Positive Positron Emission Tomography Research Articles

Postoperative 68Ga-DOTATATE positron emission tomography has a low yield in incidental appendiceal neuroendocrine tumours.

Rarely, appendiceal neuroendocrine tumours (NET) are an incidental finding when an appendicectomy is undertaken for suspected appendicitis. The role of further imaging in this setting is poorly defined. Positron emission tomography (PET) using 68Ga-DOTATATE is requested to evaluate post-surgical status, however, there is little evidence to guide how it should be employed. The aims of this project are to: (i) characterize 68Ga-DOTATATE PET findings in patients with incidental appendiceal NETs and (ii) discuss how these data might inform post-surgical imaging with PET. We reviewed 47 PET scans in 30 patients, undertaken from 2009 to 2018. Scintigraphic findings, histopathological characteristics of the initial appendiceal lesion and medical records were reviewed. Most patients (n = 15) had small (<10 mm) appendiceal NETs with low grade (Ki67 < 2%) features. Eight patients had tumours between 10 and 20 mm, and seven had tumours >20 mm. Goblet cell features were identified in two patients. Three positive PET scans were reported in one patient with an index tumour measuring 40 mm and Ki67 < 2%. The remaining 29 patients had 44 negative scans. Clinical outcome data were available in 27 patients (mean follow-up time 57 months; range 6-123 months). There was no evidence of recurrent neuroendocrine disease at the time of the last follow-up. These data indicate that in most cases, post-surgical 68Ga-DOTATATE PET is negative in patients with incidentally detected appendiceal NETs. Clinical outcome data suggest that 68Ga-DOTATATE PET should be reserved for patients with large tumours (>20 mm) or those displaying goblet cell features.

P-tau217 as a Reliable Blood-Based Marker of Alzheimer's Disease.

Amyloid plaques and tau tangles are the hallmark pathologic features of Alzheimer's disease (AD). Traditionally, these changes are identified in vivo via cerebrospinal fluid (CSF) analysis or positron emission tomography (PET) scans. However, these methods are invasive, expensive, and resource-intensive. To address these limitations, there has been ongoing research over the past decade to identify blood-based markers for AD. Despite the challenges posed by their extremely low concentrations, recent advances in mass spectrometry and immunoassay techniques have made it feasible to detect these blood markers of amyloid and tau deposition. Phosphorylated tau (p-tau) has shown greater promise in reflecting amyloid pathology as evidenced by CSF and PET positivity. Various isoforms of p-tau, distinguished by their differential phosphorylation sites, have been recognized for their ability to identify amyloid-positive individuals. Notable examples include p-tau181, p-tau217, and p-tau235. Among these, p-tau217 has emerged as a superior and reliable marker of amyloid positivity and, thus, AD in terms of accuracy of diagnosis and ability for early prognosis. In this narrative review, we aim to elucidate the utility of p-tau217 as an AD marker, exploring its underlying basis, clinical diagnostic potential, and relevance in clinical care and trials.

Optical Coherence Tomography Angiography Retinal Imaging Associations With Burden of Small Vessel Disease and Amyloid Positivity in the Brain.

Alzheimer disease (AD) and other dementias are associated with vascular changes and amyloid deposition, which may be reflected as density changes in the retinal capillaries. These changes may can be directly visualized and quantified with optical coherence tomography angiography (OCTA), making OCTA a potential noninvasive preclinical biomarker of small vessel disease and amyloid positivity. Our objective was to investigate the feasibility of retinal imaging metrics as noninvasive biomarkers of small vessel disease and amyloid positivity in the brain. We investigated associations between OCTA and neuroimaging and cognitive metrics in 41 participants without dementia from the Mayo Clinic Study of Aging and Alzheimer's Disease Research Center. OCTA metrics included superficial, deep, and full retina capillary density of the fovea, parafovea, and macula as well as the area of the foveal avascular zone (FAZ). Neuroimaging metrics included a high burden of white matter hyperintensity (WMH), presence of cerebral microbleeds (CMB), lacunar infarcts, and amyloid positivity as evidenced on positron emission tomography (PET), whereas cognitive metrics included mini-mental status examination (MMSE) score. We performed generalized estimating equations to account for measurements in each eye while controlling for age and sex to estimate associations between OCTA metrics and neuroimaging and cognitive scores. Associations between OCTA and neuroimaging metrics were restricted to the fovea. OCTA showed decreased capillary density with high burden of WMH in both the superficial (P = 0.003), deep (P = 0.004), and full retina (P = 0.01) in the fovea but not the parafovea or whole macula. Similarly, participants with amyloid PET positivity had significantly decreased capillary density in the superficial fovea (P = 0.027) and deep fovea (P = 0.03) but higher density in the superficial parafovea (P = 0.038). Participants with amyloid PET positivity also had a significantly larger FAZ (P = 0.031), whereas in those with high WMH burden the difference did not reach statistical significance (P = 0.075). There was also a positive association between MMSE and capillary density of the full retina within the fovea (P = 0.037) and in the superficial parafovea (P = 0.046). No associations were found between OCTA metrics and presence of CMB or presence of lacunar infarcts. The associations of lower foveal capillary density with cerebral WMH and amyloid positivity suggest that further research is warranted to evaluate for shared mechanisms of disease between small vessel disease and AD pathologies.

Assessing amyloid PET positivity and cognitive function in Down syndrome to guide clinical trials targeting amyloid.

Trisomy 21, or Down syndrome (DS), predisposes individuals to early-onset Alzheimer's disease (AD). While monoclonal antibodies (mAbs) targeting amyloid are approved for older AD patients, their efficacy in DS remains unexplored. This study examines amyloid positron emission tomography (PET) positivity (A+), memory function, and clinical status across ages in DS to guide mAb trial designs. Cross-sectional data from the Alzheimer Biomarker Consortium-Down Syndrome (ABC-DS) was analyzed. PET amyloid beta in Centiloids classified amyloid status using various cutoffs. Episodic memory was assessed using the modified Cued Recall Test, and clinical status was determined through consensus processes. Four hundred nine DS adults (mean age=44.83 years) were evaluated. A+ rates increased with age, with mean amyloid load rising significantly. Memory decline and cognitive impairment are also correlated with age. These findings emphasize the necessity of tailoring mAb trials for DS, considering age-related AD characteristics. There is rapid increase in prevalence of amyloid beta (Aβ) positron emission tomography (PET) positivity in Down syndrome (DS) after the age of 40 years. Aβ PET positivity thresholds have significant impact on prevalence rates in DS. There is a significant lag between Aβ PET positivity and clinical symptom onset in DS.

Radical Prostatectomy Without Prior Biopsy in Selected Patients Evaluated by 18F-Labeled Prostate-Specific Membrane Antigen-Ligand Positron Emission Tomography/Computed Tomography and Multiparameter Magnetic Resonance Imaging: A Single-Center, Prospective, Single-Arm Trial.

This study aimed to verify the feasibility and short-term prognosis of prostatectomy without biopsy. Patients with a rising PSA level ranging from 4 to 30 ng/mL were scheduled for multiparametric (mp) MRI and 18F-labeled prostate-specific membrane antigen (PSMA) positron emission tomography (PET). Forty-seven patients (cT2N0M0) with Prostate Imaging Reporting and Data System ≥ 4 and molecular imaging PSMA score ≥ 2 were enrolled. All candidates underwent robot-assisted laparoscopic radical prostatectomy without biopsy. Prostate cancer detection rate, index tumors localization correspondence rate, positive surgical margin, complications, postoperative hospital stay, and PSA level in a 6-week postoperative follow-up visit were collected. All the patients with positive mpMRI and PSMA PET were diagnosed with clinically significant prostate cancer. A total of 80 lesions were verified as cancer by pathology, of which 63 cancer lesions were clinically significant prostate cancer. Fifty-one lesions were simultaneously found by mpMRI and PSMA PET. A total of 23 lesions were invisible on either image, and all lesions were ≤ International Society of Urological Pathology 2 or ≤ 15 mm. Forty-five (95.7%) index tumors found by mpMRI combined with PSMA PET were consistent with pathology. Nine patients reported positive surgical margin. Biopsy-free prostatectomy is safe and feasible for patients with evaluation strictly by mpMRI combined with 18F-PSMA PET/CT.

Unanticipated pathological clearance in two cases of clinical T4b dMMR/MSI-h advanced colorectal cancer: the potential of immune checkpoint inhibitors despite positive positron-emission tomography results.

The standard treatment for colorectal cancer consists of surgery and chemotherapy, which can be combined to improve outcomes. Immune checkpoint inhibitors (ICI) are a significant advancement in the standard treatment of metastatic, unresectable colorectal cancer with deficient mismatch repair (dMMR). However, limited data are available about the use of ICI in the neoadjuvant and conversion settings. Here, we present two cases treated with ICI. Case 1: A 75-year-old male with a large, borderline resectable rectal cancer diagnosed as cT4bN1bM0 who underwent neoadjuvant chemotherapy, followed by combination ICI consisting of ipilimumab and nivolumab. After four courses of ICI, the tumor significantly shrank, but positron emission tomography still showed a positive result and R0 resection was performed. Pathological analysis revealed no residual cancer cells. The patient has been monitored without adjuvant chemotherapy, and no recurrences have occurred after one year. Case 2: A 60-year-old male with locally advanced sigmoid colon cancer who received neoadjuvant treatment with pembrolizumab. The tumor partially shrank after three courses, and continued pembrolizumab monotherapy resulted in further tumor shrinkage which still showed positive positron emission tomography. Curative sigmoidectomy with partial resection of the ileum and bladder was performed, and the pathological outcome was pCR. There was no viable tumor in the specimen. The patient has been monitored without adjuvant chemotherapy for six months, and no recurrence has been observed. The present study reports two cases, including a large, borderline resectable rectal cancer after failure of chemotherapy followed by combination treatment with nivolumab and ipilimumab and one case of sigmoid colon cancer after pembrolizumab treatment, which resulted in pathological complete response. However, it remains unknown whether ICI therapy can replace surgery or diminish the optimal extent of resection, or whether adjuvant chemotherapy is needed after surgery in the case of achieving pCR after ICI therapy. Overall, this case report suggests that ICI before colorectal surgery can be effective and potentially a 'watch-and-wait" strategy could be used for cases in which ICI is effective.

Factors Contributing to the Accuracy of PET Scans in Detecting Cancer Metastases in Cairo Hospitals, Egypt

Introduction: Positron emission tomography (PET) has become an important diagnostic tool in oncology, providing metabolic information that can aid in the detection and evaluation of cancer. However, the accuracy of PET scans in detecting cancer metastases can be influenced by various factors, including the type of cancer, location of metastases, and image acquisition protocol. This study aims to evaluate the factors that influence the accuracy of PET scans in detecting cancer metastases in patients at Cairo Hospital, Egypt.&#x0D; Methods: Patient data were collected retrospectively. A total of 5000 research subjects participated in this study. Data were analyzed to identify factors associated with false-positive or false-negative PET scan results.&#x0D; Results: Patients with lung or colorectal cancer were 2.45 times more likely to experience accurate positive PET scan results than patients with other types of cancer. Patients with metastases in lymph nodes were 1.93 times more likely to experience accurate positive PET scan results than patients with metastases in solid organs. Patients with a long PET scan image acquisition protocol were 1.78 times more likely to experience accurate positive PET scan results than patients with a short image acquisition protocol.&#x0D; Conclusion: PET scan is a valuable diagnostic tool in oncology, but its accuracy in detecting cancer metastases can be influenced by various factors. These factors should be considered when interpreting PET scan results and to improve cancer diagnosis and management.

Combining Blood-Based Biomarkers and Structural MRI Measurements to Distinguish Persons with and without Significant Amyloid Plaques.

Amyloid-β (Aβ) plaques play a pivotal role in Alzheimer's disease. The current positron emission tomography (PET) is expensive and limited in availability. In contrast, blood-based biomarkers (BBBMs) show potential for characterizing Aβ plaques more affordably. We have previously proposed an MRI-based hippocampal morphometry measure to be an indicator of Aβ plaques. To develop and validate an integrated model to predict brain amyloid PET positivity combining MRI feature and plasma Aβ42/40 ratio. We extracted hippocampal multivariate morphometry statistics from MR images and together with plasma Aβ42/40 trained a random forest classifier to perform a binary classification of participant brain amyloid PET positivity. We evaluated the model performance using two distinct cohorts, one from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and the other from the Banner Alzheimer's Institute (BAI), including prediction accuracy, precision, recall rate, F1 score, and AUC score. Results from ADNI (mean age 72.6, Aβ+ rate 49.5%) and BAI (mean age 66.2, Aβ+ rate 36.9%) datasets revealed the integrated multimodal (IMM) model's superior performance over unimodal models. The IMM model achieved prediction accuracies of 0.86 in ADNI and 0.92 in BAI, surpassing unimodal models based solely on structural MRI (0.81 and 0.87) or plasma Aβ42/40 (0.73 and 0.81) predictors. Our IMM model, combining MRI and BBBM data, offers a highly accurate approach to predict brain amyloid PET positivity. This innovative multiplex biomarker strategy presents an accessible and cost-effective avenue for advancing Alzheimer's disease diagnostics, leveraging diverse pathologic features related to Aβ plaques and structural MRI.

Pathophysiology characterization of Alzheimer's disease in South China's aging population: for the Greater-Bay-Area Healthy Aging Brain Study (GHABS).

The Guangdong-Hong Kong-Macao Greater-Bay-Area of South China has an 86million population and faces a significant challenge of Alzheimer's disease (AD). However, the characteristics and prevalence of AD in this area are still unclear due to the rarely available community-based neuroimaging AD cohort. Following the standard protocols of the Alzheimer's Disease Neuroimaging Initiative, the Greater-Bay-Area Healthy Aging Brain Study (GHABS) was initiated in 2021. GHABS participants completed clinical assessments, plasma biomarkers, genotyping, magnetic resonance imaging (MRI), β-amyloid (Aβ) positron emission tomography (PET) imaging, and tau PET imaging. The GHABS cohort focuses on pathophysiology characterization and early AD detection in the Guangdong-Hong Kong-Macao Greater Bay Area. In this study, we analyzed plasma Aβ42/Aβ40 (A), p-Tau181 (T), neurofilament light, and GFAP by Simoa in 470 Chinese older adults, and 301, 195, and 70 had MRI, Aβ PET, and tau PET, respectively. Plasma biomarkers, Aβ PET, tau PET, hippocampal volume, and temporal-metaROI cortical thickness were compared between normal control (NC), subjective cognitive decline (SCD), mild cognitive impairment (MCI), and dementia groups, controlling for age, sex, and APOE-ε4. The prevalence of plasma A/T profiles and Aβ PET positivity were also determined in different diagnostic groups. The aims, study design, data collection, and potential applications of GHABS are summarized. SCD individuals had significantly higher plasma p-Tau181 and plasma GFAP than the NC individuals. MCI and dementia patients showed more abnormal changes in all the plasma and neuroimaging biomarkers than NC and SCD individuals. The frequencies of plasma A+/T+ (NC; 5.9%, SCD: 8.2%, MCI: 25.3%, dementia: 64.9%) and Aβ PET positivity (NC: 25.6%, SCD: 22.5%, MCI: 47.7%, dementia: 89.3%) were reported. The GHABS cohort may provide helpful guidance toward designing standard AD community cohorts in South China. This study, for the first time, reported the pathophysiology characterization of plasma biomarkers, Aβ PET, tau PET, hippocampal atrophy, and AD-signature cortical thinning, as well as the prevalence of Aβ PET positivity in the Guangdong-Hong Kong-Macao Greater Bay Area of China. These findings provide novel insights into understanding the characteristics of abnormal AD pathological changes in South China's older population.

Involved-site Radiation Therapy is Equally Effective and Less Toxic Than Involved-field Radiation Therapy in Patients Receiving Combined Modality Treatment for Early-stage Unfavorable Hodgkin Lymphoma—An Analysis of the Randomized Phase 3 HD17 Trial of the German Hodgkin Study Group

PurposeCombined modality treatment (CMT) with chemotherapy followed by consolidation radiotherapy (RT), provides excellent outcomes for patients with early-stage Hodgkin lymphoma (HL). The international standard of care for consolidation RT, involved-site/involved-node radiotherapy (ISRT/INRT), has never been evaluated in a randomized phase III trial against the former standard involved-field radiotherapy (IFRT). Methods and materialsIn the multicenter phase III AnonymizedStudyGroupXXX AnonymizedStudyYYY trial, patients with early stage unfavorable HL were randomized between the standard CMT group and a positron-emission tomography (PET) -guided group. In the standard group, patients received two cycles of escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (eBEACOPP) and two cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) followed by 30 Gray (Gy) IFRT. In the experimental group patients received no further therapy if post-chemotherapy PET was negative, and 30 Gy AnonymizedStudyGroupXXX -INRT, comparable and therefore termed here ISRT, if PET was positive. Here, we analyze the interim PET positive patients in a post hoc analysis, and therefore the randomized comparison of IFRT versus INRT/ISRT. Results1,100 patients were randomized, of which 311 had a positive PET after chemotherapy. Kaplan-Meier estimates of 4-year progression-free survival (PFS) were 96.8 % (95% CI: 91.6% – 98.8%) in the IFRT group and 95.4% (95% CI: 89.9% – 97.9%; HR: 1.40, 95% CI: 0.44 – 4.42) in the ISRT group. Pattern of recurrence analyses indicated that none of the cases of disease progression or recurrence in the ISRT group would have been prevented by the use of IFRT. Acute grade III/IV toxicities occurred in 8.5% of IFRT patients and 2.6% of ISRT patients (p=0.03). ConclusionsFor the first time, consolidation INRT/ISRT was randomly compared to IFRT in a phase III trial. Regarding PFS, no advantage for IFRT could be demonstrated. In summary, our data confirm the place of INRT/ISRT as the current standard of care.

The Use of Event Related Potentials to Predict Amyloid PET Status Among Patients from a Memory Disorders Clinic.

Amyloid positron emission tomography (PET) scans provide in vivo evidence of Alzheimer's disease (AD); however, their high cost limits their use in standard clinical care. Event related potentials (ERPs) may represent an inexpensive and non-invasive additional method for detecting AD pathology. We investigated whether ERPs, along with neuropsychological data, serve as predictors of amyloid PET status in patients with memory complaints. Veterans aged 50-100 were recruited from a memory disorders clinic. Participants underwent a neuropsychological battery and an ERP auditory oddball protocol. Twenty-eight patients had a positive amyloid PET scan, and thirty-nine patients had a negative scan. ERP-P200 target amplitude and P200 standard latency were predictors of amyloid PET status. When submitting to ROC analysis, P200 standard latency exhibited the highest specificity and sensitivity in predicting amyloid PET positivity, correctly classifying the amyloid PET status for 86% of patients. ERP-P200 measures are strong indicators of amyloid-β presence in patients from a memory disorder clinic. Increased P200 amplitude and decreased P200 latency in patients with a positive amyloid PET scan may be attributed to hyperactivation of perceptual bottom-up processes compensating for AD-related synaptic loss in the fronto-parietal networks.

At-Home Administration of Gantenerumab by Care Partners to People with Early Alzheimer's Disease: Feasibility, Safety and Pharmacodynamic Impact.

Monoclonal antibodies that target amyloid-beta and remove amyloid plaques can slow cognitive and functional decline in early Alzheimer's disease. Gantenerumab is a subcutaneously administered fully-human anti-amyloid-beta monoclonal antibody with highest affinity for aggregated amyloid-beta. Since the phase 3 GRADUATE trials did not meet the primary endpoint (change from baseline to Week 116 in Clinical Dementia Rating scale - Sum of Boxes), development of gantenerumab in sporadic Alzheimer's disease was stopped and all ongoing trials were terminated early due to sponsor decision. Subcutaneous administration at the clinic or at home by care partner would be an important option for other therapies in this class in order to increase flexibility and reduce overall burden. The insights obtained from the experience with gantenerumab home administration by care partner in the phase 2 GRADUATION trial will serve to guide the ongoing efforts with other anti-amyloid-beta antibodies. To evaluate the pharmacodynamic effects on brain amyloid load of once weekly subcutaneous administration of gantenerumab and the safety and feasibility of home administration by care partners. Phase 2, open-label, single arm study. Multicenter trial conducted in 33 sites in 8 countries from November 2020 to March 2023. Participants aged 50 to 90 with early symptomatic Alzheimer's disease (mild cognitive impairment/mild dementia due to Alzheimer's disease), and evidence of amyloid positron emission tomography positivity. Participants could receive up to 255 mg gantenerumab once-weekly, administered subcutaneously at site or at home by healthcare professionals or non-healthcare-professional care partners. The primary endpoint was the change from baseline to Week 52 and to Week 104 in brain amyloid load as measured by PET centiloid levels. The secondary endpoints were responses to the home administration questionnaire, plasma concentrations and safety. The overall number of participants enrolled was 192, with a mean (standard deviation) amyloid PET load at baseline of 101.80 (29.80) centiloids. At the time of early study termination by sponsor, 149 participants had valid Week 52 amyloid PET data (primary endpoint), and 12 participants had an early termination PET within the pre-defined time range of Week 104. The mean change in amyloid PET from baseline to Week 52 and Week 104 was -26.19 centiloids (range: -75.6-15.8; n=149) and -35.48 centiloids (range: -63.2--7.0; n=12), respectively. Responses to the home administration questionnaire at Week 52 (n=148) indicated that the majority of care partners (88-97%) considered administration of study drug at home easy (30.4%) or very easy (57.4%), and convenient (25.7%) or very convenient (70.9%). Care partners felt confident (31.1%) or very confident (62.2%) and satisfied (29.7%) or very satisfied (64.9%) with giving the injection at home. Responses by care partners at Week 36 (n=72), Week 76 (n=126) and Week 104 (n=29) and participant (patient) assessment of convenience and satisfaction at these time points were similar. There were no new safety findings associated with gantenerumab administered subcutaneously once weekly at 255 mg or safety issues associated with at-home injections by non-healthcare professional care partners. Once-weekly subcutaneous home administration of the anti-amyloid-beta antibody gantenerumab by non-healthcare-professional care partners to participants with early Alzheimer's disease was feasible, safe, well tolerated, and considered as a convenient option by both the care partners and participants with Alzheimer's disease. Although gantenerumab's development has been stopped due to lack of efficacy, this approach has the potential to reduce the frequency of hospital/outpatient clinic visits required for treatment with other anti-amyloid-β antibodies and can increase flexibility of drug administration for people living with Alzheimer's disease and their families.

Association of Serum Liver Enzymes with Brain Amyloidopathy and Cognitive Performance.

Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) plaque accumulation and neurofibrillary tangles in the brain. Emerging evidence has suggested potential interactions between the brain and periphery, particularly the liver, in regulating Aβ homeostasis. This study aimed to investigate the association of serum liver enzymes with brain amyloidopathy and cognitive performance in patients with complaints of cognitive decline. A total of 1,036 patients (mean age 74 years, 66.2% female) with subjective cognitive decline, mild cognitive impairment, AD dementia, and other neurodegenerative diseases were included using the Smart Clinical Data Warehouse. Amyloid positron emission tomography (PET) imaging, comprehensive neuropsychological evaluations, and measurements of liver enzymes, including aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, total bilirubin, and albumin, were assessed. After propensity score matching, logistic and linear regression analyses were used to investigate the associations between liver enzymes, amyloid status, and cognitive performance. Additionally, a machine learning approach was used to assess the classification performance of liver enzymes in predicting amyloid PET positivity. Lower ALT levels and higher AST-to-ALT ratios were significantly associated with amyloid PET positivity and AD diagnosis. The AST-to-ALT ratio was also significantly associated with poor memory function. Machine learning analysis revealed that the classification performance of amyloid status (AUC = 0.642) for age, sex, and apolipoprotein E ɛ4 carrier status significantly improved by 6.2% by integrating the AST-to-ALT ratio. These findings highlight the potential association of liver function on AD and its potential as a diagnostic and therapeutic implications.

Alterations in cognitive function and blood biomarkers following transcranial direct current stimulation in patients with amyloid positron emission tomography-positive Alzheimer's disease: a preliminary study.

Alzheimer's disease (AD), the most common form of dementia, is characterized by progressive cognitive decline. To address this, we conducted a randomized, double-blinded, sham-controlled study to investigate the therapeutic potential of transcranial direct current stimulation (tDCS) on patients with amyloid positron emission tomography (PET)- positive AD. Participants already undergoing pharmacological treatment and testing positive for amyloid PET were divided into Active-tDCS (n = 8) and Sham-tDCS (n = 8) groups. For 12 weeks, participants or their caregivers administered daily bi-frontal tDCS (YMS-201B+, Ybrain Inc., Seongnam, Korea) at home (2 mA, 30 min). Pre- and post-intervention assessments included neuropsychological tests and blood sample measurements for oligomerized beta-amyloid. The Active-tDCS group demonstrated significant improvements in cognitive domains such as language abilities, verbal memory, and attention span and in frontal lobe functions compared to the Sham-tDCS group. Furthermore, the Active-tDCS group showed a marked reduction in post-intervention plasma Aβ oligomerization tendency level, suggesting changes in pivotal AD-associated biomarkers. Our results emphasize the potential therapeutic benefits of tDCS for mild AD patients with amyloid PET positivity and stress the urgency for broader research, considering the global challenges of dementia and the need to pursue innovative therapeutic strategies.

Contribution of clinical information to the predictive performance of plasma Aβ levels for Aβ PET positivity

AbstractBackgroundEarly detection of β‐amyloid (Aβ) accumulation, a major biomarker for Alzheimer’s disease (AD), has become important. While Aβ deposition can be detected by positron emission tomography (PET), practical fluid Aβ biomarker is also being developed recently. In the present study, we aimed to determine whether APOE genotypes, age, and cognitive status increase the predictive performance of fluid Aβ levels for amyloid PET positivity.MethodsWe recruited 488 participants who underwent both plasma Aβ and Aβ PET studies (Cohort 1) and 217 participants who underwent both cerebrospinal fluid (CSF) Aβ and Aβ PET studies (Cohort 2). Plasma and CSF samples were analyzed using ABtest‐MS, an antibody‐free liquid chromatography‐differential mobility spectrometry‐triple quadrupole mass spectrometry method and INNOTEST enzyme‐linked immunosorbent assay kits, respectively. To evaluate the predictive performance of plasma Aβ and CSF Aβ, respectively, logistic regression and receiver operating characteristic analyses were performed.ResultsWhen predicting Aβ PET status, both plasma Aβ42/40 ratio and CSF Aβ42 showed high accuracy (plasma Aβ area under the curve (AUC) 0.814; CSF Aβ AUC 0.848). In the plasma Aβ models, the AUC values were higher than plasma Aβ alone model, when the models were combined with either cognitive stage (p &lt; 0.001) or APOE genotype (p = 0.011). On the other hand, there was no difference between the CSF Aβ models, when these variables were added.ConclusionsPlasma Aβ might be a useful predictor of Aβ PET status as much as CSF Aβ, particularly when considered with clinical information.

A multivariate MRI model of Alzheimer’s disease risk is associated with clinical diagnosis, PET imaging, and plasma biomarkers in a mixed dementia sample

AbstractBackgroundWe sought to validate two structural MRI‐based brain health models: Spatial Pattern of Atrophy for REcognition of Alzheimer’s disease (SPARE‐AD) and SPARE‐Brain Age Gap (SPARE‐BAG), which estimates the discrepancy between biological brain age and chronological age. These models' generalization to non‐amnestic AD (naAD) syndromes and associations with positron emission tomography (PET) and plasma biomarkers remain underinvestigated. We hypothesized that SPARE‐AD scores in naAD would be lower (less abnormal) than in amnestic AD (aAD) but elevated (more abnormal) relative to controls; and that SPARE‐AD but not SPARE‐BAG scores would be associated with PET and plasma biomarkers of AD.MethodSPARE‐AD and SPARE‐BAG scores were estimated for each of 1607 MRI scans from 277 cognitively normal adults (62.8% female; mean age = 69.5 years) and 902 clinical participants (54.2% female; mean age = 73.1 years), including 585 with amnestic mild cognitive impairment (aMCI) or aAD; 56 with naAD syndromes; 28 with vascular disease; 28 with Lewy body disorders (LBD); 18 with suspected frontotemporal lobar degeneration (FTLD); 56 with non‐amnestic MCI of uncertain etiology; and 131 with other clinical diagnoses. We used mixed effects models adjusting for age, sex, and global cognition to test group differences in SPARE‐AD and SPARE‐BAG. Additionally, we assessed associations with tau (n = 122) and amyloid‐beta (n = 199) PET imaging and plasma‐based phosphorylated tau‐181 (p‐tau181) and glial fibrillary acidic protein (GFAP) (n = 358).ResultSPARE‐AD scores were elevated vs. controls in aMCI/aAD, naAD, vascular disease, FTLD, and naMCI (all p&lt;0.003) but not in LBD or other diagnoses (p&gt;0.1). NaAD patients had lower SPARE‐AD (p&lt;0.02) but higher SPARE‐BAG scores (p&lt;0.02) than aMCI/aAD patients. SPARE‐AD scores were positively associated with mean cortical tau PET uptake, amyloid PET positivity, and plasma p‐tau181 and GFAP (all p&lt;0.001). In contrast, SPARE‐BAG scores were not associated with PET or plasma biomarkers (all p&gt;0.05).ConclusionSPARE‐AD values for naAD syndromes were intermediate between those of controls and aMCI/AD patients, likely reflecting divergent, partially overlapping cortical atrophy relative to aAD. PET and plasma biomarkers of AD neuropathologic change were associated with SPARE‐AD but not with SPARE‐BAG scores, suggesting SPARE‐BAG reflects age‐related atrophy that is largely independent of AD.

Longitudinal cognitive change in older adults with elevated tau PET signal in the absence of amyloid

AbstractBackgroundMost theoretical frameworks for Alzheimer’s disease (AD) pathogenesis propose amyloid as the primary pathologic process, whereas tau in the absence of amyloid (A‐/T+) is considered a “non‐AD pathologic change” (Jack et al., 2018). Previous research has demonstrated AD‐like characteristics of the A‐/T+ biomarker profile, including poorer memory and language performance and entorhinal thinning (Weigand et al., 2022; Yoon et al., 2022). Assessment of domain‐specific longitudinal cognitive decline in this group, however, has not yet been addressed. Our study sought to evaluate 1‐year memory, language, and attention/executive function trajectories of A‐/T+ older adults.MethodWe included 756 older adults at baseline across the AD clinical continuum from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), of whom 359 had 1‐year follow‐up cognitive data. Four A/T groups were classified based on cortical amyloid‐beta and medial temporal tau positron emission tomography positivity. Linear mixed effects models examined 1‐year trajectories of each baseline A/T group in domains of memory, language, and attention/executive function. Both statistical significance and effect size estimates were evaluated.ResultThe following proportions of A/T groups were observed at baseline: 47.0% A‐/T‐, 13.2% A‐/T+, 13.4% A+/T‐, and 26.4% A+/T+. Only the A+/T+ group exhibited a statistically significant decline in language and attention/executive function domains relative to the A‐/T‐ group. Examination of effect sizes, however, revealed that the A‐/T+ group had a quantitatively similar degree of decline as the A+/T+ group in memory (A‐/T+ and A+/T+ bs = ‐0.13), and an intermediate degree of decline between the A‐/T‐ and A+/T+ groups for language (A‐/T+ b = ‐0.17) and attention/executive function (A‐/T+ b = ‐0.19). Similar patterns were observed when examining cognitively unimpaired participants only.ConclusionOlder adults with the A‐/T+ biomarker profile demonstrate a degree of cognitive decline across multiple domains consistent with a possible AD trajectory. The systematic exclusion of these individuals from AD clinical trials may hinder early intervention efforts to attenuate the cognitive decline observed in this biomarker group, and an expansion of our conceptualization of the AD continuum to include A‐/T+ individuals may offer improved insight into the pathologic and cognitive changes that occur in the context of preclinical AD.

Neuropsychiatric Symptoms and Microglial Activation in Patients with Alzheimer Disease

Neuropsychiatric symptoms are commonly encountered and are highly debilitating in patients with Alzheimer disease. Understanding their underpinnings has implications for identifying biomarkers and treatment for these symptoms. To evaluate whether glial markers are associated with neuropsychiatric symptoms in individuals across the Alzheimer disease continuum. This cross-sectional study was conducted from January to June 2023, leveraging data from the Translational Biomarkers in Aging and Dementia cohort at McGill University, Canada. Recruitment was based on referrals of individuals from the community or from outpatient clinics. Exclusion criteria included active substance abuse, major surgery, recent head trauma, safety contraindications for positron emission tomography (PET) or magnetic resonance imaging, being currently enrolled in other studies, and having inadequately treated systemic conditions. All individuals underwent assessment for neuropsychiatric symptoms (Neuropsychiatry Inventory Questionnaire [NPI-Q]), and imaging for microglial activation ([11C]PBR28 PET), amyloid-β ([18F]AZD4694 PET), and tau tangles ([18F]MK6240 PET). Of the 109 participants, 72 (66%) were women and 37 (34%) were men; the median age was 71.8 years (range, 38.0-86.5 years). Overall, 70 had no cognitive impairment and 39 had cognitive impairment (25 mild; 14 Alzheimer disease dementia). Amyloid-β PET positivity was present in 21 cognitively unimpaired individuals (30%) and in 31 cognitively impaired individuals (79%). The NPI-Q severity score was associated with microglial activation in the frontal, temporal, and parietal cortices (β = 7.37; 95% CI, 1.34-13.41; P = .01). A leave-one-out approach revealed that irritability was the NPI-Q domain most closely associated with the presence of brain microglial activation (β = 6.86; 95% CI, 1.77-11.95; P = .008). Furthermore, we found that microglia-associated irritability was associated with study partner burden measured by NPI-Q distress score (β = 5.72; 95% CI, 0.33-11.10; P = .03). In this cross-sectional study of 109 individuals across the AD continuum, microglial activation was associated with and a potential biomarker of neuropsychiatric symptoms in Alzheimer disease. Moreover, our findings suggest that the combination of amyloid-β- and microglia-targeted therapies could have an impact on relieving these symptoms.

Plasma Aβ42/Aβ40 and phospho-tau217 concentration ratios increase the accuracy of amyloid PET classification in preclinical Alzheimer's disease.

Incorporating blood-based Alzheimer's disease biomarkers such as tau and amyloid beta (Aβ) into screening algorithms may improve screening efficiency. Plasma Aβ, phosphorylated tau (p-tau)181, and p-tau217 concentration levels from AHEAD 3-45 study participants were measured using mass spectrometry. Tau concentration ratios for each proteoform were calculated to normalize for inter-individual differences. Receiver operating characteristic (ROC) curve analysis was performed for each biomarker against amyloid positivity, defined by>20 Centiloids. Mixture of experts analysis assessed the value of including tau concentration ratios into the existing predictive algorithm for amyloid positron emission tomography status. The area under the receiver operating curve (AUC) was 0.87 for Aβ42/Aβ40, 0.74 for phosphorylated variant p-tau181 ratio (p-tau181/np-tau181), and 0.92 for phosphorylated variant p-tau217 ratio (p-tau217/np-tau217). The Plasma Predicted Centiloid (PPC), a predictive model including p-tau217/np-tau217, Aβ42/Aβ40, age, and apolipoprotein E improved AUC to 0.95. Including plasma p-tau217/np-tau217 along with Aβ42/Aβ40 in predictive algorithms may streamline screening preclinical individuals into anti-amyloid clinical trials. gov Identifier: NCT04468659 HIGHLIGHTS: The addition of plasma phosphorylated variant p-tau217 ratio (p-tau217/np-tau217) significantly improved plasma biomarker algorithms for identifying preclinical amyloid positron emission tomography positivity. Prediction performance at higher NAV Centiloid levels was improved with p-tau217/np-tau217. All models generated for this study are incorporated into the Plasma Predicted Centiloid (PPC) app for public use.

5 Intraindividual Variability in Processing Speed on Digital Cognitive Assessments Differs by Amyloidosis Status in Cognitively Normal Older Adults

Objective:Intraindividual variability (IIV) is defined as fluctuations in an individual’s cognitive performance over time1. IIV has been identified as a marker of neurobiological disturbance making it a useful method for detecting changes in cognition among cognitively healthy individuals as well as those with prodromal syndromes2. IIV on laboratory-based computerized tasks has been linked with cognitive decline and conversion to mild cognitive impairment (MCI) and/or dementia (Haynes et al., 2017). Associations between IIV and AD risk factors including apolipoprotein (APOE) ε4 carrier status, neurodegeneration seen on brain imaging, and amyloid (Aß) Positron emission tomography (PET) scan status have also been observed1. Recent studies have demonstrated that evaluating IIV on smartphone-based digital cognitive assessments is feasible, has the capacity to differentiate between cognitively normal (CN) and MCI individuals, and may reduce barriers to cognitive assessment3. This study sought to evaluate whether such differences could be detected in CN participants with and without elevated AD risk.Participants and Methods:Participants (n=57) were cognitively normal older adults who previously received an Aß PET scan through the Butler Hospital Memory and Aging Program. The sample consisted of primarily non-Hispanic (n=49, 86.0%), White (n=52, 91.2%), college-educated (M=16.65 years), females (n=39, 68.4%). The average age of the sample was 68 years old. Approximately 42% of the sample (n=24) received a positive PET scan result. Participants completed brief cognitive assessments (i.e., 3-4 minutes) three times per day for eight days (i.e., 24 sessions) using the Mobile Monitoring of Cognitive Change (M2C2) application, a mobile app-based cognitive testing platform developed as part of the National Institute of Aging’s Mobile Toolbox initiative (Sliwinski et al., 2018). Participants completed visual working memory, processing speed, and episodic memory tasks on the M2C2 platform. Intraindividual standard deviations (ISDs) across trials were computed for each person at each time point (Hultsch et al., 2000). Higher ISD values indicate more variability in performance. Linear mixed effects models were utilized to examine whether differences in IIV existed based on PET scan status while controlling for age, sex at birth, and years of education.Results:n interaction between PET status and time was observed on the processing speed task such that Aß- individuals were less variable over the eight assessment days compared to Aß + individuals (B= -5.79, SE=2.67, p=.04). No main or interaction effects were observed on the visual working memory task or episodic memory task.Conclusions:Our finding that Aß- individuals demonstrate less variability over time on a measure of processing speed is consistent with prior work. No associations were found between IIV in other cognitive domains and PET status. As noted by Allaire and Marsiske (2005), IIV is not a consistent phenomenon across different cognitive domains. Therefore, identifying which tests are the most sensitive to early change is crucial. Additional studies in larger, more diverse samples are needed prior to widespread clinical use for early detection of AD.