BACKGROUND:Cerebral/cortical visual impairment (CVI) is among the leading causes of visual impairment in children. Yet, identifying the neural correlates of CVI remains challenging due to the heterogeneous underlying etiologies and visual manifestations. While previous work has focused on intra-hemispheric white matter connections, in this cross-sectional observational study, we focus on the potential contribution of inter-hemispheric white matter connections via the corpus callosum (CC) to the severity of visual dysfunction in individuals with CVI. METHODS:Seven segments of the CC were isolated in 21 participants with CVI (10 M, 11 F, mean age: 20.19 years, 8.38 s.d., range: 10-44 years) and 26 controls (10 M, 16 F, mean age: 19.00 years, 5.82 s.d., range: 10-28 years) without a history of brain injury or visual impairment. Mixed models were used to investigate within- and between-group differences in diffusion metrics. Associations between diffusion metrics of the CC segments and severity of visual dysfunctions across five domains determined by the CVI Questionnaire were calculated in an exploratory analysis within the CVI group. RESULTS:Significantly lower fractional anisotropy (FA) and higher radial diffusivity (RD) measures were observed for isthmus and splenium, as well as higher mean diffusivity (MD) for the splenium in the CVI group compared with control following correction for multiple comparisons. In our exploratory analysis, the severity of impairments in object and face processing, impairments moving in space, and anxiety-related behaviors were significantly negatively associated with diffusion properties of posterior midbody CC segments in the CVI group. Additional positive correlations between visual disinterest and AD of the rostrum were also observed. CONCLUSIONS:Our results demonstrate that while CVI is associated with atypical diffusion properties in the posterior portions of the CC, the severity of visual dysfunctions may be associated with underlying tissue composition of the anterior and mid-posterior segments of the CC.

Brain atrophy is a normal part of healthy aging, but it is aggravated by several neurodegenerative diseases. Previous studies have described a large heterogeneity in individual neurodegeneration patterns, but the underlying brain mechanisms are currently not fully understood. From a graph theory-based framework, the estimation of subject-specific focal or multifocal brain atrophy in healthy aging and in the preclinical stage of different neurodegenerative diseases, such as Alzheimer's disease (AD), will help to better understand individual atrophy networks and likely improve prediction of phenotypic heterogeneity in disease trajectories. This study aimed to develop a novel spatiotemporal connectomic method based on graph theory applied to serial MRI measurements to identify neurodegeneration focality (i.e., unifocal or multifocal atrophy patterns) in healthy aging at the single-subject level. The study included a unique sample of 79 older cognitively normal participants from the the Vallecas project who underwent longitudinal T1 MRI scanning with 8 follow-up timepoints over 9,46±1,97 years. Voxel-based morphometry was used to define the brain atrophy topology of each subject, and uni- or multifocal atrophy patterns were identified using a graph theory approach based on structural similarity between each voxel and the rest of the brain across serial gray matter measurements (Figure 1). We identified individualized atrophy phenotypes characterized by different graph morphologies (Figure 2), which could be classified into three main groups based on their connectivity behavior. One group of subjects was characterized by atrophic voxels with a coordinated behavior, another with a predominance towards divergent or discoordinated behavior, and a third group that laid between these two extremes. We present a novel analytical tool for characterizing individualized atrophy phenotypes in healthy subjects based on graph theory and structural similarity analyses of longitudinal MRI data. This method may help to describe the first structural events in preclinical AD and other neurodegenerative diseases and, therefore, could be crucial for predicting differences in disease phenotype and progression in single subjects.

The accumulation of misfolded tau proteins, an Alzheimer’s disease (AD) hallmark, starts decades before the emergence of cognitive decline and clinical diagnosis. Autopsy studies support a predictable progression of tau pathology through large-scale systems. However, less is known about the specific progression patterns. The use of connectomic metrics could enhance our understanding of the characteristics of pathology spread. We examined the spatiotemporal relationships of cortical tau accumulation using network motifs, directed graph metrics, which can reveal the underlying mechanisms governing the pathology progression routes in preclinical and clinical AD. We used longitudinal tau-PET data (1-year follow-up) from 40 adults with normal cognitive functioning and 33 adults with mild cognitive impairment from the Alzheimer’s Disease Neuroimaging Initiative (ADNI-3) (Table 1). We used individual and group-level whole-brain voxel-wise graph theory and motifs networks analyses to investigate AD-related tau pathology directional spreading (Figure 1a). Directional relations are established by using group-level association matrices and by assessing differences in between-voxels temporal relations (Time1-Time2; FDR-corrected, p<0.001) (Figure 1b). Then, the resulting association matrix representing the human connectome is decomposed into motif networks, which are three-node triangular fundamental relations (i.e., exact copies of every possible motif is searched at the voxel-level) (Figure 1c). Finally, between-group visual comparisons of each motif reveal similarities and differences in dominant pathology spreading patterns in preclinical vs. clinical AD stages (Figure 1d). Our results support that unidirectional and serial network motifs are behind misfolded tau protein spreading in AD (Figure 2). Feed-forward loops , cascade , and regulated mutual networks drive tau propagation in medial and lateral temporal and medial prefrontal regions early in the disease. Through the disease, spread out from one region to another (i.e., fan out and regulating mutual networks ) is a common characteristic of tau progression. Our results suggest that the progression of toxic tau through the brain systems occurs mainly in a unidirectional and serial manner. AD is considered a dysconnectivity disease. Thus, serial motifs could indicate biological relations arising on a sequential spatiotemporal scale. Future developments will examine the role of amyloid accumulation in tau progression in the context of AD.

The thalamus is critical for the relay and modulation of visual information. As such, injury to the developing thalamus may result in cerebral visual impairment (CVI). This study investigated quantitative volume reductions of the thalamus in cerebral visual impairment compared to controls and probed the association between thalamic volume and the severity of cerebral visual impairment-related visual dysfunctions. Thalamic volumes were quantified using T1-weighted magnetic resonance imaging (MRI) data from 23 participants with cerebral visual impairment and 42 controls. Nineteen participants with cerebral visual impairment also completed the CVI Questionnaire. Cerebral visual impairment was associated with significant volume reductions of the global thalami, anterior, lateral, and ventral thalamic regions, as well as several nuclei, particularly in those with cerebral visual impairment due to periventricular leukomalacia. Within the cerebral visual impairment group, smaller volumes of the right thalamus and lateral pulvinar were significantly associated with more reported difficulties moving through space. Together, these results provide empirical evidence supporting aberrant thalamic development as a potential mechanism underlying cerebral visual impairment.

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.

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.

Abstract 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.

It is poorly known how Aβ 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 Aβ 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 Aβ and tau pathology display distinctive spatiotemporal correlations associated with early cognitive decline. Notably, we observed that baseline Aβ 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 Aβ-to-Aβ progressions were not associated with cognitive changes. Our results revealed a multifaceted correlation of the spatiotemporal Aβ and tau associations with cognitive decline over time, in which tau-to-tau and tau–Aβ interactions, and not Aβ independently, might be critical contributors to clinical trajectories toward AD in older adults.

Mnemonic anosognosia (i.e., 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 be a sign of predementia stages. It contributes to disease severity, symptomatology worsening, and caregiver burden and is a good predictor of clinical progression. Here, we use in-vivo multi-modal neuroimaging to profile the brain phenotype of individuals presenting altered self-awareness of memory during aging. We used amyloid- and tau-PET (N = 335) and resting-state fMRI (N = 713) data of individuals from the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Disease (A4)/Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) studies (Table1A). The neurocognitive profile of unawareness was characterized using between-groups comparisons (omnibus and post-hoc analyses) of the objective (LM delayed memory, and FCSRT free and cued scores) and subjective (MACQ) memory measurements of individuals classified as unaware of their memory impairment, compared to aware, subjective-complainers and control individuals. To characterize the cortical burden of amyloid and tau and their modulatory effect on functional connectivity networks, we applied whole-brain voxel-wise GLM analyses, region-of-interest associations, and graph-theory metrics (e.g., degree centrality). Unaware and aware individuals perform worse than the control group in objective memory tests, while unaware individuals differ from aware but not from controls in MACQ (Table1B). The unaware group presents elevated amyloid and tau burden in midline core regions of the default mode network (DMN) compared to aware, complainer or control individuals (p-value<0.05) (Figure1AB). Tau spreading in controls showed significant connectivity toward DMN and lateral and medial occipito-parietal regions (Figure1C). Unawareness is characterized by an altered network connectivity pattern modulated by tau accumulation in which hyperconnectivity is observed mainly in midline DMN and posterior occipito-parietal regions (p-value<0.05) (Figure2A). Degree centrality revealed the main connectivity hubs altered by tau deposits in unaware individuals (e.g., posterior regions) (Figure2B). Mnemonic anosognosia is an early behavioral biomarker of AD pathology. Unawareness of memory decline leads to distinct brain phenotype, characterized by increased amyloid and tau burden, along with functional network connectivity disruptions, in several areas of the self-referential brain network, including the posterior cerebral cortex of the human brain.

Misfolded tau protein, an Alzheimer’s Disease (AD) hallmark, accumulates decades before the emergence of cognitive decline. Autopsy and neuroimaging studies support the locus coeruleus (LC) as an early site of tau and its contribution to disease progression. However, whether tau in LC precedes cortical tau deposition remains unclear. Understanding the topography of tau progression and the biological factors making specific neuronal systems prone to AD-related pathology is essential to target interventions appropriately. We examined the spatiotemporal relationships between LC integrity and cortical tau accumulation and its relevance to cognition., We combined longitudinal LC-integrity (T1-TSE-imaging) and tau pathology (18F-FTP-PET) data from 77 adults (Fig1A). We used whole-brain voxel-wise GLM analysis to investigate the relationship between baseline LC-integrity (inverted signal) and longitudinal tau accumulation and compared the correlation distributions in both directions. Robust regression analysis was used to examine whether the observed tau spreading pathway predicts PACC5 performance at follow-up. We used neuropathological measures from 160 cognitively unimpaired or MCI/AD adults (Fig1B) to support the in-vivo neuroimaging data. Spearman-rank partial correlations were used to relate LC tangle density to tangles in temporal cortex areas. Using AHBA, the biological backgrounds underlying the connectomic-genetic relationships related to LC were explored using a whole-brain region-wise transcriptomic similarity analysis., Correlations between baseline LC-integrity and follow-up tau were stronger than the inverse correlations, indicative of lower LC-integrity preceding tau accumulation in MTL (Fig1C-D). LC tangle density was strongly related to tangles in MTL structures (Fig1E). Longitudinal tau accumulation in the LC-MTL axis is associated with lower cognitive performance (Fig2). Common neurogenetic profiles exist between LC and MTL/limbic regions, supporting a shared connectomic-transcriptomic substrate. The genetic profile displays specific biological functions in protein transport regulation and lipid biosynthetic processes (Fig3)., Our results suggest that changes in LC-integrity may occur before tau spreads into the MTL, which jointly contributes to lower cognitive performance. The neurogenetic profiles can provide a biological framework for identifying individuals more likely to be at risk for AD disease progression. Future developments could examine the intersection between amyloid and LC-related tau progression in the context of AD.

The correlations between apolipoprotein epsilon 4 (APOE4) status and regional amyloid, tau, and cortical thickness in cognitively normal elderly are not fully understood. Our cross-sectional study aimed to compare regional amyloid/tau burden, and cortical thickness according to APOE4 carrier status and assess correlations between APOE4 and Alzheimer’s disease (AD)-related biomarker burdens. We analyzed 185 cognitively normal participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort. Participants aged 55–90 with normal cognitive function were divided into amyloid ß-positive (Aß+) APOE4 carriers (group 1, n = 27), Aß+ APOE4 non-carriers (group 2, n = 29), and Aß− normal controls (group 0, n = 129). We compared amyloid depositions, tau depositions, and cortical thickness among the three groups and assessed correlations between APOE4 existence and imaging biomarkers adjusted for age and sex. The participants in group 2 were older than those in the other groups. The regional amyloid/tau standardized uptake value ratios (SUVRs) did not differ between groups 1 and 2, but the amyloid/tau SUVRs in most regions were numerically higher after adjusting for age difference. APOE4 allele had robust correlations with increased amyloid burden in the fronto-temporo-parietal cortical areas after adjustment for age and sex, but it had weaker and mixed correlations with the regional tau burden and did not have significant correlation with cortical thickness. We identified that the presence of APOE4 allele might be more highly associated with amyloid deposition than with other AD-related biomarkers such as tau or cortical thickness in cognitively normal elderly.

Striatal changes in the pathogenesis of Alzheimer's disease (AD) is not fully understood yet. We compared structural and functional image differences in the striatum between patients with early onset AD (EOAD) and late onset AD (LOAD) to investigate whether EOAD harbors autosomal dominant AD like imaging findings. The clinical, neuropsychological and neuroimaging biomarkers of 77 probable AD patients and 107 elderly subjects with normal cognition (NC) from the Alzheimer's Disease Neuroimaging Initiative (ADNI)-2 dataset were analyzed. Enrolled each subject completed a 3-Tesla MRI, baseline 18F-FDG-PET, and baseline 18F-AV-45 (Florbetapir) amyloid PET studies. AD patients were divided into two groups based on the onset age of clinical symptoms (EOAD <65 yrs; LOAD ≥65 yrs). A standardized uptake value ratio of the striatum and subcortical structures was obtained from both amyloid and FDG-PET scans. Structural MR imaging analysis was conducted using a parametric boundary description protocol, SPHARM-PDM. Of the 77 AD patients, 18 were EOAD and 59 were LOAD. Except for age of symptom onset, there were no statistically significant differences between the groups in demographics and detailed neuropsychological test results. 18F-AV-45 amyloid PET showed marked β-amyloid accumulation in the bilateral caudate nucleus and left pallidum in the EOAD group. Intriguingly, the caudate nucleus and putamen showed maintained glucose metabolism in the EOAD group compared to the LOAD group. Our image findings in the striatum of EOAD patients suggest that sporadic EOAD may share some pathophysiological changes noted in autosomal dominant AD.

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.

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.

Amyloid‐beta (Aβ) plaques and tau neurofibrillary tangles are pathological hallmarks of Alzheimer's disease (AD); their contribution to neurodegeneration and clinical manifestations are critical in understanding preclinical AD. At present, the mechanisms related to Aβ and tau pathogenesis leading to cognitive decline in older adults remain largely unknown. Here, we examined graph theory‐based positron emission tomography (PET) analytical approaches, within and between tau and Aβ PET modalities, and tested the effects on cognitive changes in cognitively normal older adults (CN). Particularly, we focused on the network interdigitations of Aβ and tau deposits, along with cognitive test scores in CN at both baseline and 2‐year follow‐up (FU). We found highly significant Aβ‐tau network integrations in AD vulnerable areas, as well as significant associations between those Aβ‐tau interdigitations and general cognitive impairment in CN at baseline and FU. Our findings suggest a distinctive contribution of interlinking network relationships between Aβ and tau deposits in heteromodal areas of the human brain. They support a network‐based interaction between Aβ and tau accumulations as a key factor for cognitive deterioration in CN prior to dementia.

A substantial amount of amyloid-beta (Aβ) accumulates in the occipital cortices; however, it draws less attention. We investigated the clinical implications of Aβ accumulation in the occipital lobes in the Alzheimer’s disease (AD) continuum. [18F]-Florbetaben amyloid PET scans were performed in a total of 121 AD or amnestic mild cognitive impairment (aMCI) patients. Of the 121 patients, 74 Aβ positive patients were divided into occipital Aβ positive (OCC+) and occipital Aβ negative (OCC−) groups based on Aβ accumulation in the bilateral occipital lobes. The OCC+ group (41/74, 55.4%) was younger and had a younger age at onset than the OCC− group. The OCC+ group also had an increased standard uptake value ratio in the occipital lobes and greater cortical thinning in relevant areas. The OCC+ group had a higher global deterioration scale, lower performance for the copy, immediate recall, delayed recall, and recognition in Rey–Osterrieth Complex Figure tests than the OCC- group, although both groups had similar disease durations. AD or aMCI patients in the OCC+ group exhibited features noted in early onset AD with relevant neuropsychological and image findings. Occipital Aβ positivity in amyloid PET scans need to be considered as an underestimated marker of early onset AD continuum.

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.

Background and Purpose: Cerebral white matter signal abnormalities (WMSAs) are a significant radiological marker associated with brain and vascular aging. However, understanding their clinical impact is limited because of their pathobiological heterogeneity. We determined whether use of robust reliable automated procedures can distinguish WMSA classes with different clinical consequences. Methods: Data from generally healthy participants aged >50 years with moderate or greater WMSA were selected from the Human Connectome Project-Aging (n=130). WMSAs were segmented on T1 imaging. Features extracted from WMSA included total and regional volume, number of discontinuous clusters, size of noncontiguous lesion, contrast of lesion intensity relative to surrounding normal appearing tissue using a fully automated procedure. Hierarchical clustering was used to classify individuals into distinct classes of WMSA. Radiological and clinical variability was evaluated across the individual WMSA classes. Results: Class I was characterized by multiple, small, lower-contrast lesions predominantly in the deep WM; class II by large, confluent lesions in the periventricular WM; and class III by higher-contrast lesions restricted to the juxtaventricular WM. Class II was associated with lower myelin content than the other 2 classes. Class II was more prevalent in older subjects and was associated with a higher prevalence of hypertension and lower physical activity levels. Poor sleep quality was associated with a greater risk of class I. Conclusions: We classified heterogeneous subsets of cerebral white matter lesions into distinct classes that have different clinical risk factors. This new method for identifying classes of WMSA will be important in understanding the underlying pathophysiology and in determining the impact on clinical outcomes.

Reduced cerebral blood flow (CBF), an indicator of neurovascular processes and metabolic demands, is a common finding in Alzheimer's disease. However, little is known about what contributes to CBF deficits in individuals with mild cognitive impairment (MCI). We examine regional CBF differences in 17 MCI compared with 21 age-matched cognitively healthy older adults. Next, we examined associations between CBF, white matter lesion (WML) volume, amplitude of low-frequency fluctuations, and cortical thickness to better understand whether altered CBF was detectable before other markers and the potential mechanistic underpinnings of CBF deficits in MCI. MCI had significantly reduced CBF, whereas cortical thickness and amplitude of low-frequency fluctuation were not affected. Reduced CBF was associated with the WML volume but not associated with other measures. Given the presumed vascular etiology of WML and relative worsening of vascular health in MCI, it may suggest CBF deficits result from early vascular as opposed to metabolic deficits in MCI. These findings may support vascular mechanisms as an underlying component of cognitive impairment.

Regions within the default mode network (DMN) are particularly vulnerable to Alzheimer's disease pathology and mechanisms of DMN disruption in mild cognitive impairment (MCI) are still unclear. White matter lesions are presumed to be mechanistically linked to vascular dysfunction whereas cortical atrophy may be related to neurodegeneration. We examined associations between DMN seed-based connectivity, white matter lesion load, and cortical atrophy in MCI and cognitively healthy controls. MCI showed decreased functional connectivity (FC) between the precuneus-seed and bilateral lateral temporal cortex (LTC), medial prefrontal cortex (mPFC), posterior cingulate cortex, and inferior parietal lobe compared to those with controls. When controlling for white matter lesion volume, DMN connectivity differences between groups were diminished within bilateral LTC, although were significantly increased in the mPFC explained by significant regional associations between white matter lesion volume and DMN connectivity only in the MCI group. When controlling for cortical thickness, DMN FC was similarly decreased across both groups. These findings suggest that white matter lesions and cortical atrophy are differentially associated with alterations in FC patterns in MCI. Associations between white matter lesions and DMN connectivity in MCI further support at least a partial but important vascular contribution to age-associated neural and cognitive impairment.