Salivary Gland Uptake on 18F‐Florbetaben PET Did Not Demonstrate Additional Diagnostic Value for Alzheimer's Disease

Informant questionnaire on cognitive decline in the elderly (IQCODE) for classifying cognitive dysfunction as cognitively normal, mild cognitive impairment, and dementia.

Emotional and behavioral symptoms in cognitively normal older people may be direct manifestations of Alzheimer disease (AD) pathophysiology at the preclinical stage, prior to the onset of mild cognitive impairment. Loneliness is a perceived state of social and emotional isolation that has been associated with cognitive and functional decline and an increased risk of incident AD dementia. We hypothesized that loneliness might occur in association with elevated cortical amyloid burden, an in vivo research biomarker of AD. To determine whether cortical amyloid burden is associated with greater loneliness in cognitively normal older adults. Cross-sectional analyses using data from the Harvard Aging Brain Study of 79 cognitively normal, community-dwelling participants. A continuous, aggregate measure of cortical amyloid burden, determined by Pittsburgh Compound B-positron emission tomography (PiB-PET), was examined in association with loneliness in linear regression models adjusting for age, sex, apolipoprotein E ε4 (APOEε4), socioeconomic status, depression, anxiety, and social network (without and with the interaction of amyloid and APOEε4). We also quantified the association of high amyloid burden (amyloid-positive group) to loneliness (lonely group) using logistic regression, controlling for the same covariates, with the amyloid-positive group and the lonely group, each composing 32% of the sample (n = 25). Loneliness, as determined by the 3-item UCLA Loneliness Scale (possible range, 3-12, with higher score indicating greater loneliness). The 79 participants included 43 women and 36 men with a mean (SD) age of 76.4 (6.2) years. Mean (SD) cortical amyloid burden via PiB-PET was 1.230 (0.209), and the mean (SD) UCLA-3 loneliness score was 5.3 (1.8). Twenty-two (28%) had positive APOEε4 carrier status, and 25 (32%) were in the amyloid-positive group with cortical PiB distribution volume ratio greater than 1.2. Controlling for age, sex, APOEε4, socioeconomic status, depression, anxiety, and social network, we found that higher amyloid burden was significantly associated with greater loneliness: compared with individuals in the amyloid-negative group, those in the amyloid-positive group were 7.5-fold (95% CI, 1.7-fold to 34.0-fold) more likely to be classified as lonely than nonlonely (β = 3.3, partial r = 0.4, P = .002). Furthermore, the association of high amyloid burden and loneliness was stronger in APOEε4 carriers than in noncarriers. We report a novel association of loneliness with cortical amyloid burden in cognitively normal older adults, suggesting that loneliness is a neuropsychiatric symptom relevant to preclinical AD. This work will inform new research into the neural underpinnings and disease mechanisms involved in loneliness and may enhance early detection and intervention research in AD.

Blood levels of cytokines highlight the role of inflammation in Alzheimer's disease.

The receiver operating characteristic (ROC) curve is an important tool to gauge the performance of classifiers. In certain situations of high-throughput data analysis, the data is heavily class-skewed, i.e. most features tested belong to the true negative class. In such cases, only a small portion of the ROC curve is relevant in practical terms, rendering the ROC curve and its area under the curve (AUC) insufficient for the purpose of judging classifier performance. Here we define an ROC surface (ROCS) using true positive rate (TPR), false positive rate (FPR), and true discovery rate (TDR). The ROC surface, together with the associated quantities, volume under the surface (VUS) and FDR-controlled area under the ROC curve (FCAUC), provide a useful approach for gauging classifier performance on class-skewed high-throughput data. The implementation as an R package is available at http://userwww.service.emory.edu/~tyu8/ROCS/.

BackgroundSingle post‐labeling delay (PLD) pseudo‐continuous arterial spin‐labeling (pCASL) measures cerebral blood Flow (CBF). The altered CBF is associated with cognitive decline in early Alzheimer’s disease (AD). However, multi‐delay pCASL that measures multi‐parametric measurements including CBF, arterial cerebral blood volume (aCBV) and arterial transit time (ATT) has rarely been applied to AD studies and its diagnostic performance to recognize AD in early stage remains unclear. The purpose of this study is to compare the diagnostic value between the CBF measured by single PLD pCASL and the CBF/aCBV/ATT measured by multi‐PLD pCASL for early‐stage AD.MethodBoth 1 PLD and 7 PLD 3D pCASL protocols on 3T GE scanner were performed within one MR session for 26 cognitively normal (CN), 37 mild cognitive impairment (MCI) and 39 AD subjects who were recruited in Chinese Imaging, Biomarkers, and Lifestyle Study of Ageing Project (CIBL) from April to October 2021. Comparisons on CBF/aCBV/ATT in 10 regions of interest (ROIs), including left and right regions of olfactory, post cingulate, hippocampus, cuneus and precuneus, were performed across different groups. The area under the curve (AUC) were assessed through receiver operating characteristic (ROC) analysis.ResultAll ROIs showed significant decrease in CBF and increase in ATT of AD groups compared with that of CN and MCI groups (P < 0.05). There was no significant difference in aCBV between groups and CBF/ATT between CN and MCI (P > 0.05). The area under the ROC curve (AUC) of CBF in ROIs for both3D pCASL protocols was similar for discriminating AD against HC (0.949 vs. 0.965 for 1 PLD vs. 7 PLD, respectively), AD against MCI (0.836 vs. 0.830), MCI against HC (0.686 vs. 0.786). However, the combination of CBF/aCBV/ATT in ROIs measured by 7 PLD 3D pCASL could significantly improve diagnostic performance, which AUC was 1.000, 0.967 and 0.918 for identifying AD against HC, AD against MCI and MCI against HC respectively.ConclusionMulti‐parametric perfusion data from multi‐delay pCASL can improve the diagnostic value of AD in early stage, which could be a promising imaging biomarker in AD patients.

Alzheimer'S disease (ad) and mild cognitive impairment (mci) patients are characterized by increased bdnf serum levels

Longevity is influenced by a combination of genetic factors, lifestyle choices, and environmental conditions. These factors can alter microbiota composition, potentially influencing susceptibility to Alzheimer's disease (AD) and cognitive decline. We hypothesize that the microbiome in elderly individuals may be associated with different clinical stages of AD. This study aims to investigate the relationship between oral and gut microbiota composition in a Brazilian long-lived population and cognitive impairment within the AD continuum. We conducted a pilot characterization of the oral and gut microbiota of 12 elderly individuals (>65 years) recruited by the Moriguchi Institute in Veranópolis, a longevity hotspot in southern Brazil. Participants underwent clinical-cognitive assessment, including the Clinical Dementia Rating (CDR), and were classified as cognitively unimpaired (CU), mild cognitive impairment (MCI), or Alzheimer's disease (AD). Saliva and fecal samples were sequenced using Illumina MiSeq™, targeting the V3-V4 regions of the 16S rRNA gene, and processed in R using DADA2. Amplicon sequence variants (ASVs) were inferred, and taxonomic assignments were performed with SILVA. Abundance data were used for alpha and beta diversity, and relative abundance analyses. Alpha diversity was similar across groups, except for reduced salivary richness in MCI (Chao1, p=0.002; Figure 1). Rarefaction curves indicated higher richness in the feces compared to saliva. PCoA analysis showed distinct group separations in feces, with MCI and AD being more similar, while saliva samples were more uniform. Relative abundance demonstrated alterations in phylum Bacillota, Bacteroidota, and Pseudomonadota in MCI and AD compared to the CU group (Figure 2). Changes were particularly evident in fecal families Lachnospiraceae, Bacteroidaceae, and Ruminococcaceae, and genus such as Bacteroides, Blautia, and Faecalibacterium. Notably, Streptococcus was almost exclusively elevated in fecal samples of the AD group. Saliva samples were more homogeneous across groups, though changes were observed in families Prevotellaceae and Streptococcaceae, and genus Prevotella, Streptococcus, Haemophilus, and Neisseria in MCI and AD compared to CU. Fecal microbiota exhibited clinical-stage-specific changes, while salivary microbiota displayed more stability, underscoring microbial adaptations to the distinct. These findings highlight microbiome changes along the AD continuum, emphasizing the potential microbiome's role in healthy aging and resilience against neurodegeneration.

Background: Sjögren’s syndrome (SS) is a progressive autoimmune disease characterized by local mononuclear cell infiltration of the salivary and lachrymal glands. Labial biopsy demonstrates local infiltration by Th1 cells that produce pro-inflammatory cytokines, such as interleukin-2 (IL2). The aim of this study was to assess the utility of 99mTc-labelled-IL2 (99mTc-IL2) in evaluating in vivo the extent and severity of lympho-mononuclear cell infiltration in the salivary glands of patients with SS. Methods: We investigated 48 patients with primary SS and 27 control subjects using 99mTc-IL2 scintigraphy. Furthermore, in a subgroup of 30 patients, we also performed 99mTc-pertechnetate scintigraphy (99mTcO4−) for evaluation of the salivary gland function. Results: 99mTc-IL2 uptake in the salivary glands of SS patients was higher than in the control subjects (1.30 ± 0.16 vs. 0.83 ± 0.08 for parotids and 1.36 ± 0.15 vs. 1.16 ± 0.07 for submandibular glands; p < 0.0001). The salivary gland uptake of 99mTc-IL2 in patients with a longer history of disease was lower compared with the recently diagnosed patients. A significant direct correlation was found between the uptake of 99mTc-IL2 and histology. Conclusions: 99mTc-IL2 scintigraphy showed that the degree of lymphocytic infiltration of major salivary glands is variable in patients with different disease durations. Patients with a high 99mTc-IL2 uptake could be efficiently treated with immuno-modulatory drugs and the efficacy of treatment could be followed-up by 99mTc-IL2 scintigraphy.

Many medical diagnostic studies involve three ordinal diagnostic groups in which the diagnostic accuracy can be summarized by the volume or partial volume under a Receiver Operating Characteristic (ROC) surface. We study in this paper the statistical comparison of diagnostic accuracy from multiple diagnostic tests when three ordinal diagnostic groups are involved. Under the assumption that the multiple diagnostic tests follow a multivariate normal distribution within each diagnostic group, we provide the asymptotic variance and covariance for the maximum likelihood estimates of the volumes under the ROC surfaces from multiple diagnostic tests and propose statistical tests to test whether the diagnostic accuracy as measured by the volume under the ROC surface is the same for multiple diagnostic tests. We also propose a confidence interval estimate to the difference of two volumes under two ROC surfaces. Our approach depends crucially on the assumptions of normal distributions on diagnostic tests, which might not be robust when such assumptions are violated. Finally, we apply our proposed methodology to a real data set of 118 subjects to compare the diagnostic accuracy of early stage Alzheimer's disease (AD) from multiple neuropsychological tests.

S4-01-01: Identification of subgroups of Alzheimer disease

Classification of a given observation to one of three classes is an important task in many decision processes or pattern recognition applications. A general analysis of the performance of three-class classifiers results in a complex 6-D receiver operating characteristic (ROC) space, for which no simple analytical tool exists at present. We investigate the performance of an ideal observer under a specific set of assumptions that reduces the 6-D ROC space to 3-D by constraining the utilities of some of the decisions in the classification task. These assumptions lead to a 3-D ROC space in which the true-positive fraction (TPF) can be expressed in terms of the two types of false-positive fractions (FPFs). We demonstrate that the TPF is uniquely determined by, and therefore is a function of, the two FPFs. The domain of this function is shown to be related to the decision boundaries in the likelihood ratio plane. Based on these properties of the 3-D ROC space, we can define a summary measure, referred to as the normalized volume under the surface (NVUS), that is analogous to the area under the ROC curve (AUC) for a two-class classifier. We further investigate the properties of the 3-D ROC surface and the NVUS for the ideal observer under the condition that the three class distributions are multivariate normal with equal covariance matrices. The probability density functions (pdfs) of the decision variables are shown to follow a bivariate log-normal distribution. By considering these pdfs, we express the TPF in terms of the FPFs, and integrate the TPF over its domain numerically to obtain the NVUS. In addition, we performed a Monte Carlo simulation study, in which the 3-D ROC surface was generated by empirical "optimal" classification of case samples in the multidimensional feature space following the assumed distributions, to obtain an independent estimate of NVUS. The NVUS value obtained by using the analytical pdfs was found to be in good agreemen- t with that obtained from the Monte Carlo simulation study. We also found that, under all conditions studied, the NVUS increased when the difficulty of the classification task was reduced by changing the parameters of the class distributions, thereby exhibiting the properties of a performance metric in analogous to AUC. Our results indicate that, under the conditions that lead to our 3-D ROC analysis, the performance of a three-class classifier may be analyzed by considering the ROC surface, and its accuracy characterized by the NVUS.

High Activities of BACE1 in Brains with Mild Cognitive Impairment

Dear Sir, It was with particular interest that we read the article by Afshar-Oromieh et al. [1]. The authors developed a novel 68Ga-labelled prostate-specific membrane antigen (PSMA)-binding small molecule, combining the well-known urea-based inhibitory motif glutamate-urea-lysine [2] with the lipophilic N,N′-bis[2-hydroxy-5-(carboxyethyl)-benzyl]ethylenediamine-N,N′-diacetic acid (HBED-CC) chelator for 68Ga [3]. The authors reasoned that the lipophilicity of HBED-CC might improve binding to PSMA and thus enable positron emission tomography (PET)/CT imaging of prostate carcinoma (PCa) [3]. Recognizing that PSMA targeting is one of the most exciting topics of molecular imaging and targeted therapy in prostate cancer at present, the authors are to be congratulated on offering the first larger patient series of 37 individuals with relapsing PCa, examined with a 68Ga-labelled PSMA inhibitor and PET/CT. Examination of the biodistribution of the novel tracer and capability to show presumed sites of metastatic involvement were major intents of the study. The authors described excellent lesion detection with impressive contrast of presumed sites of metastatic deposits of prostate cancer in 31 of their 37 patients (83.8 %) [1]. A detailed discussion of the many clinical and technical ambiguous aspects of the study is beyond the scope of this letter. However, we think that in a study comprising 37 patients a discussion of 42 patients in the text needs clarification. In addition, we cannot follow the assumption that a prostate involved with prostate cancer and treated with local radiation therapy and androgen deprivation therapy can be regarded as a ‘normal prostate’. Also, interpretation of the clinical state of patient 21 described in the legend of Fig. 7 as harbouring probably dedifferentiated prostate cancer because of positive pelvic nodes and a serum prostate-specific antigen (PSA) concentration of 0.01 ng/ml is confusing as this patient already had a Gleason score of 9 of his primary and bone as well as soft tissue metastases (Table 1) and therapy beyond prostatectomy is not discussed. Moreover, one of the two positive nodes in this patient is an inguinal node, a localization where positive nodes from PCa are very rare. Generally, a definition of assessment criteria of assumed prostate cancer deposits and verification by some reference standard in more than the six histologically controlled patients described would have been very welcome. Interestingly, the authors try to explain 68Ga-PSMA inhibitor biodistribution with rather high tracer uptake in lacrimal and salivary glands, nasal mucosa, liver, spleen, bowel, kidneys and bladder in the context of known PSMA tissue expression. A very similar biodistribution to that described by the authors was observed in a series of seven patients, examined with the PSMA inhibitor MIP-1072 ([(S)-2-(3-((S)-1-carboxy-5-(4-iodobenzylamino)pentyl)ureido) pentanedioic acid) and MIP-1095 ([(S)-2-(3-((S)-1-carboxy-5-(3-(4-iodophenyl)pentyl)ureido) pentanedioic acid) by Barrett et al. very recently [4]. Also in this study, lesions from PCa could be imaged with high contrast using single photon emission computed tomography (SPECT)/CT as the imaging technique [4]. Studying relapsing prostate cancer with another 68Ga-PSMA inhibitor, 68Ga-DOTA-DUPA-Pep (8,11-dibenzyl-2,7,10,13,22,27-hexaoxo-1-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraaza-cyclododecan-1-yl)-3,6,9,12,21,26,28-heptaazahentriacontane-25,29,31-tricarboxylic acid) we can confirm the very favourable imaging properties of PSMA targeting with urea-based inhibitors for showing metastatic disease with PET/CT (Fig. 1a), but we observed a remarkably different biodistribution (Fig. 1b) to that described by Afshar-Oromieh et al. [5]. We found predominant tracer uptake in kidneys, urinary tract, blood pool and lesions from PCa (Fig. 1a) and only very faint uptake in salivary glands and also in gynaecomastia (Fig. 1b). Interestingly, a current paper by Pomper’s group using the 18F-labelled PSMA inhibitor N-[N-[(S)-1,3-dicarboxypropyl]carbamoyl]-4-18F-fluorobenzyl-L-cysteine (18F-DCFBC) described a strikingly similar biodistribution to that of 68Ga-DOTA-DUPA-Pep [6]. Thus, PSMA addressing through urea-based inhibitors with appropriate radiolabelled peptides seems to provide a very promising approach for targeting various stages of PCa in patients; however, factors governing extraprostatic tissue distribution need further careful analysis and consideration. Fig. 1 a A 70-year-old patient with a history of prostatectomy because of PCa 12 years before the examination, Gleason score 5 + 5, local radiation therapy and castration-resistant PCa at presentation, PSA 3 ng/ml. 11C-choline ...

REGION-SPECIFIC ATROPHY AS MEASURED BY CORTICAL GRAY MATTER VOLUME IS ASSOCIATED WITH BOTH REGIONAL AND TOTAL CORTICAL AMYLOID-BETA BURDEN IN COGNITIVELY NORMAL INDIVIDUALS AT RISK FOR ALZHEIMER'S DISEASE

The literature on cognitive markers in preclinical AD is reviewed. The findings demonstrate that impairment in multiple cognitive domains is typically observed several years before clinical diagnosis. Measures of executive functioning, episodic memory and perceptual speed appear to be most effective at identifying at-risk individuals. The fact that these cognitive domains are most implicated in normal cognitive aging suggests that the cognitive deficit observed preclinically is not qualitatively different from that observed in normal aging. The degree of cognitive impairment prior to the diagnosis of Alzheimer's disease (AD) appears to generalize relatively well across major study characteristics, including sample ascertainment procedures, age and cognitive status of participants, as well as time to diagnosis of dementia. In episodic memory, there is evidence that the size of the preclinical deficit increases with increasing cognitive demands. The global cognitive impairment observed is highly consistent with observations that multiple brain structures and functions are affected long before the diagnosis of AD. However, there is substantial overlap in the distribution of cognitive scores between those who will and those who will not be diagnosed with AD, hence limiting the clinical utility of cognitive markers for early identification of cases. Future research should consider combining cognitive indicators with other types of markers (i.e. social, somatic, genetic, brain-based) in order to increase prediction accuracy.