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INTRODUCTION Lewy body disease (LBD) is a common primary or co‐pathology in neurodegenerative syndromes. An alpha‐synuclein seed amplification assay (αSyn‐SAA) is clinically available, but clinical performance, especially lower sensitivity in amygdala‐predominant cases, is not well understood. METHODS Antemortem CSF from neuropathology‐confirmed LBD cases was tested with αSyn‐SAA (N = 56). Diagnostic performance and clinicopathological correlations were examined. RESULTS Similar to prior reports, sensitivity was 100% for diffuse and transitional LBD (9/9), and overall specificity was 96.3% (26/27). Sensitivity was lower in amygdala‐predominant (6/14, 42.8%) and brainstem‐predominant LBD (1/6, 16.7%), but early spread outside these regions (without meeting criteria for higher stage) was more common in αSyn‐SAA‐positive cases (6/7, 85.7%) than negative (2/13, 15.4%). DISCUSSION In this behavioral neurology cohort, αSyn‐SAA had excellent diagnostic performance for cortical LBD. In amygdala‐ and brainstem‐predominant cases, sensitivity was lower, but positivity was associated with anatomical spread, suggesting αSyn‐SAA detects early LBD progression in these cohorts. Highlights A cerebrospinal fluid alpha‐synuclein assay detects cortical LBD with high sensitivity/specificity. Positivity in prodromal stages of LBD was associated with early cortical spread. The assay provides precision diagnosis of LBD that could support clinical trials. The assay can also identify LBD co‐pathology, which may impact treatment responses.

Pathogenic bacteria require iron for replication within their host. Klebsiella pneumoniae and other Gram-negative pathogens produce the prototypical siderophore enterobactin (Ent) to scavenge iron in vivo . In response, mucosal surfaces secrete lipocalin 2 (Lcn2), an innate immune protein that binds Ent to disrupt bacterial iron acquisition and promote acute inflammation during colonization. A subset of K. pneumoniae isolates attempt to evade Lcn2 by producing glycosylated Ent (Gly-Ent, salmochelin) or the alternative siderophore yersiniabactin (Ybt). However, these siderophores are not functionally equivalent and differ in their abilities to promote growth in the upper respiratory tract, lungs, and serum. To understand how Lcn2 exploits functional differences between siderophores, isogenic mutants of an Ent + Gly-Ent + Ybt + K. pneumoniae strain were inoculated into Lcn2 +/+ and Lcn2 −/− mice, and the pattern of pneumonia was examined. Lcn2 effectively protected against the iroA ybtS mutant (Ent + Gly-Ent − Ybt − ). Lcn2 +/+ mice had small foci of pneumonia, whereas Lcn2 −/− mice had many bacteria in the perivascular space. The entB mutant (Ent − Ybt + Gly-Ent − ) caused moderate bronchopneumonia but did not invade the transferrin-containing perivascular space. Accordingly, transferrin blocked Ybt-dependent growth in vitro . The wild type and the iroA mutant, which both produce Ent and Ybt, had a mixed phenotype, causing a moderate bronchopneumonia in Lcn2 +/+ mice and perivascular overgrowth in Lcn2 −/− mice. Together, these data indicate that Lcn2, in combination with transferrin, confines K. pneumoniae to the airways and prevents invasion into tissue containing the pulmonary vasculature. IMPORTANCE Gram-negative bacteria are a common cause of severe hospital-acquired infections. To cause disease, they must obtain iron and secrete the small molecule enterobactin to do so. Animal models of pneumonia using Klebsiella pneumoniae indicate that enterobactin promotes severe disease. Accordingly, the host defense protein lipocalin 2 exploits this common target by binding enterobactin and disrupting its function. However, pathogenic bacteria often make additional siderophores that lipocalin 2 cannot bind, such as yersiniabactin, which could make this host defense ineffective. This work compares the pattern and severity of pneumonia caused by K. pneumoniae based on which siderophores it produces. The results indicate that enterobactin promotes growth around blood vessels that are rich in the iron-binding protein transferrin, but yersiniabactin does not. Together, transferrin and lipocalin 2 protect this space against all types of K. pneumoniae tested. Therefore, the ability to acquire iron determines where bacteria can grow in the lung. Gram-negative bacteria are a common cause of severe hospital-acquired infections. To cause disease, they must obtain iron and secrete the small molecule enterobactin to do so. Animal models of pneumonia using Klebsiella pneumoniae indicate that enterobactin promotes severe disease. Accordingly, the host defense protein lipocalin 2 exploits this common target by binding enterobactin and disrupting its function. However, pathogenic bacteria often make additional siderophores that lipocalin 2 cannot bind, such as yersiniabactin, which could make this host defense ineffective. This work compares the pattern and severity of pneumonia caused by K. pneumoniae based on which siderophores it produces. The results indicate that enterobactin promotes growth around blood vessels that are rich in the iron-binding protein transferrin, but yersiniabactin does not. Together, transferrin and lipocalin 2 protect this space against all types of K. pneumoniae tested. Therefore, the ability to acquire iron determines where bacteria can grow in the lung.

INTRODUCTION Subjective cognitive complaints (SCC) can precede Alzheimer's disease and related dementias. SCC in the absence of objective impairment is termed subjective cognitive decline (SCD). This study aimed to characterize SCC and SCD among a sample of aging individuals with and without prior repetitive head impact (RHI) exposure, the former of whom are at risk for chronic traumatic encephalopathy (CTE). METHODS RHI‐exposed (N = 167) and non–RHI‐exposed (N = 317) Boston University Alzheimer's Disease Research Center (ADRC) participants and their informants completed subjective measures assessing memory and executive function. Participants completed objective tests of these domains. RESULTS RHI exposure was associated with greater self‐ and informant‐reported SCC and with over four‐fold increased odds of SCD among cognitively unimpaired participants (odds ratio = 4.10, p < 0.001). SCC was associated with objective measures in RHI and non‐RHI participants. DISCUSSION Among RHI‐exposed individuals, SCC align with objective cognitive performance. SCD warrants investigation as potential early indicator of RHI‐related neuropathologies. Highlights Subjective cognitive complaints (SCC) are common after repetitive head impacts (RHI). RHI status is associated with increased odds of subjective cognitive decline (SCD). Neuropsychiatric symptoms are associated with SCC in RHI‐exposed individuals. SCC may indicate underlying post‐traumatic neuropathology in RHI‐exposed individuals.

: To study the dynamics of clustering semantic fluency responses and switching between clusters. : We conducted a cross-sectional study of participants ( = 60) in a study of patient reported outcomes who were given the Saint Louis University Mental Status test. Sixty-second animal naming tests were scored for the timing of responses as well as the clustering of responses into semantic categories. Time scores were detrended to correct for exponential exhaustion and normalize the time scale across individuals. : Grouped by number of responses given, low performers (LP; Carter et al., 2012) switched between clusters fewer times than medium performers (MP) and high performers (HP). Prior to detrending, LP showed increased intracluster response times when compared to the other groups, but no differences were shown in intercluster response times. After detrending, however, the difference in intracluster response times disappeared and LP showed significantly faster detrended intercluster response times compared to both MP and HP. : Prior to detrending, slower intracluster response times appear to be driving poorer performance. When time scores are detrended, our findings suggest that LP participants have quicker intercluster response times but exhaust more quickly as well. Detrending can help describe the interplay between the structure-loss and retrieval-slowing models of declining semantic fluency by isolating the component mechanisms involved in each.

Digital cognitive assessment may offer earlier Alzheimer's disease (AD) and related dementias (ADRD) detection compared with traditional neuropsychological (NP) tests. Subjective cognitive decline (SCD) is recognized as a preclinical AD/ADRD feature. We hypothesized that among cognitively unimpaired (CU) individuals by traditional NP tests, the digital clock drawing test (dCDT) would be associated with concurrent SCD and with future objective cognitive impairment. Participants from the Framingham Heart Study were followed longitudinally with assessment for SCD and NP testing, including dCDT, and were surveilled for mild cognitive impairment (MCI), AD, and all-cause dementia. This study included CU participants at analytic baseline (first visit at/after age 60). Participants with SCD at baseline or in the future, defined by SCD-plus criteria, were matched on age, sex, and education with participants without SCD. Using data from the latest CU visit, we conducted cross-sectional analyses to test associations between dCDT (overall and four composite scores-drawing efficiency, information processing, simple and complex motor, spatial reasoning-in command and copy conditions) and SCD. Additionally, we examined associations between dCDT at baseline and time to MCI, AD, and all-cause dementia. Models were adjusted for traditional NP performance (i.e., cognitive scores for executive function, language, memory), age, sex, education, APOE4 and APOE2 carrier status, and familial relatedness. Among 1,601 participants (mean age at the latest CU visit: 71.6, women: 54.7%, SCD: 32.5%), 9.5%, 2.0%, and 2.6% developed MCI, AD, and all-cause dementia, respectively. Better performance on dCDT-but not traditional NP tests-was associated with reduced odds of SCD: overall (OR=0.86, p = .007); drawing efficiency, command (OR=0.83, p = .002); information processing, command (OR=0.75, p = 1.14×10 ) and copy (OR=0.83, p = .005). Better dCDT performance, after traditional NP performance adjustment, was associated with reduced hazards of future MCI and all-cause dementia: overall dCDT (MCI: HR=0.88, p = .03; all-cause dementia: HR=0.78, p = .02), drawing efficiency, command (MCI: HR=0.88, p = .03), and information processing, command (MCI: HR=0.85, p = .01; all-cause dementia: HR=0.79, p = .03). In this community-based study of CU individuals, dCDT was associated with SCD and time to MCI and all-cause dementia, independent of traditional NP test performance. dCDT may capture subtle AD/ADRD cognitive changes not detected by traditional NP assessment.

Background Digital cognitive assessment may offer earlier Alzheimer's disease (AD) and related dementias (ADRD) detection compared with traditional neuropsychological (NP) tests. Subjective cognitive decline (SCD) is recognized as a preclinical AD/ADRD feature. We hypothesized that among cognitively unimpaired (CU) individuals by traditional NP tests, the digital clock drawing test (dCDT) would be associated with concurrent SCD and with future objective cognitive impairment. Method Participants from the Framingham Heart Study were followed longitudinally with assessment for SCD and NP testing, including dCDT, and were surveilled for mild cognitive impairment (MCI), AD, and all‐cause dementia. This study included CU participants at analytic baseline (first visit at/after age 60). Participants with SCD at baseline or in the future, defined by SCD‐plus criteria, were matched on age, sex, and education with participants without SCD. Using data from the latest CU visit, we conducted cross‐sectional analyses to test associations between dCDT (overall and four composite scores—drawing efficiency, information processing, simple and complex motor, spatial reasoning—in command and copy conditions) and SCD. Additionally, we examined associations between dCDT at baseline and time to MCI, AD, and all‐cause dementia. Models were adjusted for traditional NP performance (i.e., cognitive scores for executive function, language, memory), age, sex, education, APOE4 and APOE2 carrier status, and familial relatedness. Result Among 1,601 participants (mean age at the latest CU visit: 71.6, women: 54.7%, SCD: 32.5%), 9.5%, 2.0%, and 2.6% developed MCI, AD, and all‐cause dementia, respectively. Better performance on dCDT—but not traditional NP tests—was associated with reduced odds of SCD: overall (OR=0.86, p = .007); drawing efficiency, command (OR=0.83, p = .002); information processing, command (OR=0.75, p = 1.14×10‐5) and copy (OR=0.83, p = .005). Better dCDT performance, after traditional NP performance adjustment, was associated with reduced hazards of future MCI and all‐cause dementia: overall dCDT (MCI: HR=0.88, p = .03; all‐cause dementia: HR=0.78, p = .02), drawing efficiency, command (MCI: HR=0.88, p = .03), and information processing, command (MCI: HR=0.85, p = .01; all‐cause dementia: HR=0.79, p = .03). Conclusion In this community‐based study of CU individuals, dCDT was associated with SCD and time to MCI and all‐cause dementia, independent of traditional NP test performance. dCDT may capture subtle AD/ADRD cognitive changes not detected by traditional NP assessment.

Background Exposure to repetitive head impacts (RHI) is associated with developing chronic traumatic encephalopathy (CTE) neuropathology. Cognitive and behavioral symptoms have been associated with CTE neuropathology, but efforts to define the specific clinical syndrome are ongoing. This study characterizes the current use of centrally acting medications (CAMs), chronic pain, and number of orthopedic surgeries in former American football players and evaluates for associations with cognitive and behavioral symptoms. Methods This study analyzed data from the DIAGNOSE CTE Research Project, which includes 120 former professional football players, 60 collegiate football players, and 56 asymptomatic men without history of RHI. Medical history was obtained by self‐report, and participants completed the Montreal Cognitive Assessment (MoCA), Brief Pain Inventory, Barratt Impulsiveness Scale‐11 (BIS‐11), BRIEF‐A Behavioral Regulation Index (BRI), Beck Depression Inventory‐II (BDI‐II), Beck Anxiety Index (BAI), and Brown‐Goodwin Lifetime History of Aggression adulthood score (BGLHA). Logistic regression assessed the association of CAMs, average pain score, and orthopedic surgeries on the cognitive impairment and neurobehavioral dysregulation components of the NINDS traumatic encephalopathy syndrome (TES) research criteria, in former American football players. Linear regression assessed the associations with MoCA and behavioral scales. Models were adjusted for age, education, race, and years of football played. Results Tables 1 and 2 describe the sample and CAM burden. More orthopedic surgeries, CAMs, and higher average pain were observed in former American football players. Number of CAMs was associated with neurobehavioral dysregulation (OR = 2.18), lower MoCA (β = ‐0.47), and higher BIS‐11 (β = 2.23), BDI‐II (β = 2.01), BRI (β = 3.71), BAI (β = 2.04), and BGLHA (β = 0.68) scores. Higher average pain was associated with neurobehavioral dysregulation (OR = 1.57) and higher BIS‐11 (β = 2.20), BDI‐II (β = 1.98), BRI (β = 2.20), BAI (β = 1.84), and BGLHA (β = 0.52) scores. No associations were observed with orthopedic surgeries. Conclusions In former American football players, the number of CAMs and higher average pain were associated with neurobehavioral dysregulation. No associations were observed with diagnosis of cognitive impairment by TES criteria, though the number of CAMs was associated with decreased MoCA.

INTRODUCTION This studyexamined the independent contribution of chronic traumatic encephalopathy (CTE) neuropathology to symptoms. METHODS The sample included 614 brain donors with (n = 366) and without (n = 248) autopsy‐confirmed CTE. Brain donors with other major neurodegenerative disease diagnoses were excluded. Informants completed cognitive and neuropsychiatric measures. Dementia was determined during diagnostic consensus conferences. RESULTS CTE stage IV (of IV) was associated with 4.48 (95% confidence interval [CI] = 1.97–10.90) increased odds of having dementia. CTE stage III had an odds ratio of 2.12 (95% CI = 1.91–3.77). Higher CTE stage was associated with greater informant‐reported cognitive symptoms (p < 0.01). There were no associations with mood/behavioral scales. DISCUSSION CTE stage III/IV neuropathology was associated with dementia and cognitive symptoms: those with stage IV were 4.5 times more likely to have dementia than those without CTE. It is uncertain if low‐stage CTE clinically manifests, and mood/behavioral symptoms likely have multifactorial causes and/or a fluctuating course. Highlights Stage III and IV chronic traumatic encephalopathy (CTE) are independently associated with increased odds of having dementia. Higher CTE stage was associated with greater informant‐reported cognitive symptoms. Stage I and II CTE were not associated with cognitive symptoms or dementia. CTE of any severity was not associated with informant‐reported mood or behavioral symptoms.

The goal of this paper is to introduce the hypothesis that white matter (WM) and vascular injury are long‐term consequences of repetitive head impacts (RHI) that result in a novel T2 fluid attenuated inversion recovery (FLAIR) magnetic resonance imaging pattern. A non‐systematic literature review of autopsy and FLAIR studies of RHI‐exposed adults was first conducted as a foundation for our hypothesis. A case series of RHI‐exposed participants is presented to illustrate the unique FLAIR WM hyperintensities (WMH) pattern. Current literature shows a direct link between RHI and later‐life WM/vascular neuropathologies, and that FLAIR WMH are associated with RHI, independent of modifiable vascular risk factors. Initial observations suggest a distinctive pattern of WMH in RHI‐exposed participants, termed RHI‐associated WMH (RHI‐WMH). RHI‐WMH defining features are as follows: (1) small, punctate, non‐confluent, (2) spherical, and (3) proximal to the gray matter. Our hypothesis serves as a call for research to empirically validate RHI‐WMH and clarify their biological and clinical correlates. Highlights Repetitive head impacts (RHI) have been associated with later‐life white matter (WM) and vascular neuropathologies. T2 FLAIR MRI of RHI‐exposed participants reveals a potentially unique WM hyperintensity (WMH) pattern that is termed RHI‐associated WMH (RHI‐WMH). RHI‐WMH are characterized as (1) small, punctate, and non‐confluent, (2) spherical, and (3) proximal to the gray matter at an area anatomically susceptible to impact injury, such as the depths of the cortical sulci.

Subjective cognitive complaints (SCCs) can be an early indicator of Alzheimer's disease and related dementias. SCCs have been shown to be common in people exposed repetitive head impacts (RHI), particularly male former professional American football players. This study characterized participant and informant-reported SCCs in terms of rate, concordance with standardized neuropsychological measures, and potential associated factors among participants with diverse sources/severity of RHI exposure. The sample included participants with (n = 172) and without (n = 320) RHI from the Boston University Alzheimer's Disease Research Center Clinical Core. RHI status is based on the 2021 NINDS TES Research Diagnostic Criteria. The Cognitive Change Index (CCI) and BRIEF-A Meta-Cognition Index (MI) measured self and informant-reported SCCs. Participants completed neuropsychological assessments of memory (Craft Story 21 Recall, NAB List Learning Long Delay) and executive function (Trails B). Informants completed the Neuropsychiatric Inventory-Questionnaire (NPI-Q). ANCOVAs compared performance of RHI/non-RHI groups on the SCC measures. Pearson correlation examined agreement between participant/informant responses. Multivariable linear regression models tested associations between SCCs and neuropsychological tests and examined correlates of SCCs. All models controlled for age, sex, race, and education. p-values were false discovery rate adjusted. Table 1 describes the sample. Compared to non-RHI, the RHI group was younger, likelier to be male, and likelier to have MCI. The RHI group had significantly higher MI (B=8.084, p = 0.006), informant MI (B=9.014, p = 0.006), CCI (B=5.986, p <0.001), and informant CCI scores (B=7.062, p <0.001. Self/informant CCI and MI scores were more correlated in the RHI (r = 0.592, 0.540, respectively) vs non-RHI group (r = 0.416, 0.373, respectively). Figure 1. Within the RHI group, there were associations between participant/informant SCCs and the objective measures (e.g., B=-0.086, padj<0.001 for CCI and NAB) (Table 2). We observed fewer, weaker associations between SCCs and neuropsychological measures in the non-RHI group. NPI-Q was a consistent correlate of self/informant SCCs. Demographics (e.g., self/informant race) were also associated but to a lesser extent. In RHI settings, SCCs might be more frequent and reflect cognitive function. High SCC rates are likely multifactorial, with influence from neuropsychiatric factors. Future research should examine longitudinal change in self/informant SCCs and correlation with disease biomarkers.