Adler, Charles H.

Background Neuropsychiatric symptoms (NPS) are frequent in Alzheimer's disease (AD) dementia, but a higher NPS burden is found in dementia with Lewy bodies (DLB). Lewy body (LB) pathology frequently co-occurs with AD pathology and may not meet neuropathological criteria for DLB (ADLB). NPS trajectories over disease course in these subgroups is not well understood. Objective We investigated changes in NPS severity over time, at two time points, comparing clinicopathologically defined cohorts of AD (without LB), ADLB, DLB, and controls. Methods Cases with two available Neuropsychiatric Inventory-Questionnaire (NPIQ), at the time of enrollment and within 2.5 years of death, were selected from the Arizona Study of Aging and Neurodegenerative Disorders. Differences and rate of change in NPIQ scores were compared between AD (n = 75), ADLB (n = 48) DLB (n = 65), and controls (n = 32) with covariates for age, sex, and cognition. Results First NPIQ scores were highest in ADLB when compared to AD (p = 0.04) and controls (p = 0.01) but not different from DLB. A significant increase in NPS severity was observed in DLB and AD (p < 0.001) over a mean follow up time of 4.9 ± 3.0 years, and the rate of change was significantly greater in DLB when compared to other groups. Final NPIQ scores were highest in DLB when compared to AD (p = 0.03) but not ADLB, and in DLB, ADLB, and AD than controls ( all p < 0.001). Conclusions Early NPS burden as well as NPS severity progression rate, independently of cognitive status, might be useful clinical metrics and may help predict underlying pathological diagnoses.

AbstractBackgroundTraumatic encephalopathy syndrome (TES) is the proposed clinical syndrome of the neurodegenerative disease chronic traumatic encephalopathy (CTE). As part of the 2021 TES NINDS consensus diagnostic criteria, certainty levels of underlying CTE neuropathology can be determined (i.e., suggestive, possible, probable) partially based on the presence/absence of supportive psychiatric features including but not limited to depression, anxiety, and apathy. These are ‘supportive’ because of their non‐specificity and unclear biological correlates in this setting. We examined the association between CSF biomarkers of amyloid, tau, neurodegeneration, microglial activation and neuroinflammation and supportive psychiatric features of TES in former American football players.MethodThe sample included 180 male former football players (120 professional, 60 college) from the DIAGNOSE CTE Research Project. Participants completed a lumbar puncture, and CSF assays were conducted for biomarkers of amyloid (Aβ40, Aβ42), p‐tau (p‐tau181, p‐tau231, p‐tau217), neurodegeneration (total tau), axonal degeneration (NfL), microglial activation (strem2) and neuroinflammation (GFAP, IL‐6). Biomarkers were log‐transformed. The Apathy Evaluation Scale (AES), Beck Depression Inventory‐II (BDI‐II) and the Beck Anxiety Inventory (BAI) self‐report questionnaires were completed by participants. Multivariable regression models tested the association between each CSF biomarker and each scale, controlling for age, race, body mass index, revised Framingham stroke risk profile and Alcohol Use Disorders Identification Test. P‐values were adjusted for multiple comparisons using false discovery rate methods.Result140 participants had successful LPs and available CSF for assays. 33(22%) reported moderate/severe anxiety, 34(22%) reported moderate/severe depression, and 51(33%) had an elevated AES score. Higher CSF concentrations of IL‐6 were associated with higher scores on the BAI (unstandardized‐β=0.016, 95%CI [0.017, 0.026], padj=0.004), BDI‐II (unstandardized‐β=0.013, 95%CI [0.004, 0.021], padj=0.008) and AES (unstandardized‐β=0.014, 95%CI [0.006,0.022], padj=0.002). There were no significant relationships between other biomarkers with the BDI‐II, BAI or AES.ConclusionIn this sample of former American football players, there were significant associations between IL‐6 (a proinflammatory cytokine) and reported symptoms of depression, anxiety, and apathy. CSF biomarkers of amyloid, tau and neurodegeneration had no associations, highlighting the role of neuroinflammatory processes in the manifestation of psychiatric symptoms of TES. Continued research on the biological correlates of TES features will inform future iterations of the criteria.

AbstractBackgroundClinically meaningful cognitive impairment has typically been defined as a single impaired test score, but this approach is prone to false‐positive errors. Examining two test scores at a lower threshold (i.e., using neuropsychological criteria) can improve diagnostic reliability and has shown stronger associations with biomarkers of Alzheimer’s disease. Cognitive impairment in episodic memory and/or executive functioning is a core feature of traumatic encephalopathy syndrome (TES). However, there remains a need to improve the specificity of TES criteria. We applied 1‐ vs. 2‐test criteria for cognitive impairment in former American football players to examine whether 2‐test criteria showed stronger associations with biomarkers of tau, axonal injury, and neurodegeneration.Method169 male former American football players from the DIAGNOSE CTE Research Project completed neuropsychological assessment, lumbar puncture, and MRI (see Table). Episodic memory measures were delayed recall from Craft Story, Brief Visuospatial Memory Test, and NAB List Learning. Executive functioning measures were FAS, Stroop Interference, NAB Mazes, and Trails B. Cerebrospinal fluid (CSF) was measured using Lumipulse technology (p‐tau, t‐tau) and an in‐house ELISA (neurofilament light [NfL]). Hippocampal volumes were extracted from structural MRI using Freesurfer 7.1. Cognitive impairment was identified by 1‐test criteria (≥1.5 SD below norms on one test in either domain) and 2‐test criteria (>1 SD below norms on two tests within a domain). Regressions adjusting for age, race, education, and APOE ε4 status assessed whether meeting 1‐ or 2‐test criteria, separately, predicted log‐transformed CSF p‐tau181, p‐tau231, t‐tau, and NfL, and hippocampal volumes.Result37 of the 99 football players that were impaired by 1‐test criteria did not meet 2‐test criteria, and four uniquely met 2‐test but not 1‐test criteria (see Figure). Cognitive impairment by 2‐test but not 1‐test criteria predicted higher log‐CSF NfL (2‐test: B = 0.24, p = .007; 1‐test: B = 0.06, p = .53), smaller left hippocampal volume (2‐test: B = ‐195.84, p = .01; 1‐test: B = ‐131.52, p = .08), and smaller right hippocampal volume (2‐test: B = ‐161.19, p = .045; 1‐test: B = ‐134.88, p = .08). Neither criterion predicted p‐tau181, p‐tau231, or t‐tau.Conclusion2‐test criteria demonstrated stronger associations between cognitive impairment and markers of axonal injury and neurodegeneration. Incorporating multiple test scores to identify cognitive impairment could improve diagnostic specificity in TES.

AbstractBackgroundTraumatic encephalopathy syndrome (TES) is the proposed clinical syndrome of chronic traumatic encephalopathy (CTE), a neurodegenerative disease associated with repetitive head impacts in contact/collision sports. A core clinical feature of TES is cognitive impairment, particularly in memory and executive functions. Cognitive intraindividual variability (IIV) is the extent of variability in neuropsychological test performance (i.e., dispersion of test scores) and is believed to be an indicator of disruption in executive control, linked to altered fronto‐subcortical circuits. Here, we examined cognitive IIV as a method to detect subtle executive dysfunction in TES that may not be captured by traditional neuropsychological measures.MethodThe sample included former American football players (120 professional, 60 college); participants were males, aged 45‐74. Participants completed a baseline neuropsychological test battery (n = 8 excluded for suboptimal performance validity). A multidisciplinary diagnostic consensus conference classified participants using the 2021 NINDS Consensus Diagnostic Criteria for TES (see Table‐1): (1) No‐TES (n = 62); (2) TES‐CTE Suggestive (n = 35); (3) TES‐CTE Possible (n = 21); (4) TES‐CTE Probable (n = 54). TES‐CTE Possible and Probable were combined. The coefficient of variation (CoV) was used to measure cognitive IIV (CoV = iSD/iOTBM, iOTBM = average T‐score across neuropsychological tests; iSD = standard deviation of iOTBM). A higher CoV indicates greater score dispersion. To avoid circularity, memory and executive tests used for classifying TES groups were intentionally excluded from the CoV calculation. Analysis of covariance compared the TES groups on CoV, controlling for age, education, and race.ResultResults showed a significant difference in CoV between TES groups, F(2, 165) = 8.20 p<.001, partial η2 = .09. The TES‐CTE Possible/Probable group had the highest CoV (M = .226, SE = .007), compared with the TES‐no (M = .192, SE = .008, p<.001) and TES‐CTE Suggestive groups (M = .178, SE = .011, p<.001). CoV did not significantly differ between the TES‐no and TES‐CTE suggestive groups (Mdiff = 0.014, SE = .013, p = .293).ConclusionThe TES‐CTE possible/probable group had the highest cognitive IIV with ∼23% dispersion (vs. ∼18‐19% in TES‐no and TES‐CTE suggestive groups), suggesting greater cognitive variability in those with the greatest likelihood for having underlying CTE (based on TES criteria). This finding emphasizes the potential utility of exploring cognitive IIV as a method for detecting nuanced executive dysfunction in TES.

Abstract Former American football players are at risk for developing traumatic encephalopathy syndrome (TES), the clinical disorder associated with neuropathologically diagnosed chronic traumatic encephalopathy (CTE). The objective of this study was to determine whether hyposmia is present in traumatic encephalopathy syndrome. The study included 119 former professional American football players, 60 former college football players, and 58 same-age asymptomatic unexposed men from the DIAGNOSE CTE Research Project. All subjects included in the analysis had completed the Brief Smell Identification Test (B-SIT). Traumatic encephalopathy syndrome and the level of CTE certainty were diagnosed using the 2021 NINDS consensus diagnostic criteria. TES is categorized antemortem by provisional levels of increasing CTE certainty: Suggestive, Possible, and Probable. Former players who had traumatic encephalopathy syndrome and Probable CTE had lower B-SIT scores than those with TES and Suggestive CTE. Hyposmia was more likely in the former players with TES who were either CTE Possible or Probable than in those who did not have TES or had TES but were less likely to have CTE, or CTE Suggestive. There was no difference in B-SIT scores between all former players versus unexposed men nor overall between the football players with and without TES. We conclude that lower B-SIT scores may be a clinical biomarker for underlying CTE in former American football players.

Background and Objective: Weight loss and small intestinal bacterial overgrowth (SIBO) are common in Parkinson’s disease (PD). We aimed to study the relationship between weight loss and SIBO in PD. Methods: This was a cross-sectional study with a prospective, interventional component. Consecutive patients seen in the PD clinic who agreed to participate underwent extensive history, movement exam, SIBO breath testing and answered questionnaires. A subset of those in the weight loss group were treated with rifaximin for 14 days and returned 3 months later for an assessment of their weight, GI symptoms, quality of life and SIBO status. All analyses were adjusted for age and disease duration. Results: Fifty-one patients participated in the study; 37 without weight loss and 14 with weight loss. Total energy intake including the distribution of macronutrient intake was similar between groups while physical activity was less in those with weight loss. PD severity scores did not differ between groups; however, PD-specific quality of life scores were significantly worse for the summary index and the subscales of emotional well-being, social support and communication. The prevalence of constipation, dyspepsia and abdominal pain/discomfort was higher in those with weight loss. The prevalence of SIBO was 14% in the weight loss group and was not different between groups. Eight PD patients with weight loss were treated with rifaximin; no significant change in GI symptoms, quality of life or weight was seen 3 months later. Conclusion: Although a number of differences were identified in quality of life and gastrointestinal symptoms between groups with and without weight loss, SIBO was not associated with weight loss in patients with PD. Given the exploratory nature and small number of patients with weight loss, however, further study is suggested.

AbstractBackgroundIdiopathic rapid eye movement sleep behavior disorder (RBD) is a strong known predictor of a final clinicopathological diagnosis of a Lewy type α‐synucleinopathy (LTS). Olfactory dysfunction is an early symptom of synucleinopathies and has been repeatedly associated with the presence of post‐mortem LTS.ObjectiveTo assess the combined value of a clinician diagnosis of probable RBD (PRBD) and hyposmia in predicting the post‐mortem presence of LTS in a broader, less‐selected, volunteer elderly population.MethodsWe studied 652 autopsied subjects from the Arizona Study of Aging and Neurodegenerative Disorders, which were evaluated for PRBD, had completed annual movement and cognitive assessments, and had at least one the University of Pennsylvania Smell Identification Test (UPSIT) olfactory test.ResultsHistological evidence of LTS was significantly more frequent in those who had PRBD (112/152: 73.7%) than those without (177/494: 35.8%) (P < 0.001). LTS was more frequent in cases with PRBD and a low UPSIT score (90.8%) compared to cases with PRBD only (73.7%) (P < 0.001) or cases with a low UPSIT score only (69.4%) (P < 0.001). Sensitivity of PRBD diagnosis for predicting LTS was 38.8% and specificity 88.8%, whereas sensitivity of a low UPSIT score was 74.4% and specificity 73.4% (Youden's index = 0.276 for PRBD, 0.478 for UPSIT). When combining both measures, sensitivity was 34.3% and specificity increased to 97.2%.ConclusionPRBD, diagnosed without sleep study confirmation, combined with a reduced olfactory performance is highly specific for predicting post‐mortem presence of LTS. The combination of both measures may provide a cost‐effective means of predicting LTS in a broader community.

AbstractINTRODUCTIONBlood‐based biomarkers offer a promising approach for the detection of neuropathologies from repetitive head impacts (RHI). We evaluated plasma biomarkers of amyloid, tau, neurodegeneration, and inflammation in former football players.METHODSThe sample included 180 former football players and 60 asymptomatic, unexposed male participants (aged 45–74). Plasma assays were conducted for beta‐amyloid (Aβ) 40, Aβ42, hyper‐phosphorylated tau (p‐tau) 181+231, total tau (t‐tau), neurofilament light (NfL), glial fibrillary acidic protein (GFAP), interleukin‐6 (IL‐6), Aβ42/p‐tau181 and Aβ42/Aβ40 ratios. We evaluated their ability to differentiate the groups and associations with RHI proxies and traumatic encephalopathy syndrome (TES).RESULTSP‐tau181 and p‐tau231(padj = 0.016) were higher and Aβ42/p‐tau181 was lower(padj = 0.004) in football players compared to controls. Discrimination accuracy for p‐tau was modest (area under the curve [AUC] = 0.742). Effects were not attributable to AD‐related pathology. Younger age of first exposure (AFE) correlated with higher NfL (padj = 0.03) and GFAP (padj = 0.033). Plasma GFAP was higher in TES‐chronic traumatic encephalopathy (TES‐CTE) Possible/Probable (padj = 0.008).DISCUSSIONPlasma p‐tau181 and p‐tau231, GFAP, and NfL may offer some usefulness for the characterization of RHI‐related neuropathologies.Highlights Former football players had higher plasma p‐tau181 and p‐tau231 and lower Aβ42/ptau‐181 compared to asymptomatic, unexposed men. Younger age of first exposure was associated with increased plasma NfL and GFAP in older but not younger participants. Plasma GFAP was higher in participants with TES‐CTE possible/probable compared to TES‐CTE no/suggestive.