Individuals with Alzheimer's disease and low tau burden: Characteristics and implications.

INTRODUCTION: Abnormal amyloid-beta (Aß) and tau deposition define Alzheimer's Disease (AD), but non-elevated tau is relatively frequent in patients on the AD pathway. METHODS: We examined characteristics and regional patterns of 397 Aß+ unimpaired and impaired individuals with low tau (A+T-) in relation to their higher tau counterparts (A+T+). RESULTS: Seventy-one percent of Aß+ unimpaired and 42% of impaired Aß+ individuals were categorized as A+T- based on global tau. In impaired individuals only, A+T- status was associated with older age, male sex, and greater cardiovascular risk. α-synuclein was linked to poorer cognition, particularly when tau was low. Tau burden was most frequently elevated in a common set of temporal regions regardless of T+/T- status. DISCUSSION: Low tau is relatively common in patients on the AD pathway and is linked to comorbidities that contribute to impairment. These findings have implications for the selection of individuals for Aß- and tau-modifying therapies.

Global brain activity and its coupling with cerebrospinal fluid flow is related to tau pathology.

Amyloid-ß (Aß) and tau deposition constitute Alzheimer's disease (AD) neuropathology. Cortical tau deposits first in the entorhinal cortex and hippocampus and then propagates to neocortex in an Aß-dependent manner. Tau also tends to accumulate earlier in higher-order association cortex than in lower-order primary sensory-motor cortex. While previous research has examined the production and spread of tau, little attention has been paid to its clearance. Low-frequency (<0.1 Hz) global brain activity during the resting state is coupled with cerebrospinal fluid (CSF) flow and potentially reflects glymphatic clearance. Here we report that tau deposition in subjects with evaluated Aß, accompanied by cortical thinning and cognitive decline, is strongly associated with decreased coupling between CSF flow and global brain activity. Substantial modulation of global brain activity is also manifested as propagating waves of brain activation between higher- and lower-order regions, resembling tau spreading. Together, the findings suggest an important role of resting-state global brain activity in AD tau pathology.

Improving the Performance and Stability of TIC and ICE.

Takeuchi's Information Criterion (TIC) was introduced as a generalization of Akaike's Information Criterion (AIC) in 1976. Though TIC avoids many of AIC's strict requirements and assumptions, it is only rarely used. One of the reasons for this is that the trace term introduced in TIC is numerically unstable and computationally expensive to compute. An extension of TIC called ICE was published in 2021, which allows this trace term to be used for model fitting (where it was primarily compared to L2 regularization) instead of just model selection. That paper also examined numerically stable and computationally efficient approximations that could be applied to TIC or ICE, but these approximations were only examined on small synthetic models. This paper applies and extends these approximations to larger models on real datasets for both TIC and ICE. This work shows the practical models may use TIC and ICE in a numerically stable way to achieve superior results at a reasonable computational cost.

Optimizing quantification of MK6240 tau PET in unimpaired older adults.

Accurate measurement of Alzheimer's disease (AD) pathology in older adults without significant clinical impairment is critical to assessing intervention strategies aimed at slowing AD-related cognitive decline. The U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (POINTER) is a 2-year randomized controlled trial to evaluate the effect of multicomponent risk reduction strategies in older adults (60-79 years) who are cognitively unimpaired but at increased risk for cognitive decline/dementia due to factors such as cardiovascular disease and family history. The POINTER Imaging ancillary study is collecting tau-PET ([18F]MK6240), beta-amyloid (Aß)-PET ([18F]florbetaben [FBB]) and MRI data to evaluate neuroimaging biomarkers of AD and cerebrovascular pathophysiology in this at-risk sample. Here 481 participants (70.0±5.0; 66% F) with baseline MK6240, FBB and structural MRI scans were included. PET scans were coregistered to the structural MRI which was used to create FreeSurfer-defined reference regions and target regions of interest (ROIs). We also created off-target signal (OTS) ROIs to examine the magnitude and distribution of MK6240 OTS across the brain as well as relationships between OTS and age, sex, and race. OTS was unimodally distributed, highly correlated across OTS ROIs and related to younger age and sex but not race. Aiming to identify an optimal processing approach for MK6240 that would reduce the influence of OTS, we compared our previously validated MRI-guided standard PET processing and 6 alternative approaches. The alternate approaches included combinations of reference region erosion and meningeal OTS masking before spatial smoothing as well as partial volume correction. To compare processing approaches we examined relationships between target ROIs (entorhinal cortex (ERC), hippocampus or a temporal meta-ROI (MetaROI)) SUVR and age, sex, race, Aß and a general cognitive status measure, the Modified Telephone Interview for Cognitive Status (TICSm). Overall, the processing approaches performed similarly, and none showed a meaningful improvement over standard processing. Across processing approaches we observed previously reported relationships with MK6240 target ROIs including positive associations with age, an Aß+> Aß- effect and negative associations with cognition. In sum, we demonstrated that different methods for minimizing effects of OTS, which is highly correlated across the brain within subject, produced no substantive change in our performance metrics. This is likely because OTS contaminates both reference and target regions and this contamination largely cancels out in SUVR data. Caution should be used when efforts to reduce OTS focus on target or reference regions in isolation as this may exacerbate OTS contamination in SUVR data.

Quantification of amyloid beta and tau PET without a structural MRI.

INTRODUCTION: Relying on magnetic resonance imaging (MRI) for quantification of positron emission tomography (PET) images may limit generalizability of the results. We evaluated several MRI-free approaches for amyloid beta (Aß) and tau PET quantification relative to MRI-dependent quantification cross-sectionally and longitudinally. METHODS: We compared baseline MRI-free and MRI-dependent measurements of Aß PET ([18F]florbetapir [FBP], N = 1290, [18F]florbetaben [FBB], N = 290) and tau PET ([18F]flortaucipir [FTP], N = 768) images with respect to continuous and dichotomous agreement, effect sizes of Aß+ impaired versus Aß- unimpaired groups, and longitudinal standardized uptake value ratio (SUVR) slopes in a subset of individuals. RESULTS: The best-performing MRI-free approaches had high continuous and dichotomous agreement with MRI-dependent SUVRs for Aß PET and temporal flortaucipir (R2 ≥0.95; ± agreement ≥92%) and for Alzheimer's disease-related effect sizes; agreement was slightly lower for entorhinal flortaucipir and longitudinal slopes. DISCUSSION: There is no consistent loss of baseline or longitudinal AD-related signal with MRI-free Aß and tau PET image quantification.

Abnormal tau in amyloid PET negative individuals.

We examined the characteristics of individuals with biomarker evidence of tauopathy but without ß-amyloid (Aß) (A-T+) in relation to individuals with (A+T+) and without (A-T-) evidence of Alzheimer's disease (AD). We included 561 participants with Aß and tau PET from the Alzheimer's Disease Neuroimaging Initiative (ADNI). We compared A-T- (n = 316), A-T+ (n = 63), and A+T+ (n = 182) individuals on demographics, amyloid, tau, hippocampal volumes, and cognition. A-T+ individuals were low on apolipoprotein E ɛ4 prevalence (17%) and had no evidence of subtly elevated brain Aß within the negative range. The severity of tau deposition, hippocampal atrophy, and cognitive dysfunction in the A-T+ group was intermediate between A-T- and A+T+ (all p < 0.001). Tau uptake patterns in A-T+ individuals were heterogeneous, but approximately 29% showed tau deposition in the medial temporal lobe only, consistent with primary age-related tauopathy and an additional 32% showed a pattern consistent with AD. A-T+ individuals also share other features that are characteristic of AD such as cognitive impairment and neurodegeneration, but this group is heterogeneous and likely reflects more than one disorder.

Information-Corrected Estimation: A Generalization Error Reducing Parameter Estimation Method.

Modern computational models in supervised machine learning are often highly parameterized universal approximators. As such, the value of the parameters is unimportant, and only the out of sample performance is considered. On the other hand much of the literature on model estimation assumes that the parameters themselves have intrinsic value, and thus is concerned with bias and variance of parameter estimates, which may not have any simple relationship to out of sample model performance. Therefore, within supervised machine learning, heavy use is made of ridge regression (i.e., L2 regularization), which requires the the estimation of hyperparameters and can be rendered ineffective by certain model parameterizations. We introduce an objective function which we refer to as Information-Corrected Estimation (ICE) that reduces KL divergence based generalization error for supervised machine learning. ICE attempts to directly maximize a corrected likelihood function as an estimator of the KL divergence. Such an approach is proven, theoretically, to be effective for a wide class of models, with only mild regularity restrictions. Under finite sample sizes, this corrected estimation procedure is shown experimentally to lead to significant reduction in generalization error compared to maximum likelihood estimation and L2 regularization.

Validation of amyloid PET positivity thresholds in centiloids: a multisite PET study approach.

BACKGROUND: Inconsistent positivity thresholds, image analysis pipelines, and quantitative outcomes are key challenges of multisite studies using more than one ß-amyloid (Aß) radiotracer in positron emission tomography (PET). Variability related to these factors contributes to disagreement and lack of replicability in research and clinical trials. To address these problems and promote Aß PET harmonization, we used [18F]florbetaben (FBB) and [18F]florbetapir (FBP) data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) to derive (1) standardized Centiloid (CL) transformations and (2) internally consistent positivity thresholds based on separate young control samples. METHODS: We analyzed Aß PET data using a native-space, automated image processing pipeline that is used for PET quantification in many large, multisite AD studies and trials and made available to the research community. With this pipeline, we derived SUVR-to-CL transformations using the Global Alzheimer's Association Interactive Network data; we used reference regions for cross-sectional (whole cerebellum) and longitudinal (subcortical white matter, brain stem, whole cerebellum) analyses. Finally, we developed a FBB positivity threshold using an independent young control sample (N=62) with methods parallel to our existing FBP positivity threshold and validated the FBB threshold using a data-driven approach in ADNI participants (N=295). RESULTS: The FBB threshold based on the young sample (1.08; 18 CL) was consistent with that of the data-driven approach (1.10; 21 CL), and the existing FBP threshold converted to CL with the derived transformation (1.11; 20 CL). The following equations can be used to convert whole cerebellum- (cross-sectional) and composite- (longitudinal) normalized FBB and FBP data quantified with the native-space pipeline to CL units: [18F]FBB: CLwhole cerebellum = 157.15 × SUVRFBB - 151.87; threshold=1.08, 18 CL [18F]FBP: CLwhole cerebellum = 188.22 × SUVRFBP - 189.16; threshold=1.11, 20 CL [18F]FBB: CLcomposite = 244.20 × SUVRFBB - 170.80 [18F]FBP: CLcomposite = 300.66 × SUVRFBP - 208.84 CONCLUSIONS: FBB and FBP positivity thresholds derived from independent young control samples and quantified using an automated, native-space approach result in similar CL values. These findings are applicable to thousands of available and anticipated outcomes analyzed using this pipeline and shared with the scientific community. This work demonstrates the feasibility of harmonized PET acquisition and analysis in multisite PET studies and internal consistency of positivity thresholds in standardized units.

Contemporary management of civilian penetrating cervicothoracic arterial injuries.

BACKGROUND: The management of arterial injury at the thoracic outlet has long hinged on the fundamental principles of extensile exposure and vascular anastomosis. Nonetheless, treatment options for such injuries have evolved to include both endovascular stent placement and temporary vascular shunts. The purpose of this study was to evaluate our recent experience with penetrating cervicothoracic arterial injuries in light of these developments in trauma care. METHODS: Patients with penetrating injuries to the innominate, carotid, subclavian, or axillary arteries managed at a single civilian trauma center between 2000 and 2013 were categorized as the modern era (ME) cohort. The management strategies and outcomes pertaining to the ME group were compared to those of previously reported experience (PE) concerning injuries to the innominate, carotid, subclavian, or axillary arteries at the same institution from 1974 to 1988. RESULTS: Over the two eras, there were 202 patients: 110 in the ME group and 92 in the PE group. Most of the injuries in both groups were managed with primary repair (45% vs. 46%; p = 0.89). A similar proportion of injuries in each group was managed with anticoagulation alone (14% vs. 10%; p = 0.40). In the ME group, two cases were managed with temporary shunt placement, and endovascular stent placement was performed in 12 patients. Outcomes were similar between the groups (bivariate comparison): mortality (ME, 15% vs. PE, 14%; p = 0.76), amputation following subclavian or axillary artery injury (ME, 5% vs. PE, 4%; p = 0.58), and posttreatment stroke following carotid injury (ME, 2% vs. PE, 6%; p = 0.57). CONCLUSIONS: Experience with penetrating arterial cervicothoracic injuries at a high-volume urban trauma center remained remarkably similar with respect to both anatomic distribution of injury and treatment. Conventional operative exposure and repair remain the cornerstone of treatment for most civilian cervicothoracic arterial injuries. LEVEL OF EVIDENCE: Therapeutic study, level V.

Suction evacuation of hemothorax: A prospective study.

BACKGROUND: Although tube thoracostomy is a common procedure after thoracic trauma, incomplete evacuation of fluid places the patient at risk for retained hemothorax. As little as 300 to 500 cm of blood may result in the need for an additional thoracostomy tube or, in more severe cases, lung entrapment and empyema. We hypothesized that suction evacuation of the thoracic cavity before tube placement would decrease the incidence of late complications. METHODS: Patients requiring tube thoracostomy within 96 hours of admission were prospectively identified and underwent suction evacuation of the pleural space (SEPS) before tube placement. These patients were compared to historical controls without suction evacuation. Demographics, admission vital signs, laboratory values, details of chest tube placement, and outcomes were collected on all patients. Multivariable logistic regression was used to compare outcomes between groups. RESULTS: A total of 199 patients were identified, consisting of 100 retrospective controls and 99 SEPS patients. There were no differences in age, sex, admission injury severity score or chest abbreviated injury score, admission laboratory values or vital signs, or hospital length of stay. Mean (SD) volume of hemothorax in SEPS patients was 220 (297) cm; with only 48% having a volume greater than 100 cm at the time of tube placement. Three patients developed empyema, and 19 demonstrated retained blood; there was no difference between SEPS and control patients. Suction evacuation of the pleural space was significantly protective against recurrent pneumothorax after chest tube removal (odds ratio, 0.332; 95% confidence interval, 0.148-0.745). CONCLUSION: Preemptive suction evacuation of the thoracic cavity did not have a significant impact on subsequent development of retained hemothorax or empyema. Suction evacuation of the pleural space significantly decreased incidence of recurrent pneumothorax after thoracostomy removal. Although the mechanism is unclear, such a benefit may make this simple procedure worthwhile. A larger sample size is required for validation and to determine if preemptive thoracic evacuation has a clinical benefit. LEVEL OF EVIDENCE: Therapeutic/care management study, level IV.