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Non-invasive evaluation of glymphatic function has emerged as a crucial goal in neuroimaging, and diffusion tensor imaging along the perivascular space (DTI-ALPS) has emerged as a candidate method for this purpose. Reduced ALPS index has been suggested to indicate impaired glymphatic function. However, the potential impact of crossing fibres on the ALPS index has not been assessed, which was the aim of this cross-sectional study. For this purpose, we used DTI-ALPS in a cohort with three groups: Parkinson's disease (PD) ( n = 60, mean age 63.3 ± 1.5, 33 males), progressive supranuclear palsy (PSP) ( n = 17, mean age 70.9 ± 1.5, 9 males) and healthy controls ( n = 41, mean age 64.5 ± 8.4, 15 males). The ALPS index was calculated blinded to diagnosis, by manually placing two sets of regions of interest (ROI) on the projection and association fibres of each hemisphere. Annotation was performed twice: once on conventional diffusion-encoded colour maps weighted by fractional anisotropy and once on maps with weights adjusted for high incidence of crossing fibres. PSP patients had significantly lower conventional ALPS indices compared with both healthy controls (right hemisphere: P = 0.009; left hemisphere: P < 0.001) and PD patients (right hemisphere: P = 0.024; left hemisphere: P < 0.001). There were no differences between healthy controls and PD patients. After adjusting the ROI to avoid regions of crossing fibres, the ALPS index significantly decreased in healthy controls (right hemisphere: P < 0.001; left hemisphere: P < 0.001) and PD (right hemisphere: P < 0.001; left hemisphere: P < 0.001). In PSP, the adjusted ALPS index was lower compared with the conventional one only in the right hemisphere ( P = 0.047). Overall, this adjustment led to less significant differences among diagnostic groups. Specifically, with the adjusted ALPS index, PSP patients showed significantly lower ALPS index compared with healthy controls (right hemisphere: P = 0.044; left hemisphere: P = 0.029) and PD patients ( P = 0.003 for the left hemisphere only). Our results suggest that crossing fibres significantly inflate the ALPS index and should be considered a critical pitfall of this method. This factor could partly explain the variability observed in previous studies. Unlike previous research, we observed no differences between PD and healthy controls, likely because most patients in our cohort were in the early phase of the disease. Thus, the ALPS index may not be a sensitive indicator of glymphatic function at least in the initial stages of neurodegeneration in PD., Competing Interests: O.H. has acquired research support (for the institution) from AVID Radiopharmaceuticals, Biogen, C2N Diagnostics, Eli Lilly, Eisai, Fujirebio, GE Healthcare and Roche. In the past 2 years, he has received consultancy/speaker fees from Alzpath, BioArctic, Biogen, Bristol Meyer Squibb, Eisai, Eli Lilly, Fujirebio, Merck, Novartis, Novo Nordisk, Roche, Sanofi and Siemens. The other authors report no competing interests., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Proteomics can shed light on the dynamic and multifaceted alterations in neurodegenerative disorders like Alzheimer's disease (AD). Combining radioligands measuring β-amyloid (Aβ) plaques and tau tangles with cerebrospinal fluid proteomics, we uncover molecular events mirroring different stages of AD pathology in living humans. We found 127 differentially abundant proteins (DAPs) across the AD spectrum. The strongest Aβ-related proteins were mainly expressed in glial cells and included SMOC1 and ITGAM. A dozen proteins linked to ATP metabolism and preferentially expressed in neurons were independently associated with tau tangle load and tau accumulation. Only 20% of the DAPs were also altered in other neurodegenerative diseases, underscoring AD's distinct proteome. Two co-expression modules related, respectively, to protein metabolism and microglial immune response encompassed most DAPs, with opposing, staggered trajectories along the AD continuum. We unveil protein signatures associated with Aβ and tau proteinopathy in vivo, offering insights into complex neural responses and potential biomarkers and therapeutics targeting different disease stages., (© 2024. The Author(s).)

Importance: The lack of an in vivo measure for α-synuclein (α-syn) pathology until recently has limited thorough characterization of its brain atrophy pattern, especially during early disease stages., Objective: To assess the association of state-of-the-art cerebrospinal fluid (CSF) seed amplification assays (SAA) α-syn positivity (SAA α-syn+) with magnetic resonance imaging (MRI) structural measures, across the continuum from clinically unimpaired (CU) to cognitively impaired (CI) individuals, in 3 independent cohorts, and separately in CU and CI individuals, the latter reflecting a memory clinic population., Design, Setting, and Participants: Cross-sectional data were used from the Swedish BioFINDER-2 study (inclusion, 2017-2023) as the discovery cohort and the Swedish BioFINDER-1 study (inclusion, 2007-2015) and Alzheimer's Disease Neuroimaging Initiative (ADNI; inclusion 2005-2022) as replication cohorts. All cohorts are from multicenter studies, but the BioFINDER cohorts used 1 MRI scanner. CU and CI individuals fulfilling inclusion criteria and without missing data points in relevant metrics were included in the study. All analyses were performed from 2023 to 2024., Exposures: Presence of α-syn pathology, estimated by baseline CSF SAA α-syn., Main Outcomes and Measures: The primary outcomes were cross-sectional structural MRI measures either through voxel-based morphometry (VBM) or regions of interest (ROI) including an automated pipeline for cholinergic basal forebrain nuclei CH4/4p (nucleus basalis of Meynert [NBM]) and CH1/2/3. Secondary outcomes were domain-specific cross-sectional cognitive measures. Analyses were adjusted for CSF biomarkers of Alzheimer pathology., Results: A total of 2961 participants were included in this study: 1388 (mean [SD] age, 71 [10] years; 702 female [51%]) from the BioFINDER-2 study, 752 (mean [SD] age, 72 [6] years; 406 female [54%]) from the BioFINDER-1 study, and 821 (mean [SD] age, 75 [8] years; 449 male [55%]) from ADNI. In the BioFINDER-2 study, VBM analyses in the whole cohort revealed a specific association between SAA α-syn+ and the cholinergic NBM, even when adjusting for Alzheimer copathology. ROI-based analyses in the BioFINDER-2 study focused on regions involved in the cholinergic system and confirmed that SAA α-syn+ was indeed independently associated with smaller NBM (β = -0.271; 95% CI, -0.399 to -0.142; P <.001) and CH1/2/3 volumes (β = -0.227; 95% CI, -0.377 to -0.076; P =.02). SAA α-syn+ was also independently associated with smaller NBM volumes in the separate CU (β = -0.360; 95% CI, -0.603 to -0.117; P =.03) and CI (β = -0.251; 95% CI, -0.408 to -0.095; P =.02) groups. Overall, the association between SAA α-syn+ and NBM volume was replicated in the BioFINDER-1 study and ADNI cohort. In CI individuals, NBM volumes partially mediated the association of SAA α-syn+ with attention/executive impairments in all cohorts (BioFINDER-2, β = -0.017; proportion-mediated effect, 7%; P =.04; BioFINDER-1, β = -0.096; proportion-mediated effect, 19%; P =.04; ADNI, β = -0.061; proportion-mediated effect, 20%; P =.007)., Conclusions and Relevance: In this cohort study, SAA α-syn+ was consistently associated with NBM atrophy already during asymptomatic stages. Further, in memory clinic CI populations, SAA α-syn+ was associated with NBM atrophy, which partially mediated α-syn-induced attention/executive impairment.

Background: The medial temporal lobe (MTL) is hypothesized to be relatively spared in early-onset Alzheimer's disease (EOAD). Yet, detailed examination of MTL subfields and drivers of atrophy in amnestic EOAD is lacking., Methods: BioFINDER-2 participants with memory impairment, abnormal amyloid-β and tau-PET were included. Forty-one amnestic EOAD individuals ≤65 years and, as comparison, late-onset AD (aLOAD, ≥70 years, n = 154) and amyloid-β-negative cognitively unimpaired controls were included. MTL subregions and biomarkers of (co-)pathologies were measured., Results: AD groups showed smaller MTL subregions compared to controls. Atrophy patterns were similar across AD groups: aLOAD showed thinner entorhinal cortices than aEOAD; aEOAD showed thinner parietal regions than aLOAD. aEOAD showed lower white matter hyperintensities than aLOAD. No differences in MTL tau-PET or transactive response DNA binding protein 43-proxy positivity were found., Conclusions: We found evidence for MTL atrophy in amnestic EOAD and overall similar levels to aLOAD of MTL tau pathology and co-pathologies., (© 2024. The Author(s).)

Sulcation of the anterior cingulate may be defined by presence of a paracingulate sulcus, a tertiary sulcus developing during the third gestational trimester with implications on cognitive function and disease. In this cross-sectional study we examine task-free resting state functional connectivity and diffusion-weighted tract segmentation data from a cohort of healthy adults (< 60-year-old, n = 129), exploring the impact of ipsilateral paracingulate sulcal presence on structural and functional connectivity. Presence of a left paracingulate sulcus was associated with reduced fractional anisotropy in the left cingulum bundle and the left peri-genual and dorsal bundle segments, suggesting reduced structural organisational coherence in these tracts. This association was not observed in the offsite temporal cingulum bundle segment. Left paracingulate sulcal presence was associated with increased left peri-genual radial diffusivity and tract volume possibly suggesting increased U-fibre density in this region. Greater network dispersity was identified in individuals with an absent left paracingulate sulcus by presence of a significant, predominantly intraregional, frontal component of resting state functional connectivity which was not present in individuals with a present left paracingulate sulcus. Seed-based functional connectivity in pre-defined networks was not associated with paracingulate sulcal presence. These results identify a novel association between sulcation and structural connectivity in a healthy adult population with implications for conditions where this variation is of interest. Presence of a left paracingulate sulcus appears to alter local structural and functional connectivity, possibly as a result of the presence of a local network reliant on short association fibres., (© 2024. The Author(s).)

Age-related white matter hyperintensities are a common feature and are known to be negatively associated with structural integrity, functional connectivity, and cognitive performance. However, this has yet to be fully understood mechanistically. We analyzed multiple MRI modalities acquired in 465 non-demented individuals from the Swedish BioFINDER study including 334 cognitively normal and 131 participants with mild cognitive impairment. White matter hyperintensities were automatically quantified using fluid-attenuated inversion recovery MRI and parameters from diffusion tensor imaging were estimated in major white matter fibre tracts. We calculated fMRI resting state-derived functional connectivity within and between predefined cortical regions structurally linked by the white matter tracts. How change in functional connectivity is affected by white matter lesions and related to cognition (in the form of executive function and processing speed) was explored. We examined the functional changes using a measure of sample entropy. As expected hyperintensities were associated with disrupted structural white matter integrity and were linked to reduced functional interregional lobar connectivity, which was related to decreased processing speed and executive function. Simultaneously, hyperintensities were also associated with increased intraregional functional connectivity, but only within the frontal lobe. This phenomenon was also associated with reduced cognitive performance. The increased connectivity was linked to increased entropy (reduced predictability and increased complexity) of the involved voxels' blood oxygenation level-dependent signal. Our findings expand our previous understanding of the impact of white matter hyperintensities on cognition by indicating novel mechanisms that may be important beyond this particular type of brain lesions., Competing Interests: Declaration of competing interest OH has acquired research support (for the institution) from AVID Radiopharmaceuticals, Biogen, Eli Lilly, Eisai, GE Healthcare, Pfizer, and Roche. In the past 2 years, he has received consultancy/speaker fees from AC Immune, Alzpath, Biogen, Cerveau and Roche. The other authors have no declarations of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Synaptic dysfunction and degeneration is likely the key pathophysiology for the progression of cognitive decline in various dementia disorders. Synaptic status can be monitored by measuring synaptic proteins in CSF. In this study, both known and new synaptic proteins were investigated and compared as potential biomarkers of synaptic dysfunction, particularly in the context of Alzheimer's disease (AD). Seventeen synaptic proteins were quantified in CSF using two different targeted mass spectrometry assays in the prospective Swedish BioFINDER-2 study. The study included 958 individuals, characterized as having mild cognitive impairment (MCI, n = 205), AD dementia (n = 149) and a spectrum of other neurodegenerative diseases (n = 171), in addition to cognitively unimpaired individuals (CU, n = 443). Synaptic protein levels were compared between diagnostic groups and their associations with cognitive decline and key neuroimaging measures (amyloid-β-PET, tau-PET and cortical thickness) were assessed. Among the 17 synaptic proteins examined, 14 were specifically elevated in the AD continuum. SNAP-25, 14-3-3 zeta/delta, β-synuclein, and neurogranin exhibited the highest discriminatory accuracy in differentiating AD dementia from controls (areas under the curve = 0.81-0.93). SNAP-25 and 14-3-3 zeta/delta also had the strongest associations with tau-PET, amyloid-β-PET and cortical thickness at baseline and were associated with longitudinal changes in these imaging biomarkers [β(standard error, SE) = -0.056(0.0006) to 0.058(0.005), P < 0.0001]. SNAP-25 was the strongest predictor of progression to AD dementia in non-demented individuals (hazard ratio = 2.11). In contrast, neuronal pentraxins were decreased in all neurodegenerative diseases (except for Parkinson's disease), and NPTX2 showed the strongest associations with subsequent cognitive decline [longitudinal Mini-Mental State Examination: β(SE) = 0.57(0.1), P ≤ 0.0001; and mPACC: β(SE) = 0.095(0.024), P ≤ 0.001] across the AD continuum. Interestingly, utilizing a ratio of the proteins that displayed higher levels in AD, such as SNAP-25 or 14-3-3 zeta/delta, over NPTX2 improved the biomarkers' associations with cognitive decline and brain atrophy. We found 14-3-3 zeta/delta and SNAP-25 to be especially promising as synaptic biomarkers of pathophysiological changes in AD. Neuronal pentraxins were identified as general indicators of neurodegeneration and associated with cognitive decline across various neurodegenerative dementias. Cognitive decline and brain atrophy were best predicted by ratios of SNAP-25/NPTX2 and 14-3-3 zeta/delta/NPTX2., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Several studies have shown white matter (WM) abnormalities in Alzheimer's disease (AD) using diffusion tensor imaging (DTI). Nonetheless, robust characterization of WM changes has been challenging due to the methodological limitations of DTI. We applied fixel-based analyses (FBA) to examine microscopic differences in fiber density (FD) and macroscopic changes in fiber cross-section (FC) in early stages of AD ( N  = 393, 212 females). FBA was also compared with DTI, free-water corrected (FW)-DTI and diffusion kurtosis imaging (DKI). We further investigated the correlation of FBA and tensor-derived metrics with AD pathology and cognition. FBA metrics were decreased in the entire cingulum bundle, uncinate fasciculus and anterior thalamic radiations in Aβ-positive patients with mild cognitive impairment compared to control groups. Metrics derived from DKI, and FW-DTI showed similar alterations whereas WM degeneration detected by DTI was more widespread. Tau-PET uptake in medial temporal regions was only correlated with reduced FC mainly in the parahippocampal cingulum in Aβ-positive individuals. This tau-related WM alteration was also associated with impaired memory. Despite the spatially extensive between-group differences in DTI-metrics, the link between WM and tau aggregation was only revealed using FBA metrics implying high sensitivity but low specificity of DTI-based measures in identifying subtle tau-related WM degeneration. No relationship was found between amyloid load and any diffusion-MRI measures. Our results indicate that early tau-related WM alterations in AD are due to macrostructural changes specifically captured by FBA metrics. Thus, future studies assessing the effects of AD pathology in WM tracts should consider using FBA metrics., (Copyright © 2024 Ahmadi et al.)

Cerebrovascular pathology often co-exists with Alzheimer's disease pathology and can contribute to Alzheimer's disease-related clinical progression. However, the degree to which vascular burden contributes to Alzheimer's disease pathological progression is still unclear. This study aimed to investigate interactions between vascular burden and amyloid-β pathology on both baseline tau tangle load and longitudinal tau accumulation. We included 1229 participants from the Swedish BioFINDER-2 Study, including cognitively unimpaired and impaired participants with and without biomarker-confirmed amyloid-β pathology. All underwent baseline tau-PET (18F-RO948), and a subset (n = 677) underwent longitudinal tau-PET after 2.5 ± 1.0 years. Tau-PET uptake was computed for a temporal meta-region-of-interest. We focused on four main vascular imaging features and risk factors: microbleeds; white matter lesion volume; stroke-related events (infarcts, lacunes and haemorrhages); and the Framingham Heart Study Cardiovascular Disease risk score. To validate our in vivo results, we examined 1610 autopsy cases from an Arizona-based neuropathology cohort on three main vascular pathological features: cerebral amyloid angiopathy; white matter rarefaction; and infarcts. For the in vivo cohort, primary analyses included age-, sex- and APOE ɛ4-corrected linear mixed models between tau-PET (outcome) and interactions between time, amyloid-β and each vascular feature (predictors). For the neuropathology cohort, age-, sex- and APOE ɛ4-corrected linear models between tau tangle density (outcome) and an interaction between plaque density and each vascular feature (predictors) were performed. In cognitively unimpaired individuals, we observed a significant interaction between microbleeds and amyloid-β pathology on greater baseline tau load (β = 0.68, P < 0.001) and longitudinal tau accumulation (β = 0.11, P < 0.001). For white matter lesion volume, we did not observe a significant independent interaction effect with amyloid-β on tau after accounting for microbleeds. In cognitively unimpaired individuals, we further found that stroke-related events showed a significant negative interaction with amyloid-β on longitudinal tau (β = -0.08, P < 0.001). In cognitively impaired individuals, there were no significant interaction effects between cerebrovascular and amyloid-β pathology at all. In the neuropathology dataset, the in vivo observed interaction effects between cerebral amyloid angiopathy and plaque density (β = 0.38, P < 0.001) and between infarcts and plaque density (β = -0.11, P = 0.005) on tau tangle density were replicated. To conclude, we demonstrated that cerebrovascular pathology-in the presence of amyloid-β pathology-modifies tau accumulation in early stages of Alzheimer's disease. More specifically, the co-occurrence of microbleeds and amyloid-β pathology was associated with greater accumulation of tau aggregates during early disease stages. This opens the possibility that interventions targeting microbleeds may attenuate the rate of tau accumulation in Alzheimer's disease., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

There is increased interest in developing markers reflecting microstructural changes that could serve as outcome measures in clinical trials. This is especially important after unexpected results in trials evaluating disease-modifying therapies targeting amyloid-β (Aβ), where morphological metrics from MRI showed increased volume loss despite promising clinical treatment effects. In this study, changes over time in cortical mean diffusivity, derived using diffusion tensor imaging, were investigated in a large cohort (n = 424) of non-demented participants from the Swedish BioFINDER study. Participants were stratified following the Aβ/tau (AT) framework. The results revealed a widespread increase in mean diffusivity over time, including both temporal and parietal cortical regions, in Aβ-positive but still tau-negative individuals. These increases were steeper in Aβ-positive and tau-positive individuals and robust to the inclusion of cortical thickness in the model. A steeper increase in mean diffusivity was also associated with both changes over time in fluid markers reflecting astrocytic activity (i.e. plasma level of glial fibrillary acidic protein and CSF levels of YKL-40) and worsening of cognitive performance (all P < 0.01). By tracking cortical microstructural changes over time and possibly reflecting variations related to the astrocytic response, cortical mean diffusivity emerges as a promising marker for tracking treatments-induced microstructural changes in clinical trials., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

In Alzheimer's disease, reconfiguration and deterioration of tissue microstructure occur before substantial degeneration become evident. We explored the diffusion properties of both water, a ubiquitous marker measured by diffusion MRI, and N -acetyl-aspartate, a neuronal metabolite probed by diffusion-weighted magnetic resonance spectroscopy, for investigating cortical microstructural changes downstream of Alzheimer's disease pathology. To this aim, 50 participants from the Swedish BioFINDER-2 study were scanned on both 7 and 3 T MRI systems. We found that in cognitively impaired participants with evidence of both abnormal amyloid-beta (CSF amyloid-beta42/40) and tau accumulation (tau-PET), the N -acetyl-aspartate diffusion rate was significantly lower than in cognitively unimpaired participants ( P < 0.05). This supports the hypothesis that intraneuronal tau accumulation hinders diffusion in the neuronal cytosol. Conversely, water diffusivity was higher in cognitively impaired participants ( P < 0.001) and was positively associated with the concentration of myo-inositol, a preferentially astrocytic metabolite ( P < 0.001), suggesting that water diffusion is sensitive to alterations in the extracellular space and in glia. In conclusion, measuring the diffusion properties of both water and N -acetyl-aspartate provides rich information on the cortical microstructure in Alzheimer's disease, and can be used to develop new sensitive and specific markers to microstructural changes occurring during the disease course., Competing Interests: O.H. has acquired research support (for the institution) from ADx, AVID Radiopharmaceuticals, Biogen, Eli Lilly, Eisai, Fujirebio, GE Healthcare, Pfizer and Roche. In the past 2 years, he has received consultancy/speaker fees from AC Immune, Amylyx, Alzpath, BioArctic, Biogen, Cerveau, Eisai, Eli Lilly, Fujirebio, Genentech, Merck, Novartis, Novo Nordisk, Roche, Sanofi and Siemens., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Most research on the neurostructural basis of language abilities in children stems from small samples and surface-based measures. To complement and expand the existent knowledge, we investigated associations between grey matter volume and language performance in a large sample of 9-to-11-year-old children, using data from the Adolescent Brain Cognitive Development (ABCD) Study (N = 1865) and an alternative measure of grey matter morphology. We estimated whole-brain grey matter volume for one half of the sample (N = 939) and tested for correlations with scores on a picture vocabulary and a letter and word reading test, with and without factoring in general intelligence and total grey matter volume as additional covariates. The initial analyses yielded correlations between grey matter in the right occipital fusiform gyrus, the right lingual gyrus, and the cerebellum for both vocabulary and reading. Employing the significant clusters from the first analyses as regions of interest in the second half of the cohort (N = 926) in correlational and multiple regression analyses suggests the cluster in the right occipital fusiform and lingual gyri to be most robust. Overall, the amount of variance explained by grey matter volume is limited and factoring in additional covariates paints an inconsistent picture. The present findings reinforce existent doubt with respect to explaining individual differences in reading and vocabulary performance based on unique contributions of macrostructural brain features., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Amyloid-β (Aβ) is hypothesized to facilitate the spread of tau pathology beyond the medial temporal lobe. However, there is evidence that, independently of Aβ, age-related tau pathology might be present outside of the medial temporal lobe. We therefore aimed to study age-related Aβ-independent tau deposition outside the medial temporal lobe in two large cohorts and to investigate potential downstream effects of this on cognition and structural measures. We included 545 cognitively unimpaired adults (40-92 years) from the BioFINDER-2 study (in vivo) and 639 (64-108 years) from the Rush Alzheimer's Disease Center cohorts (ex vivo). 18F-RO948- and 18F-flutemetamol-PET standardized uptake value ratios were calculated for regional tau and global/regional Aβ in vivo. Immunohistochemistry was used to estimate Aβ load and tangle density ex vivo. In vivo medial temporal lobe volumes (subiculum, cornu ammonis 1) and cortical thickness (entorhinal cortex, Brodmann area 35) were obtained using Automated Segmentation for Hippocampal Subfields packages. Thickness of early and late neocortical Alzheimer's disease regions was determined using FreeSurfer. Global cognition and episodic memory were estimated to quantify cognitive functioning. In vivo age-related tau deposition was observed in the medial temporal lobe and in frontal and parietal cortical regions, which was statistically significant when adjusting for Aβ. This was also observed in individuals with low Aβ load. Tau deposition was negatively associated with cortical volumes and thickness in temporal and parietal regions independently of Aβ. The associations between age and cortical volume or thickness were partially mediated via tau in regions with early Alzheimer's disease pathology, i.e. early tau and/or Aβ pathology (subiculum/Brodmann area 35/precuneus/posterior cingulate). Finally, the associations between age and cognition were partially mediated via tau in Brodmann area 35, even when including Aβ-PET as covariate. Results were validated in the ex vivo cohort showing age-related and Aβ-independent increases in tau aggregates in and outside the medial temporal lobe. Ex vivo age-cognition associations were mediated by medial and inferior temporal tau tangle density, while correcting for Aβ density. Taken together, our study provides support for primary age-related tauopathy even outside the medial temporal lobe in vivo and ex vivo, with downstream effects on structure and cognition. These results have implications for our understanding of the spreading of tau outside the medial temporal lobe, also in the context of Alzheimer's disease. Moreover, this study suggests the potential utility of tau-targeting treatments in primary age-related tauopathy, likely already in preclinical stages in individuals with low Aβ pathology., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Markers of downstream events are a key component of clinical trials of disease-modifying therapies for Alzheimer's disease. Morphological metrics like cortical thickness are established measures of atrophy but are not sensitive enough to detect amyloid-beta (Aβ)- related changes that occur before overt atrophy become visible. We aimed to investigate to what extent diffusion MRI can provide sensitive markers of cortical microstructural changes and to test their associations with multiple aspects of the Alzheimer's disease pathological cascade, including both Aβ and tau accumulation, astrocytic activation and cognitive deficits. We applied the mean apparent diffusion propagator model to diffusion MRI data from 492 cognitively unimpaired elderly and patients with mild cognitive impairment from the Swedish BioFINDER-2 cohort. Participants were stratified in Aβ-negative/tau-negative, Aβ-positive/tau-negative and Aβ-positive/tau-positive based on Aβ- and tau-PET uptake. Cortical regional values of diffusion MRI metrics and cortical thickness were compared across groups. Associations between regional values of diffusion MRI metrics and both Aβ- and tau-PET uptake were also investigated along with the association with plasma level of glial fibrillary acidic protein (GFAP), a marker of astrocyte activation (available in 292 participants). Mean squared displacement revealed widespread microstructural differences already between Aβ-negative/tau-negative and Aβ-positive/tau-negative participants with a spatial distribution that closely resembled the pattern of Aβ accumulation. In contrast, differences in cortical thickness were clearly more limited. Mean squared displacement was also correlated with both Aβ- and tau-PET uptake even independently from one another and from cortical thickness. Further, the same metric exhibited significantly stronger correlations with PET uptake than cortical thickness (P < 0.05). Mean squared displacement was also positively correlated with GFAP with a pattern that resembles Aβ accumulation, and GFAP partially mediated the association between Aβ accumulation and mean squared displacement. Further, impairments in executive functions were significantly more associated with mean squared displacement values extracted from a meta-region of interest encompassing regions accumulating Aβ early in the disease process, than with cortical thickness (P < 0.05). Similarly, impairments in memory functions were significantly more associated with mean squared displacement values extracted from a temporal meta-region of interest than with cortical thickness (P < 0.05). Metrics of cortical microstructural alteration derived from diffusion MRI are highly sensitive to multiple aspects of the Alzheimer's disease pathological cascade. Of particular interest is the link with both Aβ-PET and GFAP, suggesting diffusion MRI might reflects microstructural changes related to the astrocytic response to Aβ aggregation. Therefore, metrics of cortical diffusion might be important outcome measures in anti-Aβ treatments clinical trials for detecting drug-induced changes in cortical microstructure., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background: Using multi-block methods we combined multimodal neuroimaging metrics of thalamic morphology, thalamic white matter tract diffusion metrics, and cortical thickness to examine changes in behavioural variant frontotemporal dementia. (bvFTD)., Method: Twenty-three patients with sporadic bvFTD and 24 healthy controls underwent structural and diffusion MRI scans. Clinical severity was assessed using the Clinical Dementia Rating scale and behavioural severity using the Frontal Behaviour Inventory by patient caregivers. Thalamic volumes were manually segmented. Anterior and posterior thalamic radiation fractional anisotropy and mean diffusivity were extracted using Tract-Based Spatial Statistics. Finally, cortical thickness was assessed using Freesurfer. We used shape analyses, diffusion measures, and cortical thickness as features in sparse multi-block partial least squares (PLS) discriminatory analyses to classify participants within bvFTD or healthy control groups. Sparsity was tuned with five-fold cross-validation repeated 10 times. Final model fit was assessed using permutation testing. Additionally, sparse multi-block PLS was used to examine associations between imaging features and measures of dementia severity., Results: Bilateral anterior-dorsal thalamic atrophy, reduction in mean diffusivity of thalamic projections, and frontotemporal cortical thinning, were the main features predicting bvFTD group membership. The model had a sensitivity of 96%, specificity of 68%, and was statistically significant using permutation testing (p = 0.012). For measures of dementia severity, we found similar involvement of regional thalamic and cortical areas as in discrimination analyses, although more extensive thalamo-cortical white matter metric changes., Conclusions: Using multimodal neuroimaging, we demonstrate combined structural network dysfunction of anterior cortical regions, cortical-thalamic projections, and anterior thalamic regions in sporadic bvFTD., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)

For optimal design of anti-amyloid-β (Aβ) and anti-tau clinical trials, we need to better understand the pathophysiological cascade of Aβ- and tau-related processes. Therefore, we set out to investigate how Aβ and soluble phosphorylated tau (p-tau) relate to the accumulation of tau aggregates assessed with PET and subsequent cognitive decline across the Alzheimer's disease (AD) continuum. Using human cross-sectional and longitudinal neuroimaging and cognitive assessment data, we show that in early stages of AD, increased concentration of soluble CSF p-tau is strongly associated with accumulation of insoluble tau aggregates across the brain, and CSF p-tau levels mediate the effect of Aβ on tau aggregation. Further, higher soluble p-tau concentrations are mainly related to faster accumulation of tau aggregates in the regions with strong functional connectivity to individual tau epicenters. In this early stage, higher soluble p-tau concentrations is associated with cognitive decline, which is mediated by faster increase of tau aggregates. In contrast, in AD dementia, when Aβ fibrils and soluble p-tau levels have plateaued, cognitive decline is related to the accumulation rate of insoluble tau aggregates. Our data suggest that therapeutic approaches reducing soluble p-tau levels might be most favorable in early AD, before widespread insoluble tau aggregates., (© 2022. The Author(s).)

A growing body of evidence suggests that astrocytes play a major role in the pathophysiology of Alzheimer's disease. Given that APOE is primarily expressed in astrocytes, these cells might be an important link between the APOE ε4 allele and the development of Alzheimer's disease pathology. Here, we investigate this hypothesis in vivo by measuring myo-inositol, a metabolite involved in astrocytic functions, with magnetic resonance spectroscopy. Currently, there is conflicting evidence regarding the relationship between APOE ε4 and myo-inositol concentration. Furthermore, data supporting a relationship between APOE ε4, myo-inositol and Alzheimer's disease pathology (amyloid-beta and tau proteins) in the preclinical stage of Alzheimer's disease are limited. A previous study revealed differences in myo-inositol levels between APOE ε4 carriers and non-carriers already in preclinical Alzheimer's disease participants. However, other reports showed no impact of APOE genotype on the association between myo-inositol and the rate of amyloid-beta accumulation. In the present study, we determined the effect of APOE genotype on the association between myo-inositol and both amyloid-β and tau deposition quantified by PET in 428 cognitively unimpaired elderly and patients with mild cognitive impairment from the Swedish BioFINDER-2 cohort. APOE genotype impacted the associations between myo-inositol and amyloid-β pathology as revealed by an interaction effect between APOE genotype and levels of myo-inositol ( P  < 0.001) such that higher myo-inositol concentration was related to more amyloid-beta pathology in APOE ε4 carriers only. A similar interaction effect was also found when investigating the effect of APOE on the association between myo-inositol and tau pathology ( P  < 0.01). Focusing on the APOE ε4 subsample, myo-inositol partially (17%) mediated the association between amyloid-beta and tau pathology ( P  < 0.05). Furthermore, in a subgroup of participants with available plasma levels of glial fibrillary acidic protein, a marker of astroglial activation and astrocytosis, we found that glial fibrillary acidic protein correlated with myo-inositol only in APOE e4 carriers ( APOE ε4 carriers: P  < 0.01; APOE ε4 non-carriers: P  > 0.8), suggesting that myo-inositol might reflect an aspect of the astrocytic involvement in Alzheimer's pathology which is specific to the impact of APOE ε4. Therefore, we suggest that myo-inositol is a candidate in vivo marker to study the impact of APOE ε4 on the interplay between astrocytes and the pathophysiology of Alzheimer's disease., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Objectives: To investigate the impact of Alzheimer's disease (AD) co-pathology on an in vivo structural measure of neurodegeneration in Lewy body disorders (LBD)., Methods: We studied 72 LBD patients (Parkinson disease (PD) = 2, PD-MCI = 25, PD with dementia = 10, dementia with Lewy bodies = 35) with either CSF analysis or neuropathological examination and structural MRI during life. The cohort was divided into those harboring significant AD co-pathology, either at autopsy (intermediate/high AD neuropathologic change) or with CSF signature indicating AD co-pathology (t-tau/Aβ 1-42  > 0.3) (LBD+AD, N = 19), and those without AD co-pathology (LBD-AD, N = 53). We also included a reference group of 25 patients with CSF biomarker-confirmed amnestic AD. We investigated differences in MRI cortical thickness estimates between groups, and in the 21 autopsied LBD patients (LBD-AD = 14, LBD+AD = 7), directly tested the association between antemortem MRI and post-mortem burdens of tau, Aβ, and alpha-synuclein using digital histopathology in five representative neocortical regions., Results: The LBD+AD group was characterized by cortical thinning in anterior/medial and lateral temporal regions (P < 0.05 FWE-corrected) relative to LBD-AD. In LBD+AD, cortical thinning was most pronounced in temporal neocortex, whereas the AD reference group showed atrophy that equally encompassed temporal, parietal and frontal neocortex. In autopsied LBD, we found an inverse correlation with cortical thickness and post-mortem tau pathology, while cortical thickness was not significantly associated with Aβ or alpha-synuclein pathology., Interpretation: LBD+AD is characterized by temporal neocortical thinning on MRI, and cortical thinning directly correlated with post-mortem histopathologic burden of tau, suggesting that tau pathology influences the pattern of neurodegeneration in LBD., (© 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Neurofilaments are structural components of neurons and are particularly abundant in highly myelinated axons. The levels of neurofilament light chain (NfL) in both cerebrospinal fluid (CSF) and plasma have been related to degeneration in several neurodegenerative conditions including frontotemporal dementia (FTD) and NfL is currently considered as the most promising diagnostic and prognostic fluid biomarker in FTD. Although the location and function of filaments in the healthy nervous system suggests a link between increased NfL and white matter degeneration, such a claim has not been fully elucidated in vivo, especially in the context of FTD. The present study provides evidence of an association between the plasma levels of NfL and white matter involvement in behavioral variant FTD (bvFTD) by relating plasma concentration of NfL to diffusion tensor imaging (DTI) metrics in a group of 20 bvFTD patients. The results of both voxel-wise and tract specific analysis showed that increased plasma NfL concentration is associated with a reduction in fractional anisotropy (FA) in a widespread set of white matter tracts including the superior longitudinal fasciculus, the fronto-occipital fasciculus the anterior thalamic radiation and the dorsal cingulum bundle. Plasma NfL concentration also correlated with cortical thinning in a portion of the right medial prefrontal cortex and of the right lateral orbitofrontal cortex. These results support the hypothesis that blood NfL levels reflect the global level of neurodegeneration in bvFTD and help to advance our understanding of the association between this blood biomarker for FTD and the disease process., Competing Interests: HZ has served at scientific advisory boards for Denali, Roche Diagnostics, Wave, Samumed and CogRx, has given lectures in symposia sponsored by Fujirebio, Alzecure and Biogen, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program. KB has served as a consultant, at advisory boards, or at data monitoring committees for Abcam, Axon, Biogen, JOMDD/Shimadzu. Julius Clinical, Lilly, MagQu, Novartis, Roche Diagnostics, and Siemens Healthineers, and is also a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS). These do not alter our adherence to PLOS ONE policies on sharing data and materials.

A growing body of evidence suggests that the dysregulation of neuronal iron may play a critical role in Alzheimer's disease. Recent MRI studies have established a relationship between iron accumulation and amyloid-β aggregation. The present study provides further insight demonstrating a relationship between iron and tau accumulation using magnetic resonance-based quantitative susceptibility mapping and tau-PET in n = 236 subjects with amyloid-β pathology (from the Swedish BioFINDER-2 study). Both voxel-wise and regional analyses showed a consistent association between differences in bulk magnetic susceptibility, which can be primarily ascribed to an increase in iron content, and tau-PET signal in regions known to be affected in Alzheimer's disease. Subsequent analyses revealed that quantitative susceptibility specifically mediates the relationship between tau-PET and cortical atrophy measures, thus suggesting a modulatory effect of iron burden on the disease process. We also found evidence suggesting the relationship between quantitative susceptibility and tau-PET is stronger in younger participants (age ≤ 65). Together, these results provide in vivo evidence of an association between iron deposition and both tau aggregation and neurodegeneration, which help advance our understanding of the role of iron dysregulation in the Alzheimer's disease aetiology., (© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background The differential diagnosis of progressive supranuclear palsy (PSP) and Lewy body disorders, which include Parkinson disease and dementia with Lewy bodies, is often challenging due to the overlapping symptoms. Purpose To develop a diagnostic tool based on diffusion tensor imaging (DTI) to distinguish between PSP and Lewy body disorders at the individual-subject level. Materials and Methods In this retrospective study, skeletonized DTI metrics were extracted from two independent data sets: the discovery cohort from the Swedish BioFINDER study and the validation cohort from the Penn Frontotemporal Degeneration Center (data collected between 2010 and 2018). Based on previous neuroimaging studies and neuropathologic evidence, a combination of regions hypothesized to be sensitive to pathologic features of PSP were identified (ie, the superior cerebellar peduncle and frontal white matter) and fractional anisotropy (FA) was used to compute an FA score for each individual. Classification performances were assessed by using logistic regression and receiver operating characteristic analysis. Results In the discovery cohort, 16 patients with PSP (mean age ± standard deviation, 73 years ± 5; eight women, eight men), 34 patients with Lewy body disorders (mean age, 71 years ± 6; 14 women, 20 men), and 44 healthy control participants (mean age, 66 years ± 8; 26 women, 18 men) were evaluated. The FA score distinguished between clinical PSP and Lewy body disorders with an area under the curve of 0.97 ± 0.04, a specificity of 91% (31 of 34), and a sensitivity of 94% (15 of 16). In the validation cohort , 34 patients with PSP (69 years ± 7; 22 women, 12 men), 25 patients with Lewy body disorders (70 years ± 7; nine women, 16 men), and 32 healthy control participants (64 years ± 7; 22 women, 10 men) were evaluated. The accuracy of the FA score was confirmed (area under the curve, 0.96 ± 0.04; specificity, 96% [24 of 25]; and sensitivity, 85% [29 of 34]). Conclusion These cross-validated findings lay the foundation for a clinical test to distinguish progressive supranuclear palsy from Lewy body disorders. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Shah in this issue.

The primary function of language is to communicate-that is, to make individuals reach a state of mutual understanding about a particular thought or idea. Accordingly, daily communication is truly a task of social coordination. Indeed, successful interactions require individuals to (1) track and adopt a partner's perspective and (2) continuously shift between the numerous elements relevant to the exchange. Here, we use a referential communication task to study the contributions of perspective taking and executive function to effective communication in nonaphasic human patients with behavioral variant frontotemporal dementia (bvFTD). Similar to previous work, the task was to identify a target object, embedded among an array of competitors, for an interlocutor. Results indicate that bvFTD patients are impaired relative to control subjects in selecting the optimal, precise response. Neuropsychological testing related this performance to mental set shifting, but not to working memory or inhibition. Follow-up analyses indicated that some bvFTD patients perform equally well as control subjects, while a second, clinically matched patient group performs significantly worse. Importantly, the neuropsychological profiles of these subgroups differed only in set shifting. Finally, structural MRI analyses related patient impairment to gray matter disease in orbitofrontal, medial prefrontal, and dorsolateral prefrontal cortex, all regions previously implicated in social cognition and overlapping those related to set shifting. Complementary white matter analyses implicated uncinate fasciculus, which carries projections between orbitofrontal and temporal cortices. Together, these findings demonstrate that impaired referential communication in bvFTD is cognitively related to set shifting, and anatomically related to a social-executive network including prefrontal cortices and uncinate fasciculus., (Copyright © 2019 Healey et al.)

Objective: The three recognized variants of primary progressive aphasia (PPA) are associated with different loci of degeneration-left posterior perisylvian in logopenic variant (lvPPA), left frontal operculum in non-fluent variant (nfvPPA), and left rostroventral-temporal in semantic variant (svPPA). Meanwhile, it has become apparent that patients with lvPPA, in which Alzheimer pathology is the norm, frequently have more extensive language deficits-namely semantic and grammatical problems-than is captured in the strict diagnostic recommendations for this variant. We hypothesized that this may be because the degeneration in AD-related PPA typically extends beyond the left posterior perisylvian region., Methods: Magnetic resonance images from 25 PPA patients (9AD-related PPA, 10 svPPA, 6 nfvPPA) and a healthy control cohort were used to calculate cortical thickness in three regions of interest (ROIs). The three ROIs being the left-hemispheric loci of maximal reported degeneration for each of the three variants of PPA., Results: Consistent with past studies, the most severe cortical thinning was in the posterior perisylvian ROI in AD-related PPA; the ventral temporal ROI in svPPA; and the frontal opercular ROI in nfvPPA. Significant cortical thinning in AD-related PPA, however, was evident in all three ROIs. In contrast, thinning in svPPA and nfvPPA was largely restricted to their known peak loci of degeneration., Conclusions: Although cortical degeneration in AD-related PPA is maximal in the left posterior perisylvian region, it extends more diffusely throughout the left hemisphere language network offering a plausible explanation for why the linguistic profile of lvPPA so often includes additional semantic and grammatic deficits., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Cerebrospinal fluid (CSF) neurofilament light chain (NfL) has emerged as putative diagnostic biomarker in amyotrophic lateral sclerosis (ALS), but it remains a matter of debate, whether CSF total tau (ttau), tau phosphorylated at threonine 181 (ptau) and the ptau/ttau ratio could serve as diagnostic biomarker in ALS as well. Moreover, the relationship between CSF NfL and tau measures to further axonal and (neuro)degeneration markers still needs to be elucidated. Our analysis included 89 ALS patients [median (range) age 63 (33-83) years, 61% male, disease duration 10 (0.2-190) months] and 33 age- and sex-matched disease controls [60 (32-76), 49%]. NfL was higher and the ptau/ttau ratio was lower in ALS compared to controls [8343 (1795-35,945) pg/ml vs. 1193 (612-2616), H(1) = 70.8, p < 0.001; mean (SD) 0.17 (0.04) vs. 0.2 (0.03), F(1) = 14.3, p < 0.001], as well as in upper motor neuron dominant (UMND, n = 10) compared to classic (n = 46) or lower motor neuron dominant ALS [n = 31; for NfL: 16,076 (7447-35,945) vs. 8205 (2651-35,138) vs. 8057 (1795-34,951)], Z ≥ 2.5, p ≤ 0.01; for the ptau/ttau ratio: [0.13 (0.04) vs. 0.17 (0.04) vs. 0.18 (0.03), p ≤ 0.02]. In ALS, NfL and the ptau/ttau ratio were related to corticospinal tract (CST) fractional anisotropy (FA) and radial diffusivity (ROI-based approach and whole-brain voxelwise analysis). Factor analysis of mixed data revealed a co-variance pattern between NfL (factor load - 0.6), the ptau/ttau ratio (0.7), CST FA (0.8) and UMND ALS phenotype (- 2.8). NfL did not relate to any further neuroaxonal injury marker (brain volumes, precentral gyrus thickness, peripheral motor amplitudes, sonographic cross-sectional nerve area), but a lower ptau/ttau ratio was associated with whole-brain gray matter atrophy and widespread white matter integrity loss. Higher NfL baseline levels were associated with greater UMN disease burden, more rapid disease progression, a twofold to threefold greater hazard of death and shorter survival times. The findings that higher CSF NfL levels and a reduced ptau/ttau ratio are more associated with clinical UMN involvement and with reduced CST FA offer strong converging evidence that both are markers of central motor degeneration. Furthermore, NfL is a marker of poor prognosis, while a low ptau/ttau ratio indicates extramotor pathology in ALS.

Purpose To investigate the whole-brain landscape of iron-related abnormalities in amyotrophic lateral sclerosis (ALS) by using the in vivo MRI technique of quantitative susceptibility mapping (QSM). Materials and Methods For this prospective study, 28 patients with ALS (mean age, 61 years; age range, 43-77 years; 18 men [mean age, 61 years; range, 43-77 years] and 10 women [mean age, 61 years; range, 47-74 years]) recruited between January 17, 2014, and September 4, 2015, and 39 matched control subjects (mean age, 61 years; age range, 39-77 years; 24 men [mean age, 62 years; range, 39-77 years] and 15 women [mean age, 59 years; range, 39-73 years]) were examined by using structural and susceptibility 3.0-T MRI techniques. Group data were cross sectionally compared with family-wise error (FWE) corrections by using voxel-based morphometry (random-field theory), cortical thickness analysis (Monte Carlo simulated), subcortical volumetry (Bonferroni-corrected Wilcoxon rank-sum testing), and QSM analysis (cluster-enhanced whole-brain permutation testing and Bonferroni-corrected rank-sum testing in regions of interest). In patients with ALS, a potential relationship between diffusion and susceptibility measurements in the corticospinal tracts (CSTs) was also examined by using Spearman rank-correlation tests. Results Conventional structural measures failed to identify atrophy in the present cohort (FWE P > .05). However, QSM identified several whole-brain abnormalities (FWE P < .05) in ALS. Regionally, higher susceptibility (expressed as means in parts per million ± standard errors of the mean) was confirmed in the motor cortex (ALS = 0.0188 ± 0.0003, control = 0.0173 ± 0.0003; P < .001), the left substantia nigra (ALS = 0.127 ± 0.004, control = 0.113 ± 0.003; P = .008), the right substantia nigra (ALS = 0.141 ± 0.005, control = 0.120 ± 0.003; P < .001), the globus pallidus (ALS = 0.086 ± 0.003, control = 0.075 ± 0.002; P = .003), and the red nucleus (ALS = 0.115 ± 0.004, control = 0.098 ± 0.003; P < .001). Lower susceptibility was found in CST white matter (ALS = -0.047 ± 0.001, control = -0.043 ± 0.001; P = .01). Nigral and pallidal QSM values were cross correlated in ALS (ρ 2 = 0.42, P < .001), a phenomenon visually traceable in many individual patients. QSM in the CST in ALS also correlated with diffusion-tensor metrics in this tract (ρ 2 = 0.25, P = .007). Conclusion Whole-brain MRI quantitative susceptibility mapping analysis is sensitive to tissue alterations in amyotrophic lateral sclerosis that may be relevant to pathologic changes. © RSNA, 2018.

Background: Lewy body disorders (LBD) are clinical syndromes characterized by pathological inclusions containing α-synuclein. Cognitive deficits are common or diagnostic in LBD, and may be associated with the presence of beta-amyloid (Aβ), which is a hallmark histopathologic abnormality characteristic of Alzheimer's disease (AD) that can also co-occur with LBD. Objective: In the present study we evaluated whether social decision-making difficulties in LBD are associated with Aβ burden. Methods: Decision-making abilities were measured with a simple, untimed, behavioral task previously validated in patients with behavioral variant frontotemporal dementia, and performance was related to gray matter atrophy on MRI. Aβ burden was assessed by examination of cerebrospinal fluid (CSF) level of Aβ 1-42 and by autopsy confirmation in a subgroup of patients. Results: The results revealed that LBD patients with evidence of Aβ have reduced social decision-making abilities compared to patients with no evidence of Aβ. The imaging analysis related greater decision-making difficulty in Aβ-positive patients in respect to Aβ-negative patients to gray matter atrophy in medial orbitofrontal. This region is a critical node of a decision-making network as well as a region previously associated with comorbid α-synuclein and Aβ in LBD. Conclusions: These preliminary findings suggest that cognitive difficulties in LBD extend to include deficits in social decision-making and that this may be related to the presence of Aβ.

Some extent of ambiguity is ubiquitous in everyday conversations. For example, words have multiple meaning and very common pronouns, like "he" and "she" (anaphoric pronouns), have little meaning on their own and refer to a noun that has been previously introduced in the discourse. Ambiguity triggers a decision process that is not a subroutine of language processing but rather a more general domain resource. Therefore non-aphasic patients with limited decision-making capability can encounter severe limitation in language processing due to extra linguistic limitations. In the present study, we test patients with behavioral variant frontotemporal degeneration (bvFTD), focusing on anaphora as a paradigmatic example of ambiguity resolution in the linguistic domain. bvFTD is characterized by gray matter (GM) atrophy in prefrontal cortex, but relative sparing of peri-Sylvian cortex. A group of patients with parietal disease due to corticobasal syndrome (CBS) was also tested here in order to investigate the specific role of prefrontal cortex in the task employed in the current study. Participants were presented with a pair of sentences in which the first sentence contained two nouns while the second contained a pronoun. In the experimental (ambiguous) condition, both nouns are plausible referents of the pronoun, thus requiring decision-making resources. The results revealed that bvFTD patients are significantly less accurate than healthy seniors in identifying the correct referent of a pronoun in the ambiguous condition, although CBS patients were as accurate as healthy seniors. Imaging analyses related bvFTD patients' performance to GM atrophy in ventromedial prefrontal cortex (vmPFC). These results suggest that bvFTD patients have difficulties in decision processes that involve the resolution of an ambiguity.

When the message of a speaker goes beyond the literal or logical meaning of the sentences used, a pragmatic inference is required to understand the complete meaning of an utterance. Here we study one example of pragmatic inference, called scalar implicature. Such an inference is required when a weaker term "some" is used in a sentence like "Some of the students passed the exam" because the speaker presumably had a reason not to use a stronger term like "all". We investigated the comprehension of scalar implicatures in a group of 17 non-aphasic patients with behavioral variant frontotemporal degeneration (bvFTD) in order to test the contribution of non-linguistic decision-making ability and the role of prefrontal cortex in supporting the computation of pragmatic inferences. The results of two experiments point to a deficit in producing alternative interpretations beyond a logical reading. bvFTD patients thus prefer the narrowly literal or logical interpretation of a scalar term when they must generate a possible alternative interpretation by themselves, but patients prefer a pragmatic reading when offered a choice between the logical and the pragmatic interpretation of the same sentence. An imaging analysis links bvFTD patients' spontaneous tendency toward a narrowly logical interpretation with atrophy in ventromedial prefrontal cortex. Our findings are consistent with the pragmatic tolerance hypothesis, which proposes that difficulty generating alternative interpretations of an utterance, rather than a frank inability to compute an inference, affects the comprehension of a scalar term., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Logical connectives (e.g., or, if, and not) are central to everyday conversation, and the inferences they generate are made with little effort in pragmatically sound situations. In contrast, the neural substrates of logical inference-making have been studied exclusively in abstract tasks where pragmatic concerns are minimal. Here, we used fMRI in an innovative design that employed narratives to investigate the interaction between logical reasoning and pragmatic processing in natural discourse. Each narrative contained three premises followed by a statement. In Fully-deductive stories, the statement confirmed a conclusion that followed from two steps of disjunction-elimination (e.g., Xavier considers Thursday, Friday, or Saturday for inviting his girlfriend out; he removes Thursday before he rejects Saturday and declares "I will invite her out for Friday"). In Implicated-premise stories, an otherwise identical narrative included three premises that twice removed a single option from consideration (i.e., Xavier rejects Thursday for two different reasons). The conclusion therefore necessarily prompts an implication (i.e., Xavier must have removed Saturday from consideration as well). We report two main findings. First, conclusions of Implicated-premise stories are associated with more activity than conclusions of Fully-deductive stories in a bilateral frontoparietal system, suggesting that these regions play a role in inferring an implicated premise. Second, brain connectivity between these regions increases with pragmatic abilities when reading conclusions in Implicated-premise stories. These findings suggest that pragmatic processing interacts with logical inference-making when understanding arguments in narrative discourse.

For social interactions to be successful, individuals must establish shared mental representations that allow them to reach a common understanding and "get on the same page". We refer to this process as social coordination. While examples of social coordination are ubiquitous in daily life, relatively little is known about the neuroanatomic basis of this complex behavior. This is particularly true in a language context, as previous studies have used overly complex paradigms to study this. Although traditional views of language processing and the recent interactive-alignment account of conversation focus on peri-Sylvian regions, our model of social coordination predicts prefrontal involvement. To test this hypothesis, we examine the neural basis of social coordination during conversational exchanges in non-aphasic patients with behavioral variant frontotemporal degeneration (bvFTD). bvFTD patients show impairments in executive function and social comportment due to disease in frontal and anterior temporal regions. To investigate social coordination in bvFTD, we developed a novel language-based task that assesses patients' ability to convey an object's description to a conversational partner. Experimental conditions manipulated the amount of information shared by the participant and the conversational partner, and the associated working memory demands. Our results indicate that, although patients did not have difficulty identifying the features of the objects, they did produce descriptions that included insufficient or inappropriate adjectives and thus struggled to communicate effectively. Impaired performance was related to gray matter atrophy particularly in medial prefrontal and orbitofrontal cortices. Our findings suggest an important role for non-language brain areas that belong to a large-scale neurocognitive network for social coordination., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

A growing amount of empirical data is showing that the ability to manipulate quantities in a precise and efficient fashion is rooted in cognitive mechanisms devoted to specific aspects of numbers processing. The analog number system (ANS) has a reasonable representation of quantities up to about 4, and represents larger quantities on the basis of a numerical ratio between quantities. In order to represent the precise cardinality of a number, the ANS may be supported by external algorithms such as language, leading to a "precise number system". In the setting of limited language, other number-related systems can appear. For example the parallel individuation system (PIS) supports a "chunking mechanism" that clusters units of larger numerosities into smaller subsets. In the present study we investigated number processing in non-aphasic patients with corticobasal syndrome (CBS) and posterior cortical atrophy (PCA), two neurodegenerative conditions that are associated with progressive parietal atrophy. The present study investigated these number systems in CBS and PCA by assessing the property of the ANS associated with smaller and larger numerosities, and the chunking property of the PIS. The results revealed that CBS/PCA patients are impaired in simple calculations (e.g., addition and subtraction) and that their performance strongly correlates with the size of the numbers involved in these calculations, revealing a clear magnitude effect. This magnitude effect was correlated with gray matter atrophy in parietal regions. Moreover, a numeral-dots transcoding task showed that CBS/PCA patients were able to take advantage of clustering in the spatial distribution of the dots of the array. The relative advantage associated with chunking compared to a random spatial distribution correlated with both parietal and prefrontal regions. These results shed light on the properties of systems for representing number knowledge in non-aphasic patients with CBS and PCA., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Quantifiers, like "some" or "few," are frequent in daily language. Linguists posit at least three distinct classes of quantifiers: cardinal quantifiers that rely on numerosity, majority quantifiers that additionally depend on executive resources, and logical quantifiers that rely on perceptual attention. We used BOLD fMRI to investigate the roles of frontal and parietal regions in quantifier comprehension. Participants performed a sentence-picture verification task to determine whether a sentence containing a quantifier accurately describes a picture. A whole-brain analysis identified a network involved in quantifier comprehension: This implicated bilateral inferior parietal, superior parietal and dorsolateral prefrontal cortices, and right inferior frontal cortex. We then performed region-of-interest analyses to assess the relative contribution of each region for each quantifier class. Inferior parietal cortex was equally activated across all quantifier classes, consistent with prior studies implicating the region for quantifier comprehension due in part to its role in the representation of number knowledge. Right superior parietal cortex was up-regulated in comparison to frontal regions for cardinal and logical quantifiers, but parietal and frontal regions were equally activated for majority quantifiers and each frontal region is most highly activated for majority quantifiers. This finding is consistent with the hypothesis that majority quantifiers rely on numerosity mechanisms in parietal cortex and executive mechanisms in frontal cortex. Also, right inferior frontal cortex was up-regulated for logical compared to cardinal quantifiers, which may be related to selection demands associated with logical quantifier comprehension. We conclude that distinct components of a large-scale fronto-parietal network contribute to specific aspects of quantifier comprehension, and that this biologically defined network is consistent with cognitive theories of quantifier meaning.

Whereas some studies indicate that ironic-as opposed to literal-readings of utterances take longer to process, others indicate that the 2 are processed at comparable speeds. We propose that mindreading processes are at least partly responsible for the mixed results, as we present 3 experiments that include stories having a target utterance with either an Ironic or Literal reading. Experiment 1 replicates earlier findings (Spotorno, Koun, Prado, Van Der Henst, & Noveck, 2012) showing that ironic readings take longer than literal ones when fillers include decoys, stories that call for an ironic remark but present a banal utterance instead and thus diffuse participants' expectations for irony. Starting with Experiment 2, decoys are removed, leading to effects that are arguably revealing of Theory of Mind processes. One is an Early-Late effect, which occurs when ironic utterances are read as readily as literal ones in the 2nd half of an experimental session, creating "mixed" results in the laboratory. In Experiment 3, we further added antecedents before a critical event so that, later, the target utterance would be echoing an explicitly stated thought and would facilitate irony comprehension (Gibbs, 1986; Sperber & Wilson, 1981). Results reveal an Early-Late effect here, too. Further evidence of Theory of Mind activity follows from analyses of participants' Social Skill subscale scores in the Autism-Spectrum Quotient (Baron-Cohen, Wheelwright, Skinner, Martin, & Clubley, 2001). Socially inclined participants are more likely than the socially disinclined to use a story's negative event to portend the arrival of an irony; in contrast, socially disinclined participants appear more reactive than the socially inclined to explicit antecedents., (PsycINFO Database Record (c) 2014 APA, all rights reserved.)

The combined knowledge of word meanings and grammatical rules does not allow a listener to grasp the intended meaning of a speaker's utterance. Pragmatic inferences on the part of the listener are also required. The present work focuses on the processing of ironic utterances (imagine a slow day being described as "really productive") because these clearly require the listener to go beyond the linguistic code. Such utterances are advantageous experimentally because they can serve as their own controls in the form of literal sentences (now imagine an active day being described as "really productive") as we employ techniques from electrophysiology (EEG). Importantly, the results confirm previous ERP findings showing that irony processing elicits an enhancement of the P600 component (Regel et al., 2011). More original are the findings drawn from Time Frequency Analysis (TFA) and especially the increase of power in the gamma band in the 280-400 time-window, which points to an integration among different streams of information relatively early in the comprehension of an irony. This represents a departure from traditional accounts of language processing which generally view pragmatic inferences as late-arriving. We propose that these results indicate that unification operations between the linguistic code and contextual information play a critical role throughout the course of irony processing and earlier than previously thought.

It is now well established that communicators interpret others' mental states through what has been called "Theory of Mind" (ToM). From a linguistic-pragmatics perspective, this mentalizing ability is considered critical because it is assumed that the linguistic code in all utterances underdetermines the speaker's meaning, leaving a vital role for ToM to fill the gap. From a neuroscience perspective, understanding others' intentions has been shown to activate a neural ToM network that includes the right and left temporal parietal junction (rTPJ, lTPJ), the medial prefrontal cortex (MPFC) and the precuneus (PC). Surprisingly, however, there are no studies - to our knowledge - that aim to uncover a direct, on-line link between language processing and ToM through neuroimaging. This is why we focus on verbal irony, an obviously pragmatic phenomenon that compels a listener to detect the speaker's (dissociated, mocking) attitude (Wilson, 2009). In the present fMRI investigation, we compare participants' comprehension of 18 target sentences as contexts make them either ironic or literal. Consider an opera singer who tells her interlocutor: "Tonight we gave a superb performance!" when the performance in question was clearly awful (making the statement ironic) or very good (making the statement literal). We demonstrate that the ToM network becomes active while a participant is understanding verbal irony. Moreover, we demonstrate - through Psychophysiological Interactions (PPI) analyses - that ToM activity is directly linked with language comprehension processes. The paradigm, its predictions, and the reported results contrast dramatically with those from seven prior fMRI studies on irony., (Copyright © 2012 Elsevier Inc. All rights reserved.)