Presynaptic Dopaminergic Imaging Characterizes Patients with REM Sleep Behavior Disorder Due to Synucleinopathy.

OBJECTIVE: To apply a machine learning analysis to clinical and presynaptic dopaminergic imaging data of patients with rapid eye movement (REM) sleep behavior disorder (RBD) to predict the development of Parkinson disease (PD) and dementia with Lewy bodies (DLB). METHODS: In this multicenter study of the International RBD study group, 173 patients (mean age 70.5 ± 6.3 years, 70.5% males) with polysomnography-confirmed RBD who eventually phenoconverted to overt alpha-synucleinopathy (RBD due to synucleinopathy) were enrolled, and underwent baseline presynaptic dopaminergic imaging and clinical assessment, including motor, cognitive, olfaction, and constipation evaluation. For comparison, 232 RBD non-phenoconvertor patients (67.6 ± 7.1 years, 78.4% males) and 160 controls (68.2 ± 7.2 years, 53.1% males) were enrolled. Imaging and clinical features were analyzed by machine learning to determine predictors of phenoconversion. RESULTS: Machine learning analysis showed that clinical data alone poorly predicted phenoconversion. Presynaptic dopaminergic imaging significantly improved the prediction, especially in combination with clinical data, with 77% sensitivity and 85% specificity in differentiating RBD due to synucleinopathy from non phenoconverted RBD patients, and 85% sensitivity and 86% specificity in discriminating PD-converters from DLB-converters. Quantification of presynaptic dopaminergic imaging showed that an empirical z-score cutoff of -1.0 at the most affected hemisphere putamen characterized RBD due to synucleinopathy patients, while a cutoff of -1.0 at the most affected hemisphere putamen/caudate ratio characterized PD-converters. INTERPRETATION: Clinical data alone poorly predicted phenoconversion in RBD due to synucleinopathy patients. Conversely, presynaptic dopaminergic imaging allows a good prediction of forthcoming phenoconversion diagnosis. This finding may be used in designing future disease-modifying trials. ANN NEUROL 2024;95:1178-1192.

Longitudinal flortaucipir, metabolism and volume differ between phonetic and prosodic speech apraxia.

Progressive apraxia of speech (PAOS) is a neurodegenerative motor-speech disorder that most commonly arises from a four-repeat tauopathy. Recent studies have established that progressive apraxia of speech is not a homogenous disease but rather there are distinct subtypes: the phonetic subtype is characterized by distorted sound substitutions, the prosodic subtype by slow and segmented speech and the mixed subtype by a combination of both but lack of predominance of either. There is some evidence that cross-sectional patterns of neurodegeneration differ across subtypes, although it is unknown whether longitudinal patterns of neurodegeneration differ. We examined longitudinal patterns of atrophy on MRI, hypometabolism on 18F-fluorodeoxyglucose-PET and tau uptake on flortaucipir-PET in a large cohort of subjects with PAOS that had been followed for many years. Ninety-one subjects with PAOS (51 phonetic, 40 prosodic) were recruited by the Neurodegenerative Research Group. Of these, 54 (27 phonetic, 27 prosodic) returned for annual follow-up, with up to seven longitudinal visits (total visits analysed = 217). Volumes, metabolism and flortaucipir uptake were measured for subcortical and cortical regions, for all scans. Bayesian hierarchical models were used to model longitudinal change across imaging modalities with PAOS subtypes being compared at baseline, 4 years from baseline, and in terms of rates of change. The phonetic group showed smaller volumes and worse metabolism in Broca's area and the striatum at baseline and after 4 years, and faster rates of change in these regions, compared with the prosodic group. There was also evidence of faster spread of hypometabolism and flortaucipir uptake into the temporal and parietal lobes in the phonetic group. In contrast, the prosodic group showed smaller cerebellar dentate, midbrain, substantia nigra and thalamus volumes at baseline and after 4 years, as well as faster rates of atrophy, than the phonetic group. Greater hypometabolism and flortaucipir uptake were also observed in the cerebellar dentate and substantia nigra in the prosodic group. Mixed findings were observed in the supplementary motor area and precentral cortex, with no clear differences observed across phonetic and prosodic groups. These findings support different patterns of disease spread in PAOS subtypes, with corticostriatal patterns in the phonetic subtype and brainstem and thalamic patterns in the prosodic subtype, providing insight into the pathophysiology and heterogeneity of PAOS.

Direct comparison between 18F-Flortaucipir tau PET and quantitative susceptibility mapping in progressive supranuclear palsy.

PURPOSE: The pattern of flortaucipir tau PET uptake is topographically similar to the pattern of magnetic susceptibility in progressive supranuclear palsy (PSP); both with increased signal in subcortical structures such as the basal ganglia and midbrain, suggesting that they may be closely related. However, their relationship remains unknown since no studies have directly compared these two modalities in the same PSP cohort. We hypothesized that some flortaucipir uptake in PSP is associated with magnetic susceptibility, and hence iron deposition. The aim of this study was to evaluate the regional relationship between flortaucipir uptake and magnetic susceptibility and to examine the effects of susceptibility on flortaucipir uptake in PSP. METHODS: Fifty PSP patients and 67 cognitively normal controls were prospectively recruited and underwent three Tesla MRI and flortaucipir tau PET scans. Quantitative susceptibility maps were reconstructed from multi-echo gradient-echo MRI images. Region of interest (ROI) analysis was performed to obtain flortaucipir and susceptibility values in the subcortical regions. Relationships between flortaucipir and susceptibility signals were evaluated using partial correlation analysis in the subcortical ROIs and voxel-based analysis in the whole brain. The effects of susceptibility on flortaucipir uptake were examined by using the framework of mediation analysis. RESULTS: Both flortaucipir and susceptibility were greater in PSP compared to controls in the putamen, pallidum, subthalamic nucleus, red nucleus, and cerebellar dentate (p<0.05). The ROI-based and voxel-based analyses showed that these two signals were positively correlated in these five regions (r = 0.36-0.59, p<0.05). Mediation analysis showed that greater flortaucipir uptake was partially explained by susceptibility in the putamen, pallidum, subthalamic nucleus, and red nucleus, and fully explained in the cerebellar dentate. CONCLUSIONS: These results suggest that some of the flortaucipir uptake in subcortical regions in PSP is related to iron deposition. These findings will contribute to our understanding of the mechanisms underlying flortaucipir tau PET findings in PSP and other neurodegenerative diseases.

Altered structural and functional connectivity in Posterior Cortical Atrophy and Dementia with Lewy bodies.

Posterior cortical atrophy (PCA) and dementia with Lewy bodies (DLB) show distinct atrophy and overlapping hypometabolism profiles, but it is unknown how disruptions in structural and functional connectivity compare between these disorders and whether breakdowns in connectivity relate to either atrophy or hypometabolism. Thirty amyloid-positive PCA patients, 24 amyloid-negative DLB patients and 30 amyloid-negative cognitively unimpaired (CU) healthy individuals were recruited at Mayo Clinic, Rochester, MN, and underwent a 3T head MRI, including structural MRI, resting state functional MRI (rsfMRI) and diffusion tensor imaging (DTI) sequences, as well as [18F] fluorodeoxyglucose (FDG) PET. We assessed functional connectivity within and between 12 brain networks using rsfMRI and the CONN functional connectivity toolbox and calculated regional DTI metrics using the Johns Hopkins atlas. Multivariate linear-regression models corrected for multiple comparisons and adjusted for age and sex compared DTI metrics and within-network and between-network functional connectivity across groups. Regional gray-matter volumes and FDG-PET standard uptake value ratios (SUVRs) were calculated and analyzed at the voxel-level using SPM12. We used univariate linear-regression models to investigate the relationship between connectivity measures, gray-matter volume, and FDG-PET SUVR. On DTI, PCA showed degeneration in occipito-parietal white matter, posterior thalamic radiations, splenium of the corpus collosum and sagittal stratum compared to DLB and CU, with greater degeneration in the temporal white matter and the fornix compared to CU. We observed no white-matter degeneration in DLB compared to CU. On rsfMRI, reduced within-network connectivity was present in dorsal and ventral default mode networks (DMN) and the dorsal-attention network in PCA compared to DLB and CU, with reduced within-network connectivity in the visual and sensorimotor networks compared to CU. DLB showed reduced connectivity in the cerebellar network compared to CU. Between-network analysis showed increased connectivity in both cerebellar-to-sensorimotor and cerebellar-to-dorsal attention network connectivity in PCA and DLB. PCA showed reduced anterior DMN-to-cerebellar and dorsal attention-to-sensorimotor connectivity, while DLB showed reduced posterior DMN-to-sensorimotor connectivity compared to CU. PCA showed reduced dorsal DMN-to-visual connectivity compared to DLB. The multimodal analysis revealed weak associations between functional connectivity and volume in PCA, and between functional connectivity and metabolism in DLB. These findings suggest that PCA and DLB have unique connectivity alterations, with PCA showing more widespread disruptions in both structural and functional connectivity; yet some overlap was observed with both disorders showing increased connectivity from the cerebellum.

Multimodal cross-examination of progressive apraxia of speech by diffusion tensor imaging-based tractography and Tau-PET scans.

Progressive apraxia of speech (PAOS) is a 4R tauopathy characterized by difficulties with motor speech planning. Neurodegeneration in PAOS targets the premotor cortex, particularly the supplementary motor area (SMA), with degeneration of white matter (WM) tracts connecting premotor and motor cortices and Broca's area observed on diffusion tensor imaging (DTI). We aimed to assess flortaucipir uptake across speech-language-related WM tracts identified using DTI tractography in PAOS. Twenty-two patients with PAOS and 26 matched healthy controls were recruited by the Neurodegenerative Research Group (NRG) and underwent MRI and flortaucipir-PET. The patient population included patients with primary progressive apraxia of speech (PPAOS) and non-fluent variant/agrammatic primary progressive aphasia (agPPA). Flortaucipir PET scans and DTI were coregistered using rigid registration with a mutual information cost function in subject space. Alignments between DTI and flortaucipir PET were inspected in all cases. Whole-brain tractography was calculated using deterministic algorithms by a tractography reconstruction tool (DSI-studio) and specific tracts were identified using an automatic fiber tracking atlas-based method. Fractional anisotropy (FA) and flortaucipir standardized uptake value ratios (SUVRs) were averaged across the frontal aslant tract, arcuate fasciculi, inferior frontal-occipital fasciculus, inferior and middle longitudinal fasciculi, as well as the SMA commissural fibers. Reduced FA (p < .0001) and elevated flortaucipir SUVR (p = .0012) were observed in PAOS cases compared to controls across all combined WM tracts. For flortaucipir SUVR, the greatest differentiation of PAOS from controls was achieved with the SMA commissural fibers (area under the receiver operator characteristic curve [AUROC] = 0.83), followed by the left arcuate fasciculus (AUROC = 0.75) and left frontal aslant tract (AUROC = 0.71). Our findings demonstrate that flortaucipir uptake is increased across WM tracts related to speech/language difficulties in PAOS.

Role of GBA variants in Lewy body disease neuropathology.

Rare and common GBA variants are risk factors for both Parkinson's disease (PD) and dementia with Lewy bodies (DLB). However, the degree to which GBA variants are associated with neuropathological features in Lewy body disease (LBD) is unknown. Herein, we assessed 943 LBD cases and examined associations of 15 different neuropathological outcomes with common and rare GBA variants. Neuropathological outcomes included LBD subtype, presence of a high likelihood of clinical DLB (per consensus guidelines), LB counts in five cortical regions, tyrosine hydroxylase immunoreactivity in the dorsolateral and ventromedial putamen, ventrolateral substantia nigra neuronal loss, Braak neurofibrillary tangle (NFT) stage, Thal amyloid phase, phospho-ubiquitin (pS65-Ub) level, TDP-43 pathology, and vascular disease. Sequencing of GBA exons revealed a total of 42 different variants (4 common [MAF > 0.5%], 38 rare [MAF < 0.5%]) in our series, and 165 cases (17.5%) had a copy of the minor allele for ≥ 1 variant. In analysis of common variants, p.L483P was associated with a lower Braak NFT stage (OR = 0.10, P < 0.001). In gene-burden analysis, presence of the minor allele for any GBA variant was associated with increased odds of a high likelihood of DLB (OR = 2.00, P < 0.001), a lower Braak NFT stage (OR = 0.48, P < 0.001), a lower Thal amyloid phase (OR = 0.55, P < 0.001), and a lower pS65-Ub level (ß: -0.37, P < 0.001). Subgroup analysis revealed that GBA variants were most common in LBD cases with a combination of transitional/diffuse LBD and Braak NFT stage 0-II or Thal amyloid phase 0-1, and correspondingly that the aforementioned associations of GBA gene-burden with a decreased Braak NFT stage and Thal amyloid phase were observed only in transitional or diffuse LBD cases. Our results indicate that in LBD, GBA variants occur most frequently in cases with greater LB pathology and low AD pathology, further informing disease-risk associations of GBA in PD, PD dementia, and DLB.

Insulin Signaling Differentially Regulates the Trafficking of Insulin and Amyloid Beta Peptides at the Blood-Brain Barrier.

The blood-brain barrier (BBB) is instrumental in clearing toxic metabolites from the brain, such as amyloid-ß (Aß) peptides, and in delivering essential nutrients to the brain, like insulin. In Alzheimer's disease (AD) brain, increased Aß levels are paralleled by decreased insulin levels, which are accompanied by insulin signaling deficits at the BBB. Thus, we investigated the impact of insulin-like growth factor and insulin receptor (IGF1R and IR) signaling on Aß and insulin trafficking at the BBB. Following intravenous infusion of an IGF1R/IR kinase inhibitor (AG1024) in wild-type mice, the BBB trafficking of 125I radiolabeled Aß peptides and insulin was assessed by dynamic SPECT/CT imaging. The brain efflux of [125I]iodo-Aß42 decreased upon AG1024 treatment. Additionally, the brain influx of [125I]iodoinsulin, [125I]iodo-Aß42, [125I]iodo-Aß40, and [125I]iodo-BSA (BBB integrity marker) was decreased, increased, unchanged, and unchanged, respectively, upon AG1024 treatment. Subsequent mechanistic studies were performed using an in vitro BBB cell model. The cell uptake of [125I]iodoinsulin, [125I]iodo-Aß42, and [125I]iodo-Aß40 was decreased, increased, and unchanged, respectively, upon AG1024 treatment. Further, AG1024 reduced the phosphorylation of insulin signaling kinases (Akt and Erk) and the membrane expression of Aß and insulin trafficking receptors (LRP-1 and IR-ß). These findings reveal that insulin signaling differentially regulates the BBB trafficking of Aß peptides and insulin. Moreover, deficits in IGF1R and IR signaling, as observed in the brains of type II diabetes and AD patients, are expected to increase Aß accumulation while decreasing insulin delivery to the brain, which has been linked to the progression of cognitive decline in AD.

Relationships between PET and blood plasma biomarkers in corticobasal syndrome.

INTRODUCTION: Corticobasal syndrome (CBS) can result from underlying Alzheimer's disease (AD) pathologies. Little is known about the utility of blood plasma metrics to predict positron emission tomography (PET) biomarker-confirmed AD in CBS. METHODS: A cohort of eighteen CBS patients (8 amyloid beta [Aß]+; 10 Aß-) and 8 cognitively unimpaired (CU) individuals underwent PET imaging and plasma analysis. Plasma concentrations were compared using a Kruskal-Wallis test. Spearman correlations assessed relationships between plasma concentrations and PET uptake. RESULTS: CBS Aß+ group showed a reduced Aß42/40 ratio, with elevated phosphorylated tau (p-tau)181, glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) concentrations, while CBS Aß- group only showed elevated NfL concentration compared to CU. Both p-tau181 and GFAP were able to differentiate CBS Aß- from CBS Aß+ and showed positive associations with Aß and tau PET uptake. DISCUSSION: This study supports use of plasma p-tau181 and GFAP to detect AD in CBS. NfL shows potential as a non-specific disease biomarker of CBS regardless of underlying pathology. HIGHLIGHTS: Plasma phosphorylated tau (p-tau)181 and glial fibrillary acidic protein (GFAP) concentrations differentiate corticobasal syndrome (CBS) amyloid beta (Aß)- from CBS Aß+. Plasma neurofilament light concentrations are elevated in CBS Aß- and Aß+ compared to controls. Plasma p-tau181 and GFAP concentrations were associated with Aß and tau positron emission tomography (PET) uptake. Aß42/40 ratio showed a negative correlation with Aß PET uptake.

Optimizing cutpoints for clinical interpretation of brain amyloid status using plasma p-tau217 immunoassays.

INTRODUCTION: We aimed to evaluate clinical interpretation cutpoints for two plasma phosphorylated tau (p-tau)217 assays (ALZpath and Lumipulse) as predictors of amyloid status for implementation in clinical practice. METHODS: Clinical performance of plasma p-tau217 against amyloid positron emission tomography status was evaluated in participants with mild cognitive impairment or mild dementia (n = 427). RESULTS: Using a one-cutpoint approach (negative/positive), neither assay achieved ≥ 90% in both sensitivity and specificity. A two-cutpoint approach yielding 92% sensitivity and 96% specificity provided the desired balance of false positives and false negatives, while categorizing 20% and 39% of results as indeterminate for the Lumipulse and ALZpath assays, respectively. DISCUSSION: This study provides a systematic framework for selection of assay-specific cutpoints for clinical use of plasma p-tau217 for determination of amyloid status. Our findings suggest that a two-cutpoint approach may have advantages in optimizing diagnostic accuracy while minimizing potential harm from false positive results. HIGHLIGHTS: Phosphorylated tau (p-tau)217 cutpoints for detection of amyloid pathology were established. A two-cutpoint approach exhibited the best performance for clinical laboratory use. p-tau217 assays differed in the percentage of results categorized as intermediate.

Plasma glial fibrillary acidic protein in the visual and language variants of Alzheimer's disease.

INTRODUCTION: Glial fibrillary acidic protein (GFAP) in plasma is a proxy for astrocytic activity and is elevated in amyloid-ß (Aß)-positive individuals, making GFAP a potential blood-based biomarker for Alzheimer's disease (AD). METHODS: We assessed plasma GFAP in 72 Aß-positive participants diagnosed with the visual or language variant of AD who underwent Aß- and tau-PET. Fifty-nine participants had follow-up imaging. Linear regression was applied on GFAP and imaging quantities. RESULTS: GFAP did not correlate with Aß- or tau-PET cross-sectionally. There was a limited positive correlation between GFAP and rates of tau accumulation, particularly in the language variant of AD, although associations were weaker after removing one outlier patient with the highest GFAP level. DISCUSSION: Among Aß-positive AD participants with atypical presentations, plasma GFAP did not correlate with levels of AD pathology on PET, suggesting that the associations between GFAP and AD pathology might plateau during the advanced phase of the disease.

Significance of a positive tau PET scan with a negative amyloid PET scan.

INTRODUCTION: The implications of positive tau positron emission tomography (T) with negative beta amyloid positron emission tomography (A) are not well understood. We investigated cognitive performance in participants who were T+ but A-. METHODS: We evaluated 98 participants from the Mayo Clinic who were T+ and A-. Participants were matched 2:1 to A- and T- cognitively unimpaired (CU) controls. Cognitive test scores were compared between different groups. RESULTS: The A-T+ group demonstrated lower performance than the A-T- group on the Mini-Mental Status Exam (MMSE) (p < 0.001), Wechsler Memory Scale-Revised Logical Memory I (p < 0.001) and Logical Memory II (p < 0.001), Auditory Verbal Learning Test (AVLT) delayed recall (p = 0.004), category fluency (animals p = 0.005; vegetables p = 0.021), Trail Making Test A and B (p < 0.001), and others. There were no significant differences in demographic features or apolipoprotein E (APOE) e4 genotype between CU A-T+ and CI A-T+. DISCUSSION: A-T+ participants show an association with lower cognitive performance.

Comparison of plasma biomarkers and amyloid PET for predicting memory decline in cognitively unimpaired individuals.

BACKGROUND: We compared the ability of several plasma biomarkers versus amyloid positron emission tomography (PET) to predict rates of memory decline among cognitively unimpaired individuals. METHODS: We studied 645 Mayo Clinic Study of Aging participants. Predictor variables were age, sex, education, apolipoprotein E (APOE) ε4 genotype, amyloid PET, and plasma amyloid beta (Aß)42/40, phosphorylated tau (p-tau)181, neurofilament light (NfL), glial fibrillary acidic protein (GFAP), and p-tau217. The outcome was a change in a memory composite measure. RESULTS: All plasma biomarkers, except NfL, were associated with mean memory decline in models with individual biomarkers. However, amyloid PET and plasma p-tau217, along with age, were key variables independently associated with mean memory decline in models combining all predictors. Confidence intervals were narrow for estimates of population mean prediction, but person-level prediction intervals were wide. DISCUSSION: Plasma p-tau217 and amyloid PET provide useful information about predicting rates of future cognitive decline in cognitively unimpaired individuals at the population mean level, but not at the individual person level.

Sex differences in brain atrophy in dementia with Lewy bodies.

INTRODUCTION: Sex influences neurodegeneration, but it has been poorly investigated in dementia with Lewy bodies (DLB). We investigated sex differences in brain atrophy in DLB using magnetic resonance imaging (MRI). METHODS: We included 436 patients from the European-DLB consortium and the Mayo Clinic. Sex differences and sex-by-age interactions were assessed through visual atrophy rating scales (n = 327; 73 ± 8 years, 62% males) and automated estimations of regional gray matter volume and cortical thickness (n = 165; 69 ± 9 years, 72% males). RESULTS: We found a higher likelihood of frontal atrophy and smaller volumes in six cortical regions in males and thinner olfactory cortices in females. There were significant sex-by-age interactions in volume (six regions) and cortical thickness (seven regions) across the entire cortex. DISCUSSION: We demonstrate that males have more widespread cortical atrophy at younger ages, but differences tend to disappear with increasing age, with males and females converging around the age of 75. HIGHLIGHTS: Male DLB patients had higher odds for frontal atrophy on radiological visual rating scales. Male DLB patients displayed a widespread pattern of cortical gray matter alterations on automated methods. Sex differences in gray matter measures in DLB tended to disappear with increasing age.

Plasma biomarkers of Alzheimer's disease in the continuum of dementia with Lewy bodies.

INTRODUCTION: Patients with dementia with Lewy bodies (DLB) may have Alzheimers disease (AD) pathology that can be detected by plasma biomarkers. Our objective was to evaluate plasma biomarkers of AD and their association with positron emission tomography (PET) biomarkers of amyloid and tau deposition in the continuum of DLB, starting from prodromal stages of the disease. METHODS: The cohort included patients with isolated rapid eye movement (REM) sleep behavior disorder (iRBD), mild cognitive impairment with Lewy bodies (MCI-LB), or DLB, with a concurrent blood draw and PET scans. RESULTS: Abnormal levels of plasma glial fibrillary acidic protein (GFAP) were found at the prodromal stage of MCI-LB in association with increased amyloid PET. Abnormal levels of plasma phosphorylated tau (p-tau)-181 and neurofilament light (NfL) were found at the DLB stage. Plasma p-tau-181 showed the highest accuracy in detecting abnormal amyloid and tau PET in patients with DLB. DISCUSSION: The range of AD co-pathology can be detected with plasma biomarkers in the DLB continuum, particularly with plasma p-tau-181 and GFAP.

Metformin Prevents Tumor Cell Growth and Invasion of Human Hormone Receptor-Positive Breast Cancer (HR+ BC) Cells via FOXA1 Inhibition.

Women with type 2 diabetes (T2D) have a higher risk of being diagnosed with breast cancer and have worse survival than non-diabetic women if they do develop breast cancer. However, more research is needed to elucidate the biological underpinnings of these relationships. Here, we found that forkhead box A1 (FOXA1), a forkhead family transcription factor, and metformin (1,1-dimethylbiguanide hydrochloride), a medication used to treat T2D, may impact hormone-receptor-positive (HR+) breast cancer (BC) tumor cell growth and metastasis. Indeed, fourteen diabetes-associated genes are highly expressed in only three HR+ breast cancer cell lines but not the other subtypes utilizing a 53,805 gene database obtained from NCBI GEO. Among the diabetes-related genes, FOXA1, MTA3, PAK4, FGFR3, and KIF22 were highly expressed in HR+ breast cancer from 4032 breast cancer patient tissue samples using the Breast Cancer Gene Expression Omnibus. Notably, elevated FOXA1 expression correlated with poorer overall survival in patients with estrogen-receptor-positive/progesterone-receptor-positive (ER+/PR+) breast cancer. Furthermore, experiments demonstrated that loss of the FOXA1 gene inhibited tumor proliferation and invasion in vitro using MCF-7 and T47D HR+ breast cancer cell lines. Metformin, an anti-diabetic medication, significantly suppressed tumor cell growth in MCF-7 cells. Additionally, either metformin treatment or FOXA1 gene deletion enhanced tamoxifen-induced tumor growth inhibition in HR+ breast cancer cell lines within an ex vivo three-dimensional (3D) organoid model. Therefore, the diabetes-related medicine metformin and FOXA1 gene inhibition might be a new treatment for patients with HR+ breast cancer when combined with tamoxifen, an endocrine therapy.

Evaluation of Neurodegenerative Disorders with Amyloid-ß, Tau, and Dopaminergic PET Imaging: Interpretation Pitfalls.

Antiamyloid therapies for Alzheimer disease recently entered clinical practice, making imaging biomarkers for Alzheimer disease even more relevant to guiding patient management. Amyloid and tau PET are valuable tools that can provide objective evidence of Alzheimer pathophysiology in living patients and will increasingly be used to complement 18F-FDG PET in the diagnostic evaluation of cognitive impairment and dementia. Parkinsonian syndromes, also common causes of dementia, can likewise be evaluated with a PET imaging biomarker,18F-DOPA, allowing in vivo assessment of the presynaptic dopaminergic neurons. Understanding the role of these PET biomarkers will help the nuclear medicine physician contribute to the appropriate diagnosis and management of patients with cognitive impairment and dementia. To successfully evaluate brain PET examinations for neurodegenerative diseases, knowledge of the necessary protocol details for obtaining a reliable imaging study, inherent limitations for each PET radiopharmaceutical, and pitfalls in image interpretation is critical. This review will focus on underlying concepts for interpreting PET examinations, important procedural details, and guidance for avoiding potential interpretive pitfalls for amyloid, tau, and dopaminergic PET examinations.

Quality of life following surgery for head and neck cancer: Evidence from ACRIN 6685.

BACKGROUND: This study examined the trajectory of health-related quality of life (HRQoL) for patients with clinical stage N0 HNSCC enrolled in ACRIN 6685 who underwent elective neck dissection(s). METHODS: HRQoL of 230 patients in the ACRIN 6685 trial was measured prospectively up to 2 years following surgery using the University of Washington Quality of Life instrument. RESULTS: General Health Within the Last 7 Days did not differ significantly from baseline at any follow-up. General Health Relative to Before Cancer fell significantly by 5.8 points following surgery (p = 0.048), and then returned to 3.0 points above baseline at 1 year (p = 0.65). For Overall Quality of Life, HRQoL fell significantly by 4.3 points following surgery (p = 0.031) and then returned to levels not significantly different from baseline. CONCLUSIONS: Patients with stage N0 HNSCC experience significant declines in HRQoL immediately following surgery, including neck dissection, which recovers to near or better than baseline within 1-2 years.

Synthesis and preliminary evaluation of novel PET probes for GSK-3 imaging.

Non-invasive imaging of GSK-3 expression in the brain will help to understand the role of GSK-3 in disease pathology and progression. Herein, we report the radiosynthesis and evaluation of two novel isonicotinamide based 18F labeled PET probes, [18F]2 and [18F]6 for noninvasive imaging of GSK3. Among the developed PET probes, the in vitro blood-brain permeability coefficient of 2 (38 ± 20 × 10-6 cm/s, n = 3) was found to be better than 6 (8.75 ± 3.90 × 10-6 cm/s, n = 5). The reference compounds 2 and 6 showed nanomolar affinity towards GSK-3α and GSK-3ß. PET probe [18F]2 showed higher stability (100%) in mouse and human serums compared to [18F]6 (67.01 ± 4.93%, n = 3) in mouse serum and 66.20 ± 6.38%, n = 3) in human serum at 120 min post incubation. The in vivo imaging and blocking studies were performed in wild-type mice only with [18F]2 due to its observed stability. [18F]2 showed a SUV of 0.92 ± 0.28 (n = 6) in mice brain as early as 5 min post-injection followed by gradual clearance over time.

Patterns of brain volume and metabolism predict clinical features in the progressive supranuclear palsy spectrum.

Progressive supranuclear palsy (PSP) is a neurodegenerative tauopathy that presents with highly heterogenous clinical syndromes. We perform cross-sectional data-driven discovery of independent patterns of brain atrophy and hypometabolism across the entire PSP spectrum. We then use these patterns to predict specific clinical features and to assess their relationship to phenotypic heterogeneity. We included 111 patients with PSP (60 with Richardson syndrome and 51 with cortical and subcortical variant subtypes). Ninety-one were used as the training set and 20 as a test set. The presence and severity of granular clinical variables such as postural instability, parkinsonism, apraxia and supranuclear gaze palsy were noted. Domains of akinesia, ocular motor impairment, postural instability and cognitive dysfunction as defined by the Movement Disorders Society criteria for PSP were also recorded. Non-negative matrix factorization was used on cross-sectional MRI and fluorodeoxyglucose-positron emission tomography (FDG-PET) scans. Independent models for each as well as a combined model for MRI and FDG-PET were developed and used to predict the granular clinical variables. Both MRI and FDG-PET were better at predicting presence of a symptom than severity, suggesting identification of disease state may be more robust than disease stage. FDG-PET predicted predominantly cortical abnormalities better than MRI such as ideomotor apraxia, apraxia of speech and frontal dysexecutive syndrome. MRI demonstrated prediction of cortical and more so sub-cortical abnormalities, such as parkinsonism. Distinct neuroanatomical foci were predictive in MRI- and FDG-PET-based models. For example, vertical gaze palsy was predicted by midbrain atrophy on MRI, but frontal eye field hypometabolism on FDG-PET. Findings also differed by scale or instrument used. For example, prediction of ocular motor abnormalities using the PSP Saccadic Impairment Scale was stronger than with the Movement Disorders Society Diagnostic criteria for PSP oculomotor impairment designation. Combination of MRI and FDG-PET demonstrated enhanced detection of parkinsonism and frontal syndrome presence and apraxia, cognitive impairment and bradykinesia severity. Both MRI and FDG-PET patterns were able to predict some measures in the test set; however, prediction of global cognition measured by Montreal Cognitive Assessment was the strongest. MRI predictions generalized more robustly to the test set. PSP leads to neurodegeneration in motor, cognitive and ocular motor networks at cortical and subcortical foci, leading to diverse yet overlapping clinical syndromes. To advance understanding of phenotypic heterogeneity in PSP, it is essential to consider data-driven approaches to clinical neuroimaging analyses.

Frontal hypometabolism in the diagnosis of progressive supranuclear palsy clinical variants.

OBJECTIVE: Frontal hypometabolism on FDG-PET is observed in progressive supranuclear palsy (PSP), although it is unclear whether it is a feature of all PSP clinical variants and hence whether it is a useful diagnostic feature. We aimed to compare the frequency, severity, and pattern of frontal hypometabolism across PSP variants and determine whether frontal hypometabolism is related to clinical dysfunction. METHODS: Frontal hypometabolism in prefrontal, premotor, and sensorimotor cortices was visually graded on a 0-3 scale using CortexID Z-score images in 137 PSP patients. Frontal asymmetry was recorded. Severity scores were used to categorize patients as premotor-predominant, prefrontal-predominant, sensorimotor-predominant, mixed-predominance, or no regional predominance. Frontal ratings were compared across PSP clinical variants, and Spearman correlations were used to assess relationships with the Frontal Assessment Battery (FAB). RESULTS: 97% showed evidence of frontal hypometabolism which was most common (100%) in the speech-language (PSP-SL), corticobasal (PSP-CBS), and frontal (PSP-F) variants and least common in the progressive gait freezing (PSP-PGF) variant (73%). PSP-SL and PSP-CBS showed more severe hypometabolism than Richardson's syndrome (PSP-RS), Parkinsonism (PSP-P), and PSP-PGF. A premotor-predominant pattern was most common in PSP-SL and PSP-CBS, with more mixed patterns in the other variants. Hypometabolism was most commonly asymmetric in PSP-SL, PSP-P, PSP-F and PSP-CBS. Worse hypometabolism in nearly all frontal regions correlated with worse scores on the FAB. CONCLUSIONS: Frontal hypometabolism is a common finding in PSP, although it varies in severity and pattern across PSP variants and will likely be the most diagnostically useful in PSP-SL and PSP-CBS.