Low-frequency (1 Hz) repetitive Transcranial Magnetic Stimulation (rTMS) to right dorsolateral prefrontal cortex (rDLPFC) paired with Cognitive Processing Therapy (CPT) was shown to reduce aggregate posttraumatic stress disorder (PTSD) symptom severity. PTSD, however, consists of re-experiencing, avoidance and numbing, and hyperarousal symptoms that vary in frequency and intensity. Thus, to explore the potential of more granular effects of rTMS on PTSD, the present secondary analysis examined the influence of rTMS on symptom cluster frequency and intensity. In the original study, Post-9/11 United States military veterans with combat-related PTSD were randomly assigned to receive rTMS + CPT or sham rTMS + CPT. The Clinician-Administered PTSD Scale (CAPS), including frequency and intensity ratings for the symptom clusters, was administered at baseline, treatment session 5, treatment session 9, and at 1-, 3-, and 6-months post-treatment. A significant treatment by time interaction was observed only for re-experiencing frequency; whereas other symptom-cluster frequency and intensity effects were not significant. Compared to sham + CPT, rTMS + CPT led to significantly greater, sustained reductions in re-experiencing frequency from session 9 through the 6-month timepoint. Thus, these secondary analyses provide insight into the potential clinical specificity of rTMS in augmenting CPT in PTSD and insight into the possible role of rDLPFC in PTSD.

Identifying the role of guilt in post-traumatic stress disorder (PTSD) has important implications for understanding the development and treatment of PTSD. The present study is a secondary analysis of data collected on veterans with combat-related PTSD (N = 61) who enrolled in a clinical trial. Hierarchical regression analyses were used to explore associations between action- and survivor-guilt on the Clinician Administered PTSD Scale (CAPS), PTSD symptom severity on the CAPS, and depression on the Quick Inventory of Depressive Symptomatology (QIDS). Action- and survivor-guilt independently predicted PTSD total symptom severity, but in examining PTSD symptom cluster severity, only action-guilt independently predicted avoidance and numbing severity in PTSD. However, depression symptom severity on QIDS also mediated the association between action-guilt and PTSD total symptom severity and avoidance and numbing severity. Thus, action- and survivor-guilt appear to have independent contributions to PTSD symptom severity, and action-guilt, more specifically, appears to affect avoidance and numbing severity in PTSD through depression. The findings are discussed in terms of the potential role of guilt in PTSD and in relation to previous research on guilt and depression in PTSD and PTSD treatment.

Mild cognitive impairment (MCI) and Alzheimer's Clinical Syndrome (ACS) are prevalent, incurable, and are expected to increase in incidence over the next 30 years. Finding new treatments to address the cognitive and behavioral problems in MCI and ACS represent an urgent need. Brain circuitry disruption can cause cognitive dysfunction and neuropsychiatric symptoms (NPS) in both MCI and ACS. Therefore, one promising avenue of treatment is non-invasive brain stimulation through transcranial direct current stimulation (tDCS). This scoping review examined the current knowledge base for the potential neuropsychological and neuropsychiatric effects of frontal cortex tDCS in older adults with MCI and ACS. Of the 17 randomized controlled trials reviewed, treatment parameters such as session length, current intensity, number of treatments, and time between treatments varied widely across studies, which restricted identification of optimal tDCS treatment protocols. Mixed findings on neuropsychological outcomes were observed, though significant improvements were most commonly seen in studies measuring global cognition (10) followed by executive function (6). Only three studies yielded clinically significant cognitive improvement, and few studies assessed NPS outcomes. Additional rigorous research is indicated to enhance our understanding of tDCS as a treatment for cognitive and neuropsychiatric symptoms in older adults with MCI and ACS.

Potential implications of a history of mild traumatic brain injury (mTBI) during aging are understudied. Seven plasma markers were measured in matched participants having normal cognition, mild cognitive impairment (MCI) and dementia of the Alzheimer's type (DAT) with and without a history of mTBI. Phosphorylated tau 181 showed a moderate effect size for being greater in mTBI + individuals having MCI and DAT, and effect sizes for lower amyloid-β 42/40 and higher neurofilament light were seen for mTBI + DAT individuals. This preliminary report shows a potential role of plasma-derived markers in detecting associations between mTBI history and the development of Alzheimer's disease and related disorders.

Trajectories following a diagnosis of mild cognitive impairment (MCI) are varied and may fluctuate over time. Among diverse ethnic and racial groups, social factors, medical comorbidities, and biases in assessment procedures may contribute to greater heterogeneity in the MCI diagnostic category and affect its prognostic significance for dementia. The study goal was to evaluate the frequency and variables associated with MCI transitions among non-Hispanic White (NHW) and Latinx older adults. Multistate Markov models characterized transitions across diagnostic states (cognitively unimpaired (CU), MCI, dementia) over ten years. Variables associated with transitions were assessed using hazard ratios (HR) and 95% confidence intervals (CIs). The study included 413 participants (58% female, mean age 72 ± 8, 52% Latinx ethnicity). Following an MCI diagnosis, the likelihood of converting to dementia versus reverting to CU were equally probable. Older age, NHW ethnicity, APOE ε4, diabetes, lower BMI, and higher neuropsychiatric symptoms associated with elevated risk for dementia conversion, whereas younger age and lower neuropsychiatric symptoms associated with CU reversion. Above other factors, higher baseline serum glial fibrillary acidic protein (HR = 1.762 (95% CI: 1.367-2.271)) and neurofilament light (HR = 1.467 (95% CI: 1.152-1.69)) associated with increased dementia risk. Trajectories following an MCI diagnosis were highly variable with lower dementia conversion rates among Latinx relative to NHW adults, highlighting the need for strong diverse representation in research to capture the range of exposures shaping risk and resilience for cognitive decline. Well-validated blood-based biomarkers are likely to be instrumental for further improving personalized dementia risk predictions.

This study examined how semantic characteristics of verbal cues impact naming, focusing on cue distinctiveness, defined as the degree to which a semantic cue is uniquely associated with a target. Using a novel naming paradigm, we presented word pairs representing semantic features to elicit naming responses. These verbal cues were categorized as distinctive (e.g., "moo-milk" for COW) or shared (e.g., "feathers-pink" for FLAMINGO), and targets were classified as living or nonliving. Distinctive cues significantly improved naming accuracy and speed, with a greater benefit for living items. A follow-up analysis examined graded effects of distinctiveness while accounting for associative strength. Both cue distinctiveness and associative strength facilitated naming speed overall. However, when distinctiveness was residualized against associative strength, the effect remained stronger for living items, although other semantic factors are also discussed. This study introduces a novel paradigm for evaluating semantic factors on naming, with potential future application to clinical populations.

High-definition transcranial direct current stimulation (HD-tDCS) over the prefrontal cortex showed improvement on some executive function (EF) measures in a pilot trial for mild-to-moderate Alzheimer’s dementia (AD). However, many could not finish an EF measure, the DKEFS Color Word Interference (CWI), within the administration time due to impairment, preventing an analysis of typical scores. This secondary analysis developed a novel performance metric to evaluate DFEFS-CWI outcomes within the trial. Participants were randomized to 10 sessions of HD-tDCS at 0 mA, 1 mA or 2 mA current intensities, and the DKEFS-CWI was administered pre- and immediately post-intervention. Of the total trial sample (n=23), only 14 participants from the 0 mA (n=3), 1 mA (n=6), and 2 mA (n=5) conditions understood the task and attempted the Inhibition trial. An item efficiency index score, calculated as the number of correct plus self-corrected items divided by the total administration time, was examined for these participants. Analyses of covariance compared the index score for the active groups (1 mA and 2 mA separately) to 0 mA sham group while controlling for baseline performance. No statistically significant differences between sham and either 1 mA (p=.82, d=.19) or 2 mA (p=.94, d=.07) HD-tDCS groups were found post-intervention. This HD-tDCS paradigm was not associated with a change in the DKEFS-CWI Inhibition efficiency index score. Conclusions could be limited by a substantial portion of the sample being incapable of attempting the DKEFS-CWI. Future research needs to establish which EF measures are suitable clinical trial metrics for impaired patients with AD.

Background and Objectives Clinical features of individuals with autopsy findings of chronic traumatic encephalopathy (CTE) have been described for 50 years. Clinical criteria have been proposed, although cognitive correlates of CTE remain unknown. This study examined whether CTE was related to dementia and patterns of cognitive impairment to summarize the clinicopathologic evidence. Methods A systematic review and meta-analysis was performed, composed of a multicenter interdisciplinary team. Five databases were searched from their inception to March 2025. Original studies involving participants with neuropathologic findings of CTE and neuropsychological data were included. A multistage selection approach was used, including a review by neuropathologists to ensure that studies conformed to CTE consensus criteria. Methodological quality was rated from 9 items using a modified Murad Case Report Methodological Quality Tool. The main outcomes of interest were domains of cognitive functioning, based on objective testing, and prevalence of dementia-related clinical diagnoses in individuals with CTE. A random-effects meta-analysis examined prevalence of dementia-related diagnoses, and meta-regression examined whether Alzheimer-type neuropathology or any comorbid neuropathology was a moderator. Results A total of 36 studies comprising 563 unique CTE cases were included. Only 22 CTE cases (<5%) had objective neuropsychological data available from studies (k = 10) of acceptable quality. Deficits in memory, language, and attention were the most prevalent cognitive features, but all cases had comorbid non-CTE neuropathologies that may have been associated with cognitive impairment. Diverse neuropsychological impairments were observed, resulting in no consistent cognitive pattern, even for high CTE severity. Dementia-related diagnoses were prevalent (62%; 95% CI 48%-75%) in the meta-analysis (k = 13; n = 492), yet not strongly related to non-CTE neuropathologies recorded (estimate = 0.14, 95% CI -0.62 to 0.91; p = 0.714), including Alzheimer-type neuropathology (estimate = 0.21, 95% CI -0.03 to 0.45; p = 0.084). Discussion Limited CTE cases have been published with objective neuropsychological information. CTE cases show cognitive deficits resembling Alzheimer dementia, but a direct clinicopathologic link is inconclusive. While the meta-analytic findings suggest that CTE may be associated with cognitive impairment, further investigation is needed because heterogeneity in study designs prohibits clear conclusions. To realize any clinicopathologic links and inform future iterations of clinical criteria, a transition in how cognition is investigated in CTE will be needed and several research directions are proposed.

Background Recent disease-modifying treatments for Alzheimer's disease show promise to slow cognitive decline, but show no efficacy towards reducing symptoms already manifested. Objectives To investigate the efficacy of a novel noninvasive brain stimulation technique in modulating cognitive functioning in Alzheimer's dementia (AD). Design Pilot, randomized, double-blind, parallel, sham-controlled study Setting Clinical research site at UT Southwestern Medical Center Participants Twenty-five participants with clinical diagnoses of AD were enrolled from cognition specialty clinics. Intervention Treatment consisted of high definition transcranial direct current stimulation (HD-tDCS) delivered for 20 min over the medial prefrontal cortex. Ten sessions of sham, 1 mA, or 2 mA stimulation were received. Measurements Cognitive outcomes were measured at baseline, after the last HD-tDCS session, and 8-weeks post-treatment. The primary outcome was change in total learning and delayed recall on the Rey Auditory Verbal Learning Test (RAVLT) immediately post-treatment and at 8-weeks. Secondary outcomes included measures of language, processing speed, and executive functioning. A multi-stage approach was used to examine cognitive outcomes, which included evaluation of effect sizes, statistical effects, and rate of clinically meaningful responses. Results In this pilot trial, no statistically significant differences on cognitive outcomes were found between sham and active HD-tDCS immediately post-treatment (p's > 0.05). However, moderate-to-large effect sizes were identified for enhanced RAVLT total learning (Cohen's d = 0.69-0.93) and phonemic fluency (d = 1.08-1.49) for both active HD-tDCS conditions compared to sham, with rates of clinically relevant improvement between 25 and 33%. Meaningful enhancement persisted to 8 weeks only for the 1 mA condition. Conclusions Multiple sessions of HD-tDCS over the medial prefrontal cortex appears to have potential to produce meaningful cognitive enhancements in a proportion of patients having AD with improvements maintained for at least 8 weeks in some.

Background:Word retrieval deficits are the most prominent symptoms reported in primary progressive aphasia (PPA) and related syndromes. Current treatments, such as speech and language therapy, have shown limited success, highlighting the need for alternative non-pharmacological interventions with high-definition transcranial direct current stimulation (HD-tDCS) emerging as a promising tool. Objective:This study aimed to evaluate the effects of HD-tDCS on word retrieval function in individuals with PPA by comparing two stimulation sites: the pre-supplementary motor area (pre-SMA) and the left inferior frontal gyrus (LIFG), and to assess the relative benefits of each site. Methods:Eight individuals with PPA underwent 10 sessions of open-label HD-tDCS targeting either the LIFG (n = 4) or pre-SMA (n = 4). Word retrieval was assessed at baseline, immediately post-stimulation, and at 8-week follow-up. Electrophysiological measures, including event-related potentials during a non-verbal Go-NoGo task, were also collected to explore neural mechanisms. Results:LIFG stimulation yielded statistically significant improvements in phonemic fluency at immediate post testing compared to baseline, with 25-50% showing clinically meaningful improvement. Clinically meaningful improvement was observed in category fluency in 25-50% of the patients receiving stimulation at either site. Lastly, electrophysiological measures indicated HD-tDCS targeting LIFG differentially modulated event-related potential effects during non-verbal Go-NoGo tasks. Conclusion:This research provides preliminary evidence supporting the use of both traditional (LIFG) and alternative (pre-SMA) stimulation sites for treating word retrieval deficits in individuals with PPA. The findings also suggest potential neural mechanisms of HD-tDCS intervention, which can inform future designs of non-invasive brain stimulation for cognitive symptoms in PPA. Clinical trial registration:Clinicaltrials.gov, identifier NCT05368350.

Remote traumatic brain injury (TBI) has been linked to earlier cognitive decline, potentially from reduced cognitive reserve or increased Alzheimer’s pathophysiology. However, it is unclear if mild TBI (mTBI) may have a similar association, and if so, the possible mechanism. This exploratory study examined if a history of mTBI was linked to differences in age of onset, cognition, and Alzheimer’s biomarkers in amnestic mild cognitive impairment (aMCI). Thirty-three participants with aMCI from a dementia-specialty clinic at UT Southwestern completed a TBI interview, lumbar puncture, and neuropsychological assessment. Thirteen measures were administered to assess memory, language, visuospatial, attention, and executive function. Cerebrospinal fluid (CSF) concentrations of amyloid beta 42/40, phosphorylated tau181 (Ptau181), and total tau were obtained. Remote mTBI history was present for 19 individuals (mTBI+) and absent in 14 (mTBI-). Independent samples t-tests compared each variable between groups, with effect sizes calculated. Age of symptom onset (p=.089, d=.665) and aMCI diagnosis (p=.048, d=.828) occurred 5.3-5.6 years earlier in the mTBI+ group with moderate-to-large effects. However, Ptau181 was lower for the mTBI+ than the mTBI- group with a medium-to-large effect (p=.057, d=.730). No group differences emerged on other biomarkers or cognitive performance (p>.05, d<.50). History of mTBI may be linked to earlier onset/diagnosis based on this small study, but was unrelated with reduced cognitive performance or elevated CSF-derived markers of Alzheimer’s pathophysiology. Findings suggest mTBI might make some prone to earlier aMCI onset. A mechanistic link for earlier onset is unknown though, and future work should investigate other possible mechanisms and/or biomarkers.

BACKGROUND AND OBJECTIVES:This retrospective study used data from the National Alzheimer's Coordinating Center (NACC) database and compared neuropathologic, neuropsychiatric, motor, and neuropsychological features between those with and without chronic traumatic encephalopathy neuropathologic change (CTE-NC). METHODS:Data were obtained from the NACC database from 2014 to December 2024, with the only inclusion criterion being evaluation for CTE-NC. Participants with CTE-NC were identified and matched approximately 1:4 to those without CTE-NC on demographics (age, education, sex) and staging of Alzheimer and Lewy body neuropathology. Chi-square tests and analyses of covariance (covarying for cognitive symptom duration, time to death, and cognitive diagnosis) compared neuropathologic features, history of traumatic brain injury (TBI), neuropsychiatric symptoms, parkinsonism features, and neuropsychological scores between groups. RESULTS:CTE-NC was present in 0.8% of participants (29/3,845) since 2014. Matching on a 1:4 ratio was achieved for 22 individuals and 1:3 for an additional 3, yielding a total comparison sample of 25 with CTE-NC and 97 without. All but 1 individual with CTE-NC were male with a mean age of 74.7 years (SD = 8.0). Moderate-to-severe Alzheimer neuropathology (54.0%) was common in those with CTE-NC while comorbid cortical or limbic Lewy inclusions were less frequent (8.0%). Compared with those without CTE-NC, those with CTE-NC had higher rates of hippocampal sclerosis (40.0% vs 9.6%; p < 0.001, V = 0.338), progressive supranuclear palsy (16.0% vs 3.1%; p = 0.013, V = 0.224), argyrophilic grain disease (28.0% vs 10,3%; p = 0.023, V = 0.206), other 4R tauopathies (16.7% vs 3.1%; p = 0.011, V = 0.231), other 3R + 4R tauopathies (8.3% vs 1.0%; p = 0.039, V = 0.187), aging-related tau astrogliopathy (33.0% vs 8.9%; p < 0.001, V = 0.313), and transactive response DNA binding protein 43 (TDP-43) inclusions (24.0% vs 7.0%; p = 0.017, V = 0.228). Those with CTE-NC had higher rates of TBI (45.8%) compared with those without CTE-NC (21.9%, p = 0.018, V = 0.217). Neuropsychological scores, neuropsychiatric symptoms, and parkinsonism symptoms did not differ between groups. DISCUSSION:CTE-NC was rare in NACC since 2014. Those with CTE-NC did not differ in clinical symptoms but had higher rates of hippocampal sclerosis, other tauopathies, and TDP-43 inclusions. In this clinicopathologic investigation using in vivo clinical data, although NACC lacks CTE-NC severity/distribution and repetitive head impact data for sensitivity analyses. Larger in vivo clinicopathologic studies are greatly needed to correlate CTE-NC with clinical features.

Confrontational naming is widely used in diagnosing neurodegenerative disorders like MCI and dementia, and previous research indicates that healthy Non-Hispanic Whites outperform Hispanics in such tasks. However, understanding the factors contributing to score differences among ethnic groups remains limited. This study focuses on cognitively intact Mexican Americans and Non-Hispanic White older adults from the TARCC Hispanic Cohort project. Hierarchical regression analyses reveal that sex, age, ethnicity, education level, and estimated IQ significantly predict performance on the Boston Naming Test (BNT). Notably, education level and estimated IQ more strongly influence BNT performance in Mexican Americans than in Non-Hispanic Whites. When controlling for education level, estimated IQ has a more pronounced impact on BNT performance in aging Mexican Americans compared to Non-Hispanic Whites. Conversely, after controlling for estimated IQ, the influence of education level is weaker for Mexican Americans than Non-Hispanic Whites. These findings emphasize the need for careful evaluation of confrontational naming task scores in diverse ethnic groups, emphasizing the critical role of education and estimated IQ in understanding performance disparities.

Abstract Objective Verbal-retrieval deficits often occur after traumatic brain injury (TBI), but no effective treatment is available. In this study, High-Definition Transcranial Direct Current Stimulation (HD-tDCS) was applied to examine its potential effects on cognitive, especially verbal-retrieval, performance in individuals with chronic TBI. Method Four adults (mean age 48 years; 3 females) with self-reported word-finding difficulty confirmed by objective measures following mild to moderate non-military TBIs sustained over a year ago underwent a double-blind, cross-over, randomized, sham-controlled trial. Each participant received 10 sessions of active HD-tDCS and sham stimulation over the superior medial frontal cortex. A battery of neuropsychological tests was administered including verbal-retrieval measures (i. e. letter fluency, category fluency, Boston Naming Test/BNT) at baseline, immediately, and 8 weeks post-treatment. Post-treatment performance was compared to baseline using 2-tailed paired t-tests. Results Improvements on letter fluency were observed between baseline and immediate assessments post active HD-tDCS, approaching statistical significance (p = 0.076, Cohen’s d = 0.957, 7.5 ± 5.7 more items). No immediate effects with sham HD-tDCS (p > 0.10, 1.5 ± 3.5 more items) and no sustained effects (8 weeks after) were found with either active or sham HD-tDCS (ps > 0.10). Additionally, no significant changes were observed for category fluency or BNT (all ps > 0.10). Conclusion While our pilot study suggests a potential benefit for improved letter fluency immediately following active HD-tDCS compared to sham, the lack of sustained improvement after 8 weeks and the observed variability across different tests acknowledges the need for future larger-scale investigation across multiple cognitive domains.

Abstract Objective To differentiate neurocognitive performance between those with chronic traumatic encephalopathy neuropathologic change (CTE-NC) and matched CTE-negative individuals. Methods Data were obtained from the National Alzheimer’s Coordinating Center (NACC). Participants with mild cognitive impairment (MCI) or dementia and CTE-NC (n = 22) were matched approximately 1:3 to those with MCI/dementia but without CTE-NC (n = 64) on demographics (age of initial cognitive diagnosis, education, sex) and postmortem Alzheimer’s and Lewy body neuropathology. ANCOVAs (covarying for symptom duration and cognitive diagnosis) compared neurocognitive measures between groups (MMSE and neuropsychological battery composites of Attention, Executive Function, and Speed [AEFS], Memory, and Language). Results Participants were all male, 89.3% White, and averaged 16.3 years of education. They were, on average, 74.8 years of age (SD = 7.3) when diagnosed with MCI/dementia and had 4.2 years (SD = 4.2) of cognitive symptoms prior to MCI/dementia diagnosis. Rates of comorbid moderate/severe Alzheimer’s or Lewy body pathology were high (n = 13, 54%) in the CTE-NC group. At time of cognitive diagnosis, individuals with CTE-NC performed slightly better on the MMSE (F = 4.510, p = 0.037, CTE-NC+ M = 26.03 [1.05] vs. CTE-NC- M = 23.44 [0.58]). No differences in AEFS [F = 0.280, p = 0.599], Memory [F = 2.265, p = 0.137], or Language [F = 3.424, p = 0.069] were observed between groups. Conclusions Those with CTE-NC did not greatly differ in neuropsychological domains, but had relatively higher MMSE scores compared to those without CTE-NC. This is the largest clinicopathological investigation utilizing in-vivo neurocognitive data, though NACC lacks CTE-NC severity/distribution data for sensitivity analyses. Nonetheless, results have implications for CTE clinical criteria frameworks and larger clinicopathological studies are needed to determine if CTE-NC has distinct neurocognitive features.

Multiple pharmacologic agents now have been approved in the United States and other countries as treatment to slow disease and clinical progression for Alzheimer's disease. Given these treatments have not been proven to lessen the cognitive deficits already manifested in the Alzheimer's Clinical Syndrome (ACS), and none are aimed for another debilitating dementia syndrome identified as primary progressive aphasia (PPA), there is an urgent need for new, safe, tolerable, and efficacious treatments to mitigate the cognitive deficits experienced in ACS and PPA. Noninvasive brain stimulation has shown promise for enhancing cognitive functioning, and there has been interest in its potential therapeutic value in ACS and PPA. This review critically examines the evidence of five technologies in ACS and PPA: transcranial direct current stimulation (tDCS), transcranial alternating current stimulation (tACS), transcranial random noise stimulation (tRNS), repetitive transcranial magnetic stimulation (rTMS), and noninvasive vagus nerve stimulation (nVNS). Many randomized controlled trials of tDCS and rTMS report positive treatment effects on cognition in ACS and PPA that persist out to at least 8 weeks, whereas there are few trials for tACS and none for tRNS and nVNS. However, most positive trials did not identify clinically meaningful changes, underscoring that clinical efficacy has yet to be established in ACS and PPA. Much is still to be learned about noninvasive brain stimulation in ACS and PPA, and shifting the focus to prioritize clinical significance in addition to statistical significance in trials could yield greater success in understanding its potential cognitive effects and optimal parameters.