Promoting Growth in Behavioral Neurology: A Path Forward.

Behavioral neurology & neuropsychiatry (BNNP) is a field that seeks to understand brain-behavior relationships, including fundamental brain organization principles and the many ways that brain structures and connectivity can be disrupted, leading to abnormalities of behavior, cognition, emotion, perception, and social cognition. In North America, BNNP has existed as an integrated subspecialty through the United Council for Neurologic Subspecialties since 2006. Nonetheless, the number of behavioral neurologists across academic medical centers and community settings is not keeping pace with increasing clinical and research demand. In this commentary, we provide a brief history of BNNP followed by an outline of the current challenges and opportunities for BNNP from the behavioral neurologist's perspective across clinical, research, and educational spheres. We provide a practical guide for promoting BNNP and addressing the shortage of behavioral neurologists to facilitate the continued growth and development of the subspecialty. We also urge a greater commitment to recruit trainees from diverse backgrounds so as to dismantle persistent obstacles that hinder inclusivity in BNNP-efforts that will further enhance the growth and impact of the subspecialty. With rapidly expanding diagnostic and therapeutic approaches across a range of conditions at the intersection of neurology and psychiatry, BNNP is well positioned to attract new trainees and expand its reach across clinical, research, and educational activities.

Advancing mental imagery research from an interdisciplinary sport science perspective: a commentary on Frank et al. (2023).

Frank et al.'s (2023) perceptual-cognitive scaffold meaningfully extends the cognitive action architecture approach and we support this interdisciplinary advancement. However, there are theoretical and applied aspects that could be further developed within this research to maximise practical impact across domains such as sport. In particular, there is a need to consider how these mechanisms (1) might critically inform or relate to other prominent theories within sport (e.g., constrained action hypothesis and ecological approaches) and, (2) reflect the real-world challenges experienced by athletes. With these ideas in mind, this commentary aims to stimulate discussion and enhance the translational application of Frank et al.'s research.

Attentional Focus Effects on Lower-Limb Muscular Strength in Athletes: A Systematic Review.

ABSTRACT: Pompa, D, Carson, HJ, Beato, M, di Fronso, S, and Bertollo, M. Attentional focus effects on lower-limb muscular strength in athletes: A systematic review. J Strength Cond Res 38(2): 419-434, 2024-Evidence links an athlete's focus of attention to enhancing strength performance. However, additional research is needed to investigate the applicability of studies beyond the tasks and population currently examined. Therefore, we aimed to systematically review studies concerning attentional focus effects on strength characteristics on lower-limb tasks in athletes. Scopus, Web of Science, and EBSCO databases were searched using PRISMA PERSIST guidelines and keywords related to the focus of attention, force production processes, and athletes. Subjects were categorized: world class (tier 5); elite (tier 4); highly trained (tier 3); trained/developmental (tier 2); nonathletes (tiers 1-0); and mixed (different levels). Fifteen of 296 studies met the inclusion criteria. Included studies investigated the focus of attention effects on performance ( n = 6), between skill levels ( n = 2), and for learning ( n = 5), with respect to subject preference ( n = 1); one study did not state the aim. Studies achieved an average risk of bias score of "excellent"; however, findings suffered in the assessment of certainty. Only 2 studies reported an advantage for one type of attentional focus (external focus) across conditions ( g = 0.13-0.42) with tier 2 and mixed tier athletes. Research does not address the needs of elite athletes, and there is limited evidence on each type of strength characteristics and muscle action. There is also a need to incorporate methodological steps to promote task-relevant instructions. Research should focus on contextualized information within professional practice to offer stronger translational implications for athletes and coaches.

When a bad day at the golf course is a bad day at the office: occupational stressors, institutional supports, and the mental health of NCAA golf coaches.

This study examined the mental health of NCAA collegiate golf coaches. Utilizing the person-environment fit theory and previous literature on coaches' well-being, this study examined four outcomes among 48 participants, namely: depressive and anxiety symptoms, burnout, and job turnover intentions. Results suggested that coaching stressors (e.g., administrative tasks, practice plans, pressure to win) only associate with greater burnout. More consistent evidence showed that workplace stress (e.g., lack of control and autonomy, poor work-family balance) associated with higher levels of all outcomes. Finally, greater perceived organizational support had a beneficial association with each outcome. The findings of the current study suggest golf coaches are at risk of mental health problems because of the stressors of this job. Taken as a whole, athletic departments, coaches, and student-athletes must reconsider norms that overemphasize performance and underemphasize self-care and work-life balance.

What differences exist between the lead and trail wrist in extensor carpi ulnaris activity and golf swing joint kinematics in sub-elite golfers?

This study assessed the lead and trail arm peak and average extensor carpi ulnaris (ECU) muscle activity in association with tri-planar angular velocities of the lead and trail wrists during the golf swing. Fifteen sub-elite, male right-handed golfers (Mage = 34.7 years ±13.3, Mhandicap = 1.5 ± 2.2) were recruited to execute five shots each with their pitching wedge, 7-iron and driver clubs in an indoor golf simulator. Surface electromyography (EMG) sensors were placed over the ECU muscle belly and inertial measurement unit sensors were placed bi-laterally on the distal forearm and dorsum of the hand. There was a statistically greater recruitment of the trail ECU muscle during the downswing (p < 0.001) for all clubs. The lead ECU muscle was recruited more during the backswing (p < 0.001) and follow through (p < 0.024) phases. There were statistically different tri-planar movement patterns between the lead and trail wrist throughout all three phases of the golf swing. No significant relationships were found between downswing EMG data and clubhead kinematics at impact. In conclusion, differing wrist kinematics and associated muscle activity may contribute to the asymmetrical injury pattern seen clinically.

[18F]PI-2620 Binding Patterns in Patients with Suspected Alzheimer Disease and Frontotemporal Lobar Degeneration.

Tau PET has enabled the visualization of paired helical filaments of 3 or 4 C-terminal repeat tau in Alzheimer disease (AD), but its ability to detect aggregated tau in frontotemporal lobar degeneration (FTLD) spectrum disorders is uncertain. We investigated 2-(2-([18F]fluoro)pyridin-4-yl)-9H-pyrrolo[2,3-b:4,5c']dipyridine ([18F]PI-2620), a newer tracer with ex vivo evidence for binding to FTLD tau, in a convenience sample of patients with suspected FTLD and AD using a static acquisition protocol and parametric SUV ratio (SUVr) images. Methods: We analyzed [18F]PI-2620 PET data from 65 patients with clinical diagnoses associated with AD or FTLD neuropathology; most (60/65) also had amyloid-ß (Aß) PET. Scans were acquired 30-60 min after injection; SUVr maps (reference, inferior cerebellar cortex) were created for the full acquisition and for 10-min truncated sliding windows (30-40, 35-45,…50-60 min). Age- and sex-adjusted z score maps were computed for each patient, relative to 23 Aß-negative cognitively healthy controls (HC). Mean SUVr in the globus pallidus, substantia nigra, subthalamic nuclei, dentate nuclei, white matter, and temporal gray matter was extracted for the full and truncated windows. Results: Patients with suspected AD neuropathology (Aß-positive patients with mild cognitive impairment or AD dementia) showed high-intensity temporoparietal cortex-predominant [18F]PI-2620 binding. At the group level, patients with clinical diagnoses associated with FTLD (progressive supranuclear palsy with Richardson syndrome [PSP Richardson syndrome], corticobasal syndrome, and nonfluent-variant primary progressive aphasia) exhibited higher globus pallidus SUVr than did HCs; pallidal retention was highest in the PSP Richardson syndrome group, in whom SUVr was correlated with symptom severity (ρ = 0.53, P = 0.05). At the individual level, only half of PSP Richardson syndrome, corticobasal syndrome, and nonfluent-variant primary progressive aphasia patients had a pallidal SUVr above that of HCs. Temporal SUVr discriminated AD patients from HCs with high accuracy (area under the receiver operating characteristic curve, 0.94 [95% CI, 0.83-1.00]) for all time windows, whereas discrimination between patients with PSP Richardson syndrome and HCs using pallidal SUVr was fair regardless of time window (area under the receiver operating characteristic curve, 0.77 [95% CI, 0.61-0.92] at 30-40 min vs. 0.81 [95% CI, 0.66-0.96] at 50-60 min; P = 0.67). Conclusion: [18F]PI-2620 SUVr shows an intense and consistent signal in AD but lower-intensity, heterogeneous, and rapidly decreasing binding in patients with suspected FTLD. Further work is needed to delineate the substrate of [18F]PI-2620 binding and the usefulness of [18F]PI2620 SUVr quantification outside the AD continuum.

Head-to-head comparison between plasma p-tau217 and flortaucipir-PET in amyloid-positive patients with cognitive impairment.

BACKGROUND: Plasma phosphorylated tau (p-tau) has emerged as a promising biomarker for Alzheimer's disease (AD). Studies have reported strong associations between p-tau and tau-PET that are mainly driven by differences between amyloid-positive and amyloid-negative patients. However, the relationship between p-tau and tau-PET is less characterized within cognitively impaired patients with a biomarker-supported diagnosis of AD. We conducted a head-to-head comparison between plasma p-tau217 and tau-PET in patients at the clinical stage of AD and further assessed their relationships with demographic, clinical, and biomarker variables. METHODS: We retrospectively included 87 amyloid-positive patients diagnosed with MCI or dementia due to AD who underwent structural MRI, amyloid-PET (11C-PIB), tau-PET (18F-flortaucipir, FTP), and blood draw assessments within 1 year (age = 66 ± 10, 48% female). Amyloid-PET was quantified in Centiloids (CL) while cortical tau-PET binding was measured using standardized uptake value ratios (SUVRs) referenced against inferior cerebellar cortex. Plasma p-tau217 concentrations were measured using an electrochemiluminescence-based assay on the Meso Scale Discovery platform. MRI-derived cortical volume was quantified with FreeSurfer. Mini-Mental State Examination (MMSE) scores were available at baseline (n = 85) and follow-up visits (n = 28; 1.5 ± 0.7 years). RESULTS: Plasma p-tau217 and cortical FTP-SUVR were correlated (r = 0.61, p < .001), especially in temporo-parietal and dorsolateral frontal cortices. Both higher p-tau217 and FTP-SUVR values were associated with younger age, female sex, and lower cortical volume, but not with APOE-ε4 carriership. PIB-PET Centiloids were weakly correlated with FTP-SUVR (r = 0.26, p = 0.02), but not with p-tau217 (r = 0.10, p = 0.36). Regional PET-plasma associations varied with amyloid burden, with p-tau217 being more strongly associated with tau-PET in temporal cortex among patients with moderate amyloid-PET burden, and with tau-PET in primary cortices among patients with high amyloid-PET burden. Higher p-tau217 and FTP-SUVR values were independently associated with lower MMSE scores cross-sectionally, while only baseline FTP-SUVR predicted longitudinal MMSE decline when both biomarkers were included in the same model. CONCLUSION: Plasma p-tau217 and tau-PET are strongly correlated in amyloid-PET-positive patients with MCI or dementia due to AD, and they exhibited comparable patterns of associations with demographic variables and with markers of downstream neurodegeneration.

Social Cognition and Other Determinants of Perceived Social Support in Individuals With Serious Mental Illness.

ABSTRACT: Social support provides protective effects for those with serious mental illness (SMI), but these effects may be attenuated by factors that hinder positive perceptions of support. Improved understanding of social support and its determinants may hold relevance for clinical interventions and provide avenues to promote recovery and improve functioning. The present study is a cross-sectional, correlational analysis investigating the relationships among social cognition (Mayer-Salovey-Caruso Emotional Intelligence Test-Managing Emotions subscale), social anxiety (Liebowitz Social Anxiety Scale), negative symptoms (Scale for the Assessment of Negative Symptoms), and perceived social support (Interpersonal Support Evaluation List) among individuals with SMI. Data were analyzed for 59 participants from a psychosocial rehabilitation treatment study at a public, urban academic-affiliated medical center in the Midwest. Bivariate Pearson correlations revealed statistically significant associations among perceived social support and social cognition (total perceived social support, p < 0.05; appraisal support, p < 0.01), negative symptoms (appraisal support, p < 0.05), and social anxiety (self-esteem support, p < 0.05). Further, multiple linear regression revealed social cognition remained a significant predictor of perceived social support ( p < 0.05) when controlling for social anxiety and negative symptoms. Overall findings suggest a correlative relationship between social cognition and perceived social support. Conclusions, limitations, and future directions are discussed.

Evaluation of Plasma Phosphorylated Tau217 for Differentiation Between Alzheimer Disease and Frontotemporal Lobar Degeneration Subtypes Among Patients With Corticobasal Syndrome.

Importance: Plasma phosphorylated tau217 (p-tau217), a biomarker of Alzheimer disease (AD), is of special interest in corticobasal syndrome (CBS) because autopsy studies have revealed AD is the driving neuropathology in up to 40% of cases. This differentiates CBS from other 4-repeat tauopathy (4RT)-associated syndromes, such as progressive supranuclear palsy Richardson syndrome (PSP-RS) and nonfluent primary progressive aphasia (nfvPPA), where underlying frontotemporal lobar degeneration (FTLD) is typically the primary neuropathology. Objective: To validate plasma p-tau217 against positron emission tomography (PET) in 4RT-associated syndromes, especially CBS. Design, Setting, and Participants: This multicohort study with 6, 12, and 24-month follow-up recruited adult participants between January 2011 and September 2020 from 8 tertiary care centers in the 4RT Neuroimaging Initiative (4RTNI). All participants with CBS (n = 113), PSP-RS (n = 121), and nfvPPA (n = 39) were included; other diagnoses were excluded due to rarity (n = 29). Individuals with PET-confirmed AD (n = 54) and PET-negative cognitively normal control individuals (n = 59) were evaluated at University of California San Francisco. Operators were blinded to the cohort. Main Outcome and Measures: Plasma p-tau217, measured by Meso Scale Discovery electrochemiluminescence, was validated against amyloid-ß (Aß) and flortaucipir (FTP) PET. Imaging analyses used voxel-based morphometry and bayesian linear mixed-effects modeling. Clinical biomarker associations were evaluated using longitudinal mixed-effect modeling. Results: Of 386 participants, 199 (52%) were female, and the mean (SD) age was 68 (8) years. Plasma p-tau217 was elevated in patients with CBS with positive Aß PET results (mean [SD], 0.57 [0.43] pg/mL) or FTP PET (mean [SD], 0.75 [0.30] pg/mL) to concentrations comparable to control individuals with AD (mean [SD], 0.72 [0.37]), whereas PSP-RS and nfvPPA showed no increase relative to control. Within CBS, p-tau217 had excellent diagnostic performance with area under the receiver operating characteristic curve (AUC) for Aß PET of 0.87 (95% CI, 0.76-0.98; P < .001) and FTP PET of 0.93 (95% CI, 0.83-1.00; P < .001). At baseline, individuals with CBS-AD (n = 12), defined by a PET-validated plasma p-tau217 cutoff 0.25 pg/mL or greater, had increased temporoparietal atrophy at baseline compared to individuals with CBS-FTLD (n = 39), whereas longitudinally, individuals with CBS-FTLD had faster brainstem atrophy rates. Individuals with CBS-FTLD also progressed more rapidly on a modified version of the PSP Rating Scale than those with CBS-AD (mean [SD], 3.5 [0.5] vs 0.8 [0.8] points/year; P = .005). Conclusions and Relevance: In this cohort study, plasma p-tau217 had excellent diagnostic performance for identifying Aß or FTP PET positivity within CBS with likely underlying AD pathology. Plasma P-tau217 may be a useful and inexpensive biomarker to select patients for CBS clinical trials.

Plasma inflammation for predicting phenotypic conversion and clinical progression of autosomal dominant frontotemporal lobar degeneration.

BACKGROUND: Measuring systemic inflammatory markers may improve clinical prognosis and help identify targetable pathways for treatment in patients with autosomal dominant forms of frontotemporal lobar degeneration (FTLD). METHODS: We measured plasma concentrations of IL-6, TNFα and YKL-40 in pathogenic variant carriers (MAPT, C9orf72, GRN) and non-carrier family members enrolled in the ARTFL-LEFFTDS Longitudinal Frontotemporal Lobar Degeneration consortium. We evaluated associations between baseline plasma inflammation and rate of clinical and neuroimaging changes (linear mixed effects models with standardised (z) outcomes). We compared inflammation between asymptomatic carriers who remained clinically normal ('asymptomatic non-converters') and those who became symptomatic ('asymptomatic converters') using area under the curve analyses. Discrimination accuracy was compared with that of plasma neurofilament light chain (NfL). RESULTS: We studied 394 participants (non-carriers=143, C9orf72=117, GRN=62, MAPT=72). In MAPT, higher TNFα was associated with faster functional decline (B=0.12 (0.02, 0.22), p=0.02) and temporal lobe atrophy. In C9orf72, higher TNFα was associated with faster functional decline (B=0.09 (0.03, 0.16), p=0.006) and cognitive decline (B=-0.16 (-0.22, -0.10), p<0.001), while higher IL-6 was associated with faster functional decline (B=0.12 (0.03, 0.21), p=0.01). TNFα was higher in asymptomatic converters than non-converters (ß=0.29 (0.09, 0.48), p=0.004) and improved discriminability compared with plasma NfL alone (ΔR2=0.16, p=0.007; NfL: OR=1.4 (1.03, 1.9), p=0.03; TNFα: OR=7.7 (1.7, 31.7), p=0.007). CONCLUSIONS: Systemic proinflammatory protein measurement, particularly TNFα, may improve clinical prognosis in autosomal dominant FTLD pathogenic variant carriers who are not yet exhibiting severe impairment. Integrating TNFα with markers of neuronal dysfunction like NfL could optimise detection of impending symptom conversion in asymptomatic pathogenic variant carriers and may help personalise therapeutic approaches.

Therapeutic alliance in a cognitive rehabilitation programme for people with serious mental illness: A qualitative analysis.

OBJECTIVE: Therapeutic alliance is an important element of evidence-based treatments for people diagnosed with a serious mental illness. Cognitive enhancement therapy (CET) is an efficacious cognitive rehabilitation programme that emphasizes coach-participant relationships. The purpose of this study was to examine experiences of therapeutic alliance among CET participants. DESIGN: We used an exploratory qualitative approach. METHODS: Semi-structured interviews were conducted with 24 participants diagnosed with a serious mental illness. Interview transcripts were analysed by three independent coders using thematic analysis. RESULTS: Four themes related to therapeutic alliance emerged: (1) positive regard; (2) collaboration; (3) authenticity; (4) negative alliance. CONCLUSIONS: Findings suggest that therapeutic alliance is an important component of CET that bolsters the learning environment and ensures a positive group experience. Our qualitative analyses contribute greater understanding of how strong therapeutic relationships impact people with serious mental illnesses participating in evidence-based treatments beyond psychotherapy context.

Show Me, Tell Me: An Investigation Into Learning Processes Within Skateboarding as an Informal Coaching Environment.

Coach education is a learner-centred process, which often fails to consider the preferences of the consumer. Historically, research into performers' experiences of coaching have been influenced by the social constructivism of learning: in short, an expressed preference for what the performer has experienced as determined by their coach, rather than their own personal preferences. Therefore, this research used skateboarding as a natural laboratory in order to explore the current practices and preferences of performers in a coach-free environment. Ninety-one skateboarders from parks in the United Kingdom and New Zealand offered information relating to their current learning practices, how they learnt about learning, and how the top-level performers in their environment were differentiated. Findings suggest that a number of learning tools are used by performers, which are closely aligned with a more traditional, cognitive view of coaching (e.g., demonstration, drills, and error usage). Results also suggest that performers deployed a number of cognitive skills (e.g., imagery, analogy, and understanding) to enhance storage of a movement as an internal representation. Finally, in the absence of formal coaching, performers use their knowledge of learning to appoint informal leaders. Implications for practice are discussed.

Lower White Matter Volume and Worse Executive Functioning Reflected in Higher Levels of Plasma GFAP among Older Adults with and Without Cognitive Impairment.

OBJECTIVE: There are minimal data directly comparing plasma neurofilament light (NfL) and glial fibrillary acidic protein (GFAP) in aging and neurodegenerative disease research. We evaluated associations of plasma NfL and plasma GFAP with brain volume and cognition in two independent cohorts of older adults diagnosed as clinically normal (CN), mild cognitive impairment (MCI), or Alzheimer's dementia. METHODS: We studied 121 total participants (Cohort 1: n = 50, age 71.6 ± 6.9 years, 78% CN, 22% MCI; Cohort 2: n = 71, age 72.2 ± 9.2 years, 45% CN, 25% MCI, 30% dementia). Gray and white matter volumes were obtained for total brain and broad subregions of interest (ROIs). Neuropsychological testing evaluated memory, executive functioning, language, and visuospatial abilities. Plasma samples were analyzed in duplicate for NfL and GFAP using single molecule array assays (Quanterix Simoa). Linear regression models with structural MRI and cognitive outcomes included plasma NfL and GFAP simultaneously along with relevant covariates. RESULTS: Higher plasma GFAP was associated with lower white matter volume in both cohorts for temporal (Cohort 1: ß = -0.33, p = .002; Cohort 2: ß = -0.36, p = .03) and parietal ROIs (Cohort 1: ß = -0.31, p = .01; Cohort 2: ß = -0.35, p = .04). No consistent findings emerged for gray matter volumes. Higher plasma GFAP was associated with lower executive function scores (Cohort 1: ß = -0.38, p = .01; Cohort 2: ß = -0.36, p = .007). Plasma NfL was not associated with gray or white matter volumes, or cognition after adjusting for plasma GFAP. CONCLUSIONS: Plasma GFAP may be more sensitive to white matter and cognitive changes than plasma NfL. Biomarkers reflecting astroglial pathophysiology may capture complex dynamics of aging and neurodegenerative disease.

Retinal imaging demonstrates reduced capillary density in clinically unimpaired APOE ε4 gene carriers.

INTRODUCTION: Apolipoprotein E (APOE) ε4, the strongest non-Mendelian genetic risk factor for Alzheimer's disease (AD), has been shown to affect brain capillaries in mice, with potential implications for AD-related neurodegenerative disease. However, human brain capillaries cannot be directly visualized in vivo. We therefore used retinal imaging to test APOE ε4 effects on human central nervous system capillaries. METHODS: We collected retinal optical coherence tomography angiography, cognitive testing, and brain imaging in research participants and built statistical models to test genotype-phenotype associations. RESULTS: Our analyses demonstrate lower retinal capillary densities in early disease, in cognitively normal APOE ε4 gene carriers. Furthermore, through regression modeling with a measure of brain perfusion (arterial spin labeling), we provide support for the relevance of these findings to cerebral vasculature. DISCUSSION: These results suggest that APOE ε4 affects capillary health in humans and that retinal capillary measures could serve as surrogates for brain capillaries, providing an opportunity to study microangiopathic contributions to neurodegenerative disorders directly in humans.

The Role of Siblings in Talent Development: Implications for Sport Psychologists and Coaches.

Developing talent requires consideration of social networks that can facilitate or inhibit progression. Of fundamental influence in this regard is the family, with recent investigation extending its focus from parents to the role of siblings. As such, the purpose of this Conceptual Analysis article is to, firstly, review the characteristics of the sibling relationship that may support or inhibit talent development. Secondly, the analysis then provides empirically derived practical examples to emphasize the holistic and complex role that siblings can play in talent development. Thirdly, strategies are proposed to support practitioners identify specific sibling characteristics, alongside recommendations for how the relationship can be utilized within both the formal and informal environments by coaches and psychologists. Finally, and crucially, important implications of these characteristics are considered to support effective coach and sport psychologist decision making.

The Impact of Amyloid Burden and APOE on Rates of Cognitive Impairment in Late Life Depression.

BACKGROUND: Cognitive impairment (CI) is a key feature of late life depression (LLD), but the contribution of underlying neurodegenerative pathology remains unclear. OBJECTIVE: To evaluate cognitive dysfunction in LLD relative to a sample of nondepressed (ND) older adults with matched levels of memory impairment and amyloid-ß (Aß) burden. METHODS: Participants included 120 LLD and 240 ND older adults matched on age, education, sex, Mini-Mental State Exam, mild cognitive impairment diagnosis, and PET Aß burden. RESULTS: LLD showed higher rates of impairment relative to ND with 54.6% of the LLD sample demonstrating impairment in at least one cognitive domain compared to 42.9% of controls (H = 7.13, p = 0.008). LLD had poorer performance and higher rates of impairment on Rey Auditory Verbal Learning Test learning and memory compared to controls. In the overall sample, Aß positivity was associated with worse performance on Logical Memory I (p = 0.044), Logical Memory II (p = 0.011), and Trail Making Test -B (p = 0.032), and APOEɛ4 genotype was associated with worse performance on Logical Memory I (p = 0.022); these relationships did not differ between LLD and ND. CONCLUSION: LLD showed higher rates of CI driven by focal deficits in verbal learning and memory. Alzheimer's disease (AD) biomarkers were associated with worse performance on timed set-shifting and story learning and memory, and these relationships were not impacted by depression status. These findings suggest that AD may account for a portion of previously reported multi-domain CI in LLD and highlight the potential for AD to confound studies of cognition in LLD.

Multimodal MRI staging for tracking progression and clinical-imaging correlation in sporadic Creutzfeldt-Jakob disease.

Diffusion imaging is very useful for the diagnosis of sporadic Creutzfeldt-Jakob disease, but it has limitations in tracking disease progression as mean diffusivity changes non-linearly across the disease course. We previously showed that mean diffusivity changes across the disease course follow a quasi J-shaped curve, characterized by decreased values in earlier phases and increasing values later in the disease course. Understanding how MRI metrics change over-time, as well as their correlations with clinical deficits are crucial steps in developing radiological biomarkers for trials. Specifically, as mean diffusivity does not change linearly and atrophy mainly occurs in later stages, neither alone is likely to be a sufficient biomarker throughout the disease course. We therefore developed a model combining mean diffusivity and Volume loss (MRI Disease-Staging) to take into account mean diffusivity's non-linearity. We then assessed the associations between clinical outcomes and mean diffusivity alone, Volume alone and finally MRI Disease-Staging. In 37 sporadic Creutzfeldt-Jakob disease subjects and 30 age- and sex-matched healthy controls, high angular resolution diffusion and high-resolution T1 imaging was performed cross-sectionally to compute z-scores for mean diffusivity (MD) and Volume. Average MD and Volume were extracted from 41 GM volume of interest (VOI) per hemisphere, within the images registered to the Montreal Neurological Institute (MNI) space. Each subject's volume of interest was classified as either "involved" or "not involved" using a statistical threshold of ±â€¯2 standard deviation (SD) for mean diffusivity changes and/or -2 SD for Volume. Volumes of interest were MRI Disease-Staged as: 0 = no abnormalities; 1 = decreased mean diffusivity only; 2 = decreased mean diffusivity and Volume; 3 = normal ("pseudo-normalized") mean diffusivity, reduced Volume; 4 = increased mean diffusivity, reduced Volume. We correlated Volume, MD and MRI Disease-Staging with several clinical outcomes (scales, score and symptoms) using 4 major regions of interest (Total, Cortical, Subcortical and Cerebellar gray matter) or smaller regions pre-specified based on known neuroanatomical correlates. Volume and MD z-scores correlated inversely with each other in all four major ROIs (cortical, subcortical, cerebellar and total) highlighting that ROIs with lower Volumes had higher MD and vice-versa. Regarding correlations with symptoms and scores, higher MD correlated with worse Mini-Mental State Examination and Barthel scores in cortical and cerebellar gray matter, but subjects with cortical sensory deficits showed lower MD in the primary sensory cortex. Volume loss correlated with lower Mini-Mental State Examination, Barthel scores and pyramidal signs. Interestingly, for both Volume and MD, changes within the cerebellar ROI showed strong correlations with both MMSE and Barthel. Supporting using a combination of MD and Volume to track sCJD progression, MRI Disease-Staging showed correlations with more clinical outcomes than Volume or MD alone, specifically with Mini-Mental State Examination, Barthel score, pyramidal signs, higher cortical sensory deficits, as well as executive and visual-spatial deficits. Additionally, when subjects in the cohort were subdivided into tertiles based on their Barthel scores and their percentile of disease duration/course ("Time-Ratio"), subjects in the lowest (most impaired) Barthel tertile showed a much greater proportion of more advanced MRI Disease-Stages than the those in the highest tertile. Similarly, subjects in the last Time-Ratio tertile (last tertile of disease) showed a much greater proportion of more advanced MRI Disease-Stages than the earliest tertile. Therefore, in later disease stages, as measured by time or Barthel, there is overall more Volume loss and increasing MD. A combined multiparametric quantitative MRI Disease-Staging is a useful tool to track sporadic Creutzfeldt-Jakob- disease progression radiologically.

Late-Life Depression Is Associated With Reduced Cortical Amyloid Burden: Findings From the Alzheimer's Disease Neuroimaging Initiative Depression Project.

BACKGROUND: We evaluated the role of cortical amyloid deposition as a factor contributing to memory dysfunction and increased risk of dementia associated with late-life depression (LLD). METHODS: A total of 119 older adult participants with a current diagnosis of major depression (LLD) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) Depression Project study and 119 nondepressed (ND) cognitively unimpaired participants matched on age, sex, and APOE genotype were obtained from the ADNI database. RESULTS: Thirty-three percent of LLD participants met ADNI criteria for mild cognitive impairment. Compared with ND individuals, the LLD group exhibited less global amyloid beta (Aß) accumulation (p = .05). The proportion of amyloid positivity in the LLD group was 19.3% compared with 31.1% for the ND participants (p = .02). Among LLD participants, global Aß was not associated with lifetime number of depressive episodes, lifetime length of depression, length of lifetime selective serotonin reuptake inhibitor use, or lifetime length of untreated depression (p > .21 for all). Global Aß was associated with worse memory performance (p = .05). Similar results were found in secondary analyses restricting comparisons to the cognitively unimpaired LLD participants as well as when comparing the LLD group with an ND group that included participants with mild cognitive impairment. CONCLUSIONS: Contrary to expectation, the LLD group showed less Aß deposition than the ND group and Aß deposition was not associated with depression history characteristics. Aß was associated with memory, but this relationship did not differ between LLD and ND. Our results suggest that memory deficits and accelerated cognitive decline reported in previous studies of LLD are not due to greater cortical Aß accumulation.

Deformation-based shape analysis of the hippocampus in the semantic variant of primary progressive aphasia and Alzheimer's disease.

BACKGROUND: Increasing evidence shows that the semantic variant of primary progressive aphasia (svPPA) is characterized by hippocampal atrophy. However, less is known about disease-related morphological hippocampal changes. The goal of the present study is to conduct a detailed characterization of the impact of svPPA on global hippocampus volume and morphology compared with control subjects and patients with Alzheimer's disease (AD). METHODS: We measured hippocampal volume and deformation-based shape differences in 22 patients with svPPA compared with 99 patients with AD and 92 controls. Multiple Automatically Generated Templates Brain Segmentation Algorithm (MAGeT-Brain) was used on MRI images obtained at the diagnostic visit. RESULTS: Comparable left and right hippocampal atrophy were observed in svPPA and AD. Deformation-based shape analysis showed a common pattern of morphological deformation in svPPA and AD compared with controls. More specifically, both svPPA and AD showed inward deformations in the dorsal surface of the hippocampus, from head to tail on the left side, and more limited to the anterior portion of the body in the right hemisphere. These results also pointed out that both diseases are characterized by a lateral displacement of the central part (body) of the hippocampus. DISCUSSION: Our study provides critical new evidence of hippocampal morphological changes in svPPA, similar to those found in AD. These findings highlight the importance of considering morphological hippocampal changes as part of the anatomical profile of patients with svPPA.