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BackgroundWhile Alzheimer disease (AD) and vascular dementia (VaD) may be accelerated by hypercholesterolemia, the mechanisms underlying this association are unclear. We tested whether dysregulation of cholesterol catabolism, through its conversion to primary bile acids (BAs), was associated with dementia pathogenesis.Methods and findingsWe used a 3-step study design to examine the role of the primary BAs, cholic acid (CA), and chenodeoxycholic acid (CDCA) as well as their principal biosynthetic precursor, 7α-hydroxycholesterol (7α-OHC), in dementia. In Step 1, we tested whether serum markers of cholesterol catabolism were associated with brain amyloid accumulation, white matter lesions (WMLs), and brain atrophy. In Step 2, we tested whether exposure to bile acid sequestrants (BAS) was associated with risk of dementia. In Step 3, we examined plausible mechanisms underlying these findings by testing whether brain levels of primary BAs and gene expression of their principal receptors are altered in AD. Step 1: We assayed serum concentrations CA, CDCA, and 7α-OHC and used linear regression and mixed effects models to test their associations with brain amyloid accumulation (N = 141), WMLs, and brain atrophy (N = 134) in the Baltimore Longitudinal Study of Aging (BLSA). The BLSA is an ongoing, community-based cohort study that began in 1958. Participants in the BLSA neuroimaging sample were approximately 46% male with a mean age of 76 years; longitudinal analyses included an average of 2.5 follow-up magnetic resonance imaging (MRI) visits. We used the Alzheimer's Disease Neuroimaging Initiative (ADNI) (N = 1,666) to validate longitudinal neuroimaging results in BLSA. ADNI is an ongoing, community-based cohort study that began in 2003. Participants were approximately 55% male with a mean age of 74 years; longitudinal analyses included an average of 5.2 follow-up MRI visits. Lower serum concentrations of 7α-OHC, CA, and CDCA were associated with higher brain amyloid deposition (p = 0.041), faster WML accumulation (p = 0.050), and faster brain atrophy mainly (false discovery rate [FDR] p = 4 million registrants from general practice clinics in the United Kingdom, we tested whether patients using BAS (BAS users; 3,208 with ≥2 prescriptions), which reduce circulating BAs and increase cholesterol catabolism, had altered dementia risk compared to those on non-statin lipid-modifying therapies (LMT users; 23,483 with ≥2 prescriptions). Patients in the study (BAS/LMT) were approximately 34%/38% male and with a mean age of 65/68 years; follow-up time was 4.7/5.7 years. We found that BAS use was not significantly associated with risk of all-cause dementia (hazard ratio (HR) = 1.03, 95% confidence interval (CI) = 0.72-1.46, p = 0.88) or its subtypes. We found a significant difference between the risk of VaD in males compared to females (p = 0.040) and a significant dose-response relationship between BAS use and risk of VaD (p-trend = 0.045) in males.Step 3: We assayed brain tissue concentrations of CA and CDCA comparing AD and control (CON) samples in the BLSA autopsy cohort (N = 29). Participants in the BLSA autopsy cohort (AD/CON) were approximately 50%/77% male with a mean age of 87/82 years. We analyzed single-cell RNA sequencing (scRNA-Seq) data to compare brain BA receptor gene expression between AD and CON samples from the Religious Orders Study and Memory and Aging Project (ROSMAP) cohort (N = 46). ROSMAP is an ongoing, community-based cohort study that began in 1994. Participants (AD/CON) were approximately 56%/36% male with a mean age of 85/85 years. In BLSA, we found that CA and CDCA were detectable in postmortem brain tissue samples and were marginally higher in AD samples compared to CON. In ROSMAP, we found sex-specific differences in altered neuronal gene expression of BA receptors in AD. Study limitations include the small sample sizes in the BLSA cohort and likely inaccuracies in the clinical diagnosis of dementia subtypes in primary care settings.ConclusionsWe combined targeted metabolomics in serum and amyloid positron emission tomography (PET) and MRI of the brain with pharmacoepidemiologic analysis to implicate dysregulation of cholesterol catabolism in dementia pathogenesis. We observed that lower serum BA concentration mainly in males is associated with neuroimaging markers of dementia, and pharmacological lowering of BA levels may be associated with higher risk of VaD in males. We hypothesize that dysregulation of BA signaling pathways in the brain may represent a plausible biologic mechanism underlying these results. Together, our observations suggest a novel mechanism relating abnormalities in cholesterol catabolism to risk of dementia.

BackgroundPulmonary hypertension (PH) is a known complication of HCM and is a strong predictor of mortality. We aim to investigate the relationship between microvascular dysfunction measured by quantitative PET and PH in HCM patients.MethodsEighty-nine symptomatic HCM patients were included in the study. Each patient underwent two 20-min 13N-NH3 dynamic PET scans for rest and stress conditions, respectively. A 2-tissue irreversible compartmental model was used to fit the segments time activity curves for estimating segmental and global myocardial blood flow (MBF) and myocardial flow reserve (MFR). Echocardiographic derived PASP was utilized to estimate PH.ResultsPatients were categorized into two groups across PASP: PH (PASP > 36 mmHg) and no-PH (PASP ≤ 36 mmHg). patients with PH had larger left atrium, ratio of higher inflow early diastole (E) and atrial contraction (A) waves, E/A, and ratio of inflow and peak early diastolic waves, E/e', significantly reduced global stress MBF (1.85 ± 0.52 vs. 2.13 ± 0.56 ml/min/g; p = 0.024) and MFR (2.21 ± 0.57 vs. 2.62 ± 0.75; p = 0.005), while the MBFs at rest between the two groups were similar. There were significant negative correlations between global stress MBF/MFR and PASP (stress MBF: r = -0.23, p = 0.03; MFR: r = -0.32, p = 0.002); for regional MBF and MFR measurements, the highest linear correlation coefficients were observed in the septal wall (stress MBF: r = -0.27, p = 0.01; MFR: r = -0.31, p = 0.003). Global MFR was identified to be independent predictor for PH in multivariate regression analysis.ConclusionEchocardiography-derived PASP is negatively correlated with global MFR measured by 13N-NH3 dynamic PET. Global MFR is suggested to be an index of PH in HCM patients.

Cerebrospinal fluid (CSF) biomarkers, such as α-synuclein (α-syn), amyloid beta peptide 1-42 (Aβ1-42), phosphorylated tau (181P) (p-tau), and total tau (t-tau), have long been associated with the development of Parkinson disease (PD) and other neurodegenerative diseases. In this investigation, we reported the assessment of CSF biomarkers and their correlations with vesicular monoamine transporter 2 (VMAT2) bindings measured with 18F-9-fluoropropyl-(+)-dihydrotetrabenazine (18F-AV133) that is being developed as a biomarker for PD. We test the hypothesis that monoaminergic degeneration was correlated with CSF biomarker levels in untreated PD patients.The available online data from the Parkinson's Progression Markers Initiative study (PPMI) project were collected and analyzed, which include demographic information, clinical evaluations, CSF biomarkers (α-syn, Aβ1-42, p-tau, and t-tau), 18F-AV133 brain PET, and T1 weighted MRIs. Region of interest (ROI) and voxel-wise Pearson correlation between standardized uptake value ratio (SUVR) and CSF biomarkers were calculated.Our major findings are: 1) Compared with controls, CSF α-syn and tau levels decreased significantly in PD; 2) α-syn was closely correlated with Aβ1-42 and tau in PD, especially in early-onset patients; and 3) hypothesis-driven ROI analysis found a significant negative correlation between CSF Aβ1-42 levels and VMAT2 densities in post cingulate, left caudate, left anterior putamen, and left ventral striatum in PDs. CSF t-tau and p-tau levels were significantly negatively related to VMAT2 SUVRs in substantia nigra and left ventral striatum, respectively. Voxel-wise analysis showed that left caudate, parahippocampal gyrus, insula and temporal lobe were negatively correlated with Aβ1-42. In addition, superior frontal gyrus and transverse temporal gyrus were negatively correlated with CSF p-tau levels.These results suggest that monoaminergic degeneration in PD is correlated with CSF biomarkers associated with cognitive impairment in neurodegenerative diseases including Alzheimer's disease. The association between loss of dopamine synaptic function and pathologic protein accumulations in PD indicates an important role of CSF biomarkers in PD development.

Abstract Background Retinal microvascular signs are accessible measures of early alterations in microvascular dysregulation and have been associated with dementia; it is unclear if they are associated with AD (Alzheimer’s disease) pathogenesis as a potential mechanistic link. This study aimed to test the association of retinal microvascular abnormalities in mid and late life and late life cerebral amyloid. Methods Participants from the ARIC‐PET (Atherosclerosis Risk in Communities‐Positron Emission Tomography) study with a valid retinal measure (N = 285) were included. The associations of mid- and late-life retinal signs with late-life amyloid-β (Aβ) by florbetapir PET were tested. Two different measures of Aβ burden were included: (1) elevated amyloid (SUVR > 1.2) and (2) continuous amyloid SUVR. The retinal measures’ association with Aβ burden was assessed using logistic and robust linear regression models. A newly created retinal score, incorporating multiple markers of retinal abnormalities, was also evaluated in association with greater Aβ burden. Results Retinopathy in midlife (OR (95% CI) = 0.36 (0.08, 1.40)) was not significantly associated with elevated amyloid burden. In late life, retinopathy was associated with increased continuous amyloid standardized value uptake ratio (SUVR) (β (95%CI) = 0.16 (0.02, 0.32)) but not elevated amyloid burden (OR (95%CI) = 2.37 (0.66, 9.88)) when accounting for demographic, genetic and clinical risk factors. A high retinal score in late life, indicating a higher burden of retinal abnormalities, was also significantly associated with increased continuous amyloid SUVR (β (95% CI) = 0.16 (0.04, 0.32)) independent of vascular risk factors. Conclusions Retinopathy in late life may be an easily obtainable marker to help evaluate the mechanistic vascular pathway between retinal measures and dementia, perhaps acting via AD pathogenesis. Well-powered future studies with a greater number of retinal features and other microvascular signs are needed to test these findings.

Background/aims: Although disturbed sleep is associated with cognitive deficits, the association between sleep disturbance and Alzheimer’s disease pathology is unclear. In this pilot study, we examined the extent to which sleep duration, sleep quality, and sleep-disordered breathing are associated with β-amyloid (Aβ) deposition in the brains of living humans. Methods: We studied 13 older adults (8 with normal cognition and 5 with mild cognitive impairment). Participants completed neuropsychological testing, polysomnography, and Aβ imaging with [ 11 C]-Pittsburgh compound B. Results: Among participants with mild cognitive impairment, higher apnea–hypopnea index and oxygen desaturation index were associated with greater Aβ deposition, globally and regionally in the precuneus. There were no significant associations between sleep-disordered breathing and Aβ deposition among cognitively normal participants. There were no significant associations between sleep duration or sleep fragmentation and Aβ deposition. Conclusion: These preliminary results suggest that among older adults with mild cognitive impairment, greater sleep-disordered breathing severity is associated with greater Aβ deposition.

The rewarding effects of nicotine are associated with activation of nicotine receptors. However, there is increasing evidence that the endogenous opioid system is involved in nicotine's rewarding effects. We employed PET imaging with [11C]carfentanil to test the hypotheses that acute cigarette smoking increases release of endogenous opioids in the human brain and that smokers have an upregulation of mu opioid receptors (MORs) when compared to nonsmokers. We found no significant changes in binding potential (BPND) of [11C]carfentanil between the placebo and the active cigarette sessions, nor did we observe differences in MOR binding between smokers and nonsmokers. Interestingly, we showed that in smokers MOR availability in bilateral superior temporal cortices during the placebo condition was negatively correlated with scores on the Fagerström Test for Nicotine Dependence (FTND). Also in smokers, smoking-induced decreases in [11C]carfentanil binding in frontal cortical regions were associated with self-reports of cigarette liking and wanting. Although we did not show differences between smokers and nonsmokers, the negative correlation with FTND corroborates the role of MORs in superior temporal cortices in nicotine addiction and provides preliminary evidence of a role of endogenous opioid signaling in frontal cortex in nicotine reward.

Abstract INTRODUCTION This study aimed to assess whether social relationships in mid‐life reduce the risk of dementia related to amyloid burden. METHODS Participants in the Atherosclerosis Risk in Communities (ARIC) study were assessed for social support and isolation (visit 2; 1990–1992). A composite measure, “social relationships,” was generated. Brain amyloid was evaluated with florbetapir positron emission tomography (PET); (visit 5; 2012–2014). Incident dementia cases were identified following visit 5 through 2019 using ongoing surveillance. Relative contributions of mid‐life social relationships and elevated brain amyloid to incident dementia were evaluated with Cox regression models. RESULTS Among 310 participants without dementia, strong mid‐life social relationships were associated independently with lower dementia risk. Elevated late‐life brain amyloid was associated with greater dementia risk. DISCUSSION Although mid‐life social relationships did not moderate the relationship between amyloid burden and dementia, these findings affirm the importance of strong social relationships as a potentially protective factor against dementia.

Long-term alteration of dopaminergic neurotransmission is known to modulate the D2/D3 receptor expression in the brain. The modulation can occur as a response to pathological processes or pharmacological intervention. The receptor density can be monitored by in vivo positron emission tomography (PET) of [C11] raclopride. To obtain accurate measurements of receptor-ligand interaction, it is essential to estimate binding parameters at true (if transient) equilibrium of bound and unbound ligand quantities. We designed this study as a comparison of two quantitative approaches to transient equilibrium, the TRansient EquilibriuM BoLus Estimation (TREMBLE) method and the Transient Equilibrium Model (TEM) method, to determine binding parameters at transient equilibrium with bolus injection of the radioligand. The data demonstrates that TREMBLE unlike TEM identified the time at which equilibrium existed. TREMBLE revealed that equilibrium prevailed at one or more times after bolus injection and identified differences of receptor density among regions such as putamen and caudate nucleus. We demonstrated that TREMBLE is a quantitative approach suitable for the study of pathophysiological conditions of certain types of neurotransmission the brain.

Background White matter abnormalities are a common feature of aging and Alzheimer disease, and tend to be more severe among Black individuals. However, the extent to which white matter abnormalities relate to amyloid deposition, a marker of Alzheimer pathology, remains unclear. This cross‐sectional study examined the association of white matter abnormalities with cortical amyloid in a community sample of older adults without dementia and examined the moderating effect of race. Methods and Results Participants from the ARIC‐PET (Atherosclerosis Risk in Communities‐Positron Emission Tomography) study underwent brain magnetic resonance imaging, which quantified white matter hyperintensity volume and microstructural integrity using diffusion tensor imaging. Participants received florbetapir positron emission tomography imaging to measure brain amyloid. Associations between measures of white matter structure and elevated amyloid status were examined using multivariable logistic regression. Among 322 participants (43% Black), each SD increase in white matter hyperintensity volume was associated with a greater odds of elevated amyloid (odds ratio [OR], 1.37; 95% CI, 1.03–1.83) after adjusting for demographic and cardiovascular risk factors. In race‐stratified analyses, a greater white matter hyperintensity volume was more strongly associated with elevated amyloid among Black participants (OR, 2.00; 95% CI, 1.15–3.50), compared with White participants (OR, 1.29; 95% CI, 0.89–1.89). However, the race interaction was not statistically significant (P interaction=0.09). We found no association between white matter microstructure and elevated amyloid. Conclusions The results suggest a modest positive relationship between white matter hyperintensity and elevated amyloid in older adults without dementia. Although the results indicate that this association is nonsignificantly stronger among Black participants, these findings will need to be confirmed or refuted using larger multiracial cohorts.

Background Atrial fibrillation (AF) is a risk factor for cognitive decline, possibly from silent brain infarction. Left atrial changes in structure or function (atrial cardiopathy) can lead to AF but may impact cognition independently. It is unknown if AF or atrial cardiopathy also acts on Alzheimer disease–specific mechanisms, such as deposition of β‐amyloid. Methods and Results A total of 316 dementia‐free participants from the ARIC (Atherosclerosis Risk in Communities) study underwent florbetapir positron emission tomography, electrocardiography, and 2‐dimensional echocardiography. Atrial cardiopathy was defined as ≥1: (1) left atrial volume index >34 mL/m2; (2) P‐wave terminal force >5000 µV×ms; and (3) serum NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide) >250 pg/mL. Cross‐sectional associations between global cortical β‐amyloid (>1.2 standardized uptake value ratio) and adjudicated history of AF and atrial cardiopathy, each, were evaluated using multivariable logistic regression. Participants (mean age, 76 years) were 56% women and 42% Black individuals. Odds of elevated florbetapir standardized uptake value ratio were significantly increased among those with atrial cardiopathy (odds ratio, 1.81; 95% CI, 1.02–3.22) and doubled for those with enlarged left atrial volume index after adjustment for demographics/risk factors (95% CI, 1.04–4.61). There was no association between P‐wave terminal force or NT‐proBNP and elevated florbetapir standardized uptake value ratio, nor between AF and elevated standardized uptake value ratio. Conclusions Among healthy, nondemented community‐dwelling older individuals, we report an association between atrial cardiopathy, left atrial volume index, and elevated brain amyloid, by positron emission tomography, without a similar association in individuals with AF. Potential limitations include reverse causation and survival bias. Ongoing work will help determine if changes in cardiac structure and function precede or occur simultaneously with amyloid deposition.

Multiple lines of evidence suggest that a deficiency of Fragile X Mental Retardation Protein (FMRP) mediates dysfunction of the metabotropic glutamate receptor subtype 5 (mGluR5) in the pathogenesis of fragile X syndrome (FXS), the most commonly known single-gene cause of inherited intellectual disability (ID) and autism spectrum disorder (ASD). Nevertheless, animal and human studies regarding the link between FMRP and mGluR5 expression provide inconsistent or conflicting findings about the nature of those relationships. Since multiple clinical trials of glutamatergic agents in humans with FXS did not demonstrate the amelioration of the behavioral phenotype observed in animal models of FXS, we sought measure if mGluR5 expression is increased in men with FXS to form the basis for improved clinical trials. Unexpectedly marked reductions in mGluR5 expression were observed in cortical and subcortical regions in men with FXS. Reduced mGluR5 expression throughout the living brains of men with FXS provides a clue to examine FMRP and mGluR5 expression in FXS. In order to develop the findings of our previous study and to strengthen the objective tools for future clinical trials of glutamatergic agents in FXS, we sought to assess the possible value of measuring both FMRP levels and mGluR5 expression in men with FXS. We aimed to show the value of measurement of FMRP levels and mGluR5 expression for the diagnosis and treatment of individuals with FXS and related conditions. We administered 3-[18F]fluoro-5-(2-pyridinylethynyl)benzonitrile ([18F]FPEB), a specific mGluR5 radioligand for quantitative measurements of the density and the distribution of mGluR5s, to six men with the full mutation (FM) of FXS and to one man with allele size mosaicism for FXS (FXS-M). Utilizing the seven cortical and subcortical regions affected in neurodegenerative disorders as indicator variables, adjusted linear regression of mGluR5 expression and FMRP showed that mGluR5 expression was significantly reduced in the occipital cortex and the thalamus relative to baseline (anterior cingulate cortex) if FMRP levels are held constant (F(7,47) = 6.84, p < 0.001).These findings indicate the usefulness of cerebral mGluR5 expression measured by PET with [18F]FPEB and FMRP values in men with FXS and related conditions for assessments in community facilities within a hundred-mile radius of a production center with a cyclotron. These initial results of this pilot study advance our previous study regarding the measurement of mGluR5 expression by combining both FMRP levels and mGluR5 expression as tools for meaningful clinical trials of glutamatergic agents for men with FXS. We confirm the feasibility of this protocol as a valuable tool to measure FMRP levels and mGluR5 expression in clinical trials of individuals with FXS and related conditions and to provide the foundations to apply precision medicine to tailor treatment plans to the specific needs of individuals with FXS and related conditions.

Glutamatergic receptor expression is mostly unknown in adults with fragile X syndrome (FXS). Favorable behavioral effects of negative allosteric modulators (NAMs) of the metabotropic glutamate receptor subtype 5 (mGluR5) in fmr1 knockout (KO) mouse models have not been confirmed in humans with FXS. Measurement of cerebral mGluR5 expression in humans with FXS exposed to NAMs might help in that effort. We used positron emission tomography (PET) to measure the mGluR5 density as a proxy of mGluR5 expression in cortical and subcortical brain regions to confirm target engagement of NAMs for mGluR5s. The density and the distribution of mGluR5 were measured in two independent samples of men with FXS (N = 9) and typical development (TD) (N = 8). We showed the feasibility of this complex study including MRI and PET, meaning that this challenging protocol can be accomplished in men with FXS with an adequate preparation. Analysis of variance of estimated mGluR5 expression showed that mGluR5 expression was significantly reduced in cortical and subcortical regions of men with FXS in contrast to age-matched men with TD.

In demented older adults, in vivo amyloid imaging shows agreement with diagnostic neuropathologic assessment of β-amyloid (Aβ). However, the extent of agreement in nondemented older adults remains unclear. Objective: To compare Aβ quantified using in vivo carbon 11-labeled Pittsburgh Compound B positron emission tomography and postmortem neuropathologic assessment of Aβ in older adults. Design: Case series. Setting: Community-dwelling older adults who came to autopsy. Participants: Five nondemented and 1 demented participant from the Baltimore Longitudinal Study of Aging. Main Outcome Measure: Agreement between the mean cortical distribution volume ratio and the Consortium to Establish a Registry for AD(CERAD) neuritic plaque (NP) score used for pathologic diagnosis of Alzheimer disease. Results: Of the 6 participants, 4 had moderate NPs, 2 had sparse or no detectable NPs, and 3 had microscopic findings of cerebral amyloid angiopathy at autopsy. On in vivo imaging, the mean cortical distribution volume ratio ranged from 0.96 to 1.59. Although there was agreement between in vivo amyloid imaging and CERAD NP scores in participants with either high or negligible Aβ levels in vivo, only limited agreement was observed among those with intermediate levels of Aβ. The best overall agreement was achieved at a distribution volume ratio of 1.2. Conclusions: In older adults, variable agreement between in vivo imaging and CERAD NP score was observed. The limited agreement may, in part, reflect differences in typical measurements of Aβ using imaging compared with the CERAD neuropathologic protocol. Direct quantification of regional Aβ in relation to in vivo imaging is necessary to further enhance our understanding of the imaging-pathologic assessment correlation. [ABSTRACT FROM AUTHOR]

Histamine H1-receptor (H1R) antagonists, or antihistamines, often induce sedative side effects when used for the treatment of allergic disorders. This study compared the sedative profiles of the second-generation antihistamines, fexofenadine and cetirizine, using 3 different criteria: subjective sleepiness evaluated by the Stanford Sleepiness Scale, objective psychomotor tests (simple and choice reaction time tests and visual discrimination tests at 4 different exposure durations), and measurement of histamine H1-receptor occupancy (H1RO) in the brain. Subjective sleepiness and psychomotor performance were measured in 20 healthy Japanese volunteers atbaseline and 90 min after administration of fexofenadine 120 mg or cetirizine 20 mg in a double-blind, placebo-controlled crossover study. Hydroxyzine 30 mg was included as a positive control. H1RO was measured using positron emission tomography (PET) with 11C-doxepin in 12 of the 20 subjects, and a further 11 volunteers were recruited to act as controls. In psychomotor tests, fexofenadine was not significantly different-from placebo and significantly less impairing than cetirizine on some tasks, as well as significantly less impairing than hydroxyzine on all tasks. For subjective sleepiness, fexofenadine was not significantly different from placebo,whereas cetirizine showed a trend toward increased sleepiness compared with fexofenadine and placebo. H1RO was negligible with fexofenadine (-0.1%) but moderately high with cetirizine (26.0%). In conclusion, fexofenadine 120 mg is distinguishable from cetirizine 20mg, as assessed by H1RO and psychomotor testing. [ABSTRACT FROM AUTHOR]

Background: Studies suggest associations between long-term ambient air pollution exposure and outcomes related to Alzheimer’s disease (AD). Whether a link exists between pollutants and brain amyloid accumulation, a biomarker of AD, is unclear. We assessed whether long-term air pollutant exposures are associated with late-life brain amyloid deposition in Atherosclerosis Risk in Communities (ARIC) study participants. Methods: We used a chemical transport model with data fusion to estimate ambient concentrations of PM2.5 and its components, NO2, NOx, O3 (24-hour and 8-hour), CO, and airborne trace metals. We linked concentrations to geocoded participant addresses and calculated 10-year mean exposures (2002 to 2011). Brain amyloid deposition was measured using florbetapir amyloid positron emission tomography (PET) scans in 346 participants without dementia in 2012–2014, and we defined amyloid positivity as a global cortical standardized uptake value ratio ≥ the sample median of 1.2. We used logistic regression models to quantify the association between amyloid positivity and each air pollutant, adjusting for putative confounders. In sensitivity analyses, we considered whether use of alternate air pollution estimation approaches impacted findings for PM2.5, NO2, NOx, and 24-hour O3. Results: At PET imaging, eligible participants (N = 318) had a mean age of 78 years, 56% were female, 43% were Black, and 27% had mild cognitive impairment. We did not find evidence of associations between long-term exposure to any pollutant and brain amyloid positivity in adjusted models. Findings were materially unchanged in sensitivity analyses using alternate air pollution estimation approaches for PM2.5, NO2, NOx, and 24-hour O3. Conclusions: Air pollution may impact cognition and dementia independent of amyloid accumulation, though whether air pollution influences AD pathogenesis later in the disease course or at higher exposure levels deserves further consideration.

Decryption of brain images is the basis for the necessary translation of the findings from imaging to information required to meet the demands of clinical intervention. Tools of brain imaging, therefore, must satisfy the conditions dictated by the needs for interpretation in terms of diagnosis and prognosis. In addition, the applications must serve as fundamental research tools that enable the understanding of new therapeutic drugs, including compounds as diverse as antipsychotics, antidepressants, anxiolytics, and drugs serving the relief of symptoms from neurochemical disorders as unrelated as multiple sclerosis, stroke, and dementia. Here we review and explain the kinetics of methods that enable researchers to describe the brain’s work and functions. We focus on methods invented by neurokineticists and expanded upon by practitioners during decades of experimental work and on the methods that are particularly useful to predict possible future approaches to the treatment of neurochemical disorders. We provide an overall description of the basic elements of kinetics and the underlying quantification methods, as well as the mathematics of modeling the recorded brain dynamics embedded in the images we obtain in vivo. The complex presentation to follow is necessary to justify the contribution of modeling to the development of methods and to support the specifications dictated by the proposed use in clinical settings. The quantification and kinetic modeling processes are equally essential to image reconstruction and labeling of brain regions of structural or functional interest. The procedures presented here are essential tools of scientific approaches to all conventional and novel forms of brain imaging. The foundations of the kinetic and quantitative methods are keys to the satisfaction of clinicians that actively engage in treating the neurochemical disorders of mammalian brains in the fields of neurology, neurosurgery, and neuropsychiatry.

Psilocybin (a serotonin 2A, or 5-HT2A, receptor agonist) has shown preliminary efficacy as a treatment for mood and substance use disorders. The current report utilized positron emission tomography (PET) with the selective 5-HT2A receptor inverse agonist radioligand [11C]MDL 100,907 (a.k.a. M100,907) and cortical regions of interest (ROIs) derived from resting-state functional connectivity-based brain parcellations in 4 healthy volunteers (2 females) to determine regional occupancy/target engagement of 5-HT2A receptors after oral administration of a psychoactive dose of psilocybin (10 mg/70 kg). Average 5-HT2A receptor occupancy across all ROIs was 39.5% (± 10.9% SD). Three of the ROIs with greatest occupancy (between 63.12 and 74.72% occupancy) were within the default mode network (subgenual anterior cingulate and bilateral angular gyri). However, marked individual variability in regional occupancy was observed across individuals. These data support further investigation of the relationship between individual differences in the acute and enduring effects of psilocybin and the degree of regional 5-HT2A receptor occupancy.

Abstract Introduction Tau pathology, a hallmark of Alzheimer's disease, is observed in the brains of virtually all individuals over 70 years. Methods Using 18F‐AV‐1451 (18F‐flortaucipir) positron emission tomography, we evaluated tau pathology in 54 cognitively normal participants (mean age: 77.5 years, SD: 8.9) from the Baltimore Longitudinal Study of Aging. We assessed associations between positron emission tomography signal and age, sex, race, and amyloid positivity. We investigated relationships between regional signal and retrospective rates of change in regional volumes and cognitive function adjusting for age, sex, and amyloid status. Results Greater age, male sex, black race, and amyloid positivity were associated with higher 18F‐AV‐1451 retention in distinct brain regions. Retention in the entorhinal cortex was associated with lower entorhinal volume (β = −1.124, SE = 0.485, P = .025) and a steeper decline in memory performance (β = −0.086, SE = 0.039, P = .029). Discussion Assessment of medial temporal tau pathology will provide insights into early structural brain changes associated with later cognitive impairment and Alzheimer's disease.

A low-cost quantitative structured office measurement of movements in the extremities of people with Parkinson's disease [1,2] was performed on people with Parkinson's disease, multiple system atrophy, and age-matched healthy volunteers. Participants underwent twelve videotaped procedures rated by a trained examiner while connected to four accelerometers [1,2] generating a trace of the three location dimensions expressed as spreadsheets [3,4]. The signals of the five repetitive motion items [1,2] underwent processing to fast Fourier [5] and continuous wavelet transforms [6]. The dataset [7] includes the coding form with scores of the live ratings [1,2], the raw files [3], the converted spreadsheets [4], and the fast Fourier [5] and continuous wavelet transforms [6]. All files are unfiltered.The data also provide findings suitable to compare and contrast with data obtained by investigators applying the same procedure to other populations. Since this is an inexpensive procedure to quantitatively measure motions in Parkinson's disease and other movement disorders, this will be a valuable resource to colleagues, particularly in underdeveloped regions with limited budgets. The dataset will serve as a template for other investigations to develop novel techniques to facilitate the diagnosis, monitoring, and treatment of Parkinson's disease, other movement disorders, and other nervous and mental conditions. The procedure will provide the basis to obtain objective quantitative measurements of participants in clinical trials of new agents.

Abstract Introduction Affective changes precede cognitive decline in mild Alzheimer's disease and may relate to increased connectivity in a “salience network” attuned to emotionally significant stimuli. The trajectory of affective changes in preclinical Alzheimer's disease, and its relationship to this network, is unknown. Methods One hundred one cognitively normal older adults received longitudinal assessments of affective symptoms, then amyloid‐PET. We hypothesized amyloid‐positive individuals would show enhanced emotional reactivity associated with salience network connectivity. We tested whether increased global connectivity in key regions significantly related to affective changes. Results In participants later found to be amyloid positive, emotional reactivity increased with age, and interpersonal warmth declined in women. These individuals showed higher global connectivity within the right insula and superior temporal sulcus; higher superior temporal sulcus connectivity predicted increasing emotional reactivity and decreasing interpersonal warmth. Conclusions Affective changes should be considered an early preclinical feature of Alzheimer's disease. These changes may relate to higher functional connectivity in regions critical for social‐emotional processing.

Neuropathological and neuroimaging studies have consistently demonstrated degeneration of monoamine systems, especially the serotonin system, in normal aging and Alzheimer's disease. The evidence for degeneration of the serotonin system in mild cognitive impairment is limited. Thus, the goal of the present study was to measure the serotonin transporter in vivo in mild cognitive impairment and healthy controls. The serotonin transporter is a selective marker of serotonin terminals and of the integrity of serotonin projections to cortical, subcortical and limbic regions and is found in high concentrations in the serotonergic cell bodies of origin of these projections (raphe nuclei).Twenty-eight participants with mild cognitive impairment (age 66.6 ± 6.9, 16 males) and 28 healthy, cognitively normal, demographically matched controls (age 66.2 ± 7.1, 15 males) underwent magnetic resonance imaging for measurement of grey matter volumes and high-resolution positron emission tomography with well-established radiotracers for the serotonin transporter and regional cerebral blood flow. Beta-amyloid imaging was performed to evaluate, in combination with the neuropsychological testing, the likelihood of subsequent cognitive decline in the participants with mild cognitive impairment. The following hypotheses were tested: 1) the serotonin transporter would be lower in mild cognitive impairment compared to controls in cortical and limbic regions, 2) in mild cognitive impairment relative to controls, the serotonin transporter would be lower to a greater extent and observed in a more widespread pattern than lower grey matter volumes or lower regional cerebral blood flow and 3) lower cortical and limbic serotonin transporters would be correlated with greater deficits in auditory-verbal and visual-spatial memory in mild cognitive impairment, not in controls.Reduced serotonin transporter availability was observed in mild cognitive impairment compared to controls in cortical and limbic areas typically affected by Alzheimer's disease pathology, as well as in sensory and motor areas, striatum and thalamus that are relatively spared in Alzheimer's disease. The reduction of the serotonin transporter in mild cognitive impairment was greater than grey matter atrophy or reductions in regional cerebral blood flow compared to controls. Lower cortical serotonin transporters were associated with worse performance on tests of auditory-verbal and visual-spatial memory in mild cognitive impairment, not in controls.The serotonin system may represent an important target for prevention and treatment of MCI, particularly the post-synaptic receptors (5-HT4 and 5-HT6), which may not be as severely affected as presynaptic aspects of the serotonin system, as indicated by the observation of lower serotonin transporters in MCI relative to healthy controls.

Abstract Objective To test the hypothesis that among cognitively healthy individuals, distinct groups exist in terms of amyloid and phosphorylated‐tau accumulation rates; that if rapid accumulator groups exist, their membership can be predicted by Alzheimer's disease (AD) risk factors, and that time points of significant increase in AD protein accumulation will be evident. Methods The analysis reports data from 263 individuals from the BIOCARD and 184 individuals from the Baltimore Longitudinal Study of Aging with repeated cerebrospinal fluid (CSF) and positron emission tomography (PET) sampling, respectively. We used latent class mixed‐effect models to identify distinct classes of amyloid (CSF and PET) and p‐Tau (CSF) accumulation rates and generalized additive modeling to investigate non‐linear changes to AD biomarkers. Results For both amyloid and p‐Tau latent class models we confirmed the existence of two separate classes: accumulators and non‐accumulators. The accumulator and non‐accumulator groups differed significantly in terms of baseline AD protein levels and slope of change. APOE ε4 carrier status and episodic memory predicted amyloid class membership. Non‐linear models revealed time points of significant increase in the rate of amyloid and p‐Tau accumulation whereby APOE ε4 carrier status associated with earlier age at onset of rapid accumulation. Conclusions The current analysis demonstrates the existence of distinct classes of amyloid and p‐Tau accumulators. Predictors of class membership were identified but the overall accuracy of the models was modest, highlighting the need for additional biomarkers that are sensitive to early disease phenotypes.

Minimally-invasive monitoring of electrophysiological neural activities in real-time—that enables quantification of neural functions without a need for invasive craniotomy and the longer time constants of fMRI and PET—presents a very challenging yet significant task for neuroimaging. In this paper, we present in vivo functional PA (fPA) imaging of chemoconvulsant rat seizure model with intact scalp using a fluorescence quenching-based cyanine voltage-sensitive dye (VSD) characterized by a lipid vesicle model mimicking different levels of membrane potential variation. The framework also involves use of a near-infrared VSD delivered through the blood-brain barrier (BBB), opened by pharmacological modulation of adenosine receptor signaling. Our normalized time-frequency analysis presented in vivo VSD response in the seizure group significantly distinguishable from those of the control groups at sub-mm spatial resolution. Electroencephalogram (EEG) recording confirmed the changes of severity and frequency of brain activities, induced by chemoconvulsant seizures of the rat brain. The findings demonstrate that the near-infrared fPA VSD imaging is a promising tool for in vivo recording of brain activities through intact scalp, which would pave a way to its future translation in real time human brain imaging.

While the ApoE ε4 allele is a known risk factor for mild cognitive impairment (MCI) and Alzheimer's disease, brain region specific effects remain elusive. In this study, we investigate whether the ApoE ε4 allele exhibits brain region specific effects in longitudinal glucose uptake among patients with MCI from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Preprocessed FDG PET images, MRIs, and demographic information were downloaded from the ADNI database. An iterative reblurred Van Cittertiteration method was used for partial volume correction (PVC) on all PET images. Structural MRIs were used for PET spatial normalization and region of interest (ROI) definition in standard space. Longitudinal changes in ROI FDG standardized uptake value ratio (SUVR) relative to cerebellum in 24 ApoE ε4 carriers and 24 age-matched ApoE ε4 non-carriers were measured for up to 84-months (median 72 months, SD = 11.2 months) and compared using a generalized linear mixed effects model controlling for gender, education, baseline age, and follow-up period. Additionally, voxelwise analysis was performed by implementing a paired t-test comparing matched baseline and 72 month FDG SUVR images in ApoE carriers and non-carriers separately. Results with PVC were compared with ones from non-PVC based analysis. After applying PVC, the superior fontal, parietal, lateral temporal, medial temporal, caudate, thalamus, and post-cingulate, and amygdala regions had greater longitudinal decreases in FDG uptake in ApoE ε4 carriers with MCI compared to non-carriers with MCI. Similar forebrain and limbic clusters were found through voxelwise analysis. Compared to the PVC based analysis, fewer significant ApoE-associated regions and clusters were found in the non-PVC based PET analysis. Our findings suggest that the ApoE ε4 genotype is associated with a longitudinal decline in glucose uptake in 8 forebrain and limbic brain regions in the context of MCI. In conclusion, this 84-months longitudinal FDG PET study demonstrates a novel ApoE ε4-associated brain-region specific glucose metabolism pattern in patients with MCI. Partial volume correction improved FDG PET quantification. Keywords: Alzheimer's disease, Mild cognitive impairment, ApoE ε4, FDG PET, Longitudinal, Partial volume correction

Objective: Amyloid positivity is a biomarker of AD pathology, yet the associations between amyloid positivity and brain volumetric changes, especially in the hippocampus, are inconsistent. We hypothesize that sex differences in associations may contribute to inconsistent findings among cognitively normal older adults. Methods: Using linear mixed effects models, we examined the association of amyloid positivity with prospective volumetric changes (mean = 3.3 visits) of parahippocampal gyrus (phg), hippocampus, entorhinal cortex (erc), precuneus, and fusiform gyrus among 171 Baltimore Longitudinal Study of Aging participants aged ≥55 years. Amyloid positivity was defined by a mean 11C-Pittsburgh Compound B (PiB) distribution volume ratio (DVR) cut-off of 1.062. All analyses included age, race, sex, education, APOE e4 carrier status, and two-way interactions of these covariates with time. Two-way interaction between sex and PiB+/− status and three-way interaction of sex and PiB+/− status with time were added to assess whether sex modified associations. Results: PiB+ status was associated with greater volumetric declines in the phg (β = −0.036, SE = 0.011, p = 0.001) and erc (β = −0.019, SE = 0.009, p = 0.045). Sex modified the association of PiB+ status and rates of volumetric declines in fusiform (β = −0.117, SE = 0.049, p = 0.019). PiB+ males had steeper rates of volumetric declines in phg (β = −0.051, SE = 0.013, p

Beta-amyloid (Aβ) plaque deposition is a key feature of Alzheimer’s disease (AD), and occurs years before the onset of symptoms. Aβ plaque deposition has been shown to be present in ~30% of cognitively normal older adults using amyloid C-11 labeled Pittsburgh Compound B (11C-PiB) Positron Emission Tomography (PET) imaging. Prior studies have reported a link between reduced vestibular function and poorer cognition in healthy older adults. It is unknown whether vestibular impairment occurs in association with AD pathology among individuals in the preclinical phase of AD, which could contribute to the observed association between vestibular and cognitive function in healthy older adults. Using the Baltimore Longitudinal Study of Aging (BLSA), we analyzed the association between a comprehensive set of vestibular function measures and PiB status in 98 healthy participants with a mean age of 77.3 (±8.26). We did not observe a significant relationship between any vestibular function measure and PiB status in cognitively-intact older adults in the BLSA. This finding suggests that Aβ deposition does not explain the observed association between reduced vestibular function and poorer cognition in healthy older adults.