Pittsburg Compound Research Articles

Multicenter Experience with Good Manufacturing Practice Production of [11C]PiB for Amyloid Positron Emission Tomography Imaging.

Alzheimer's disease (AD) is a neurodegenerative disorder with increasing global prevalence and accounts for over half of all dementia cases. Early diagnosis is paramount for not only the management of the disease, but also for the development of new AD treatments. The current golden standard for diagnosis is performed by positron emission tomography (PET) scans with the tracer [11C]Pittsburg Compound B ([11C]PiB), which targets amyloid beta protein (Aβ) that builds up as plaques in the brain of AD patients. The increasing demand for AD diagnostics is in turn expected to drive an increase in [11C]PiB-PET scans and the setup of new [11C]PiB production lines at PET centers globally. Here, we present the [11C]PiB production setups, experiences, and use from four Danish PET facilities and discuss the challenges and potential pitfalls of [11C]PiB production. We report on the [11C]PiB production performed with the 6-OH-BTA-0 precursor dissolved in either dry acetone or 2-butanone and by using either [11C]CO2 or [11C]CH4 as 11C- precursors on three different commercial synthesis modules: TracerLab FX C Pro, ScanSys, or TracerMaker. It was found that the [11C]CO2 method gives the highest radioactive yield (1.5 to 3.2 GBq vs. 0.8 ± 0.3 GBq), while the highest molar activity (98.0 ± 61.4 GBq/μmol vs. 21.2 to 95.6 GBq/μmol) was achieved using [11C]CH4. [11C]PiB production with [11C]CO2 on a TracerLab FX C Pro offered the most desirable results, with the highest yield of 3.17 ± 1.20 GBq and good molar activity of 95.6 ± 44.2 GBq/μmol. Moreover, all reported methods produced [11C]PiB in quantities suitable for clinical applications, thus providing a foundation for other PET facilities seeking to establish their own [11C]PiB production.

B-025 Evaluation of Bias Between Alzheimer’s Disease Blood-Based Biomarkers Assays and Their Concordance With Amyloid-PET on the Fujirebio Lumipulse and Quanterix Simoa Platforms

Abstract Background Blood-based biomarkers (BBBs) are a growing area of study for improving Alzheimer’s disease (AD) clinical evaluation. BBBs have been demonstrated to correlate with AD CSF biomarkers as well as neuroimaging results for assessment of amyloid pathology. Currently BBBs may be used as a screening tool for patient selection in clinical trials, and alongside more well characterized biomarkers like amyloid-PET and CSF markers for evaluation of individuals presenting with cognitive impairment. A comparative study of several AD BBBs assays was performed to assess bias between two platforms, as well as correlation to markers of amyloid pathology. Methods The study included 146 plasma samples from 112 cognitively normal (CN), and 34 mild cognitive impairment (MCI) or AD dementia individuals. Plasma Aβ42, Aβ40, and pTau181 concentrations were obtained using the Fujirebio Lumipulse and Quanterix Simoa immunoassays. Assay comparison between Fujirebio and Quanterix were performed for Aβ42, Aβ40, Aβ42/Aβ40 ratio, pTau181, and pTau181/Aβ42 ratio using Passing-Bablok regression and regression slopes were obtained. Amyloid-PET was performed using Pittsburg Compound B, and a standard uptake value ratio (SUVR) of 1.48 was used to classify amyloid status. In the CN group, 69 were amyloid negative, and 43 were amyloid positive. In the MCI/AD dementia group, 8 were amyloid negative and 26 were amyloid positive. Spearman’s rank correlation coefficient (rho) was used to determine correlation between assays and correlation of each with Amyloid-PET SUVRs. Results Between Fujirebio (y) and Quanterix (x) assays, measured Aβ42 and Aβ40 concentrations showed a large bias with y = 5.23x − 14.25, and y = 4.42x − 264.87, respectively. A moderate to strong correlation was observed between assays for Aβ42 and Aβ40 with rho values of 0.641 (P < 0.0001), and 0.498 (P < 0.0001), respectively. The ratio of Aβ42/Aβ40 corrected this bias with y = 0.96x + 0.03 and rho = 0.509 (P < 0.0001). pTau181 showed little bias between methods with y = 0.92x + 0.48, and a rho = 0.592 (P < 0.0001). However, the pTau181/Aβ42 ratio showed a large bias driven mostly by differences in the Aβ42 concentrations with y = 0.27x + 0.04 and rho = 0.574 (P < 0.0001). Quanterix assay results correlated with amyloid-PET SUVR yielded rho coefficients of AB42/40 ratio = −0.219 (P = 0.079), pTau181 = 0.380 (P < 0.0001), and pTau181/Aβ42 ratio = 0.466 (P < 0.0001). Fujirebio assay results correlated with amyloid-PET SUVR showed AB42/40 ratio rho = −0.551 (P < 0.0001), pTau181 rho = 0.370 (P < 0.0001), and pTau181/Aβ42 ratio rho = 0.391 (P < 0.0001). Conclusion This study demonstrates that some BBBs methods differ significantly between manufacturers. Little bias was observed between the Aβ42/Aβ40 and pTau181 determinations for the evaluated platforms; however, significant bias was observed in Aβ42, Aβ40, and the pTau181/Aβ42 ratio. The Fujirebio platform demonstrated stronger correlation of the Aβ42/Aβ40 ratio with amyloid-PET SUVR, while Quanterix showed better correlation of the pTau181/Aβ42 ratio. The pTau181 assays showed similar correlation to amyloid-PET SUVR. Bias between assays as well as clinical correlation differences may preclude the generalization of clinical performance of AD BBBs assays between platforms.

Body mass index and 2‐year change of in vivo Alzheimer's disease pathologies in cognitively normal older adults

AbstractBackgroundMultiple studies supported that low body mass index (BMI) or underweight status in late‐life was associated with increased risk of dementia. We tried to test the hypothesis that lower late‐life BMI is related with greater increase of in vivo AD pathology including Aβ and tau deposition for two years in cognitively healthy individuals. Additionally, we explored the same relationship in each sex separately, considering previous reports that showed prominent sex differences for the relationship between BMI and AD dementia risk.MethodTotal 194 cognitive normal older adults from the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer’s Disease (KBASE) were included. All participants underwent comprehensive clinical assessment including BMI measurement, [11C] Pittsburg compound B and [18F] AV‐1451 PET at baseline. The same brain imaging scans were repeated at a year follow‐up assessment. The association of baseline BMI with longitudinal changes of AD biomarkers were analyzed using linear mixed effect models.ResultLower BMI at baseline was significantly associated with greater increase of tau deposition in AD‐signature region for 2 years. In contrast, BMI was not related with 2‐year change of global Aβ deposition. In additional exploratory analysis for each sex, lower baseline BMI was associated with greater increase of both Aβ and tau deposition in male, whereas neither Aβ nor tau change was not related with baseline BMI in female.ConclusionThe present study suggest that lower late‐life BMI may accelerate the accumulation of AD pathology in the brain, especially in male. To prevent AD, more attention is needed to be paid to avoiding underweight in old age and maintaining an appropriate BMI status.

Gut microbiome alterations in preclinical Alzheimer's disease.

Although some human studies have reported gut microbiome changes in individuals with Alzheimer's disease (AD) dementia or mild cognitive impairment (MCI), gut microbiome alterations in preclinical AD, i.e., cerebral amyloidosis without cognitive impairment, is largely unknown. We aimed to identify gut microbial alterations associated with preclinical AD by comparing cognitively normal (CN) older adults with cerebral Aβ deposition (Aβ+ CN) and those without cerebral Aβ deposition (Aβ- CN). Seventy-eight CN older participants (18 Aβ+ CN and 60 Aβ- CN) were included, and all participants underwent clinical assessment and Pittsburg compound B-positron emission tomography. The V3-V4 region of the 16S rRNA gene of genomic DNA extracted from feces was amplified and sequenced to establish the microbial community. Generalized linear model analysis revealed that the genera Megamonas (B = 3.399, q<0.001), Serratia (B = 3.044, q = 0.005), Leptotrichia (B = 5.862, q = 0.024) and Clostridium (family Clostridiaceae) (B = 0.788, q = 0.034) were more abundant in the Aβ+ CN group than the Aβ- CN group. In contrast, genera CF231 (B = -3.237, q< 0.001), Victivallis (B = -3.447, q = 0.004) Enterococcus (B = -2.044, q = 0.042), Mitsuokella (B = -2.119, q = 0.042) and Clostridium (family Erysipelotrichaceae) (B = -2.222, q = 0.043) were decreased in Aβ+ CN compared to Aβ- CN. Notably, the classification model including the differently abundant genera could effectively distinguish Aβ+ CN from Aβ- CN (AUC = 0.823). Our findings suggest that specific alterations of gut bacterial taxa are related to preclinical AD, which means these changes may precede cognitive decline. Therefore, examining changes in the microbiome may be helpful in preclinical AD screening.

The many faces of globular glial tauopathy: A clinical and imaging study.

Globular glial tauopathy (GGT) has been associated with frontotemporal dementia syndromes; little is known about the clinical and imaging characteristics of GGT and how they differ from other non-globular glial 4-repeat tauopathies (N4GT) such as progressive supranuclear palsy (PSP) or corticobasal degeneration (CBD). For this case-control study the Mayo Clinic brain banks were queried for all cases with an autopsy-confirmed diagnosis of GGT between 1 January 2011 and 31 October 2021. Fifty patients with N4GT (30 PSP, 20 CBD) were prospectively recruited and followed by the Neurodegenerative Research Group at Mayo Clinic, Minnesota. Magnetic resonance imaging was used to characterize patterns of gray/white matter atrophy, MR-parkinsonism index, midbrain volume, and white matter hyperintensities.18 F-Fluorodeoxyglucose-, 11 C Pittsburg compound-, and 18 F-flortaucipir-positron emission tomography scans were reviewed. Twelve patients with GGT were identified: 83% were women compared to 42% in NG4T (p=0.02) with median age at death 76.5 years (range: 55-87). The most frequent clinical features were eye movement abnormalities, parkinsonism, behavioral changes followed by pyramidal tract signs and motor speech abnormalities. Lower motor neuron involvement was present in 17% and distinguished GGT from NG4T (p=0.035). Primary progressive apraxia of speech was the most frequent initial diagnosis (25%); 50% had a Parkinson-plus syndrome before death. Most GGT patients had asymmetric frontotemporal atrophy with matching hypometabolism. GGT patients had more gray matter atrophy in temporal lobes, normal MR-parkinsonism index, and larger midbrain volumes. Female sex, lower motor neuron involvement in the context of a frontotemporal dementia syndrome, and asymmetric brain atrophy with preserved midbrain might be suggestive of underlying GGT.

Quantitative analysis of regional distribution of tau pathology with 11C-PBB3-PET in a clinical setting.

PurposeThe recent developments of tau-positron emission tomography (tau-PET) enable in vivo assessment of neuropathological tau aggregates. Among the tau-specific tracers, the application of 11C-pyridinyl-butadienyl-benzothiazole 3 (11C-PBB3) in PET shows high sensitivity to Alzheimer disease (AD)-related tau deposition. The current study investigates the regional tau load in patients within the AD continuum, biomarker-negative individuals (BN) and patients with suspected non-AD pathophysiology (SNAP) using 11C-PBB3-PET.Materials and methodsA total of 23 memory clinic outpatients with recent decline of episodic memory were examined using 11C-PBB3-PET. Pittsburg compound B (11C-PIB) PET was available for 17, 18F-flurodeoxyglucose (18F-FDG) PET for 16, and cerebrospinal fluid (CSF) protein levels for 11 patients. CSF biomarkers were considered abnormal based on Aβ42 (< 600 ng/L) and t-tau (> 450 ng/L). The PET biomarkers were classified as positive or negative using statistical parametric mapping (SPM) analysis and visual assessment. Using the amyloid/tau/neurodegeneration (A/T/N) scheme, patients were grouped as within the AD continuum, SNAP, and BN based on amyloid and neurodegeneration status. The 11C-PBB3 load detected by PET was compared among the groups using both atlas-based and voxel-wise analyses.ResultsSeven patients were identified as within the AD continuum, 10 SNAP and 6 BN. In voxel-wise analysis, significantly higher 11C-PBB3 binding was observed in the AD continuum group compared to the BN patients in the cingulate gyrus, tempo-parieto-occipital junction and frontal lobe. Compared to the SNAP group, patients within the AD continuum had a considerably increased 11C-PBB3 uptake in the posterior cingulate cortex. There was no significant difference between SNAP and BN groups. The atlas-based analysis supported the outcome of the voxel-wise quantification analysis.ConclusionOur results suggest that 11C-PBB3-PET can effectively analyze regional tau load and has the potential to differentiate patients in the AD continuum group from the BN and SNAP group.

Determination of optimal regularization factor in Bayesian penalized likelihood reconstruction of brain PET images using [18 F]FDG and [11 C]PiB.

The Bayesian penalized likelihood (BPL) reconstruction algorithm, Q.Clear, can achieve a higher signal-to-noise ratio on images and more accurate quantitation than ordered subset-expectation maximization (OSEM). The reconstruction parameter (β) in BPL requires optimization according to the radiopharmaceutical tracer. The present study aimed to define the optimal β value in BPL required to diagnose Alzheimer disease from brain positron emission tomography (PET) images acquired using 18 F-fluoro-2-deoxy-D-glucose ([18 F]FDG) and 11 C-labeled Pittsburg compound B ([11 C]PiB). Images generated from Hoffman 3D brain and cylindrical phantoms were acquired using a Discovery PET/computed tomography (CT) 710 and reconstructed using OSEM+time-of-flight (TOF) under clinical conditions and BPL+TOF (β=20-1000). Contrast was calculated from images generated by the Hoffman 3D brain phantom, and noise and uniformity were calculated from those generated by the cylindrical phantom. Five cognitively healthy controls and five patients with Alzheimer disease were assessed using [18 F]FDG and [11 C]PiB PET to validate the findings from the phantom study. The β values were restricted by the findings of the phantom study, then one certified nuclear medicine physician and two certified nuclear medicine technologists visually determined optimal β values by scoring the quality parameters of image contrast, image noise, cerebellar stability, and overall image quality of PET images from 1 (poor) to 5 (excellent). The contrast in BPL satisfied the Japanese Society of Nuclear Medicine (JSNM) criterion of ≥55% and exceeded that of OSEM at ranges of β=20-450 and 20-600 for [18 F]FDG and [11 C]PiB, respectively. The image noise in BPL satisfied the JSNM criterion of ≤15% and was below that in OSEM when β=150-1000 and 400-1000 for [18 F]FDG and [11 C]PiB, respectively. The phantom study restricted the ranges of β values to 100-300 and 300-500 for [18 F]FDG and [11 C]PiB, respectively. The BPL scores for gray-white matter contrast and image noise, exceeded those of OSEM in [18 F]FDG and [11 C]PiB images regardless of β values. Visual evaluation confirmed that the optimal β values were 200 and 450 for [18 F]FDG and [11 C]PiB, respectively. The BPL achieved better image contrast and less image noise than OSEM, while maintaining quantitative standardized uptake value ratios (SUVR) due to full convergence, more rigorous noise control, and edge preservation. The optimal β values for [18 F]FDG and [11 C]PiB brain PET were apparently 200 and 450, respectively. The present study provides useful information about how to determine optimal β values in BPL for brain PET imaging.

The utility of positron emission tomography in cardiac amyloidosis.

Cardiac amyloidosis, characterized by progressive restrictive cardiomyopathy, presents unusual diagnostic challenges. Conventional cardiac scintigraphy has shown limited utility in the quantification of disease burden and serial follow-up of cardiac amyloidosis. The advent of specialized positron emission tomography with specific amyloid-binding radiotracers has the potential to change currently employed diagnostic algorithms for the imaging of cardiac amyloidosis. This review aims to discuss the diagnostic utility of amyloid-binding radiotracers, including Pittsburg compound B, florbetapir, florbetapan, and sodium fluoride. These tracers have promising potential for the early detection of the particular type of cardiac amyloidosis, pursuing relevant medical intervention, assessing amyloid burden, monitoring treatment response, and overall prognostication.

Abstract 6: The Effect of Vascular Amyloid on White Matter Disease is Mediated by Vascular Dysfunction in Cerebral Amyloid Angiopathy

Background: Cerebral amyloid angiopathy (CAA) is associated with white matter hyperintensities (WMH) but the physiopathological mechanisms remain unclear. We hypothesized that the relationship between vascular amyloid load and WMH is mediated by vascular dysfunction. Methods: The study cohort included 38 non-demented probable CAA patients who underwent advanced multimodal structural and functional MRI (fMRI) and amyloid PET scans. White matter hyperintensity volume was quantified using FreeSurfer and expressed as a percent of total intracranial volume (pWMHv). Time-to-peak [TTP] of blood oxygen level-dependent [BOLD] response to visual stimulation using fMRI was used as an established measure of vascular dysfunction. Mean cortical Pittsburg Compound B uptake representing amyloid load was calculated. A bootstrapping procedure was used to test the mediation hypothesis adjusting for age, sex, and presence of intracerebral hemorrhage (ICH). Results: Of 38 patients with CAA (mean age 70±7.1, 86.8% male), 25 (65.8%) had ICH, while the remaining 13 patients (34.2%) presented with multiple strictly cortical microbleeds. Higher amyloid load correlated with prolonged TTP response (r=0.373, p=0.021) and higher pWMHv (r=0.337, p=0.039), and prolonged TTP response correlated with higher pWMHv (r=0.485, p=0.002). Amyloid load no longer predicted pWMHv (p=0.254) after controlling for TTP. In the bootstrapping model, TTP response had a significant indirect effect (ab=0.977, 95% CI: 0.15-2.42), showing that the association between amyloid load and pWMHv is mediated by TTP. Discussion: Our findings confirm the hypothesis that the effect of vascular amyloid load on the extent of white matter disease is mediated by vascular dysfunction in patients with CAA. Amyloid lowering strategies might prevent pathophysiological processes leading to vascular dysfunction, therefore limiting ischemic brain injury.

Trajectory of clinical symptoms accelerates after 10 years of amyloid

AbstractBackgroundUnderstanding the time between amyloid biomarker detection and the onset of cognitive and functional symptoms will be critical in making care planning decisions and determining an optimal time period for potential interventions. Previous studies have suggested that amyloid, as measured with Pittsburg compound B (PiB), can be detected 15‐20 years before symptom onset. However, the designs of these studies do not—on an individual basis—provide an understanding of the duration between amyloid accumulation and symptom onset. Recent research from several groups has suggested that the rate of amyloid accumulation is consistent across individuals, making it possible to estimate the chronicity of amyloid positivity from a single PET scan. In relation to this measure of amyloid chronicity, we examined trajectories of cognitive and functional symptoms, as measured by the Clinical Dementia Rating Scale (CDR).MethodThe sample included 347 study visits from 84 amyloid positive (A+) participants enrolled in the Wisconsin Registry for Alzheimer’s Prevention or the Wisconsin Alzheimer’s Disease Research Center (Table 1). For participant visits that administered the Quick Dementia Rating System (QDRS), the equivalent CDR sum of boxes (CDR‐SB) score was calculated. A mixed effects model with random slope and intercept was used to evaluate the association between chronicity and CDR‐SB (with covariates APOE4 carriage, sex and baseline age). To investigate potential non‐linearity in chronicity’s association with CDR‐SB, a chronicity‐by‐baseline chronicity category (&lt;0, 0‐5, 5‐10, 10‐15, 15‐20 and &gt;20 years) interaction was examined (&lt;0=reference range).ResultSpaghetti plots display the trajectories of CDR‐SB values in relation to amyloid chronicity; shading indicates clinical guidelines for interpreting CDR‐SB (Figure 1). The results of the model indicate that the trajectory of CDR‐SB is significantly greater after 10 years of amyloid chronicity (Table 2 &amp; Figure 2).ConclusionLargely consistent with previous studies, the results indicate that clinical symptoms begin to emerge after 10 years of amyloid positivity. However, symptom severity appeared to vary greatly between 10 – 30 years of amyloid chronicity. Future research will aim to identify other processes that may contribute to decline as well as genetic and modifiable factors that may promote resiliency and delay the onset of clinical symptoms.

Associative memory and in vivo brain pathology in asymptomatic presenilin-1 E280A carriers.

To determine whether performance on the Free and Cued Selective Reminding Test (FCSRT) is associated with PET in vivo markers of brain pathology and whether it can distinguish those who will develop dementia later in life due to autosomal-dominant Alzheimer disease (AD) from age-matched controls. Twenty-four cognitively unimpaired Presenilin-1 E280A carriers (mean age 36 years) and 28 noncarriers (mean age 37 years) underwent Pittsburg compound B-PET (amyloid), flortaucipir-PET (tau), and cognitive testing, including the FCSRT (immediate and delayed free and cued recall scores). Linear regressions were used to examine the relationships among FCSRT scores, age, mean cortical amyloid, and regional tau burden. Free and total recall scores did not differ between cognitively unimpaired mutation carriers and noncarriers. Greater age predicted lower free recall and delayed free and total recall scores in carriers. In cognitively impaired carriers, delayed free recall predicted greater amyloid burden and entorhinal tau, while worse immediate free recall scores predicted greater tau in the inferior temporal and entorhinal cortices. In turn, in all carriers, lower free and total recall scores predicted greater amyloid and regional tau pathology. FCSRT scores were associated with in vivo markers of AD-related pathology in cognitively unimpaired individuals genetically determined to develop dementia. Difficulties on free recall, particularly delayed recall, were evident earlier in the disease trajectory, while difficulties on cued recall were seen only as carriers neared the onset of dementia, consistent with the pathologic progression of the disease. Findings suggest that the FCSRT can be a useful measure to track disease progression in AD.

Prognostic plasma protein panel for Aβ deposition in the brain in Alzheimer’s disease

Alzheimer’s disease (AD) is the most common age-associated dementia. Many studies have sought to predict cerebral amyloid deposition, the major pathological hallmark of AD, using body fluids such as blood or cerebral spinal fluid (CSF). The use of blood in diagnostic procedures is widespread in medicine; however, existing blood biomarkers for AD remain unreliable. We sought to discover blood biomarkers that discriminate Aβ deposition status in the brain. This study used 107 individuals who were cognitively normal (CN), 107 patients with mild cognitive impairment (MCI), and 40 AD patients with Pittsburg compound B positron emission tomography (PiB-PET) amyloid imaging data available. We found five plasma biomarker candidates via mass spectrometry (MS) based-proteomic analysis and validated these proteins using enzyme-linked immunosorbent assay (ELISA). Our integrated models were highly predictive of brain amyloid deposition, exhibiting 0.871 accuracy with 79% sensitivity and 84% specificity overall, and 0.836 accuracy with 68% sensitivity and 90% specificity in patients with MCI. These results indicated that a combination of proteomic-based blood proteins might be a possible biomarker set for predicting cerebral amyloid deposition.

Amyloid burden and white matter hyperintensities mediate age-related cognitive differences

This study examined the additive versus synergistic contribution of beta-amyloid (Aβ) and white matter hyperintensities (WMHs) across 7 cognitive domains in 104 cognitively normal older adults. It also measured the extent to which age-related differences in cognition are driven by measurable brain pathology. All participants underwent neuropsychological assessment along with magnetic resonance imaging and Pittsburg compound B–positron emission tomography imaging for Aβ quantification. WMH severity was quantified using the age-related white matter changes scale. Stepwise regressions, moderation, and mediation modeling were performed. Our findings show that Aβ deposition single-handedly predicts poorer episodic memory performance and that Aβ and WMHs contribute additively to poorer performance in working memory and language while carrying synergistic associations with executive functions and attention. Through mediation modeling, we demonstrated that the influence of age over episodic memory, working memory, executive functions, and language is fully mediated by brain pathology. This study permits to conclude that, in healthy older adults, (1) Aβ burden and WMHs have synergistic associations with some cognitive domains and (2) age-related differences in most cognitive domains are driven by brain pathology associated with dementia.

Efecto del ejercicio físico en la enfermedad de Alzheimer. Una revisión sistemática

ObjectiveThe objective of this review is to analyze through a the scientific evidence about the effects of physical activity in patients with Alzheimer's disease (AD) as a preventive and non-pharmacological treatment. DesignSystematic review. Data sources: We have identified articles from Pubmed, Science Direct, Medline and Scopus databases, with the keywords Alzheimer, Exercise, Neuroimaging, MRI, PET y Physical Activity. Selected articles: We included those studies that evaluated the effects of physical activity on Alzheimer's disease and those which also included magnetic resonance imaging or positron emission tomography with Pittsburg Compound B marker (PiB) analyzing brain atrophy or increase of the beta-amyloid deposit respectively. We excluded studies including other types of dementia, different of AD. We also excluded articles which not included neuroimaging tests, single cases or non-English language articles. Data extraction: The PRISMA quality scale was used for the critical lecture of the studies. The researchers independently assessed the articles and the discrepancies were resolved by consensus. ResultsWe identified 75 articles, of which 23 were finally included in the review. ConclusionsMost of the studies included do not allow us to know the impact of physical exercise on cognition and the cerebral structural-functional changes in patients at risk of developing AD or in patients who already have the disease. Without being able to rule out a possible beneficial effect, more studies are needed with a better design and methodological rigor that allows a better known about this association.

18F]Amylovis as a Potential PET Probe for β-Amyloid Plaque: Synthesis, In Silico, In vitro and In vivo Evaluations.

BackgroundAlzheimer’s disease (AD) is the most common form of dementia. Neuroimaging methods have widened the horizons for AD diagnosis and therapy. The goals of this work are the synthesis of 2-(3-fluoropropyl)-6-methoxynaphthalene (5) and its [18F]-radiolabeled counterpart ([18F]Amylovis), the in silico and in vitro comparative evaluations of [18F]Amylovis and [11C]Pittsburg compound B (PIB) and the in vivo preclinical evaluation of [18F]Amylovis in transgenic and wild mice.MethodsIron-catalysis cross coupling reaction, followed by fluorination and radiofluorination steps were carried out to obtain 5 and 18F-Amylovis. Protein/Aß plaques binding, biodistribution, PET/CT Imaging and immunohistochemical studies were conducted in healthy/transgenic mice.ResultsThe synthesis of 5 was successful obtained. Comparative in silico studies predicting that 5 should have affinity to the Aβ-peptide, mainly through π-π interactions. According to a dynamic simula-tion study the ligand-Aβ peptide complexes are stable in simulation-time (ΔG = -5.31 kcal/mol). [18F]Amylovis was obtained with satisfactory yield, high radiochemical purity and specific activity. The [18F]Amylovis log Poct/PBS value suggests its potential ability for crossing the blood brain barrier (BBB). According to in vitro assays, [18F]Amylovis has an adequate stability in time. Higher affinity to Aβ plaques were found for [18F]Amylovis (Kd 0.16 nmol/L) than PIB (Kd 8.86 nmol/L) in brain serial sections of 3xTg-AD mice. Biodistribution in healthy mice showed that [18F]Amylovis crosses the BBB with rapid uptake (7%ID/g at 5 min) and good washout (0.11±0.03%ID/g at 60 min). Comparative PET dynamic studies of [18F]Amylovis in healthy and transgenic APPSwe/PS1dE9 mice, revealed a significant high uptake in the mice model.ConclusionThe in silico, in vitro and in vivo results justify that [18F]Amylovis should be studied as a promissory PET imaging agent to detect the presence of Aβ senile plaques.

Longitudinal tau accumulation and atrophy in aging and alzheimer disease.

To determine the rate of tau accumulation in healthy older adults (OA) and patients with Alzheimer disease (AD), as well as the relationship of tau accumulation to cortical atrophy. Two longitudinal flortaucipir (FTP) positron emission tomography (PET) and magnetic resonance imaging (MRI) scans were acquired from 42 OA (21 Pittsburg compound B [PiB]+ , age = 77.6 ± 4.6 years, 25 female [F]/17 male [M]) and 19 PiB+ patients with AD (age = 63.1 ± 10.3 years, 12 F/7 M) over 1 to 3 years of follow-up. FTP change, structural MRI measures of atrophy, and cross-modal correlations were examined on a voxelwise level. Regional annual percentage change in FTP was also calculated. Voxelwise FTP change in AD showed the greatest increases in lateral and medial frontal lobes. Atrophy over the same interval was more widespread and included posteromedial cortical areas, where tau accumulation rates were lower. In OA, FTP binding increased in bilateral temporal lobe and retrosplenial cortex, accompanied by atrophy in the same regions. There were no associations between voxelwise change in FTP and sex, PiB, or APOE. Regional FTP significantly increased at follow-up in OA and patients with AD. Mixed effects models showed greater FTP increases in AD compared to OA, and no differences within OA based on PiB status. Our findings indicate that tau accumulates even in amyloid-negative healthy OA and this process can be measured with in vivo tau-PET. In OA, tau accumulation and atrophy share a similar topography. In AD, tau increases more rapidly and accumulation occurs in frontal regions that are not yet undergoing significant atrophy. Ann Neurol 2019; 1-12 ANN NEUROL 2019;85:229-240.

Obstructive Sleep Apnea Severity Affects Amyloid Burden in Cognitively Normal Elderly. A Longitudinal Study.

Recent evidence suggests that obstructive sleep apnea (OSA) may be a risk factor for developing mild cognitive impairment and Alzheimer's disease. However, how sleep apnea affects longitudinal risk for Alzheimer's disease is less well understood. To test the hypothesis that there is an association between severity of OSA and longitudinal increase in amyloid burden in cognitively normal elderly. Data were derived from a 2-year prospective longitudinal study that sampled community-dwelling healthy cognitively normal elderly. Subjects were healthy volunteers between the ages of 55 and 90, were nondepressed, and had a consensus clinical diagnosis of cognitively normal. Cerebrospinal fluid amyloid β was measured using ELISA. Subjects received Pittsburgh compound B positron emission tomography scans following standardized procedures. Monitoring of OSA was completed using a home sleep recording device. We found that severity of OSA indices (AHIall [F1,88 = 4.26; P < 0.05] and AHI4% [F1,87 = 4.36; P < 0.05]) were associated with annual rate of change of cerebrospinal fluid amyloid β42 using linear regression after adjusting for age, sex, body mass index, and apolipoprotein E4 status. AHIall and AHI4% were not associated with increases in ADPiB-mask (Alzheimer's disease vulnerable regions of interest Pittsburg compound B positron emission tomography mask) most likely because of the small sample size, although there was a trend for AHIall (F1,28 = 2.96, P = 0.09; and F1,28 = 2.32, not significant, respectively). In a sample of cognitively normal elderly, OSA was associated with markers of increased amyloid burden over the 2-year follow-up. Sleep fragmentation and/or intermittent hypoxia from OSA are likely candidate mechanisms. If confirmed, clinical interventions for OSA may be useful in preventing amyloid build-up in cognitively normal elderly.

Hippocampal hypometabolism in older adults with memory complaints and increased amyloid burden.

To identify the functional and pathologic correlates underlying subjective memory complaints (SMCs) in cognitively normal older adults. Two hundred fifty-one older adults underwent resting-state fluorodeoxyglucose (FDG)-PET and Pittsburg compound B-PET β-amyloid (Aβ) imaging and filled out a questionnaire regarding SMCs. Participants were classified into 2 groups based on their Aβ burden. Age-adjusted voxel-wise correlations were used to examine SMCs, amyloid status (Aβ+ vs Aβ-), and the interaction between SMCs and Aβ status as predictors of metabolism. Region-of-interest (ROI) analyses were performed to confirm the whole-brain analyses and to test for additional covariates. Greater SMCs correlated with decreased FDG metabolism in the bilateral precuneus, bilateral inferior parietal lobes, right inferior temporal lobe, right medial frontal gyrus, and right orbitofrontal gyrus. A significant interaction effect between SMCs and amyloid burden was found such that Aβ+ individuals with increased complaints had decreased FDG metabolism in the bilateral medial temporal lobes. ROI analyses confirmed the voxel-wise analyses result in that decreased precuneus metabolism was associated with greater SMCs regardless of Aβ status, age, or thickness, whereas the relationship between hippocampal metabolism and SMCs was a function of Aβ, even after adjustment for age, hippocampal volume, or depressive symptoms. These data show the relevant role of posterior and anterior midline regions in SMCs in older individuals. Decreased hippocampal metabolism may be a specific marker of subclinical changes in cognition due to amyloid pathology. However, longitudinal studies are needed to determine whether our findings foreshadow clinical decline.

Delayed-onset dementia after stroke or transient ischemic attack

IntroductionPatients surviving stroke without immediate dementia are at high risk of delayed-onset dementia. Mechanisms underlying delayed-onset dementia are complex and may involve vascular and/or neurodegenerative diseases. MethodsDementia-free patients with stroke and/or transient ischemic attack (TIA; n = 919) were studied for 3 years prospectively, excluding those who developed dementia 3 to 6 months after stroke and/or TIA. ResultsForty subjects (4.4%) developed dementia during the study period. Imaging markers of severe small vessel disease (SVD), namely presence of ≥3 lacunes and confluent white matter changes; history of hypertension and diabetes mellitus independently predicted delayed-onset dementia after adjustment for age, gender, and education. Only 6 of 31 (19.4%) subjects with delayed cognitive decline harbored Alzheimer's disease–like Pittsburg compound B (PiB) retention. Most PiB cases (16/25, 64%) had evidence of severe SVD. DiscussionSevere SVD contributes importantly to delayed-onset dementia after stroke and/or TIA. Future clinical trials aiming to prevent delayed-onset dementia after stroke and/or TIA should target this high-risk group.

Fluid Biomarkers in Clinical Trials of Alzheimer's Disease Therapeutics.

With the demographic shift of the global population toward longer life expectancy, the number of people living with Alzheimer’s disease (AD) has rapidly expanded and is projected to triple by the year 2050. Current treatments provide symptomatic relief but do not affect the underlying pathology of the disease. Therapies that prevent or slow the progression of the disease are urgently needed to avoid this growing public health emergency. Insights gained from decades of research have begun to unlock the pathophysiology of this complex disease and have provided targets for disease-modifying therapies. In the last decade, few therapeutic agents designed to modify the underlying disease process have progressed to clinical trials and none have been brought to market. With the focus on disease modification, biomarkers promise to play an increasingly important role in clinical trials. Six biomarkers have now been included in diagnostic criteria for AD and are regularly incorporated into clinical trials. Three biomarkers are neuroimaging measures – hippocampal atrophy measured by magnetic resonance imaging (MRI), amyloid uptake as measured by Pittsburg compound B positron emission tomography (PiB-PET), and decreased fluorodeoxyglucose (18F) uptake as measured by PET (FDG-PET) – and three are sampled from fluid sources – cerebrospinal fluid levels of amyloid β42 (Aβ42), total tau, and phosphorylated tau. Fluid biomarkers are important because they can provide information regarding the underlying biochemical processes that are occurring in the brain. The purpose of this paper is to review the literature regarding the existing and emerging fluid biomarkers and to examine how fluid biomarkers have been incorporated into clinical trials.