarkers of ongoing amyloid-related pathological processes. Previous MRS studies have found that in a typical AD spectrum, mI is elevated and NAA is decreased. However, relatively little is known about the time course of these changes as well as the interplay between MRS and established biomarkers/risk-factors for the disease. In Study III, MRS spectra of non-demented individuals at varying degrees of risk for AD was examined in conjunction with information about Aβ, tau and APOE ε4 carriership – the main genetic risk factor for AD. Our findings highlight the very early involvement of brain mI in AD. We show that this metabolite is changed already at presymptomatic disease stages, and that elevated mI is linked to a higher Aβ plaque load. Study IV is an extensive follow-up of Study III, and the first longitudinal MRS study, taking into account individual amyloid status. We demonstrate that during a four-year follow-up, non-demented individuals with pathological baseline Aβ accumulate mI at a higher rate, suggesting that mI may have the ability not only to detect but also to track ongoing Aβ pathology. Ultimately, we hope that non-invasive cost-efficient MRS markers may be useful for early patient screening and evaluation of disease-modifying strategies

Altered structural network organization in cognitively normal individuals with amyloid pathology

Recent findings show that structural network topology is disrupted in Alzheimer's disease (AD), with changes occurring already at the prodromal disease stages. Amyloid accumulation, a hallmark of AD, begins several decades before symptom onset, and its effects on brain connectivity at the earliest disease stages are not fully known. We studied global and local network changes in a large cohort of cognitively healthy individuals (N = 299, Swedish BioFINDER study) with and without amyloid-β (Aβ) pathology (based on cerebrospinal fluid Aβ42/Aβ40 levels). Structural correlation matrices were constructed based on magnetic resonance imaging cortical thickness data. Despite the fact that no significant regional cortical atrophy was found in the Aβ-positive group, this group exhibited an altered global network organization, including decreased global efficiency and modularity. At the local level, Aβ-positive individuals displayed fewer and more disorganized modules as well as a loss of hubs. Our findings suggest that changes in network topology occur already at the presymptomatic (preclinical) stage of AD and may precede detectable cortical thinning

The effects of intracranial volume adjustment approaches on multiple regional MRI volumes in healthy aging and Alzheimer's disease

In neurodegeneration research, normalization of regional volumes by intracranial volume (ICV) is important to estimate the extent of disease-driven atrophy. There is little agreement as to whether raw volumes, volume-to-ICV fractions or regional volumes from which the ICV factor has been regressed out should be used for volumetric brain imaging studies. Using multiple regional cortical and subcortical volumetric measures generated by Freesurfer (51 in total), the main aim of this study was to elucidate the implications of these adjustment approaches. Magnetic resonance imaging (MRI) data were analyzed from two large cohorts, the population-based PIVUS cohort (N=406, all subjects age 75) and the Alzheimer disease Neuroimaging Initiative (ADNI) cohort (N=724). Further, we studied whether the chosen ICV normalization approach influenced the relationship between hippocampus and cognition in the three diagnostic groups of the ADNI cohort (Alzheimer’s disease, mild cognitive impairment and healthy individuals). The ability of raw vs adjusted hippocampal volumes to predict diagnostic status was also assessed. In both cohorts raw volumes correlate positively with ICV, but do not scale directly proportionally with it. The correlation direction is reversed for all volume-to-ICV fractions, except the lateral and third ventricles. Most grey matter fractions are larger in females, while lateral ventricle fractions are greater in males. Residual correction effectively eliminated the correlation between the regional volumes and ICV and removed gender differences. The association between hippocampal volumes and cognition was not altered by ICV normalization. Comparing prediction of diagnostic status using the different approaches, small but significant differences were found. The choice of normalization approach should be carefully considered when designing a volumetric brain imaging study

Data from: Brain myo-inositol as a potential marker of amyloid-related pathology: a longitudinal study.

Objective: To investigate the association between longitudinal changes in proton magnetic spectroscopy (MRS) metabolites and amyloid pathology in non-demented individuals; to explore the relationship between MRS and cognitive decline. Methods: In this longitudinal multiple time point study (a subset of the Swedish BioFINDER) we included cognitively healthy participants, individuals with subjective cognitive decline and mild cognitive impairment (MCI). MRS was acquired serially in 294 participants (670 individual spectra) from the posterior cingulate/precuneus. Using mixed-effects models, we assessed the association between MRS and baseline amyloid β42 (Aβ), and between MRS and longitudinal MMSE, accounting for APOE, age and sex. Results: While baseline MRS metabolites were similar in Aβ positive (Aβ+) and negative (Aβ-) individuals, in the Aβ+ group, the estimated rate of change was +1.9%/year for myo-inositol/creatine (mI/Cr) and -2.0%/year for N-acetyl-aspartate/myo-inositol (NAA/mI). In the Aβ- group, mI/Cr and NAA/mI yearly change was -0.05% and +1.2%, however this was not significant across time points. MCI Aβ+ group showed the steepest MRS changes, with an estimated rate of +2.93%/year (p=0.07) for mI/Cr and -3.55%/year (p<0.01) for NAA/mI. Further, in the entire cohort, we found that Aβ+ individuals with low baseline NAA/mI had a significantly higher rate of cognitive decline than Aβ+ individuals with high baseline NAA/mI. Conclusions: We demonstrate that the longitudinal change in mI/Cr and NAA/mI is associated with underlying amyloid pathology. MRS may be a useful non-invasive marker of Aβ-related processes over time. Further, we show that in Aβ+ individuals, baseline NAA/mI may predict the rate of future cognitive decline

Dryad Additional Methods

Flowchart describing how the final number of s study participants was arrived at

Dryad Additional Results

1) Tables reporting concentrations of MRS metabolites in the precuneus/PCC region across the different diagnostic/amyloid groups, at baseline, visit 1 and visit 2. 2) Boxplots presenting serial spectroscopic data groups based on baseline Aβ status

Brain myoinositol as a potential marker of amyloid-related pathology : A longitudinal study

ObjectiveTo investigate the association between longitudinal changes in proton magnetic resonance spectroscopy (MRS) metabolites and amyloid pathology in individuals without dementia, and to explore the relationship between MRS and cognitive decline.MethodsIn this longitudinal multiple time point study (a subset of the Swedish BioFINDER), we included cognitively healthy participants, individuals with subjective cognitive decline, and individuals with mild cognitive impairment. MRS was acquired serially in 294 participants (670 individual spectra) from the posterior cingulate/precuneus. Using mixed-effects models, we assessed the association between MRS and baseline β-amyloid (Aβ), and between MRS and the longitudinal Mini-Mental State Examination, accounting for APOE, age, and sex.ResultsWhile baseline MRS metabolites were similar in Aβ positive (Aβ+) and negative (Aβ-) individuals, in the Aβ+ group, the estimated rate of change was +1.9%/y for myo-inositol (mI)/creatine (Cr) and -2.0%/y for N-acetylaspartate (NAA)/mI. In the Aβ- group, mI/Cr and NAA/mI yearly change was -0.05% and +1.2%; however, this was not significant across time points. The mild cognitive impairment Aβ+ group showed the steepest MRS changes, with an estimated rate of +2.93%/y (p = 0.07) for mI/Cr and -3.55%/y (p < 0.01) for NAA/mI. Furthermore, in the entire cohort, we found that Aβ+ individuals with low baseline NAA/mI had a significantly higher rate of cognitive decline than Aβ+ individuals with high baseline NAA/mI.ConclusionWe demonstrate that the longitudinal change in mI/Cr and NAA/mI is associated with underlying amyloid pathology. MRS may be a useful noninvasive marker of Aβ-related processes over time. In addition, we show that in A7beta;+ individuals, baseline NAA/mI may predict the rate of future cognitive decline

Myo-inositol changes precede amyloid pathology and relate to APOE genotype in Alzheimer disease

Objective: We aimed to test whether in vivo levels of magnetic resonance spectroscopy (MRS) metabolites myo-inositol (mI), N-acetylaspartate (NAA), and choline are abnormal already during preclinical Alzheimer disease (AD), relating these changes to amyloid or tau pathology, and functional connectivity. Methods: In this cross-sectional multicenter study (a subset of the prospective Swedish BioFINDER study), we included 4 groups, representing the different stages of predementia AD: (1) cognitively healthy elderly with normal CSF β-amyloid 42 (Aβ42), (2) cognitively healthy elderly with abnormal CSF Aβ42, (3) patients with subjective cognitive decline and abnormal CSF Aβ42, (4) patients with mild cognitive decline and abnormal CSF Aβ42 (N total 352). Spectroscopic markers measured in the posterior cingulate/precuneus were considered alongside known disease biomarkers: CSF Aβ42, phosphorylated tau, total tau, [18 F]-flutemetamol PET, f-MRI, and the genetic risk factor APOE. Results: Amyloid-positive cognitively healthy participants showed a significant increase in mI/creatine and mI/NAA levels compared to amyloid-negative healthy elderly (p <0.05). In amyloid-positive healthy elderly, mI/creatine and mI/NAA correlated with cortical retention of [18 F] flutemetamol tracer (0.44, p 0.02 and 0.51, p 0.01, respectively). Healthy elderly APOE ϵ4 carriers with normal CSF Aβ42 levels had significantly higher mI/creatine levels (p <0.001) than ϵ4 noncarriers. Finally, elevated mI/creatine was associated with decreased functional connectivity within the default mode network (r pearson-0.16, p 0.02), independently of amyloid pathology. Conclusions: mI levels are elevated already at asymptomatic stages of AD. Moreover, mI/creatine concentrations were increased in healthy APOE ϵ4 carriers with normal CSF Aβ42 levels, suggesting that mI levels may reveal regional brain consequences of APOE ϵ4 before detectable amyloid pathology