Quantitative Susceptibility Mapping (QSM) MRI at 7 Tesla and 11-Carbon Pittsburgh-Compound-B PET were used for investigating the relationship between brain iron and Amyloid beta (Aβ) plaque-load in a context of increased risk for Alzheimer's disease (AD), as reflected by the Apolipoprotein E ε4 (APOE-e4) allele and mild cognitive impairment (MCI) in elderly subjects. Carriers of APOE-e4 with normal cognition had higher cortical Aβ-plaque-load than non-carriers. In MCI an association between APOE-e4 and higher Aβ-plaque-load was observable both for cortical and subcortical brain-regions. APOE-e4 and MCI was also associated with higher cortical iron. Moreover, cerebral iron significantly affected functional coupling, and was furthermore associated with increased Aβ-plaque-load (R2-adjusted = 0.80, p < 0.001) and APOE-e4 carrier status (p < 0.001) in MCI. This study confirms earlier reports on an association between increased brain iron-burden and risk for neurocognitive dysfunction due to AD, and indicates that disease-progression is conferred by spatial colocalization of brain iron deposits with Aβ-plaques.

Reading is a difficult task that, at a minimum, requires recognizing a visual stimulus and linking it with its corresponding sound and meaning. Neurologically, this involves an anatomically distributed set of brain regions cooperating to solve the problem. It has been hypothesized that the supramarginal gyrus (SMG) contributes preferentially to phonological aspects of word processing and thus plays an important role in visual word recognition. Here, we used chronometric transcranial magnetic stimulation (TMS) to investigate the functional specificity and timing of SMG involvement in reading visually presented words. Participants performed tasks designed to focus on either the phonological, semantic, or visual aspects of written words while double pulses of TMS (delivered 40 ms apart) were used to temporarily interfere with neural information processing in the left SMG at five different time windows. Stimulation at 80/120, 120/160, and 160/200 ms post-stimulus onset significantly slowed subjects’ reaction times in the phonological task. This inhibitory effect was specific to the phonological condition, with no effect of TMS in the semantic or visual tasks, consistent with claims that SMG contributes preferentially to phonological aspects of word processing. The fact that the effect began within 80–120 ms of the onset of the stimulus and continued for approximately 100 ms, indicates that phonological processing initiates early and is sustained over time. These findings are consistent with accounts of visual word recognition that posit parallel activation of orthographic, phonological, and semantic information that interact over time to settle into a distributed, but stable, representation of a word.

The accumulation of β-amyloid plaques is a hallmark of Alzheimer's disease (AD), and recently published data suggest that increased brain iron burden may reflect pathologies that synergistically contribute to the development of cognitive dysfunction. While preclinical disease stages are considered most promising for therapeutic intervention, the link between emerging AD-pathology and earliest clinical symptoms remains largely unclear. In the current study we therefore investigated local correlations between iron and β-amyloid plaques, and their possible association with cognitive performance in healthy older adults. 116 older adults (mean age 75 ± 7.4 years) received neuropsychological testing to calculate a composite cognitive score of performance in episodic memory, executive functioning, attention, language and communication. All participants were scanned on a combined PET-MRI instrument and were administered T1-sequences for anatomical mapping, quantitative susceptibility mapping (QSM) for assessing iron, and 18F-Flutemetamol-PET for estimating β-amyloid plaque load. Biological parametric mapping (BPM) was used to generate masks indicating voxels with significant (p < 0.05) correlation between susceptibility and 18F-Flutemetamol-SUVR. We found a bilateral pattern of clusters characterized by a statistical relationship between magnetic susceptibility and 18F-Flutemetamol-SUVR, indicating local correlations between iron and β-amyloid plaque deposition. For two bilateral clusters, located in the frontal and temporal cortex, significant relationships (p<0.05) between local β-amyloid and the composite cognitive performance score could be observed. No relationship between whole-cortex β-amyloid plaque load and cognitive performance was observable. Our data suggest that the local correlation of β-amyloid plaque load and iron deposition may provide relevant information regarding cognitive performance of healthy older adults. Further studies are needed to clarify pathological correlates of the local interaction of β-amyloid, iron and other causes of altered magnetic susceptibility.