Qualitative and quantitative reviews of the neuroimaging literature show that overlapping brain regions support theory of mind (ToM) and autobiographical memory (AM). This overlap has been taken to ...suggest that individuals draw on past personal experiences to infer others’ mental states, but work with amnesic people shows that ToM does not always depend on AM. One variable that may determine the extent to which one relies on AM when inferring another's thoughts and feelings during ToM is whether that individual is personally known. To test this possibility, participants were scanned with fMRI as they remembered past experiences in response to personal photos (‘AM’ condition) and imagined others’ experiences in response to photos of personally familiar (‘pToM’ condition) and unfamiliar (‘ToM’ condition) others. Spatiotemporal Partial Least Squares was used to identify the spatial and temporal characteristics of neural activation patterns associated with AM, pToM, and ToM. We found that the brain regions supporting pToM more closely resembled those supporting AM relative to ToM involving unfamiliar others, with the greatest degree of overlap within midline regions. A complementary finding was the observation of striking differences between pToM and ToM such that midline regions associated with AM predominated during pToM, whereas more lateral regions associated with social semantic memory predominated during ToM. Overall, this study demonstrates that ToM involves a dynamic interplay between AM and social semantic memory that is biased towards AM when a personally familiar other is the subject of the mental state inference.
► fMRI study of theory of mind for known (pToM) vs. unknown (ToM) others. ► pToM and autobiographical memory activate overlapping midline regions. ► Lateral frontal activity during ToM, resembling semantic memory.
Longitudinal neuroimaging studies aid our understanding of recovery mechanisms in moderate-to-severe traumatic brain injury (TBI); however, there is a dearth of longitudinal functional connectivity ...research. Our aim was to characterize longitudinal functional connectivity patterns in two clinically important brain networks, the frontoparietal network (FPN) and the default mode network (DMN), in moderate-to-severe TBI. This inception cohort study of prospectively collected longitudinal data used resting-state functional magnetic resonance imaging (fMRI) to characterize functional connectivity patterns in the FPN and DMN. Forty adults with moderate-to-severe TBI (mean ± standard deviation SD; age = 39.53 ± 16.49 years, education = 13.92 ± 3.20 years, lowest Glasgow Coma Scale score = 6.63 ± 3.24, sex = 70% male) were scanned at approximately 0.5, 1-1.5, and 3+ years post-injury. Seventeen healthy, uninjured participants (mean ± SD; age = 38.91 ± 15.57 years, education = 15.11 ± 2.71 years, sex = 29% male) were scanned at baseline and approximately 11 months afterwards. Group independent component analyses and linear mixed-effects modeling with linear splines that contained a knot at 1.5 years post-injury were employed to investigate longitudinal network changes, and associations with covariates, including age, sex, and injury severity. In patients with TBI, functional connectivity in the right FPN increased from approximately 0.5 to 1.5 years post-injury (unstandardized estimate = 0.19, standard error SE = 0.07,
0.009), contained a slope change in the opposite direction, from positive to negative at 1.5 years post-injury (estimate = -0.21, SE = 0.11,
0.009), and marginally declined afterwards (estimate = -0.10, SE = 0.06,
0.079). Functional connectivity in the DMN increased from approximately 0.5 to 1.5 years (estimate = 0.15, SE = 0.05,
0.006), contained a slope change in the opposite direction, from positive to negative at 1.5 years post-injury (estimate = -0.19, SE = 0.08,
0.021), and was estimated to decline from 1.5 to 3+ years (estimate = -0.04, SE = 0.04,
0.303). Similarly, the left FPN increased in functional connectivity from approximately 0.5 to 1.5 years post-injury (estimate = 0.15, SE = 0.05,
0.002), contained a slope change in the opposite direction, from positive to negative at 1.5 years post-injury (estimate = -0.18, SE = 0.07,
0.008), and was estimated to decline thereafter (estimate = -0.04, SE = 0.03,
0.254). At approximately 0.5 years post-injury, patients showed hypoconnectivity compared with healthy, uninjured participants at baseline. Covariates were not significantly associated in any of the models. Findings of early improvement but a tapering and possible decline in connectivity thereafter suggest that compensatory effects are time-limited. These later reductions in connectivity mirror growing evidence of behavioral and structural decline in chronic moderate-to-severe TBI. Targeting such declines represents a novel avenue of research and offers potential for improving clinical outcomes.
Females show a disproportionate burden of Alzheimer's disease pathology and higher Alzheimer's disease dementia prevalences compared to males, yet the mechanisms driving these vulnerabilities are ...unknown. There is sexual dimorphism in immunological functioning, and neuroimmune processes are implicated in Alzheimer's disease genesis. Using neuropathology indicators from human brain tissue, we examined the mediational role of microglial activation on the relationship between amyloid and tau and how it differs by sex. 187 decedents (64% female; 89 mean age at death; 62% non-demented) from the Rush Memory and Aging Project completed neuropathological evaluations with brain tissue quantified for microglial activation, amyloid-β and tau. Proportion of morphologically activated microglia was determined via immunohistochemistry (HLA-DP-DQ-DR) and morphological staging (stage I, II or III). Amyloid-β and tau burden were quantified via immunohistochemistry (M00872 or AT8, respectively). Using causal counterfactual modelling, we estimated the mediational effect of microglial activation on the amyloid-β to tau relationship in the whole sample and stratified by sex (amyloid-β → microglial activation → tau). Alternative models tested the role of microglia activation as the precipitating event (microglial activation → amyloid-β → tau). Microglial activation significantly mediated 33% 95% confidence interval (CI) 10-67 of the relationship between amyloid-β and tau in the whole sample; stratified analyses suggested this effect was stronger and only statistically significant in females. 57% (95% CI 22-100) of the effect of amyloid-β on tau was mediated through microglial activation in females, compared to 19% (95% CI 0-64) in males. Regional analyses suggested that mediational effects were driven by greater cortical versus subcortical microglial activation. Relationships were independent of cerebrovascular disease indices. Alternative models suggested that in females, microglial activation was a significant exposure both preceding the amyloid-β to tau relationship (mediational effect: 50%, 95% CI 23-90) and directly related to tau burden (microglia direct effect: 50%, 95% CI 10-77). By contrast, in males, only the direct effect of microglial activation to tau reached significance (74%, 95% CI 32-100) (mediational effect: 26%, 95% CI 0-68). Our models suggest a reciprocal, bidirectional relationship between amyloid-β and microglial activation that significantly accounts for tau burden in females. By contrast, in males, direct independent (non-mediational) relationships between microglial activation or amyloid-β with tau were observed. Microglial activation may be disproportionately important for Alzheimer's disease pathogenesis in females. Determining sex-specific vulnerabilities to Alzheimer's disease development both inform fundamental pathophysiology and support precision health approaches for this heterogeneous disease.
The antihypertensive angiotensin receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACE-Is) have similar indications and mechanisms of action, but prior work suggests divergence ...in their effects on cognition.
Participants in the National Alzheimer's Coordinating Center database with a clinical diagnosis of dementia due to Alzheimer's disease (AD) using an ACE-I or an ARB at any visit were selected. The primary outcome was delayed recall memory on the Wechsler Memory Scale Revised - Logical Memory IIA. Other cognitive domains were explored, including attention and psychomotor processing speed (Trail Making Test TMT-A and Digit Symbol Substitution Test DSST), executive function (TMT-B), and language and semantic verbal fluency (Animal Naming, Vegetable Naming, and Boston Naming Tests). Random slopes mixed-effects models with inverse probability of treatment weighting were used, yielding rate ratios (RR) or regression coefficients (B), as appropriate to the distribution of the data. Apolipoprotein (APOE) ε4 status and blood-brain barrier (BBB) penetrance were investigated as effect modifiers.
Among 1689 participants with AD, ARB use (n = 578) was associated with 9.4% slower decline in delayed recall performance over a mean follow-up of 2.28 years compared with ACE-I use (n = 1111) RR = 1.094, p = 0.0327; specifically, users of BBB-crossing ARBs (RR = 1.25, p = 0.002), BBB-crossing ACE-Is (RR = 1.16, p = 0.010), and non-BBB-crossing ARBs (RR = 1.20, p = 0.005) had better delayed recall performance over time compared with non-BBB-crossing ACE-I users. An interaction with APOE ε4 status (drug × APOE × time RR = 1.196, p = 0.033) emerged; ARBs were associated with better delayed recall scores over time than ACE-Is in non-carriers (RR = 1.200, p = 0.003), but not in carriers (RR = 1.003, p = 0.957). ARB use was also associated with better performance over time on the TMT-A (B = 2.023 s, p = 0.0004) and the DSST (B = 0.573 symbols, p = 0.0485), and these differences were significant among APOE ε4 non-carriers (B = 4.066 s, p = 0.0004; and B = 0.982 symbols, p = 0.0230; respectively). Some differences were seen also in language and verbal fluency among APOE ε4 non-carriers.
Among APOE ε4 non-carriers with AD, ARB use was associated with greater preservation of memory and attention/psychomotor processing speed, particularly compared to ACE-Is that do not cross the blood-brain-barrier.
Our objective was to investigate the effect of sex on cognitive decline within the context of amyloid β (Aβ) burden and apolipoprotein E genotype.
We analyzed sex-specific effects on Aβ-positron ...emission tomography, apolipoprotein, and rates of change on the Preclinical Alzheimer Cognitive Composite-5 across three cohorts, such as the Alzheimer's Disease Neuroimaging Initiative, Australian Imaging, Biomarker and Lifestyle, and Harvard Aging Brain Study (n = 755; clinical dementia rating = 0; age (standard deviation) = 73.6 (6.5); female = 55%). Mixed-effects models of cognitive change by sex, Aβ-positron emission tomography, and apolipoprotein ε4 were examined with quadratic time effects over a median of 4 years of follow-up.
Apolipoprotein ε4 prevalence and Aβ burden did not differ by sex. Sex did not directly influence cognitive decline. Females with higher Aβ exhibited faster decline than males. Post hoc contrasts suggested that females who were Aβ and apolipoprotein ε4 positive declined faster than their male counterparts.
Although Aβ did not differ by sex, cognitive decline was greater in females with higher Aβ. Our findings suggest that sex may play a modifying role on risk of Alzheimer's disease–related cognitive decline.
Deep Brain Stimulation (DBS) has been investigated as a treatment option for patients with refractory psychiatric illness. Over the past two decades, neuroimaging developments have helped to advance ...the field, particularly the use of diffusion tensor imaging (DTI) and tractographic reconstruction of white-matter pathways. In this article, we review translational considerations and how DTI and tractography have been used to improve targeting during DBS surgery for depression, obsessive compulsive disorder (OCD) and post-traumatic stress disorder (PTSD).
Patient expectations, including both positive (placebo) and negative (nocebo) effects, influence treatment outcomes, yet their impact on acute repetitive transcranial magnetic stimulation (rTMS) for ...treatment-resistant depression (TRD) is unclear.
In this single-center retrospective chart review, 208 TRD patients completed the Stanford Expectation of Treatment Scale (SETS) before starting open-label rTMS treatment. Patients were offered two excitatory rTMS protocols (deep TMS or intermittent theta-burst stimulation), which stimulated the left dorsolateral prefrontal cortex. A minimum of 20 once daily treatments were provided, delivered over 4–6 weeks. Primary outcomes were 1) remission, measured by a post-treatment score of <8 on the Hamilton Depression Rating Scale (HAMD-17), and 2) premature discontinuation. The change in HAMD-17 scores over time was used as a secondary outcome. Physicians were blinded to SETS scores. Logistic and linear regression, adjusting for covariates, assessed SETS and HAMD-17 relationships.
Of 208 patients, 177 had baseline and covariate data available. The mean positivity bias score (positive expectancy minus negative expectancy subscale averages) was 0.48 ± 2.21, indicating the cohort was neutral regarding the expectations of their treatment on average. Higher positive expectancy scores were significantly associated with greater odds of remission (OR = 1.90, p = 0.003) and greater reduction in HAMD-17 scores (β = 1.30, p = 0.005) at the end of acute treatment, after adjusting for covariates. Negative expectancy was not associated with decreased odds of remission (p = 0.2) or treatment discontinuation (p = 0.8).
Higher pre-treatment positive expectations were associated with greater remission rates with open-label rTMS in a naturalistic cohort of patients with TRD.
•Positive pre-treatment expectancy boosts remission odds in Treatment-Resistant Depression (TRD) after acute rTMS.•Negative pre-treatment expectancy did not impact treatment discontinuation or lower remission odds following rTMS.•Understanding the impact of expectations on rTMS for TRD may help shape trial design and treatment outcomes.
Introduction
The apolipoprotein E (APOE) genotype is a driver of cognitive decline and dementia. We used causal mediation methods to characterize pathways linking the APOE genotype to late‐life ...cognition through Alzheimer's disease (AD) and non‐AD neuropathologies.
Methods
We analyzed autopsy data from 1671 individuals from the Religious Orders Study, Memory and Aging Project, and Minority Aging Research Study (ROS/MAP/MARS) studies with cognitive assessment within 5 years of death and autopsy measures of AD (amyloid beta (Aβ), neurofibrillary tangles), vascular (athero/arteriolo‐sclerosis, micro‐infarcts/macro‐infarcts), and non‐AD neurodegenerative neuropathologies (TAR DNA protein 43 TDP‐43, Lewy bodies, amyloid angiopathy, hippocampal sclerosis).
Results
The detrimental effect of APOE ε4 on cognition was mediated by summary measures of AD and non‐AD neurodegenerative neuropathologies but not vascular neuropathologies; effects were strongest in individuals with dementia. The protective effect of APOE ε2 was partly mediated by AD neuropathology and stronger in women than in men.
Discussion
The APOE genotype influences cognition and dementia through multiple neuropathological pathways, with implications for different therapeutic strategies targeting people at increased risk for dementia.
Highlights
Both apolipoprotein E (APOE) ε2 and APOE ε4 effects on late‐life cognition are mediated by AD neuropathology.
The estimated mediated effects of most measures of AD neuropathology were similar.
Non–Alzheimer's disease (AD) neurodegenerative pathologies mediate the effect of ε4 independently from AD.
Non‐AD vascular pathologies did not mediate the effect of the APOE genotype on cognition.
The protective effect of APOE ε2 on cognition was stronger in women.
Abstract
The blood–brain barrier (BBB) protects the brain but is also an important obstacle for the effective delivery of therapeutics in Alzheimer’s disease and other neurodegenerative disorders. ...Transcranial magnetic resonance-guided focused ultrasound (MRgFUS) has been shown to reversibly disrupt the BBB. However, treatment of diffuse regions across the brain along with the effect on Alzheimer’s disease relevant pathology need to be better characterized. This study is an open-labelled single-arm trial (NCT03739905) to investigate the feasibility of modulating BBB permeability in the default mode network and the impact on cognition, amyloid and tau pathology as well as BBB integrity. Nine participants mean age 70.2 ± 7.2 years, mean Mini-Mental State Examination (MMSE) 21.9 underwent three biweekly procedures with follow-up visits up to 6 months. The BBB permeability of the bilateral hippocampi, anterior cingulate cortex and precuneus was transiently increased without grade 3 or higher adverse events. Participants did not experience worsening trajectory of cognitive decline (ADAS-cog11, MMSE). Whole brain vertex-based analysis of the 18F-florbetaben PET imaging demonstrated clusters of modest SUVR reduction in the right parahippocampal and inferior temporal lobe. However, CSF and blood biomarkers did not demonstrate any amelioration of Alzheimer’s disease pathology (P-tau181, amyloid-β42/40 ratio), nor did it show persistent BBB dysfunction (plasma PDGFRbeta and CSF-to-plasma albumin ratio). This study provides neuroimaging and fluid biomarker data to characterize the safety profile of MRgFUS BBB modulation in neurodegeneration as a potential strategy for enhanced therapeutic delivery.
In an open-label single-arm trial, Meng et al. investigate the feasibility and tolerability of opening the blood–brain barrier in the default mode network with MR-guided focused ultrasound in patients with Alzheimer’s disease. The study intervention led to local amyloid reduction on PET imaging, but no change in disease-specific markers in plasma or CSF.
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