In contrast to the well established macaque monkey, little is known about functional connectivity patterns of common marmoset monkey (Callithrix jacchus) that is poised to become the leading transgenic primate model. Here, we used resting-state ultra-high-field fMRI data collected from anesthetized marmosets and macaques along with awake human subjects, to examine and compare the brain's functional organization, with emphasis on the saccade system. Exploratory independent component analysis revealed eight resting-state networks in marmosets that greatly overlapped with corresponding macaque and human networks including a distributed frontoparietal network. Seed-region analyses of the superior colliculus (SC) showed homolog areas in macaques and marmosets. The marmoset SC displayed the strongest frontal functional connectivity with area 8aD at the border to area 6DR. Functional connectivity of this frontal region revealed a similar functional connectivity pattern as the frontal eye fields in macaques and humans. Furthermore, areas 8aD, 8aV, PG,TPO, TE2, and TE3 were identified as major hubs based on region-wise evaluation of betweeness centrality, suggesting that these cortical regions make up the functional core of the marmoset brain. The results support an evolutionarily preserved frontoparietal system and provide a starting point for invasive neurophysiological studies in the marmoset saccade and visual systems.

Objective:Mild cognitive impairment (MCI) is an at-risk state for dementia, however not all individuals with MCI transition to dementia, and some revert to normal cognition. Here, we investigate whether mild behavioral impairment (MBI), the late-life onset of persistent neuropsychiatric symptoms (NPS), improves the prognostic specificity of MCI.Methods:Participants with MCI from the National Alzheimer's Coordinating Center Uniform Data Set were included. Neuropsychiatric symptoms were operationalized with the neuropsychiatric inventory questionnaire (NPI-Q) to identify participants without NPS and those with MBI (persistent, late-onset NPS). Individuals with late-onset NPS not meeting the MBI persistence criterion (NPS_NOT_MBI) were retained for secondary analyses. Progression to dementia, stable MCI, and reversion to NC after 3 years of follow-up were defined as per NIA-AA and Petersen criteria.Results:The primary sample consisted of 739 participants (NPS- n=409 and MBI+ n=330; 75.16±8.6 years old, 40.5% female). After 3 years, 238 participants (33.6%) progressed to dementia and 90 (12.2%) reverted to NC. Compared to participants without NPS, participants with MBI were significantly more likely to progress to dementia (Adjusted Odds Ratio [AOR]=2.13, 95%CI 1.52-2.99), with an annual progression rate of 14.7% (vs 8.3% for MCI participants without NPS). Compared to participants without NPS, MBI participants were less likely to revert to NC (AOR=0.48, 95%CI 0.28-0.83, 2.5% vs 5.3% annual reversion rate). The NPS_NOT_MBI group (n=331, 76.5±8.6 years old 45.9% female), were more likely to progress to dementia (AOR=2.18, 95%CI 1.56-3.03, 14.3% annual progression rate) but not less likely to revert to NC than those without NPS. Accordingly, both NPS_NOT_MBI and MBI+ participants had lower MMSE scores than NPS- participants after 3 years.Discussion:Late-onset NPS improve the specificity of MCI as an at-risk state for progression to dementia. However, only persistent late-onset NPS are associated with a lower likelihood of reversion to NC, with transient NPS (i.e., NPS_NOT_MBI) not differing from the NPS- group. Clinical prognostication can be improved by incorporating late-onset NPS, especially those that persist (i.e., MBI), into risk assessments. Clinical trials may benefit from enrichment with these higher-risk MCI participants.

Objective:Plasma p-tau181, a well-validated marker of Alzheimer’s disease (AD) pathological change, could be a more efficient way to diagnose AD than invasive or expensive biomarkers requiring cerebrospinal fluid or positron emission tomography. In some individuals, neuropsychiatric symptoms (NPS) are the earliest manifestation of AD, observed in advance of clear cognitive decline. However, the few studies assessing AD biomarkers in association with NPS have often suffered from imprecision in capturing behavioral symptoms that represent sequalae of neurodegenerative disease. Thus, the mild behavioral impairment (MBI) construct was developed, framing NPS in a way to improve the precision of risk estimates for disease. MBI core criteria stipulate that NPS emergede novoin later-life and persist for at least six months. Here, cross-sectionally and longitudinally, we investigated associations of MBI with p-tau181, neuropsychological test performance, and incident AD.Methods:Cognitively unimpaired and mild cognitive impairment (MCI) Alzheimer Disease Neuroimaging Initiative participants were selected. MBI status was derived from the Neuropsychiatric Inventory (NPI) using a published algorithm. NPI total scores at baseline and year-one visits were used to operationalize MBI (score>0 at both visits), NPS not meeting MBI criteria (NPS-not-MBI, score>0 at only one visit), and no-NPS (score=0 at both visits). Linear regressions were fitted for cross-sectional analyses; multilevel linear mixed-effects and Cox proportional hazards models were implemented to examine longitudinal associations of MBI with changes in p-tau181 and cognition, and incident dementia.Results:The sample included 571 participants (age 72.2, 46.8% female, 64.8% MCI). Cross-sectionally (Beta=8.1%, 95%CI:1.4%-15.2%,p=0.02) MBI was associated with higher plasma ptau-181 levels compared to no-NPS; NPS-not-MBI was not. Longitudinally, MBI was associated with higher p-tau181 (Beta=0.014%, 95%CI:0.003-0.026,p=0.02), in addition to a decline in memory and executive function. Survival analyses demonstrated a 3.92-fold greater dementia incidence in MBI, with no significant differences between NPS-not-MBI and no-NPS.Discussion:These findings extend the evidence base that MBI is associated with elevated risk of cognitive decline and dementia, and a sequela of emerging Alzheimer-related proteinopathies. MBI offers a substantial improvement over current approaches that explore behavior as a proxy marker for Alzheimer-related proteinopathies, with both clinical and AD trial enrichment implications.

The common marmoset ( Callithrix jacchus) is a small-bodied New World primate increasing in prominence as a model animal for neuroscience research. The lissencephalic cortex of this primate species provides substantial advantages for the application of electrophysiological techniques such as high-density and laminar recordings, which have the capacity to advance our understanding of local and laminar cortical circuits and their roles in cognitive and motor functions. This is particularly the case with respect to the oculomotor system, as critical cortical areas of this network such as the frontal eye fields (FEF) and lateral intraparietal area (LIP) lie deep within sulci in macaques. Studies of cytoarchitecture and connectivity have established putative homologies between cortical oculomotor fields in marmoset and macaque, but physiological investigations of these areas, particularly in awake marmosets, have yet to be carried out. Here we addressed this gap by probing the function of posterior parietal cortex of the common marmoset with electrical microstimulation. We implanted two animals with 32-channel Utah arrays at the location of the putative area LIP and applied microstimulation while they viewed a video display and made untrained eye movements. Similar to previous studies in macaques, stimulation evoked fixed-vector and goal-directed saccades, staircase saccades, and eyeblinks. These data demonstrate that area LIP of the marmoset plays a role in the regulation of eye movements, provide additional evidence that this area is homologous with that of the macaque, and further establish the marmoset as a valuable model for neurophysiological investigations of oculomotor and cognitive control. NEW & NOTEWORTHY The macaque monkey has been the preeminent model for investigations of oculomotor control, but studies of cortical areas are limited, as many of these areas are buried within sulci in this species. Here we applied electrical microstimulation to the putative area LIP of the lissencephalic cortex of awake marmosets. Similar to the macaque, microstimulation evoked contralateral saccades from this area, supporting the marmoset as a valuable model for studies of oculomotor control.

Background Mild behavioral impairment (MBI) is a syndrome that uses later‐life emergent and persistent neuropsychiatric symptoms (NPS) to identify a group at high risk for incident dementia. MBI is associated with neurodegenerative disease markers in advance of syndromic dementia. Functional connectivity (FC) correlates of MBI are understudied and could provide further insights into mechanisms early in the disease course. We used resting‐state functional magnetic resonance imaging (rs‐fMRI) to test the hypothesis that FC within the default mode network (DMN) and salience network (SN) of persons with MBI (MBI+) is reduced, relative to those without (MBI–). Methods From two harmonized dementia‐free cohort studies, using a score of ≥6 on the MBI Checklist to define MBI status, 32 MBI+ and 63 MBI– individuals were identified (mean age: 71.7 years; 54.7% female). Seed‐based connectivity analysis was implemented in each MBI group using the CONN fMRI toolbox (v20.b), with the posterior cingulate cortex (PCC) as the seed region within the DMN and anterior cingulate cortex (ACC) as the seed within the SN. The average time series from the PCC and ACC were used to determine FC with other regions within the DMN (medial prefrontal cortex, lateral inferior parietal cortex) and SN (anterior insula, supramarginal gyrus, rostral prefrontal cortex), respectively. Age, sex, years of education, and Montreal Cognitive Assessment scores were included as model covariates. The false discovery rate approach was used to correct for multiple comparisons, with a p ‐value of .05 considered significant. Results For the DMN, MBI+ individuals exhibited reduced FC between the PCC and the medial prefrontal cortex, compared to MBI–. For the SN, MBI+ individuals exhibited reduced FC between the ACC and left anterior insula. Conclusion MBI in dementia‐free older adults is associated with reduced FC in networks known to be disrupted in dementia. Our results complement the evidence linking MBI with Alzheimer's disease biomarkers. Highlights Resting‐state functional magnetic resonance imaging was completed in 95 dementia‐free persons from FAVR and COMPASS‐ND studies. Participants were stratified by informant‐rated Mild Behavioral Impairment Checklist (MBI‐C) score, ≥6 for MBI+. MBI+ participants showed reduced functional connectivity (FC) within the default mode network and salience network. These FC changes are consistent with those seen in early‐stage Alzheimer's disease. MBI may help identify persons with early‐stage neurodegenerative disease.