Lower Locus Coeruleus Integrity Signals Elevated Entorhinal Tau and Clinical Progression in Asymptomatic Older Individuals.

OBJECTIVE: Elevated entorhinal cortex (EC) tau in low beta-amyloid individuals can predict accumulation of pathology and cognitive decline. We compared the accuracy of magnetic resonance imaging (MRI)-derived locus coeruleus integrity, neocortical beta-amyloid burden by positron emission tomography (PET), and hippocampal volume in identifying elevated entorhinal tau signal in asymptomatic individuals who are considered beta-amyloid PET-negative. METHODS: We included 188 asymptomatic individuals (70.78 ± 11.51 years, 58% female) who underwent 3T-MRI of the locus coeruleus, Pittsburgh compound-B (PiB), and Flortaucipir (FTP) PET. Associations between elevated EC tau and neocortical PiB, hippocampal volume, or locus coeruleus integrity were evaluated and compared using logistic regression and receiver operating characteristic analyses in the PiB- sample with a clinical dementia rating (CDR) of 0. Associations with clinical progression (CDR-sum-of-boxes) over a time span of 6 years were evaluated with Cox proportional hazard models. RESULTS: We identified 26 (21%) individuals with high EC FTP in the CDR = 0/PiB- sample. Locus coeruleus integrity was a significantly more sensitive and specific predictor of elevated EC FTP (area under the curve [AUC] = 85%) compared with PiB (AUC = 77%) or hippocampal volume (AUC = 76%). Based on the Youden-index, locus coeruleus integrity obtained a sensitivity of 77% and 85% specificity. Using the resulting locus coeruleus Youden cut-off, lower locus coeruleus integrity was associated with a two-fold increase in clinical progression, including mild cognitive impairment. INTERPRETATION: Locus coeruleus integrity has promise as a low-cost, non-invasive screening instrument to detect early cortical tau deposition and associated clinical progression in asymptomatic, low beta-amyloid individuals. ANN NEUROL 2024.

Tau propagation in the brain olfactory circuits is associated with smell perception changes in aging.

The direct access of olfactory afferents to memory-related cortical systems has inspired theories about the role of the olfactory pathways in the development of cortical neurodegeneration in Alzheimer's disease (AD). In this study, we used baseline olfactory identification measures with longitudinal flortaucipir and PiB PET, diffusion MRI of 89 cognitively normal older adults (73.82 ± 8.44 years; 56% females), and a transcriptomic data atlas to investigate the spatiotemporal spreading and genetic vulnerabilities of AD-related pathology aggregates in the olfactory system. We find that odor identification deficits are predominantly associated with tau accumulation in key areas of the olfactory pathway, with a particularly strong predictive power for longitudinal tau progression. We observe that tau spreads from the medial temporal lobe structures toward the olfactory system, not the reverse. Moreover, we observed a genetic background of odor perception-related genes that might confer vulnerability to tau accumulation along the olfactory system.

Locus coeruleus integrity and left frontoparietal connectivity provide resilience against attentional decline in preclinical alzheimer's disease.

BACKGROUND: Autopsy work reported that neuronal density in the locus coeruleus (LC) provides neural reserve against cognitive decline in dementia. Recent neuroimaging and pharmacological studies reported that left frontoparietal network functional connectivity (LFPN-FC) confers resilience against beta-amyloid (Aß)-related cognitive decline in preclinical sporadic and autosomal dominant Alzheimer's disease (AD), as well as against LC-related cognitive changes. Given that the LFPN and the LC play important roles in attention, and attention deficits have been observed early in the disease process, we examined whether LFPN-FC and LC structural health attenuate attentional decline in the context of AD pathology. METHODS: 142 participants from the Harvard Aging Brain Study who underwent resting-state functional MRI, LC structural imaging, PiB(Aß)-PET, and up to 5 years of cognitive follow-ups were included (mean age = 74.5 ± 9.9 years, 89 women). Cross-sectional robust linear regression associated LC integrity (measured as the average of five continuous voxels with the highest intensities in the structural LC images) or LFPN-FC with Digit Symbol Substitution Test (DSST) performance at baseline. Longitudinal robust mixed effect analyses examined associations between DSST decline and (i) two-way interactions of baseline LC integrity (or LFPN-FC) and PiB or (ii) the three-way interaction of baseline LC integrity, LFPN-FC, and PiB. Baseline age, sex, and years of education were included as covariates. RESULTS: At baseline, lower LFPN-FC, but not LC integrity, was related to worse DSST performance. Longitudinally, lower baseline LC integrity was associated with a faster DSST decline, especially at PiB > 10.38 CL. Lower baseline LFPN-FC was associated with a steeper decline on the DSST but independent of PiB. At elevated PiB levels (> 46 CL), higher baseline LFPN-FC was associated with an attenuated decline on the DSST, despite the presence of lower LC integrity. CONCLUSIONS: Our findings demonstrate that the LC can provide resilience against Aß-related attention decline. However, when Aß accumulates and the LC's resources may be depleted, the functioning of cortical target regions of the LC, such as the LFPN-FC, can provide additional resilience to sustain attentional performance in preclinical AD. These results provide critical insights into the neural correlates contributing to individual variability at risk versus resilience against Aß-related cognitive decline.

Spatiotemporal patterns of locus coeruleus integrity predict cortical tau and cognition.

Autopsy studies indicated that the locus coeruleus (LC) accumulates hyperphosphorylated tau before allocortical regions in Alzheimer's disease. By combining in vivo longitudinal magnetic resonance imaging measures of LC integrity, tau positron emission tomography imaging and cognition with autopsy data and transcriptomic information, we examined whether LC changes precede allocortical tau deposition and whether specific genetic features underlie LC's selective vulnerability to tau. We found that LC integrity changes preceded medial temporal lobe tau accumulation, and together these processes were associated with lower cognitive performance. Common gene expression profiles between LC-medial temporal lobe-limbic regions map to biological functions in protein transport regulation. These findings advance our understanding of the spatiotemporal patterns of initial tau spreading from the LC and LC's selective vulnerability to Alzheimer's disease pathology. LC integrity measures can be a promising indicator for identifying the time window when individuals are at risk of disease progression and underscore the importance of interventions mitigating initial tau spread.

Multi-modal Neuroimaging Phenotyping of Mnemonic Anosognosia in the Aging Brain.

BACKGROUND: Unawareness is a behavioral condition characterized by a lack of self-awareness of objective memory decline. In the context of Alzheimer's Disease (AD), unawareness may develop in predementia stages and contributes to disease severity and progression. Here, we use in-vivo multi-modal neuroimaging to profile the brain phenotype of individuals presenting altered self-awareness of memory during aging. METHODS: Amyloid- and tau-PET (N = 335) and resting-state functional MRI (N = 713) imaging data of individuals from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4)/Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) Study were used in this research. We applied whole-brain voxel-wise and region-of-interest analyses to characterize the cortical intersections of tau, amyloid, and functional connectivity networks underlying unawareness in the aging brain compared to aware, complainer and control groups. RESULTS: Individuals with unawareness present elevated amyloid and tau burden in midline core regions of the default mode network compared to aware, complainer or control individuals. Unawareness is characterized by an altered network connectivity pattern featuring hyperconnectivity in the medial anterior prefrontal cortex and posterior occipito-parietal regions co-locating with amyloid and tau deposition. CONCLUSIONS: Unawareness is an early behavioral biomarker of AD pathology. Failure of the self-referential system in unawareness of memory decline can be linked to amyloid and tau burden, along with functional network connectivity disruptions, in several medial frontal and parieto-occipital areas of the human brain.

Lack of self-awareness of cognitive changes, such as memory decline, occurs in people who later go on to develop Alzheimer's disease. In the present study, we investigated various characteristics of the brains of people who were unaware they were experiencing memory loss and likely to develop Alzheimer's disease due to their age. We identified individuals with low performance in memory tests and a lack of sense of their memory decline. Compared to aware individuals, they had more deposits of proteins known to be present at higher levels in people with Alzheimer's disease. The results of this investigation suggest that unawareness of memory decline is an early behavioral sign that a person might develop Alzheimer's disease. This knowledge might enable such people to be more easily identified in the future, and treatments to be started sooner.

Spatiotemporal Correlation between Amyloid and Tau Accumulations Underlies Cognitive Changes in Aging.

It is poorly known how Aß and tau accumulations associate at the spatiotemporal level in the in vivo human brain to impact cognitive changes in older adults prior to AD symptoms onset. In this study, we used a graph theory-based spatiotemporal analysis to characterize the cortical patterns of Aß and tau deposits and their relationship with cognitive changes in the Harvard Aging Brain Study (HABS) cohort. We found that the temporal accumulations of interlinked Aß and tau pathology display distinctive spatiotemporal correlations associated with early cognitive decline. Notably, we observed that baseline Aß deposits-Thal amyloid phase Ⅱ-related to future increase of tau deposits, Braak stages Ⅰ-Ⅳ, both displaying linkage to the decline in multi-domain cognitive scores. We also found unimodal tau-to-tau and cognitive impairment associations in broad areas of Braak stages Ⅰ-Ⅳ. The unimodal Aß-to-Aß progressions were not associated with cognitive changes. Our results revealed a multifaceted correlation of the spatiotemporal Aß and tau associations with cognitive decline over time, in which tau-to-tau and tau-Aß interactions, and not Aß independently, might be critical contributors to clinical trajectories toward AD in older adults.

Creativity at rest: Exploring functional network connectivity of creative experts.

The neuroscience of creativity seeks to disentangle the complex brain processes that underpin the generation of novel ideas. Neuroimaging studies of functional connectivity, particularly functional magnetic resonance imaging (fMRI), have revealed individual differences in brain network organization associated with creative ability; however, much of the extant research is limited to laboratory-based divergent thinking measures. To overcome these limitations, we compare functional brain connectivity in a cohort of creative experts (n = 27) and controls (n = 26) and examine links with creative behavior. First, we replicate prior findings showing reduced connectivity in visual cortex related to higher creative performance. Second, we examine whether this result is driven by integrated or segregated connectivity. Third, we examine associations between functional connectivity and vivid distal simulation separately in creative experts and controls. In accordance with past work, our results show reduced connectivity to the primary visual cortex in creative experts at rest. Additionally, we observe a negative association between distal simulation vividness and connectivity to the lateral visual cortex in creative experts. Taken together, these results highlight connectivity profiles of highly creative people and suggest that creative thinking may be related to, though not fully redundant with, the ability to vividly imagine the future.

Intentionality of Self-Generated Thought: Contributions of Mind Wandering to Creativity.

Studies suggest that internally oriented cognitive processes are central to creativity. Here, we distinguish between intentional and unintentional forms of mind wandering and explore their behavioral and neural correlates. We used a sample of 155 healthy adults from the mind-brain-body dataset, all of whom completed resting-state fMRI scans and trait-level measures of mind wandering. We analyzed intentional and unintentional mind wandering tendencies using self-report measures. Next, we explored the relationship between mind wandering tendencies and creativity, as measured by a divergent thinking task. Finally, we describe patterns of resting-state network connectivity associated with mind wandering, using graph theory analysis. At the behavioral level, results showed a significant positive association between creativity and both intentional and unintentional mind wandering. Neuroimaging analysis revealed higher weighted degree connectivity associated with both forms of mind wandering, implicating core regions of the default network and the left temporal pole. We observed topological connectivity differences within the default network: intentional mind wandering was associated with degree connectivity in posterior regions, whereas unintentional mind wandering showed greater involvement of prefrontal areas. Overall, the findings highlight patterns of resting-state network connectivity associated with intentional and unintentional mind wandering, and provide novel evidence of a link between mind wandering and creativity.

Two different brain networks underlying picture naming with familiar pre-existing native words and new vocabulary.

The present research used fMRI to longitudinally investigate the impact of learning new vocabulary on the activation pattern of the language control network by measuring BOLD signal changes during picture naming tasks with familiar pre-existing native words (old words) and new vocabulary. Nineteen healthy participants successfully learned new synonyms for already known Spanish words, and they performed a picture naming task using the old words and the new words immediately after learning and two weeks after learning. The results showed that naming with old words, compared to naming with newly learned words, produced activations in a cortical network involving frontal and parietal regions, whereas the opposite contrast showed activation in a broader cortical/subcortical network, including the SMA/ACC, the hippocampus, and the midbrain. These two networks are maintained two weeks after learning. These results suggest that the language control network can be separated into two functional circuits for diverse cognitive purposes.

Network Tau spreading is vulnerable to the expression gradients of APOE and glutamatergic-related genes.

A key hallmark of Alzheimer's disease (AD) pathology is the intracellular accumulation of tau protein in the form of neurofibrillary tangles across large-scale networks of the human brain cortex. Currently, it is still unclear how tau accumulates within specific cortical systems and whether in situ genetic traits play a role in this circuit-based propagation progression. In this study, using two independent cohorts of cognitively normal older participants, we reveal the brain network foundation of tau spreading and its association with using high-resolution transcriptomic genetic data. We observed that specific connectomic and genetic gradients exist along the tau spreading network. In particular, we identified 577 genes whose expression is associated with the spatial spreading of tau. Within this set of genes, APOE and glutamatergic synaptic genes, such as SLC1A2, play a central role. Thus, our study characterizes neurogenetic topological vulnerabilities in distinctive brain circuits of tau spreading and suggests that drug development strategies targeting the gradient expression of this set of genes should be explored to help reduce or prevent pathological tau accumulation.

Connectomic-genetic signatures in the cerebral small vessel disease.

Small vessel disease (SVD) is a disorder that causes vascular lesions in the entire parenchyma of the human brain. At present, it is not well understood how primary and secondary damage interact to give rise to the complex scenario of white matter (WM) and grey matter (GM) lesions. Using novel cross-sectional and longitudinal connectomic approaches, we unveil the bidirectional nature of GM and WM changes, that is, primary cortical neurodegeneration that leads to secondary alterations in vascular border zones, and WM lesions that lead to secondary neurodegeneration in cortical projecting areas. We found this GM-WM interaction to be essential for executive cognitive performance. Moreover, we also observed that the interlocked degeneration of GM and WM over time associates with prototypical expression levels of genes potentially linked to SVD. Among these connectomic-genetic intersections, we found that the Androgen Receptor (AR) gene, is a particularly central candidate gene that might confer key vulnerability for brain lesion development in SVD. In conclusion, this study advances in the understanding of the bidirectional relationships between GM and WM lesions, primary and secondary vascular neurodegeneration, and sheds light on the genetic signatures of SVD.

Neurogenetic traits outline vulnerability to cortical disruption in Parkinson's disease.

The genetic traits that underlie vulnerability to neuronal damage across specific brain circuits in Parkinson's disease (PD) remain to be elucidated. In this study, we characterized the brain topological intersection between propagating connectivity networks in controls and PD participants and gene expression patterns across the human cortex - such as the SNCA gene. We observed that brain connectivity originated from PD-related pathology epicenters in the brainstem recapitulated the anatomical distribution of alpha-synuclein histopathology in postmortem data. We also discovered that the gene set most related to cortical propagation patterns of PD-related pathology was primarily involved in microtubule cellular components. Thus, this study sheds light on new avenues for enhancing detection of PD neuronal vulnerability via an evaluation of in vivo connectivity trajectories across the human brain and successful integration of neuroimaging-genetic strategies.

Divergent connectomic organization delineates genetic evolutionary traits in the human brain.

The relationship between human brain connectomics and genetic evolutionary traits remains elusive due to the inherent challenges in combining complex associations within cerebral tissue. In this study, insights are provided about the relationship between connectomics, gene expression and divergent evolutionary pathways from non-human primates to humans. Using in vivo human brain resting-state data, we detected two co-existing idiosyncratic functional systems: the segregation network, in charge of module specialization, and the integration network, responsible for information flow. Their topology was approximated to whole-brain genetic expression (Allen Human Brain Atlas) and the co-localization patterns yielded that neuron communication functionalities-linked to Neuron Projection-were overrepresented cell traits. Homologue-orthologue comparisons using dN/dS-ratios bridged the gap between neurogenetic outcomes and biological data, summarizing the known evolutionary divergent pathways within the Homo Sapiens lineage. Evidence suggests that a crosstalk between functional specialization and information flow reflects putative biological qualities of brain architecture, such as neurite cellular functions like axonal or dendrite processes, hypothesized to have been selectively conserved in the species through positive selection. These findings expand our understanding of human brain function and unveil aspects of our cognitive trajectory in relation to our simian ancestors previously left unexplored.

Cortical Networks of Creative Ability Trace Gene Expression Profiles of Synaptic Plasticity in the Human Brain.

The ability to produce novel ideas is central to societal progress and innovation; however, little is known about the biological basis of creativity. Here, we investigate the organization of brain networks that support creativity by combining functional neuroimaging data with gene expression information. Given the multifaceted nature of creative thinking, we hypothesized that distributed connectivity would not only be related to individual differences in creative ability, but also delineate the cortical distributions of genes involved in synaptic plasticity. We defined neuroimaging phenotypes using a graph theory approach that detects local and distributed network circuits, then characterized the spatial associations between functional connectivity and cortical gene expression distributions. Our findings reveal strong spatial correlations between connectivity maps and sets of genes devoted to synaptic assembly and signaling. This connectomic-transcriptome approach thus identifies gene expression profiles associated with high creative ability, linking cognitive flexibility to neural plasticity in the human brain.

Enhanced frontoparietal connectivity in multiple sclerosis patients and healthy controls in response to an intensive computerized training focused on working memory.

BACKGROUND: Working memory (WM) deficits are common in multiple sclerosis (MS) patients. Computerized cognitive training may enhance WM capabilities but its efficacy in MS patients has not been sufficiently explored. METHODS: This study examines the effects of n-back training on cognitive performance and functional connectivity (FC) in 29 MS patients and 29 healthy controls (HC). Baseline (S1) performance on 2- and 3-back tasks and FC within the fronto-parietal network were assessed before randomly splitting the sample into four subgroups: trained MS (MSt, n = 15), trained HC (HCt, n = 14), untrained MS (MSu, n = 14), and untrained HC (HCu, n = 15). The trained subgroups underwent adaptive n-back training (60 min/day; 4 days) and n-back task performance and FC were reassessed in a second session (S2). RESULTS: As revealed by mixed two-way ANOVAs, trained participants (MSt and HCt) exhibited a significant increase in the number of correct responses and significantly reduced reaction times in S2. These performance improvements were accompanied by an increase in FC in the fronto-parietal pathways and statistically significant correlations between both effects were found. CONCLUSIONS: Computerised WM training results in behavioural and neuroplasticity positive effects that may be useful when trying to prevent or attenuate cognitive decline in MS patients.

The adhesio interthalamica as a neuroanatomical marker of structural differences in healthy adult population.

The adhesio interthalamica (AI) is a small midline brain structure that connects the left and right thalamus. According to in vivo data, between 2.3 and 22.3% of the general population lack the AI, and the question of whether this absence is more prevalent in males than in females is a matter of debate. Despite the existence of these demographic figures, it remains unclear how this distinctive feature affects healthy people, or what specific anatomic profile is related to the presence or absence of the AI. The aim of this study was to investigate whole-brain gray matter (GM) volumetric differences depending on the presence or absence of the AI. A total of 240 healthy adult volunteers completed one MRI scanning session. After the AI assessment, the data from 110 participants were included in the final sample, of which 12.9% of the participants (n = 31) presented complete AI absence vs. 32.9% of participants (n = 79) who presented complete AI presence. Then, whole-brain group comparison analysis revealed that the absent AI brain, compared to the present AI brain, was associated with lower GM volume in the premotor cortex, inferior frontal gyrus, and anterior temporal cortex. Interestingly, neuroscience research has linked emotional and cognitive control brain processing to the latter two regions. The importance of these findings lies in providing a neuroanatomical profile for the absent AI brain in healthy human adults.

The manifestation of individual differences in sensitivity to punishment during resting state is modulated by eye state.

Structural and functional neuroimaging studies have shown that brain areas associated with fear and anxiety (defensive system areas) are modulated by individual differences in sensitivity to punishment (SP). However, little is known about how SP is related to brain functional connectivity and the factors that modulate this relationship. In this study, we investigated whether a simple methodological manipulation, such as performing a resting state with eyes open or eyes closed, can modulate the manifestation of individual differences in SP. To this end, we performed an exploratory fMRI resting state study in which a group of participants (n = 88) performed a resting state with eyes closed and another group (n = 56) performed a resting state with eyes open. All participants completed the Sensitivity to Punishment and Sensitivity to Reward Questionnaire. Seed-based functional connectivity analyses were performed in the amygdala, hippocampus, and periaqueductal gray (PAG). Our results showed that the relationship between SP and left amygdala-precuneus and left hippocampus-precuneus functional connectivity was modulated by eye state. Moreover, in the eyes open group, SP was negatively related to the functional connectivity between the PAG and amygdala and between the PAG and left hippocampus, and it was positively related to the functional connectivity between the amygdala and hippocampus. Together, our results may suggest underlying differences in the connectivity between anxiety-related areas based on eye state, which in turn would affect the manifestation of individual differences in SP.

Sustained and transient gray matter volume changes after n-back training: A VBM study.

Working memory training causes functional adaptations in the brain, which include changes in activation and functional connectivity that remain stable over time. Few studies have investigated gray matter (GM) changes after working memory training, and they have produced heterogeneous results without clarifying the stable effects of training. The present study was designed to test for sustained and transient anatomic changes after only 200 min of working memory training. The voxel-based morphometry technique was used in order to investigate the GM changes produced by a brief single n-back training, immediately and 5 weeks after finishing it. The sample was composed by 59 human participants who underwent MRI scanning and were assigned to either a training group or a passive control group. Results showed sustained GM volume enlargement in the right superior parietal cortex and a transient GM decrease in the right putamen. The brain adaptation in the right superior parietal cortex was stronger in individuals who showed greater improvements in performance. The results provide further evidence that a brief working memory training is able to produce brain plasticity in structures related to the trained task.

Opening or closing eyes at rest modulates the functional connectivity of V1 with default and salience networks.

Current evidence suggests that volitional opening or closing of the eyes modulates brain activity and connectivity. However, how the eye state influences the functional connectivity of the primary visual cortex has been poorly investigated. Using the same scanner, fMRI data from two groups of participants similar in age, sex and educational level were acquired. One group (n = 105) performed a resting state with eyes closed, and the other group (n = 63) performed a resting state with eyes open. Seed-based voxel-wise functional connectivity whole-brain analyses were performed to study differences in the connectivity of the primary visual cortex. This region showed higher connectivity with the default mode and sensorimotor networks in the eyes closed group, but higher connectivity with the salience network in the eyes open group. All these findings were replicated using an open source shared dataset. These results suggest that opening or closing the eyes may set brain functional connectivity in an interoceptive or exteroceptive state.

Locating neural transfer effects of n-back training on the central executive: a longitudinal fMRI study.

The large number of behavioral studies testing whether working memory training improves performance on an untrained task have yielded inconclusive results. Moreover, some studies have investigated the possible neural changes during the performance of untrained tasks after training. Here, we studied the transfer from n-back training to the Paced Auditory Serial Addition Test (PASAT), two different tasks that use the central executive system to maintain verbal stimuli. Participants completed fMRI sessions at baseline, immediately after one week of training, and at the five-week follow-up. Although behavioral transfer effects were not obtained, training was associated with decreased activation in the anterior dorsolateral prefrontal cortex (DLPFC; BA 9/46) while performing the PASAT that remained stable five weeks later. Consistent with our hypothesis, the changes in the anterior DLFPC largely overlapped with the n-back task fMRI activations. In conclusion, working memory training improves efficiency in brain areas involved in the trained task that may affect untrained tasks, specifically in brain areas responsible for the same cognitive processes.