Single-cell analysis of VACV infection reveals pathogen-driven timing of early and late phases and host-limited dynamics of virus production.

The extent and origin of variation in the replication dynamics of complex DNA viruses is not well-defined. Here, we investigate the vaccinia virus (VACV) infection cycle at the single-cell level, quantifying the temporal dynamics of early and post(dna)-replicative phase gene expression across thousands of infections. We found that viral factors determine the initiation time of these phases, and this is influenced by the multiplicity of infection (MOI). In contrast, virus production dynamics are largely constrained by the host cell. Additionally, between-cell variability in infection start time and virus production rate were strongly influenced by MOI, providing evidence for cooperativity between infecting virions. Blocking programmed cell death by pan-caspase inhibition increased infection frequency but not virus production at the population level due to a concurrent attenuation of per-cell virus yield, suggesting a dual role for caspase signaling in VACV infection. Our findings provide key insights into the pivotal factors influencing heterogeneity in the infection cycle of a large DNA virus at the single-cell level.

Connectivity-based parcellation of normal and anatomically distorted human cerebral cortex.

For over a century, neuroscientists have been working toward parcellating the human cortex into distinct neurobiological regions. Modern technologies offer many parcellation methods for healthy cortices acquired through magnetic resonance imaging. However, these methods are suboptimal for personalized neurosurgical application given that pathology and resection distort the cerebrum. We sought to overcome this problem by developing a novel connectivity-based parcellation approach that can be applied at the single-subject level. Utilizing normative diffusion data, we first developed a machine-learning (ML) classifier to learn the typical structural connectivity patterns of healthy subjects. Specifically, the Glasser HCP atlas was utilized as a prior to calculate the streamline connectivity between each voxel and each parcel of the atlas. Using the resultant feature vector, we determined the parcel identity of each voxel in neurosurgical patients (n = 40) and thereby iteratively adjusted the prior. This approach enabled us to create patient-specific maps independent of brain shape and pathological distortion. The supervised ML classifier re-parcellated an average of 2.65% of cortical voxels across a healthy dataset (n = 178) and an average of 5.5% in neurosurgical patients. Our patient dataset consisted of subjects with supratentorial infiltrating gliomas operated on by the senior author who then assessed the validity and practical utility of the re-parcellated diffusion data. We demonstrate a rapid and effective ML parcellation approach to parcellation of the human cortex during anatomical distortion. Our approach overcomes limitations of indiscriminately applying atlas-based registration from healthy subjects by employing a voxel-wise connectivity approach based on individual data.

Host lysolipid differentially modulates virulence factor expression and antimicrobial susceptibility in Pseudomonas aeruginosa.

Lysophosphatidic acid (LPA) occurs naturally in inflammatory exudates and has previously been shown to increase the susceptibility of Pseudomonas aeruginosa to ß-lactam antibiotics whilst concomitantly reducing accumulation of the virulence factors pyoverdine and elastase. Here it is demonstrated that LPA can also exert inhibitory effects upon pyocyanin production in P. aeruginosa, as well as influencing susceptibility to a wide range of chemically diverse non ß-lactam antimicrobials. Most strikingly, LPA markedly antagonizes the effect of the polycationic antibiotics colistin and tobramycin at a concentration of 250 µg ml-1 whilst conversely enhancing their efficacy at the lower concentration of 8.65 µg ml-1, approximating the maximal physiological concentrations found in inflammatory exudates. Transcriptomic responses of the virulent strain UCBPP-PA14 to LPA were analysed using RNA-sequencing along with BioLog phenoarrays and whole cell assays in attempts to delineate possible mechanisms underlying these effects. The results strongly suggest involvement of LPA-induced carbon catabolite repression together with outer-membrane (OM) stress responses whilst raising questions about the effect of LPA upon other P. aeruginosa virulence factors including type III secretion. This could have clinical relevance as it suggests that endogenous LPA may, at concentrations found in vivo, differentially modulate antibiotic susceptibility of P. aeruginosa whilst simultaneously regulating expression of virulence factors, thereby influencing host-pathogen interactions during infection. The possibility of applying exogenous LPA locally as an enhancer of select antibiotics merits further investigation.

Eigenvector PageRank difference as a measure to reveal topological characteristics of the brain connectome for neurosurgery.

PURPOSE: Applying graph theory to the human brain has the potential to help prognosticate the impacts of intracerebral surgery. Eigenvector (EC) and PageRank (PR) centrality are two related, but uniquely different measures of nodal centrality which may be utilized together to reveal varying neuroanatomical characteristics of the brain connectome. METHODS: We obtained diffusion neuroimaging data from a healthy cohort (UCLA consortium for neuropsychiatric phenomics) and applied a personalized parcellation scheme to them. We ranked parcels based on weighted EC and PR, and then calculated the difference (EP difference) and correlation between the two metrics. We also compared the difference between the two metrics to the clustering coefficient. RESULTS: While EC and PR were consistent for top and bottom ranking parcels, they differed for mid-ranking parcels. Parcels with a high EC centrality but low PR tended to be in the medial temporal and temporooccipital regions, whereas PR conferred greater importance to multi-modal association areas in the frontal, parietal and insular cortices. The EP difference showed a weak correlation with clustering coefficient, though there was significant individual variation. CONCLUSIONS: The relationship between PageRank and eigenvector centrality can identify distinct topological characteristics of the brain connectome such as the presence of unimodal or multimodal association cortices. These results highlight how different graph theory metrics can be used alone or in combination to reveal unique neuroanatomical features for further clinical study.

Unexpected hubness: a proof-of-concept study of the human connectome using pagerank centrality and implications for intracerebral neurosurgery.

INTRODUCTION: Understanding the human connectome by parcellations allows neurosurgeons to foretell the potential effects of lesioning parts of the brain during intracerebral surgery. However, it is unclear whether there exist variations among individuals such that brain regions that are thought to be dispensable may serve as important networking hubs. METHODS: We obtained diffusion neuroimaging data from two healthy cohorts (OpenNeuro and SchizConnect) and applied a parcellation scheme to them. We ranked the parcellations on average using PageRank centrality in each cohort. Using the OpenNeuro cohort, we focused on parcellations in the lower 50% ranking that displayed top quartile ranking at the individual level. We then queried whether these select parcellations with over 3% prevalence would be reproducible in the same manner in the SchizConnect cohort. RESULTS: In the OpenNeuro (n = 68) and SchizConnect cohort (n = 195), there were 27.9% and 43.1% of parcellations, respectively, in the lower half of all ranks that displayed top quartile ranks. We noted three outstanding parcellations (L_V6, L_a10p, and L_7PL) in the OpenNeuro cohort that also appeared in the SchizConnect cohort. In the larger Schizconnect cohort, L_V6, L_a10p, and L_7PL had unexpected hubness in 3.08%, 5.13%, and 8.21% of subjects, respectively. CONCLUSIONS: We demonstrated that lowly-ranked parcellations may serve as important hubs in a subset of individuals, highlighting the importance of studying parcellation ranks at the personalized level in planning supratentorial neurosurgery.

Uncovering the molecular mechanisms behind disease-associated leptin variants.

The pleiotropic hormone leptin has a pivotal role in regulating energy balance by inhibiting hunger and increasing energy expenditure. Homozygous mutations found in the leptin gene are associated with extreme obesity, marked hyperphagia, and impaired immune function. Although these mutations have been characterized in vivo, a detailed understanding of how they affect leptin structure and function remains elusive. In the current work, we used NMR, differential scanning calorimetry, molecular dynamics simulations, and bioinformatics calculations to characterize the effects of these mutations on leptin structure and function and binding to its cognate receptor. We found that mutations identified in patients with congenital leptin deficiency not only cause leptin misfolding or aggregation, but also cause changes in the dynamics of leptin residues on the receptor-binding interface. Therefore, we infer that mutation-induced leptin deficiency may arise from several distinct mechanisms including (i) blockade of leptin receptor interface II, (ii) decreased affinity in the second step of leptin's interaction with its receptor, (iii) leptin destabilization, and (iv) unsuccessful threading through the covalent loop, leading to leptin misfolding/aggregation. We propose that this expanded framework for understanding the mechanisms underlying leptin deficiency arising from genetic mutations may be useful in designing therapeutics for leptin-associated disorders.

Clonal hematopoiesis in patients with dyskeratosis congenita.

Dyskeratosis congenita (DC) is a rare inherited telomeropathy most frequently caused by mutations in a number of genes all thought to be involved in telomere maintenance. The main causes of mortality in DC are bone marrow failure as well as malignancies including leukemias and solid tumors. The clinical picture including the degree of bone marrow failure is highly variable and factors that contribute to this variability are poorly understood. Based on the recent finding of frequent clonal hematopoiesis in related bone marrow failure syndromes, we hypothesized that somatic mutations may also occur in DC and may contribute at least in part to the variability in blood production. To evaluate for the presence of clonal hematopoiesis in DC, we used a combination of X-inactivation, comparative whole exome sequencing (WES) and single nucleotide polymorphism array (SNP-A) analyses. We found that clonal hematopoiesis in DC is common, as suggested by skewed X-inactivation in 8 out of 9 female patients compared to 3 out of 10 controls, and by the finding of acquired copy neutral loss-of-heterozygosity on SNP-A analysis. In addition, 3 out of 6 independent DC patients were found to have acquired somatic changes in their bone marrow by WES, including a somatic reversion in DKC1, as well as missense mutations in other protein coding genes. Our results indicate that clonal hematopoiesis is a common feature of DC, and suggest that such somatic changes, though commonly expected to indicate malignancy, may lead to improved blood cell production or stem cell survival. Am. J. Hematol. 91:1227-1233, 2016. © 2016 Wiley Periodicals, Inc.

Sleep/wake behaviour of endurance cyclists before and during competition.

Good sleep is critical for optimising recovery and athletic performance. Yet, few studies have investigated how athletes sleep before and during competition. The aim of this study was to determine whether such sleep is poorer than that before a usual training day. Twenty-one male endurance cyclists' (age: 19.9 ± 1.7 years) sleep/wake behaviour was assessed using wrist activity monitors for 11 nights, including a six-night baseline training phase, three nights before competition and two nights during competition. Cyclists had less sleep on the night before competition (6.5 ± 0.9 h) and during the first night of competition (6.8 ± 0.8 h) than at baseline (7.4 ± 0.6 h). Cyclists also went to bed and woke up earlier during competition than at baseline. Competition schedules and competition itself can disrupt the sleep/wake behaviour of athletes during competition. Future investigations should examine sleep during three stages of competition (i.e. before, during and after competition). This will help coaches develop a greater understanding of how sleep changes during different phases of competition and enable them to plan post-competition training programmes to ensure appropriate rest and recovery is obtained.

Imaging in congenital pulmonary vein anomalies: the role of computed tomography.

Pulmonary venous anomalies comprise a wide spectrum of anatomical variations and their clinical presentations may vary from the relatively benign single partial anomalous pulmonary venous connection (PAPVC) to the critical obstructed total anomalous pulmonary venous connection (TAPVC). We briefly review the common anomalies encountered, while highlighting the utility that computed tomographic angiography (CTA) provides for this spectrum of extracardiac vascular malformations and connections. CTA has established itself as an invaluable imaging modality in these patients. A detailed knowledge of the CTA imaging findings in pulmonary venous anomalies is crucial to guide clinical decision-making in these patients.

Functional connectivity analysis of the depression connectome provides potential markers and targets for transcranial magnetic stimulation.

BACKGROUND: Despite efforts to improve targeting accuracy of the dorsolateral prefrontal cortex (DLPFC) as a repetitive transcranial magnetic stimulation (rTMS) target for Major Depressive Disorder (MDD), the heterogeneity in clinical response remains unexplained. OBJECTIVE: We sought to compare the patterns of functional connectivity from the DLPFC treatment site in patients with MDD who were TMS responders to those who were TMS non-responders. METHODS: Baseline anatomical T1 magnetic resonance imaging (MRI), resting-state functional MRI, and diffusion weighted imaging scans were obtained from 37 participants before they underwent a course of rTMS to left Brodmann area 46. A novel machine learning method was utilized to identify brain regions associated with each item of the Beck's Depression Inventory II (BDI-II), and for 26 participants who underwent rTMS treatment over the left Brodmann area 46, identify regions differentiating rTMS responders and non-responders. RESULTS: Nine parcels of the Human Connectome Project Multimodal Parcellation Atlas matched to at least three items of the Beck's Depression Inventory II (BDI-II) as predictors of response to rTMS, with many in the temporal, parietal and cingulate cortices. Additionally, pre-treatment mapping for 17 items of the BDI-II demonstrated significant variability in symptom to parcel mapping. When parcels associated with symptom presence and symptom resolution were compared, 15 parcels were uniquely associated with resolution (potential targets), and 12 parcels were associated with both symptom presence and resolution (blockers or biomarkers). CONCLUSIONS: Machine learning approaches show promise for the development of pathoanatomical diagnosis and treatment algorithms for MDD. Prospective studies are required to facilitate clinical translation.

Parcellation-Based Connectivity Model of the Judgement Core.

Judgement is a higher-order brain function utilized in the evaluation process of problem solving. However, heterogeneity in the task methodology based on the many definitions of judgement and its expansive and nuanced applications have prevented the identification of a unified cortical model at a level of granularity necessary for clinical translation. Forty-six task-based fMRI studies were used to generate activation-likelihood estimations (ALE) across moral, social, risky, and interpersonal judgement paradigms. Cortical parcellations overlapping these ALEs were used to delineate patterns in neurocognitive network engagement for the four judgement tasks. Moral judgement involved the bilateral superior frontal gyri, right temporal gyri, and left parietal lobe. Social judgement demonstrated a left-dominant frontoparietal network with engagement of right-sided temporal limbic regions. Moral and social judgement tasks evoked mutual engagement of the bilateral DMN. Both interpersonal and risk judgement were shown to involve a right-sided frontoparietal network with accompanying engagement of the left insular cortex, converging at the right-sided CEN. Cortical activation in normophysiological judgement function followed two separable patterns involving the large-scale neurocognitive networks. Specifically, the DMN was found to subserve judgement centered around social inferences and moral cognition, while the CEN subserved tasks involving probabilistic reasoning, risk estimation, and strategic contemplation.

Functional connectivity in ADHD children doing Go/No-Go tasks: An fMRI systematic review and meta-analysis.

Attention deficit hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders diagnosed in childhood. Two common features of ADHD are impaired behavioural inhibition and sustained attention. The Go/No-Go experimental paradigm with concurrent functional magnetic resonance imaging (fMRI) scanning has previously revealed important neurobiological correlates of ADHD such as the supplementary motor area and the prefrontal cortex. The coordinate-based meta-analysis combined with quantitative techniques, such as activation likelihood estimate (ALE) generation, provides an unbiased and objective method of summarising these data to understand the brain network architecture and connectivity in ADHD children. Go/No-Go task-based fMRI studies involving children and adolescent subjects were selected. Coordinates indicating foci of activation were collected to generate ALEs using threshold values (voxel-level: p < 0.001; cluster-level: p < 0.05). ALEs were matched to one of seven canonical brain networks based on the cortical parcellation scheme derived from the Human Connectome Project. Fourteen studies involving 457 children met the eligibility criteria. No significant convergence of Go/No-Go related brain activation was found for ADHD groups. Three significant ALE clusters were detected for brain activation relating to controls or ADHD < controls. Significant clusters were related to specific areas of the default mode network (DMN). Network-based analysis revealed less extensive DMN, dorsal attention network, and limbic network activation in ADHD children compared to controls. The presence of significant ALE clusters may be due to reduced homogeneity in the selected sample demographic and experimental paradigm. Further investigations regarding hemispheric asymmetry in ADHD subjects would be beneficial.

Symptom-circuit mappings of the schizophrenia connectome.

OBJECTIVE: This paper aims to model the anatomical circuits underlying schizophrenia symptoms, and to explore patterns of abnormal connectivity among brain networks affected by psychopathology. METHODS: T1 magnetic resonance imaging (MRI), diffusion weighted imaging (DWI), and resting-state functional MRI (rsfMRI) were obtained from a total of 126 patients with schizophrenia who were recruited for the study. The images were processed using the Omniscient software (https://www.o8t. com). We further apply the use of the Hollow-tree Super (HoTS) method to gain insights into what brain regions had abnormal connectivity that might be linked to the symptoms of schizophrenia. RESULTS: The Positive and Negative Symptom Scale is characterised into 6 factors. Each symptom is mapped with specific anatomical abnormalities and circuits. Comparison between factors reveals co-occurrence in parcels in Factor 1 and Factor 2. Multiple large-scale networks are involved in SCZ symptomatology, with functional connectivity within Default Mode Network (DMN) and Central Executive Network (CEN) regions most frequently associated with measures of psychopathology. CONCLUSION: We present a summary of the relevant anatomy for regions of the cortical areas as part of a larger effort to understand its contribution in schizophrenia. This unique machine learning-type approach maps symptoms to specific brain regions and circuits by bridging the diagnostic subtypes and analysing the features of the connectome.

An agile, data-driven approach for target selection in rTMS therapy for anxiety symptoms: Proof of concept and preliminary data for two novel targets.

INTRODUCTION: Data-driven approaches to transcranial magnetic stimulation (TMS) might yield more consistent and symptom-specific results based on individualized functional connectivity analyses compared to previous traditional approaches due to more precise targeting. We provide a proof of concept for an agile target selection paradigm based on using connectomic methods that can be used to detect patient-specific abnormal functional connectivity, guide treatment aimed at the most abnormal regions, and optimize the rapid development of new hypotheses for future study. METHODS: We used the resting-state functional MRI data of 28 patients with medically refractory generalized anxiety disorder to perform agile target selection based on abnormal functional connectivity patterns between the Default Mode Network (DMN) and Central Executive Network (CEN). The most abnormal areas of connectivity within these regions were selected for subsequent targeted TMS treatment by a machine learning based on an anomalous functional connectivity detection matrix. Areas with mostly hyperconnectivity were stimulated with continuous theta burst stimulation and the converse with intermittent theta burst stimulation. An image-guided accelerated theta burst stimulation paradigm was used for treatment. RESULTS: Areas 8Av and PGs demonstrated consistent abnormalities, particularly in the left hemisphere. Significant improvements were demonstrated in anxiety symptoms, and few, minor complications were reported (fatigue (n = 2) and headache (n = 1)). CONCLUSIONS: Our study suggests that a left-lateralized DMN is likely the primary functional network disturbed in anxiety-related disorders, which can be improved by identifying and targeting abnormal regions with a rapid, data-driven, agile aTBS treatment on an individualized basis.

Real world demonstration of hand motor mapping using the structural connectivity atlas.

BACKGROUND: Locating the hand-motor-cortex (HMC) is an essential component within many neurosurgeries. Despite advancements in these localization methods there are still downfalls for each. Additionally, the importance of presurgical planning calls for increasingly accurate and efficient methods of locating specific cortical regions. OBJECTIVE: In this study we aimed to test the ability of the Structural Connectivity Atlas (SCA), a machine-learning based method to parcellate the human cortex, to locate the HMC in a small cohort study. METHODS: Using MRI and DTI images obtained from adult subjects (n = 11), personalized brain maps were created for each individual based on a SCA paired with the Brainnetome region for the HMC. Subjects received single pulse TMS, over the HMC region through the use of a neuronavigation system. If they responded with motor movement, this was recorded. The SCA identified HMC region was compared to the visual-determined HMC through identifying the Omega fold on the Precentral Gyrus, which was completed by a trained neuroanatomist. A Kendall's Tau B correlation was conducted between anatomical match and visual movement. RESULTS: This study concluded that the SCA was capable of locating the HMC in healthy and distorted brains. Overall, the SCA defined the anatomical area of the HMC in 90 % of subjects and triggered a motor response in 61 %. CONCLUSION: The SCA could be suitable for incorporation into presurgical planning practices due to its ability to map anatomically abnormal brains. Further studies on larger cohorts and targeting different areas of cortex could be beneficial.

Neural tube defects in mice with reduced levels of inositol 1,3,4-trisphosphate 5/6-kinase.

Inositol 1,3,4-trisphosphate 5/6-kinase (ITPK1) is a key regulatory enzyme at the branch point for the synthesis of inositol hexakisphosphate (IP(6)), an intracellular signaling molecule implicated in the regulation of ion channels, endocytosis, exocytosis, transcription, DNA repair, and RNA export from the nucleus. IP(6) also has been shown to be an integral structural component of several proteins. We have generated a mouse strain harboring a beta-galactosidase (betagal) gene trap cassette in the second intron of the Itpk1 gene. Animals homozygous for this gene trap are viable, fertile, and produce less ITPK1 protein than wild-type and heterozygous animals. Thus, the gene trap represents a hypomorphic rather than a null allele. Using a combination of immunohistochemistry, in situ hybridization, and betagal staining of mice heterozygous for the hypomorphic allele, we found high expression of Itpk1 in the developing central and peripheral nervous systems and in the paraxial mesoderm. Examination of embryos resulting from homozygous matings uncovered neural tube defects (NTDs) in some animals and axial skeletal defects or growth retardation in others. On a C57BL/6 x 129(P2)Ola background, 12% of mid-gestation embryos had spina bifida and/or exencephaly, whereas wild-type animals of the same genetic background had no NTDs. We conclude that ITPK1 is required for proper development of the neural tube and axial mesoderm.

LNK (SH2B3) inhibition expands healthy and Fanconi anemia human hematopoietic stem and progenitor cells.

Hematopoietic stem cell transplantation (HSCT) remains the only curative treatment for a variety of hematological diseases. Allogenic HSCT requires hematopoietic stem cells (HSCs) from matched donors and comes with cytotoxicity and mortality. Recent advances in genome modification of HSCs have demonstrated the possibility of using autologous HSCT-based gene therapy to alleviate hematologic symptoms in monogenic diseases, such as the inherited bone marrow failure (BMF) syndrome Fanconi anemia (FA). However, for FA and other BMF syndromes, insufficient HSC numbers with functional defects results in delayed hematopoietic recovery and increased risk of graft failure. We and others previously identified the adaptor protein LNK (SH2B3) as a critical negative regulator of murine HSC homeostasis. However, whether LNK controls human HSCs has not been studied. Here, we demonstrate that depletion of LNK via lentiviral expression of miR30-based short hairpin RNAs results in robust expansion of transplantable human HSCs that provided balanced multilineage reconstitution in primary and secondary mouse recipients. Importantly, LNK depletion enhances cytokine-mediated JAK/STAT activation in CD34+ hematopoietic stem and progenitor cells (HSPCs). Moreover, we demonstrate that LNK depletion expands primary HSPCs associated with FA. In xenotransplant, engraftment of FANCD2-depleted FA-like HSCs was markedly improved by LNK inhibition. Finally, targeting LNK in primary bone marrow HSPCs from FA patients enhanced their colony forming potential in vitro. Together, these results demonstrate the potential of targeting LNK to expand HSCs to improve HSCT and HSCT-based gene therapy.

Using a ResNet-18 Network to Detect Features of Alzheimer's Disease on Functional Magnetic Resonance Imaging: A Failed Replication. Comment on Odusami et al. Analysis of Features of Alzheimer's Disease: Detection of Early Stage from Functional Brain Changes in Magnetic Resonance Images Using a Finetuned ResNet18 Network. Diagnostics 2021, 11, 1071.

There is considerable interest in developing effective tools to detect Alzheimer's Disease (AD) early in its course, prior to clinical progression [...].

SMAD proteins: Mediators of diverse outcomes during infection.

Understanding the relationship between host and pathogen is key to combatting disease. SMAD transcription factors, which transmit TGF-ß superfamily signalling, mediate an array of outcomes during embryogenesis, inflammation, cancer, and immunity. Surprisingly, these activities can sometimes be directly opposed; for example, SMAD3 has been reported as tumour suppressor by arresting cell cycle progression but conversely promotes cancer metastasis. A growing body of literature has identified SMADs as prominent targets during viral and bacterial infection for modulating host signalling. During infection, the activity of SMAD-containing transcriptional complexes can be finely tuned by pathogens to enhance infectivity and spread. SMAD signalling can be modulated at many levels, such as upstream at the ligand and receptor, or by direct interactions with SMADs. These alterations can increase pathogen dissemination, induce fibrosis, over-activate, or attenuate the host immune response. Here, we summarise the diverse mechanisms by which pathogens have evolved to sway SMAD signalling in their favour. Understanding the intricacies of host-pathogen interactions through this lens may elucidate aspects of SMAD function in cancer development, homoeostasis, and immune signalling previously overlooked. These insights are an opportunity to identify novel TGF-ß or BMP-targeted therapeutics for applications to infectious disease contexts.

Machine Learning Decomposition of the Anatomy of Neuropsychological Deficit in Alzheimer's Disease and Mild Cognitive Impairment.

Objective: Alzheimer's Disease (AD) is a progressive condition characterized by cognitive decline. AD is often preceded by mild cognitive impairment (MCI), though the diagnosis of both conditions remains a challenge. Early diagnosis of AD, and prediction of MCI progression require data-driven approaches to improve patient selection for treatment. We used a machine learning tool to predict performance in neuropsychological tests in AD and MCI based on functional connectivity using a whole-brain connectome, in an attempt to identify network substrates of cognitive deficits in AD. Methods: Neuropsychological tests, baseline anatomical T1 magnetic resonance imaging (MRI), resting-state functional MRI, and diffusion weighted imaging scans were obtained from 149 MCI, and 85 AD patients; and 140 cognitively unimpaired geriatric participants. A novel machine learning tool, Hollow Tree Super (HoTS) was utilized to extract feature importance from each machine learning model to identify brain regions that were associated with deficit and absence of deficit for 11 neuropsychological tests. Results: 11 models attained an area under the receiver operating curve (AUC-ROC) greater than 0.65, while five models had an AUC-ROC ≥ 0.7. 20 parcels of the Human Connectome Project Multimodal Parcelation Atlas matched to poor performance in at least two neuropsychological tests, while 14 parcels were associated with good performance in at least two tests. At a network level, most parcels predictive of both presence and absence of deficit were affiliated with the Central Executive Network, Default Mode Network, and the Sensorimotor Networks. Segregating predictors by the cognitive domain associated with each test revealed areas of coherent overlap between cognitive domains, with the parcels providing possible markers to screen for cognitive impairment. Conclusion: Approaches such as ours which incorporate whole-brain functional connectivity and harness feature importance in machine learning models may aid in identifying diagnostic and therapeutic targets in AD.