PET Measurements Research Articles

Florbetapir PET Measurements of Amyloid Plaque Deposition are More Closely Correlated with Cross‐Sectional and Longitudinal Cognitive and Clinical Measurements Using a White Matter Reference Region of Interest

AbstractBackgroundWe previously reported stronger associations of FDG‐PET measured glucose hypometabolism with florbetapir PET measured Aβ deposition quantified using Standard Uptake Value Ratio (SUVR) with a cerebral white matter reference region (SUVRwm) compared to the commonly used SUVR with cerebellar reference region (SUVRcrblm) both cross‐sectionally and longitudinally (Wang et al., AAIC 2021). This study compared cross‐sectional and longitudinal associations of SUVRwm and SUVRcrblm with various cognitive/clinical measuresMethodOur study population consisted of 1133 participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) including 206 participants clinically diagnosed with AD dementia, 563 with Mild Cognitive Impairment (MCI), and 364 cognitively unimpaired individuals (CU). We computed partial correlation of SUVRwm or SUVRcrblm, covarying out baseline age and years of education, with Mini Mental State Exam (MMSE); Clinical Dementia Rating Scale Sum Boxes and Global (CDR‐SB and CDGlobal); Alzheimer’s Disease Assessment Scale (ADAS11, ADAS13); Auditory Verbal Learning Test – Short Term Memory, Long Term Memory, and Total (AVLT STM, AVLT LTM, and AVLT Total respectively). Steiger’s Z‐test was used to compare SUVRwm and SUVRcrblm correlation coefficient differences with each of these cognitive/clinical measures at uncorrected p = 0.05 significance. Analyses were carried out over all subjects and within each diagnostic group, first for baseline data and then longitudinally.ResultCross sectionally, correlations were significantly stronger with SUVRwm than with SUVRcrblm for all subjects in all cognitive/clinical measures (all p<1.314E‐04) with the strongest correlation of SUVRwmRef with MMSE (r = ‐0.4717 for SUVRwm and r = ‐0.3463 for SUVRcrblm; p = 1.93E‐13). The strongest correlation within AD subjects was found between SUVRwm and MMSE (r = ‐0.1432 for SUVRwm and r = 0.0459 for SUVRcrblm; p = 9.7063E‐04).Longitudinally, stronger SUVRwm correlations than SUVRcrblm with each of these cognitive measures were also observed over all subjects (p<0.05), and significance with CDR‐SB and AVLT Total in AD; with MMSE, ADAS11, ADAS13, CDGlobal, CDR‐SB, AVLT Total in MCI; and with CDGlobal in CU.ConclusionThe use of cerebral white matter reference region for florbetapir PET SUVR quantification demonstrated stronger associations between amyloid deposition and cognitive measures than cerebellar reference region.

A 2.5D residual U‐Net for improved amyloid PET harmonization preserving spatial information

AbstractBackgroundMultiple amyloid tracers with varying characteristics pose a significant challenge to standardized interpretation and quantification of amyloid PET measurements. We previously demonstrated that a deep learning based 2D residual inception encoder‐decoder network (RIED‐Net) architecture improved harmonization of florbetapir (FBP) and PiB PET. However, 2D networks fail to capture spatial information among image slices and 3D networks with more parameters require larger datasets and powerful computation for training. Here, we investigate the performance of a 2.5D approach to further improve harmonization preserving spatial information.Method92 PiB‐FBP image pairs from Open Access Series of Imaging Studies (OASIS) were processed using established pipelines to extract regional standard uptake value ratios (SUVRs), mean cortical SUVRs (mcSUVRs), and SUVR images. A 2.5D U‐Net model with residual connections was implemented to learn the nonlinear mappings from the image pairs. Input to the network is a stack of 3 adjacent FBP slices along a particular view, providing extra spatial information about volumetric data. The output of network is a stack of corresponding 3 PiB slices. Multi‐slice output avoids averaging/blurry effects common in traditional 2.5D approaches. 10‐fold cross‐validation was implemented on axial, coronal and sagittal views separately to generate synthetic PiB SUVR imaging from FBP data. The average synthetic PiB image from axial, coronal and sagittal views was used for performance evaluation. Correlation was evaluated between the virtual PiB mcSUVR derived from imputed PiB vs. the real PiB mcSUVR and voxel‐wise between the imputed vs. real PiB SUVR images.ResultThe agreement of mcSUVR improved from r = 0.90 between PiB and FBP to r = 0.95 between synthetic and real PiB SUVR images (p<0.0001) in cross‐validation dataset. Additionally, imputed PiB SUVR images were visually more similar to real PiB SUVR images than FBP. Voxel‐wise correlation improved from 0.88 to 0.93 (p<0.0001).ConclusionOur proposed 2.5D Residual U‐Net for synthetic imaging was able to learn voxel‐wise nonlinear associations between FBP and PiB images. The model trained in 2.5D approach with additional spatial information, was able to significantly improve agreements of amyloid burden measurement from two tracers and generate PiB SUVR images that are visually more similar to real PiB SUVR images than FBP.

Long-term prognostic value of [15O]H2O PET imaging in patients suspected for cerebral hemodynamic insufficiency

ObjectivesQuantitative regional cerebral perfusion (rCBF) measurements using [15O]H2O PET with arterial cannulation and acetazolamide (ACZ) challenge have been reserved to identify high-risk patients that are candidates for by-pass operation. We aimed to assess the prognostic value of various parameters in quantitative [15O]H2O PET measurements in patients not subsequently undergoing surgery. MethodsWe identified 32 eligible patients who underwent [15O]H2O brain PET imaging for suspicion of hemodynamic insufficiency between 2009 and 2020. Cerebrovascular events were defined as new ischemic lesions on MRI, stroke, transient ischemic attack, vascular dementia. Follow-up period was 91 months (range: 26-146). rCBF before (rCBFbase) and after (rCBFacz) ACZ challenge and the relative increase (CVR), were examined in the anterior (ACA), middle (MCA), and posterior (PCA) cerebral artery territories of the affected hemisphere, and the most recent MRI scans were scored for infarcts and white matter lesions. ResultsReceiver operating characteristic (ROC) curve analysis showed higher prognostic accuracy for rCBFacz(AUC:0.82) compared to CVR (AUC:0.72) and rCBFbase (AUC:0.77). ROC AUC, optimal thresholds (and corresponding sensitivity/specificity/accuracy) for rCBFacz after ACZ in individual territories were 0.79 and 37.8 mL 100g−1 min−1 (0.81/0.63/0.72) for the ACA, 0.84 and 32 mL 100g−1 min−1 (0.81/0.75/0.78) for the MCA, and 0.70 and 43.9 ml/(mL 100g−1 min−1 (0.81/0.43/0,62) for the PCA. Kaplan Meier survival curve showed longer event-free survival in patients with rCBFacz below cut-off (p=0.007). In multivariate analysis rCBFacz remained a significant predictor when correcting for age. ConclusionQuantitative rCBF measurements after ACZ challenge with [15O]H2O PET provided high prognostic value for future cerebrovascular events.

A novel model-based equation for size dependent mean recovery coefficients for spheres and other shapes

BackgroundIn NM-imaging, theoretical curves for the recovery coefficient (RC) of the signal maximum and mean are known for spheres and cubes, if a 3D Gaussian PSF is assumed. The RC of the maximum is also known for cylinders. For these and other shapes empirical equations with one or two fit-parameters have been utilized. MethodsAn equation for the RC for large objects of arbitrary shape is derived and generalized into an empirical equation for smaller objects, which is verified by numerical simulations. The proposed equation is compared to published results on SPECT kidney phantom measurements and to PET measurements on the NEMA IEC PET body phantom with six spheres. ResultsThe signal loss (1-RC) for large spheres is inversely proportional to the radius, where the slope is proportional to the FWHM of the spatial resolution. For non-spherical shapes the generalized instead of the volume equivalent radius should be utilized. For smaller objects, an equation with one added empirical fit-parameter is presented. It is demonstrated that the EANM-guidelines’ two-parameter logistic function results in a poor fit if the theoretical slope and inverse proportionality are forced and it gives a suboptimal fit when both parameters are fitted. ConclusionsA novel model-based equation for the mean RC-curve is derived. It can be used for arbitrary shapes as long as the sphericity is taken into account and it is accurate down to RC = 10 %. One parameter is directly related to the spatial resolution, while the other is a shape depending fit-parameter.

The regional pattern of age-related synaptic loss in the human brain differs from gray matter volume loss: in vivo PET measurement with [11C]UCB-J.

Aging is a major societal concern due to age-related functional losses. Synapses are crucial components of neural circuits, and synaptic density could be a sensitive biomarker to evaluate brain function. [11C]UCB-J is a positron emission tomography (PET) ligand targeting synaptic vesicle glycoprotein 2A (SV2A), which can be used to evaluate brain synaptic density in vivo. We evaluated age-related changes in gray matter synaptic density, volume, and blood flow using [11C]UCB-J PET and magnetic resonance imaging (MRI) in a wide age range of 80 cognitive normal subjects (21-83 years old). Partial volume correction was applied to the PET data. Significant age-related decreases were found in 13, two, and nine brain regions for volume, synaptic density, and blood flow, respectively. The prefrontal cortex showed the largest volume decline (4.9% reduction per decade: RPD), while the synaptic density loss was largest in the caudate (3.6% RPD) and medial occipital cortex (3.4% RPD). The reductions in caudate are consistent with previous SV2A PET studies and likely reflect that caudate is the site of nerve terminals for multiple major tracts that undergo substantial age-related neurodegeneration. There was a non-significant negative relationship between volume and synaptic density reductions in 16 gray matter regions. MRI and [11]C-UCB-J PET showed age-related decreases of gray matter volume, synaptic density, and blood flow; however, the regional patterns of the reductions in volume and SV2A binding were different. Those patterns suggest that MR-based measures of GM volume may not be directly representative of synaptic density.

Multimodal prediction of neoadjuvant treatment outcome by serial FDG PET and MRI in women with locally advanced breast cancer

PurposeTo investigate combined MRI and 18F-FDG PET for assessing breast tumor metabolism/perfusion mismatch and predicting pathological response and recurrence-free survival (RFS) in women treated for breast cancer.MethodsPatients undergoing neoadjuvant chemotherapy (NAC) for locally-advanced breast cancer were imaged at three timepoints (pre, mid, and post-NAC), prior to surgery. Imaging included diffusion-weighted and dynamic contrast-enhanced (DCE-) MRI and quantitative 18F-FDG PET. Tumor imaging measures included apparent diffusion coefficient, peak percent enhancement (PE), peak signal enhancement ratio (SER), functional tumor volume, and washout volume on MRI and standardized uptake value (SUVmax), glucose delivery (K1) and FDG metabolic rate (MRFDG) on PET, with percentage changes from baseline calculated at mid- and post-NAC. Associations of imaging measures with pathological response (residual cancer burden [RCB] 0/I vs. II/III) and RFS were evaluated.ResultsThirty-five patients with stage II/III invasive breast cancer were enrolled in the prospective study (median age: 43, range: 31–66 years, RCB 0/I: N = 11/35, 31%). Baseline imaging metrics were not significantly associated with pathologic response or RFS (p > 0.05). Greater mid-treatment decreases in peak PE, along with greater post-treatment decreases in several DCE-MRI and 18F-FDG PET measures were associated with RCB 0/I after NAC (p < 0.05). Additionally, greater mid- and post-treatment decreases in DCE-MRI (peak SER, washout volume) and 18F-FDG PET (K1) were predictive of prolonged RFS. Mid-treatment decreases in metabolism/perfusion ratios (MRFDG/peak PE, MRFDG/peak SER) were associated with improved RFS.ConclusionMid-treatment changes in both PET and MRI measures were predictive of RCB status and RFS following NAC. Specifically, our results indicate a complementary relationship between DCE-MRI and 18F-FDG PET metrics and potential value of metabolism/perfusion mismatch as a marker of patient outcome.

Assessing vaccine hesitancy and support for vaccination requirements for pets and potential Spillovers from humans

BackgroundGrowing vaccination hesitancy is well-document among humans. However, we know very little about vaccination hesitancy for pets as well as whether the two phenomena are interconnected. Moreover, support for pet vaccination requirements also remain underassessed. MethodsWe fielded a large, national survey (N = 3,958) on August 18 and August 19, 2023, to assess U.S. public opinion about the vaccination status of dogs (rabies, canine parvovirus, canine distemper, canine influenza, and Lyme disease) and cats (rabies, feline panleukopenia (parvo), feline herpesvirus-1, feline chlamydia, and feline Bordetella) in the United States. We also queried respondents about their support for vaccination requirements for the 10 diseases. ResultsWe find that the vast majority of cats and dogs are vaccinated. However, a substantial minority of pets is not, particularly for cats and for non-core vaccines. We find that attitudinal measures of human and pet vaccine hesitancy are closely related to each other. Moreover, they are strong predictors of vaccine behavior. Measures of vaccine hesitancy are also strong predictors of support for vaccination mandates. Common measures used to assess human vaccine hesitancy showed inconsistent effects. However, pet vaccinations appear to be less politically polarizing. ConclusionThe high correlation between pet and human measures raises the stake for public health efforts to improve attitudes about vaccines and vaccination rates across the board. Strong support for vaccination requirements should encourage policymakers to explore policy change. Moreover, veterinarians and their associations should consider expanding the number of core vaccinations.

Poorer aging trajectories are associated with elevated serotonin synthesis capacity.

The dorsal raphe nucleus (DRN) is one of the earliest targets of Alzheimer's disease-related tau pathology and is a major source of brain serotonin. We used [18F]Fluoro-m-tyrosine ([18F]FMT) PET imaging to measure serotonin synthesis capacity in the DRN in 111 healthy adults (18-85 years-old). Similar to reports in catecholamine systems, we found elevated serotonin synthesis capacity in older adults relative to young. To establish the structural and functional context within which serotonin synthesis capacity is elevated in aging, we examined relationships among DRN [18F]FMT net tracer influx (Ki) and longitudinal changes in cortical thickness using magnetic resonance imaging, longitudinal changes in self-reported depression symptoms, and AD-related tau and β-amyloid (Aβ) pathology using cross-sectional [18F]Flortaucipir and [11C]Pittsburgh compound-B PET respectively. Together, our findings point to elevated DRN [18F]FMT Ki as a marker of poorer aging trajectories. Older adults with highest serotonin synthesis capacity showed greatest temporal lobe cortical atrophy. Cortical atrophy was associated with increasing depression symptoms over time, and these effects appeared to be strongest in individuals with highest serotonin synthesis capacity. We did not find direct relationships between serotonin synthesis capacity and AD-related pathology. Exploratory analyses revealed nuanced effects of sex within the older adult group. Older adult females showed the highest DRN synthesis capacity and exhibited the strongest relationships between entorhinal cortex tau pathology and increasing depression symptoms. Together these findings reveal PET measurement of the serotonin system to be a promising marker of aging trajectories relevant to both AD and affective changes in older age.

Structural and molecular cholinergic imaging markers of cognitive decline in Parkinson's disease.

Cognitive decline in Parkinson's disease is related to cholinergic system degeneration, which can be assessed in vivo using structural MRI markers of basal forebrain volume and PET measures of cortical cholinergic activity. In the present study we aimed to examine the interrelation between basal forebrain degeneration and PET-measured depletion of cortical acetylcholinesterase activity as well as their relative contribution to cognitive impairment in Parkinson's disease. This cross-sectional study included 143 Parkinson's disease participants without dementia and 52 healthy control participants who underwent structural MRI, PET scanning with 11C-methyl-4-piperidinyl propionate (PMP) as a measure of cortical acetylcholinesterase activity, and a detailed cognitive assessment. Based on the fifth percentile of the overall cortical PMP PET signal from the control group, people with Parkinson's disease were subdivided into a normo-cholinergic (n = 94) and a hypo-cholinergic group (n = 49). Volumes of functionally defined posterior and anterior basal forebrain subregions were extracted using an established automated MRI volumetry approach based on a stereotactic atlas of cholinergic basal forebrain nuclei. We used Bayesian t-tests to compare basal forebrain volumes between controls, and normo- and hypo-cholinergic Parkinson's participants after covarying out age, sex and years of education. Associations between the two cholinergic imaging measures were assessed across all people with Parkinson's disease using Bayesian correlations and their respective relations with performance in different cognitive domains were assessed with Bayesian ANCOVAs. As a specificity analysis, hippocampal volume was added to the analysis. We found evidence for a reduction of posterior basal forebrain volume in the hypo-cholinergic compared to both normo-cholinergic Parkinson's disease [Bayes factor against the null model (BF10) = 8.2] and control participants (BF10 = 6.0), while for the anterior basal forebrain the evidence was inconclusive (BF10 < 3). In continuous association analyses, posterior basal forebrain volume was significantly associated with cortical PMP PET signal in a temporo-posterior distribution. The combined models for the prediction of cognitive scores showed that both cholinergic markers (posterior basal forebrain volume and cortical PMP PET signal) were independently related to multi-domain cognitive deficits, and were more important predictors for all cognitive scores, including memory scores, than hippocampal volume. We conclude that degeneration of the posterior basal forebrain in Parkinson's disease is accompanied by functional cortical changes in acetylcholinesterase activity and that both PET and MRI cholinergic imaging markers are independently associated with multi-domain cognitive deficits in Parkinson's disease without dementia. Comparatively, hippocampal atrophy only seems to have minimal involvement in the development of early cognitive impairment in Parkinson's disease.

Neurovascular coupling is optimized to compensate for the increase in proton production from nonoxidative glycolysis and glycogenolysis during brain activation and maintain homeostasis of pH, pCO2, and pO2.

During transient brain activation cerebral blood flow (CBF) increases substantially more than cerebral metabolic rate of oxygen consumption (CMRO2) resulting in blood hyperoxygenation, the basis of BOLD-fMRI contrast. Explanations for the high CBF versus CMRO2 slope, termed neurovascular coupling (NVC) constant, focused on maintenance of tissue oxygenation to support mitochondrial ATP production. However, paradoxically the brain has a 3-fold lower oxygen extraction fraction (OEF) than other organs with high energy requirements, like heart and muscle during exercise. Here, we hypothesize that the NVC constant and the capillary oxygen mass transfer coefficient (which in combination determine OEF) are co-regulated during activation to maintain simultaneous homeostasis of pH and partial pressure of CO2 and O2 (pCO2 and pO2). To test our hypothesis, we developed an arteriovenous flux balance model for calculating blood and brain pH, pCO2, and pO2 as a function of baseline OEF (OEF0), CBF, CMRO2, and proton production by nonoxidative metabolism coupled to ATP hydrolysis. Our model was validated against published brain arteriovenous difference studies and then used to calculate pH, pCO2, and pO2 in activated human cortex from published calibrated fMRI and PET measurements. In agreement with our hypothesis, calculated pH, pCO2, and pO2 remained close to constant independently of CMRO2 in correspondence to experimental measurements of NVC and OEF0. We also found that the optimum values of the NVC constant and OEF0 that ensure simultaneous homeostasis of pH, pCO2, and pO2 were remarkably similar to their experimental values. Thus, the high NVC constant is overall determined by proton removal by CBF due to increases in nonoxidative glycolysis and glycogenolysis. These findings resolve the paradox of the brain's high CBF yet low OEF during activation, and may contribute to explaining the vulnerability of brain function to reductions in blood flow and capillary density with aging and neurovascular disease.

Characterization of a Novel M4 PAM PET Radioligand [11C]PF06885190 in Nonhuman Primates (NHP).

Muscarinic acetylcholine receptors (mAChR), including M4, draw attention as therapeutic targets for several neurodegenerative diseases including Alzheimer's disease (AD). PET imaging of M4 positive allosteric modulator (PAM) allows qualification of the distribution as well as the expression of this receptor under physiological conditions and thereby helps to assess the receptor occupancy (RO) of a drug candidate. In this study, our aims were (a) to synthesize a novel M4 PAM PET radioligand [11C]PF06885190 (b) to evaluate the brain distribution of [11C]PF06885190 in nonhuman primates (NHP) and (c) to analyze its radiometabolites in the blood plasma of NHP. Radiolabeling of [11C]PF06885190 was accomplished via N-methylation of the precursor. Six PET measurements were performed using two male cynomolgus monkeys, where three PET measurements were at baseline, two after pretreatment with a selective M4 PAM compound CVL-231 and one after pretreatment with donepezil. The total volume of distribution (VT) of [11C]PF06885190 was examined using Logan graphical analysis with arterial input function. Radiometabolites were analyzed in monkey blood plasma using gradient HPLC system. Radiolabeling of [11C]PF06885190 was successfully accomplished and the radioligand was found to be stable in the formulation, with radiochemical purity exceeding 99% 1 h after the end of the synthesis. [11C]PF06885190 was characterized in the cynomolgus monkey brain where a moderate brain uptake was found at the baseline condition. However, it showed fast wash-out as it dropped to half of the peak at around 10 min. Change of VT from baseline was around -10% after pretreatment with a M4 PAM, CVL-231. Radiometabolite studies showed relatively fast metabolism. Although sufficient brain uptake of [11C]PF06885190 was observed, these data suggest that [11C]PF06885190 might have too low specific binding in the NHP brain to be further applied in PET imaging.

Thalamic‐insomnia phenotype in genetic E200K Creutzfeldt‐Jakob disease: A PET/MRI study

AbstractBackgroundInsomnia and thalamic involvement are hallmarks of fatal familial insomnia; however, it was occasionally reported that genetic E200K Creutzfeldt‐Jakob disease (CJD) patients had also manifested thalamic‐insomnia phenotype. The study aimed to explore the clinical and neuroimage characteristics of genetic E200K CJD by comprehensive neuroimage analysis.MethodsSix genetic CJD patients carried Glu to Lys change at codon 200 (E200K) mutations on prion protein gene (PRNP), thirteen sporadic CJD (sCJD), and twenty‐two age‐ and sex‐matched normal controls were enrolled in the study. All participants completed hybrid positron emission tomography/ magnetic resonance imaging (PET/MRI) examinations. The high signal was visually inspected on diffusion weighted imaging (DWI) sequence. 18F‐fluorodeoxyglucose positron emission tomography (18F‐FDG‐PET) and structural images were quantitively analyzed by statistically parameter mapping (SPM). Clinical and image characteristics are compared between genetic E200K CJD patients and sporadic CJD patients.ResultsThere was no group difference in age (49.0±7.1 versus 55.0±4.9 versus 52.7±7.3, p = 0.193) and gender (3/3 versus 4/9 versus 11/11, p = 0.513) between genetic E200K CJD, sCJD, and normal controls. Insomnia was the main complaint in the genetic E200K CJD patients’ group (4/2 versus 1/12, p = 0.007). Hyperintensity, hypometabolism but not predominant atrophy of the thalamus was found by visual inspection in genetic E200K CJD patients. A decreased trend was found on gray matter volume (uncorrected p&lt;0.0001) and metabolism (FWE corrected) of the thalamus in genetic E200K patients.ConclusionThe clinical and image characteristics of genetic E200K CJD mimic fatal familial insomnia, manifested as a thalamic‐insomnia phenotype, indicating some specific underlying pathological changes might exist in E200K mutations. PET measurement is a sensitive approach to help identify the functional changes of the thalamus in prion disease.

Weight increases and decreases show distinct association with Alzheimer’s Disease in different age and APOE‐ε4 status

AbstractBackgroundHigh and low body mass index (BMI) may increase the risk of Alzheimer’s disease (AD) in mid‐life (age&lt;65) and late‐life (age≥65) respectively. However, it is still not fully understood about the associations of BMI changes with AD progression as well as how APOE‐ε4 allele modulates their relationships in mid‐life and late‐life. In this study, we aimed to determine how BMI changes and APOE‐ε4 allele relate to longitudinal β‐amyloid (Aβ) accumulation, tau aggregation, neurodegeneration and cognitive decline in mid‐life and late‐life.MethodWe examined 325 cognitively unimpaired and 391 mild cognitive impairment Alzheimer’s Disease Neuroimaging Initiative participants with longitudinal 18F‐florbetapir (FBP) Aβ PET and BMI measurements. Among of them, 486, 707 and 710 had longitudinal 18F‐fluorodeoxyglucos (FDG) PET, adjusted hippocampal volume (aHCV) and memory scores, and 246 participants had follow‐up 18F‐flortaucipir (FTP) tau PET data measured at a median of 5.5 years post baseline FBP scan. We investigated the associations of BMI slopes with longitudinal changes of AD typical summary cortical region FBP PET and FDG PET, aHCV and memory scores, and follow‐up Temporal‐metaROI FTP PET in different Aβ status (Aβ‐ and Aβ+), APOE‐ε4 status (carriers and non‐carriers), age (mid‐life and late‐life).ResultWe found faster BMI decreases accelerated the rates of Aβ accumulation (Fig.1D, standardized β (βstd) = ‐0.29, p = 0.002), hypometabolism (Fig.3D, βstd = 0.24, p = 0.03), hippocampal atrophy (Fig.3H, βstd = 0.29, p = 0.002), and memory decline (Fig.4D, βstd = 0.28, p = 0.005), and induced marginally higher follow‐up tau deposition (Fig.2D, βstd = ‐0.26, p = 0.09) in Aβ+ late‐life APOE‐ε4 non‐carriers but not in APOE‐ε4 carriers. In contrast, BMI increases were related to faster (Fig.1C, βstd = 0.80, p &lt; 0.001) rates of Aβ accumulation in Aβ+ mid‐life APOE‐ε4 carriers but not in APOE‐ε4 non‐carriers.ConclusionThese findings suggest that weight increase in mid‐life APOE‐ε4 carriers and weight loss in late‐life APOE‐ε4 non‐carriers are environmental risk factors of AD, highlighting the importance of tracking BMI data in Aβ+ individuals.

Increased spatial extent of cerebral tau PET elevations in former NFL and college football players from the DIAGNOSE CTE Research Project

AbstractBackgroundWe previously found greater spatial extent of flortaucipir (tau) PET elevations in Arizona‐Boston (DETECT) Study of 26 former National Football League (NFL) players than in 31 normal controls—using a voxel‐based Majority Count Statistics (MCS) algorithm which enabled us to detect tau PET abnormalities in the player group free from the inflated Type 1 error associated with voxel‐wise multiple comparisons (Stern et al, NEJM 2019). We now confirm this finding in a larger group of former NFL players, former college football players and asymptomatic controls without exposure to repetitive head impacts from the DIAGNOSE CTE Research Project.MethodFlortaucipir PET images were acquired in 106 former NFL players, 51 former college players, and 53 unexposed controls, 57.71+8.37 years of age. An automated algorithm (SPM12) and co‐registered MRIs were used to spatially normalize PET images into Montreal Neurological Institute template, and compute statistical brain maps of group differences in regional cerebral‐to‐cerebellar crus1 standard uptake value ratio (SUVR), controlling for the participants’ age and race with P≤0.005, uncorrected for multiple comparisons. Our MCS was then applied with 1,000 iterations to test the hypothesis that there would be a greater number of cerebral voxels with SUVR elevations in each and combined player group versus control group, as well as between the NFL versus college player groups.ResultAs predicted, the NFL, college player and aggregate player groups each had significantly more cerebral voxels with flortaucipir SUVR elevations than in the control group (postulated vs opposite directions: 53,879 vs 79, 79,552 vs 89 and 100,837 vs 86 voxels), respectively, MCS P&lt;0.001, but not between former NFL and former college players (482 versus 306, p = 0.305).ConclusionUsing a voxel based MCS analysis, former NFL and college football players have a greater spatial extent of elevations in tau PET measurements than asymptomatic controls. Additional work is needed to clarify the biological nature of these small but spatially extensive elevations, the extent to which they are related to symptom severity, cognitive performance, repetitive head impact exposure, and other risk or resilience factors, and the extent to which they are associated with subsequent clinical decline.

New PET Measures of Functional Brain Fractal Dimensions Show Significant Differences for Cortical Grey and White Matter and also in Near Normal vs. Insulin Resistant Patients

New PET Measures of Functional Brain Fractal Dimensions Show Significant Differences for Cortical Grey and White Matter and also in Near Normal vs. Insulin Resistant Patients

Parasagittal dural space hypertrophy and amyloid-β deposition in Alzheimer's disease.

One of the pathological hallmarks of Alzheimer's and related diseases is the increased accumulation of protein amyloid-β in the brain parenchyma. As such, recent studies have focused on characterizing protein and related clearance pathways involving perivascular flow of neurofluids, but human studies of these pathways are limited owing to limited methods for evaluating neurofluid circulation non-invasively in vivo. Here, we utilize non-invasive MRI methods to explore surrogate measures of CSF production, bulk flow and egress in the context of independent PET measures of amyloid-β accumulation in older adults. Participants (N = 23) were scanned at 3.0 T with 3D T2-weighted turbo spin echo, 2D perfusion-weighted pseudo-continuous arterial spin labelling and phase-contrast angiography to quantify parasagittal dural space volume, choroid plexus perfusion and net CSF flow through the aqueduct of Sylvius, respectively. All participants also underwent dynamic PET imaging with amyloid-β tracer 11C-Pittsburgh Compound B to quantify global cerebral amyloid-β accumulation. Spearman's correlation analyses revealed a significant relationship between global amyloid-β accumulation and parasagittal dural space volume (rho = 0.529, P = 0.010), specifically in the frontal (rho = 0.527, P = 0.010) and parietal (rho = 0.616, P = 0.002) subsegments. No relationships were observed between amyloid-β and choroid plexus perfusion nor net CSF flow. Findings suggest that parasagittal dural space hypertrophy, and its possible role in CSF-mediated clearance, may be closely related to global amyloid-β accumulation. These findings are discussed in the context of our growing understanding of the physiological mechanisms of amyloid-β aggregation and clearance via neurofluids.

Plasma NfL is associated with the APOE ε4 allele, brain imaging measurements of neurodegeneration, and lower recall memory scores in cognitively unimpaired late-middle-aged and older adults

BackgroundPlasma neurofilament light (NfL) is an indicator of neurodegeneration and/or neuroaxonal injury in persons with Alzheimer’s disease (AD) and a wide range of other neurological disorders. Here, we characterized and compared plasma NfL concentrations in cognitively unimpaired (CU) late-middle-aged and older adults with two, one, or no copies of the APOE ε4 allele, the major genetic risk factor for AD. We then assessed plasma NfL associations with brain imaging measurements of AD-related neurodegeneration (hippocampal atrophy and a hypometabolic convergence index [HCI]), brain imaging measurements of amyloid-β plaque burden, tau tangle burden and white matter hyperintensity volume (WMHV), and delayed and total recall memory scores.MethodsPlasma NfL concentrations were measured in 543 CU 69 ± 9 year-old participants in the Arizona APOE Cohort Study, including 66 APOE ε4 homozygotes (HM), 165 heterozygotes (HT), and 312 non-carriers (NC). Robust regression models were used to characterize plasma NfL associations with APOE ε4 allelic dose before and after adjustment for age, sex, and education. They were also used to characterize plasma NfL associations with MRI-based hippocampal volume and WMHV measurements, an FDG PET-based HCI, mean cortical PiB PET measurements of amyloid-β plaque burden and meta-region-of-interest (meta-ROI) flortaucipir PET measurements of tau tangle burden, and Auditory Verbal Learning Test (AVLT) Delayed and Total Recall Memory scores.ResultsAfter the adjustments noted above, plasma NfL levels were significantly greater in APOE ε4 homozygotes and heterozygotes than non-carriers and significantly associated with smaller hippocampal volumes (r = − 0.43), greater tangle burden in the entorhinal cortex and inferior temporal lobes (r = 0.49, r = 0.52, respectively), and lower delayed (r = − 0.27), and total (r = − 0.27) recall memory scores (p < 0.001). NfL levels were not significantly associated with PET measurements of amyloid-β plaque or total tangle burden.ConclusionsPlasma NfL concentrations are associated with the APOE ε4 allele, brain imaging biomarkers of neurodegeneration, and less good recall memory in CU late-middle-aged and older adults, supporting its value as an indicator of neurodegeneration in the preclinical study of AD.

Change in Cerebrospinal Fluid Tau Microtubule Binding Region Detects Symptom Onset, Cognitive Decline, Tangles, and Atrophy in Dominantly Inherited Alzheimer's Disease.

Identifying cerebrospinal fluid measures of the microtubule binding region of tau (MTBR-tau) species that reflect tau aggregation could provide fluid biomarkers that track Alzheimer's disease related neurofibrillary tau pathological changes. We examined the cerebrospinal fluid (CSF) MTBR-tau species in dominantly inherited Alzheimer's disease (DIAD) mutation carriers to assess the association with Alzheimer's disease (AD) biomarkers and clinical symptoms. Cross-sectional and longitudinal CSF from 229 DIAD mutation carriers and 130 mutation non-carriers had sequential characterization of N-terminal/mid-domain phosphorylated tau (p-tau) followed by MTBR-tau species and tau positron emission tomography (tau PET), other soluble tau and amyloid biomarkers, comprehensive clinical and cognitive assessments, and brain magnetic resonance imaging of atrophy. CSF MTBR-tau species located within the putative "border" region and one species corresponding to the "core" region of aggregates in neurofibrillary tangles (NFTs) increased during the presymptomatic stage and decreased during the symptomatic stage. The "border" MTBR-tau species were associated with amyloid pathology and CSF p-tau; whereas the "core" MTBR-tau species were associated stronger with tau PET and CSF measures of neurodegeneration. The ratio of the border to the core species provided a continuous measure of increasing amounts that tracked clinical progression and NFTs. Changes in CSF soluble MTBR-tau species preceded the onset of dementia, tau tangle increase, and atrophy in DIAD. The ratio of 4R-specific MTBR-tau (border) to the NFT (core) MTBR-tau species corresponds to the pathology of NFTs in DIAD and change with disease progression. The dynamics between different MTBR-tau species in the CSF may serve as a marker of tau-related disease progression and target engagement of anti-tau therapeutics. ANN NEUROL 2023;93:1158-1172.

Secretin modulates appetite via brown adipose tissue-brain axis

PurposeSecretin activates brown adipose tissue (BAT) and induces satiation in both mice and humans. However, the exact brain mechanism of this satiety inducing, secretin-mediated gut-BAT-brain axis is largely unknown.Methods and resultsIn this placebo-controlled, single-blinded neuroimaging study, firstly using [18F]-fluorodeoxyglucose (FDG) PET measures (n = 15), we established that secretin modulated brain glucose consumption through the BAT-brain axis. Predominantly, we found that BAT and caudate glucose uptake levels were negatively correlated (r = -0.54, p = 0.037) during secretin but not placebo condition. Then, using functional magnetic resonance imaging (fMRI; n = 14), we found that secretin improved inhibitory control and downregulated the brain response to appetizing food images. Finally, in a PET-fMRI fusion analysis (n = 10), we disclosed the patterned correspondence between caudate glucose uptake and neuroactivity to reward and inhibition, showing that the secretin-induced neurometabolic coupling patterns promoted satiation.ConclusionThese findings suggest that secretin may modulate the BAT-brain metabolic crosstalk and subsequently the neurometabolic coupling to induce satiation. The study advances our understanding of the secretin signaling in motivated eating behavior and highlights the potential role of secretin in treating eating disorders and obesity.Trial registrationEudraCT no. 2016-002373-35, registered 2 June 2016; Clinical Trials no. NCT03290846, registered 25 September 2017.

Brain aerobic glycolysis and resilience in Alzheimer disease

The distribution of brain aerobic glycolysis (AG) in normal young adults correlates spatially with amyloid-beta (Aβ) deposition in individuals with symptomatic and preclinical Alzheimer disease (AD). Brain AG decreases with age, but the functional significance of this decrease with regard to the development of AD symptomatology is poorly understood. Using PET measurements of regional blood flow, oxygen consumption, and glucose utilization-from which we derive AG-we find that cognitive impairment is strongly associated with loss of the typical youthful pattern of AG. In contrast, amyloid positivity without cognitive impairment was associated with preservation of youthful brain AG, which was even higher than that seen in cognitively unimpaired, amyloid negative adults. Similar findings were not seen for blood flow nor oxygen consumption. Finally, in cognitively unimpaired adults, white matter hyperintensity burden was found to be specifically associated with decreased youthful brain AG. Our results suggest that AG may have a role in the resilience and/or response to early stages of amyloid pathology and that age-related white matter disease may impair this process.