Alterations in cerebral blood flow (CBF) are associated with risk of cognitive decline and Alzheimer’s disease (AD). Although apolipoprotein E (APOE) ε4 and greater vascular risk burden have both been linked to reduced CBF in older adults, less is known about how APOE ε4 status and vascular risk may interact to influence CBF. We aimed to determine whether the effect of vascular risk on CBF varies by gene dose of APOE ε4 alleles (i.e., number of e4 alleles) in older adults without dementia.

144 older adults without dementia from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) underwent arterial spin labeling (ASL) and T1-weighted MRI, APOE genotyping, fluorodeoxyglucose positron emission tomography (FDG-PET), lumbar puncture, and blood pressure assessment. Vascular risk was assessed using pulse pressure (systolic blood pressure -diastolic blood pressure), which is thought to be a proxy for arterial stiffening. Participants were classified by number of APOE ε4 alleles (n0 alleles = 87, m allele = 46, n2 alleles = 11). CBF in six FreeSurfer-derived a priori regions of interest (ROIs) vulnerable to AD were examined: entorhinal cortex, hippocampus, inferior temporal cortex, inferior parietal cortex, rostral middle frontal gyrus, and medial orbitofrontal cortex. Linear regression models tested the interaction between categorical APOE ε4 dose (0, 1, or 2 alleles) and continuous pulse pressure on CBF in each ROI, adjusting for age, sex, cognitive diagnosis (cognitively unimpaired vs. mild cognitive impairment), antihypertensive medication use, cerebral metabolism (FDG-PET composite), reference CBF region (precentral gyrus), and AD biomarker positivity defined using the ADNI-optimized phosphorylated tau/ß-amyloid ratio cut-off of > 0.0251 pg/ml.

A significant pulse pressure X APOE ε4 dose interaction was found on CBF in the entorhinal cortex, hippocampus, and inferior parietal cortex (ps < .005). Among participants with two e4 alleles, higher pulse pressure was significantly associated with lower CBF (ps < .001). However, among participants with zero or one ε4 allele, there was no significant association between pulse pressure and CBF (ps > .234). No significant pulse pressure X APOE ε4 dose interaction was found in the inferior temporal cortex, rostral middle frontal gyrus, or medial orbitofrontal cortex (ps > .109). Results remained unchanged when additionally controlling for general vascular risk assessed via the modified Hachinski Ischemic Scale.

These findings demonstrate that the cross-sectional association between pulse pressure and region-specific CBF differs by APOE ε4 dose. In particular, a detrimental effect of elevated pulse pressure on CBF in AD-vulnerable regions was found only among participants with the e4/e4 genotype. Our findings suggest that pulse pressure may play a mechanistic role in neurovascular unit dysregulation for those genetically at greater risk for AD. Given that pulse pressure is just one of many potentially modifiable vascular risk factors for AD, future studies should seek to examine how these other factors (e.g., diabetes, high cholesterol) may interact with APOE genotype to affect cerebrovascular dysfunction.

Higher educational attainment is associated with reduced risk for Alzheimer's disease (AD) dementia, and its protective effect may act through alterations in cerebral blood flow (CBF) that allow for better coping with accumulating neuropathology. Additionally, there are sex differences in both the risk of developing AD as well as the potential protective effects of education. We therefore sought to investigate whether education moderates the association of hippocampal CBF and memory in cognitively unimpaired older adults, and to examine if these interactions were moderated by sex.

Cognitively unimpaired older adults from the Alzheimer's Disease Neuroimaging Initiative (ADNI; 51 men, 50 women) underwent neuropsychological evaluation and arterial spin labeling MRI, which was used to quantify bilateral hippocampal CBF. Sex was defined as sex at birth. Multiple linear regressions assessed (1) the independent associations among education, CBF, and memory performance separately in men and women and (2) the three-way interactions among CBF, sex, and education, followed by sex-stratified analyses. Three outcome measures were examined: Logical Memory Story A immediate and delayed recall, and Rey Auditory Verbal Learning Test (RAVLT) intrusions. All models adjusted for age and APOE epsilon-4 allele frequency, and all models with CBF additionally adjusted for cerebral metabolism (baseline FDG-PET composite) and pulse pressure.

CBF was not associated with education or memory in either women or men. There was a positive association between education and delayed memory in women (ß=0.14, t=2.64, p=0.008) as well as trending, positive associations between education and immediate memory in women (ß=0.09, t=1.79, p=0.074) and education and delayed memory in men (ß=0.09, t=1.94, p=0.054). Three-way interactions among sex, CBF, and education were significant on immediate recall (ß=2.55, t=2.53, p=0.013), delayed recall (ß=2.56, t=2.44, p=0.017), and RAVLT intrusions (ß=-2.28, t=-2.27, p=0.026). In women, there were interactions between education and hippocampal CBF on both immediate (ß=2.49, t=2.90, p=0.006) and delayed recall (ß=2.30, t=2.78, p=0.009), such that as education increased, the strength of the association between CBF and immediate memory increased. There was also an interaction between education and hippocampal CBF on RAVLT intrusions in women (ß=-2.42, t=-3.05, p=0.004), such that as education increased, the strength of the association between CBF and number of intrusions decreased; there was a main effect where in women with lower education, as CBF increased, the number of intrusions increased (ß=0.76, t=2.59, p=0.032); in women with higher education, there was no association between CBF and intrusions. In men, none of these two-way interactions were significant.

These results suggest that, in cognitively unimpaired older women, the relationship between hippocampal CBF and memory is moderated by education level, even when adjusting for several other factors. Specifically, higher education may serve as a protective factor in the hippocampal CBF-memory relationship, and this relationship was sex-dependent, occurring in women only. Further research is needed to examine these relationships longitudinally across the clinical continuum of AD. Additionally, this work needs to be conducted in more diverse samples to allow for analyses investigating the impact of education on the intersection of race/ethnicity and sex/gender.

Persistent brain fog is common in adults with Post-Acute Sequelae of SARS-CoV-2 infection (PASC), in whom it causes distress and in many cases interferes with performance of instrumental activities of daily living (IADL) and return-to-work. There are no interventions with rigorous evidence of efficacy for this new, often disabling condition. The purpose of this pilot is to evaluate the efficacy, on a preliminary basis, of a new intervention for this condition termed Constraint-Induced Cognitive therapy (CICT). CICT combines features of two established therapeutic approaches: cognitive speed of processing training (SOPT) developed by the laboratory of K. Ball and the Transfer Package and task-oriented training components of Constraint-Induced Movement therapy developed by the laboratory of E. Taub and G. Uswatte.

Participants were > 3 months after recovery from acute COVID symptoms and had substantial brain fog and impairment in IADL. Participants were randomized to CICT immediately or after a 3-month delay. CICT involved 36 hours of outpatient therapy distributed over 4-6 weeks. Sessions had three components: (a) videogamelike training designed to improve how quickly participants process sensory input (SOPT), (b) training on IADLs following shaping principles, and (c) a set of behavioral techniques designed to transfer gains from the treatment setting to daily life, i.e., the Transfer Package. The Transfer Package included (a) negotiating a behavioral contract with participants and one or more family members about the responsibilities of the participants, family members, and treatment team; (b) assigning homework during and after the treatment period; (c) monitoring participants’ out-of-session behavior; (d) supporting problem-solving by participants and family members about barriers to performance of IADL; and (e) making follow-up phone calls. IADL performance, brain fog severity, and cognitive impairment were assessed using validated, trans-diagnostic measures before and after treatment and three months afterwards in the immediate-CICT group and on parallel occasions in the delayed-CICT group (aka waitlist controls).

To date, five were enrolled in the immediate-CICT group; four were enrolled in the wait-list group. All had mild cognitive impairment, except for one with moderate impairment in the immediate-CICT group. Immediate-CICT participants, on average, had large reductions in brain fog severity on the Mental Clutter Scale (MCS, range = 0 to 10 points, mean change = -3.7, SD = 2.0); wait-list participants had small increases (mean change = 1.0, SD = 1.4). Notably, all five in the immediate-CICT group had clinically meaningful improvements (i.e., changes > 2 points) in performance of IADL outside the treatment setting as measured by the Canadian Occupational Performance Measure (COPM) Performance scale; only one did in the wait-list group. The advantage for the immediate-CICT group was very large on both the MCS and COPM (d’s = 1.7, p’s < .05). In follow-up, immediate-CICT group gains were retained or built-upon.

These preliminary findings warrant confirmation by a large-scale randomized controlled trial. To date, CICT shows high promise as an efficacious therapy for brain fog due to PASC. CICT participants had large, meaningful improvements in IADL performance outside the treatment setting, in addition to large reductions in brain fog severity.

CI Cognitive Therapy (CICT) is a combination of behavioral techniques derived from CI Movement Therapy (CIMT) modified to apply to the cognitive domain, and Speed of (Cognitive) Processing Training (SOPT). SOPT is effective in improving cognitive function in the treatment setting and driving ability in everyday situations. The data concerning the effect of SOPT on other cognition-based instrumental activities of daily living (IADL) in everyday situations is incomplete. The strengths of CIMT, based on its Transfer Package (TP), are to facilitate 1) transfer of improved function from the treatment setting to IADL in everyday settings, and 2) long-term retention of the improved performance of IADL. This study sought to determine in a preliminary case series whether the TP of CI Movement Therapy combined with SOPT would have the same effect on a wide range of impaired cognition-based ADL.

Participants were 6 adults with chronic stroke: mean chronicity = 36.2 months, (range, 16-56 months); mean age = 59.7 years, (range, 47-55); 1 female; 3 African American and 3 European American. Five had mild cognitive impairment, while one had moderate impairment. Participants received 35 hours of outpatient treatment in 10-15 sessions distributed over 2-6 weeks, depending on the participants’ availability. Sessions began with 1 hour of SOPT training followed by training of cognition-based ADL by the process of shaping, a common method in the behavior analysis field. Other behavior analysis methods employed in the TP of CI Movement Therapy were used, including: 1) behavior contracting, daily assignment of homework, participation of a family member in the training and monitoring process, daily administration of a structured interview assessing amount and quality of performance of 30 IADL, problem solving to overcome perceived (or real) barriers to performance of IADL. Participants were given daily homework assignments in follow-up and were contacted in periodic, pre-arranged phone calls to determine status, compliance and problem-solve.

All six participants showed marked improvement on the SOPT test similar to that in the Ball et al studies. However, here transfer to IADL outside the treatment setting was substantial. On the main real-world outcome, the Canadian Occupational Performance Measure (COPM), there were increases of 2.7±1.3 and 2.1±1.6 on the two scales (d’s = 1.9 & 1.3, respectively). (Changes on the COPM > 2 points are considered clinically meaningful and changes in d’ >.8 are considered large). On two other real-word measures, the Cognitive Task Activity Log (CTAL) and inventory of Improved and New Cognitive Activities (INCA), there was a marked increase during the acquisition phase of training. There was no loss in retention over the 6-16 months (mean = 12.2) of follow-up to date. Instead, the INCA showed strong further improvement after the end of treatment-setting training, especially in the New Activities Not Performed Since Before Stroke Onset category, going from a mean of 8.2 after training to 14.6 at the end of follow-up.

These very preliminary results suggest that CICT may be an efficacious therapy for mild to moderate cognitive impairment in chronic stroke and possibly other disorders.

We identify a set of essential recent advances in climate change research with high policy relevance, across natural and social sciences: (1) looming inevitability and implications of overshooting the 1.5°C warming limit, (2) urgent need for a rapid and managed fossil fuel phase-out, (3) challenges for scaling carbon dioxide removal, (4) uncertainties regarding the future contribution of natural carbon sinks, (5) intertwinedness of the crises of biodiversity loss and climate change, (6) compound events, (7) mountain glacier loss, (8) human immobility in the face of climate risks, (9) adaptation justice, and (10) just transitions in food systems.

The Intergovernmental Panel on Climate Change Assessment Reports provides the scientific foundation for international climate negotiations and constitutes an unmatched resource for researchers. However, the assessment cycles take multiple years. As a contribution to cross- and interdisciplinary understanding of climate change across diverse research communities, we have streamlined an annual process to identify and synthesize significant research advances. We collected input from experts on various fields using an online questionnaire and prioritized a set of 10 key research insights with high policy relevance. This year, we focus on: (1) the looming overshoot of the 1.5°C warming limit, (2) the urgency of fossil fuel phase-out, (3) challenges to scale-up carbon dioxide removal, (4) uncertainties regarding future natural carbon sinks, (5) the need for joint governance of biodiversity loss and climate change, (6) advances in understanding compound events, (7) accelerated mountain glacier loss, (8) human immobility amidst climate risks, (9) adaptation justice, and (10) just transitions in food systems. We present a succinct account of these insights, reflect on their policy implications, and offer an integrated set of policy-relevant messages. This science synthesis and science communication effort is also the basis for a policy report contributing to elevate climate science every year in time for the United Nations Climate Change Conference.

We highlight recent and policy-relevant advances in climate change research – with input from more than 200 experts.

Multiple sclerosis (MS) is a debilitating neurological disease associated with a variety of psychological, cognitive, and motoric symptoms. Walking is among the most important functions compromised by MS. Dual-task walking (DTW), an everyday activity in which people walk and engage in a concurrent, discrete task, has been assessed in MS, but little is known about how it relates to other MS symptoms. Self-awareness theory suggests that DTW may be a function of the interactions among psychological, cognitive, and motor processes.

Cognitive testing, self-report assessments for depression and falls self-efficacy (FSE), and walk evaluations [DTW and single-task walk (STW)] were assessed in seventy-three people with MS in a clinical care setting. Specifically, we assessed whether psychological factors (depression and FSE) that alter subjective evaluations regarding one’s abilities would moderate the relationships between physical and cognitive abilities and DTW performance.

DTW speed is related to diverse physical and cognitive predictors. In support of self-awareness theory, FSE moderated the relationship between STW and DTW speeds such that lower FSE attenuated the strength of the relationship between them. DTW costs – the change in speed normalized by STW speed – did not relate to cognitive and motor predictors. DTW costs did relate to depressive symptoms, and depressive symptoms moderated the effect of information processing on DTW costs.

Findings indicate that an interplay of physical ability and psychological factors – like depression and FSE – may enhance understanding of walking performance under complex, real-world, DTW contexts.

Patients with functional neurological disorders (FND) often present with multiple motor, sensory, psychological and cognitive symptoms. In order to explore the relationship between these common symptoms, we performed a detailed clinical assessment of motor, non-motor symptoms, health-related quality of life (HRQoL) and disability in a large cohort of patients with motor FND. To understand the clinical heterogeneity, cluster analysis was used to search for subgroups within the cohort.

One hundred fifty-two patients with a clinically established diagnosis of motor FND were assessed for motor symptom severity using the Simplified Functional Movement Disorder Rating Scale (S-FMDRS), the number of different motor phenotypes (i.e. tremor, dystonia, gait disorder, myoclonus, and weakness), gait severity and postural instability. All patients then evaluated each motor symptom type severity on a Likert scale and completed questionnaires for depression, anxiety, pain, fatigue, cognitive complaints and HRQoL.

Significant correlations were found among the self-reported and all objective motor symptoms severity measures. All self-reported measures including HRQoL correlated strongly with each other. S-FMDRS weakly correlated with HRQoL. Hierarchical cluster analysis supplemented with gap statistics revealed a homogenous patient sample which could not be separated into subgroups.

We interpret the lack of evidence of clusters along with a high degree of correlation between all self-reported and objective measures of motor or non-motor symptoms and HRQoL within current neurobiological models as evidence to support a unified pathophysiology of ‘functional’ symptoms. Our results support the unification of functional and somatic syndromes in classification schemes and for future mechanistic and therapeutic research.