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.

Clinical and Product Features Associated with Outcome of DLBCL Patients to CD19-Targeted CAR T-Cell Therapy.

CD19-directed CAR T-cells have been remarkably successful in treating patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) and transformed follicular lymphoma (t-FL). In this cohort study, we treated 60 patients with axicabtagene ciloleucel or tisagenlecleucel. Complete and partial metabolic responses (CMR/PMR) were obtained in 40% and 23% of patients, respectively. After 6.9 months of median follow-up, median progression-free survival (mPFS) and overall survival (mOS) were estimated at 3.1 and 12.3 months, respectively. Statistical analyses revealed that CMR, PFS, and OS were all significantly associated with age-adjusted international prognostic index (aaIPI, p < 0.05). T-cell subset phenotypes in the apheresis product tended to correlate with PFS. Within the final product, increased percentages of both CD4 and CD8 CAR+ effector memory cells (p = 0.02 and 0.01) were significantly associated with CMR. Furthermore, higher CMR/PMR rates were observed in patients with a higher maximal in vivo expansion of CAR T-cells (p = 0.05) and lower expression of the LAG3 and Tim3 markers of exhaustion phenotype (p = 0.01 and p = 0.04). Thus, we find that aaIPI at the time of infusion, phenotype of the CAR T product, in vivo CAR T-cell expansion, and low levels of LAG3/Tim3 are associated with the efficacy of CAR T-cell therapy in DLBCL patients.

Hepatobiliary Scintigraphy and Glass 90Y Radioembolization with Personalized Dosimetry: Dynamic Changes in Treated and Nontreated Liver.

BACKGROUND: The functional changes that occur over time in the liver following 90Y-radioembolization (RE) using personalized dosimetry (PD) remain to be investigated. METHODS: November 2016-October 2019: we retrospectively included hepatocellular carcinoma (HCC) patients treated by 90Y-glass RE using PD, who underwent hepatobiliary scintigraphy (HBS) at baseline and at 15 days, 1, 2, 3, and 6 months after RE. RESULTS: There were 16 patients with unilobar disease (100%) included, and 64 HBS were performed. Whole liver function significantly decreased over time. The loss was maximal at 2 weeks: -32% (p = 0.002) and remained below baseline at 1 (-15%; p = 0.002), 2 (-25%; p < 0.001), and 3 months (-16%; p = 0.027). No radioembolization-induced liver disease was observed. Treated liver function strongly decreased to reach -64% (p < 0.001) at 2 months. Nontreated liver function decreased at 2 weeks (-21%; p = 0.027) and remained below baseline before reaching +20% (p = 0.002) and +59% (p < 0.001) at 3 and 6 months, respectively. Volumetric and functional changes exhibited parallel evolutions in the treated livers (p = 0.01) but independent evolutions in the nontreated livers (p = 0.08). CONCLUSION: RE using PD induces significant regional changes in liver function over time. As early as 15 days following RE, both the treated and nontreated livers showed a decreased function. Nontreated liver function recovered after 3 months and greatly increased afterwards.

Equivalence Randomized Trial to Compare Treatment on the Basis of Sentinel Node Biopsy Versus Neck Node Dissection in Operable T1-T2N0 Oral and Oropharyngeal Cancer.

PURPOSE: Sentinel node (SN) biopsy is accurate in operable oral and oropharyngeal cT1-T2N0 cancer (OC), but, to our knowledge, the oncologic equivalence of SN biopsy and neck lymph node dissection (ND; standard treatment) has never been evaluated. METHODS: In this phase III multicenter trial, 307 patients with OC were randomly assigned to (1) the ND arm or (2) the SN arm (experimental arm: biopsy alone if negative, or followed by ND if positive, during primary tumor surgery). The primary outcome was neck node recurrence-free survival (RFS) at 2 years. Secondary outcomes were 5-year neck node RFS, 2- and 5-year disease-specific survival (DSS), and overall survival (OS). Other outcomes were hospital stay length, neck and shoulder morbidity, and number of physiotherapy prescriptions during the 2 years after surgery. RESULTS: Data on 279 patients (139 ND and 140 SN) could be analyzed. Neck node RFS was 89.6% (95% CI, 0.83% to 0.94%) at 2 years in the ND arm and 90.7% (95% CI, 0.84% to 0.95%) in the SN arm, confirming the equivalence with P < .01. The 5-year RFS and the 2- and 5-year DSS and OS were not significantly different between arms. The median hospital stay length was 8 days in the ND arm and 7 days in the SN arm (P < .01). The functional outcomes were significantly worse in the ND arm until 6 months after surgery. CONCLUSION: This study demonstrated the oncologic equivalence of the SN and ND approaches, with lower morbidity in the SN arm during the first 6 months after surgery, thus establishing SN as the standard of care in OC.

Rhythm disturbances as a potential early marker of Parkinson's disease in idiopathic REM sleep behavior disorder.

OBJECTIVE: We aimed to identify timing distortions in production and perception of rhythmic events in patients with idiopathic REM sleep behavior disorder (iRBD) as early markers of Parkinson's disease (PD). METHODS: Rhythmic skills, clinical characteristics, dysautonomia, depression, and olfaction were compared in 97 participants, including 21 participants with iRBD, 38 patients with PD, and 38 controls, matched for age, gender, and education level. Rhythmic disturbances can be easily detected with dedicated motor tasks via a tablet application. Rhythm production was tested in two conditions: to examine the ability to generate a spontaneous endogenous rhythm, tapping rate and variability in a finger tapping task without external stimulation was measured, while the ability to synchronize to an external rhythm was tested with finger tapping to external auditory cues. Rhythm perception was measured with a task, in which the participants had to detect a deviation from a regular rhythm. Participants with iRBD had dopamine transporter imaging. RESULTS: Participants with iRBD and PD revealed impaired spontaneous rhythm production and poor rhythm perception compared to controls. Impaired rhythm production was correlated with olfaction deficits, dysautonomia, impaired non-motor aspects of daily living, and dopamine uptake measures. CONCLUSIONS: Participants with iRBD show impaired rhythm production and perception; this impairment is correlated with other early markers for PD. Testing rhythmic skills with short and inexpensive tests may be promising for screening for potential future PD in iRBD patients.

Cerebrospinal Fluid and Plasma Biomarkers do not Differ in the Presenile and Late-Onset Behavioral Variants of Frontotemporal Dementia.

BACKGROUND: Memory troubles and hippocampal atrophy are considered more frequent and focal atrophy less severe in late-onset (>65 years) than in presenile behavioral variant of frontotemporal dementia (bvFTD). OBJECTIVE: To compare cerebrospinal fluid (CSF) and plasma biomarkers in late-onset and presenile bvFTD. METHODS: Multicentric retrospective study (2007-2017) on patients with clinical diagnosis of bvFTD. RESULTS: This study included 44 patients (67%) with presenile and 22 (33%) with late-onset bvFTD (comparable mean disease duration; n = 11 with causal mutations). Hippocampal atrophy was more frequent (80% versus 25.8%) and severe in late-onset bvFTD (median Scheltens score: 3 [0-4] versus 1 [0-3]), without difference after adjustment for age. Lobar atrophy and focal hypometabolism/hypoperfusion were not different between groups. The median CSF Aß1-42 and phosphorylated tau (P-tau) concentrations were in the normal range and comparable between groups. Axonal neurodegeneration biomarkers were within the normal range (CSF T-tau; plasma T-tau in late-onset bvFTD) or higher (plasma neurofilament light chain (NFL); plasma T-tau in presenile bvFTD) than the normal values, but globally not different between bvFTD groups. Plasma glial fibrillary acid protein (GFAP) was strongly increased in both bvFTD groups compared with the values in controls of the same age. CONCLUSION: The CSF and plasma biomarker profiles did not suggest a more aggressive neurodegeneration in the presenile group (comparable T-tau, NFL, and GFAP levels) or the co-existence of Alzheimer's disease in the late-onset group (comparable and within normal range CSF Aß1-42 and P-tau). The severity of the neurodegenerative process seems comparable in presenile and late-onset bvFTD.

Absence of Relationship Between Self-Reported Sleep Measures and Amyloid Load in Elderly Subjects.

Objective: To determine the relationships between self-reported sleep profile and cortical amyloid load in elderly subjects without dementia. Methods: This cross-sectional study included 143 community-dwelling participants aged ≥70 years (median: 73 years [70-85]; 87 females) with spontaneous memory complaints but dementia-free. Sociodemographic characteristics, health status, neuropsychological tests, sleep, and 18F-florbetapir (amyloid) PET data were collected. The clinical sleep interview evaluated nighttime sleep duration, but also daytime sleep duration, presence of naps, and restless leg syndrome (RLS) at time of study. Validated questionnaires assessed daytime sleepiness, insomnia, and risk of sleep apnea. The cortical standardized uptake value ratio (SUVr) was computed across six cortical regions. The relationship between sleep parameters and SUVr (cut-off ratio>1.17 and tertiles) was analyzed using logistic regression models. Results: Amyloid-PET was positive in 40.6% of participants. Almost 40% were at risk for apnea, 13.5% had RLS, 35.5% insomnia symptoms, 22.1% daytime sleepiness, and 18.8% took sleep drugs. No significant relationship was found between positive amyloid PET and nighttime sleep duration (as a continuous variable, or categorized into <6; 6-7; ≥7 h per night). Logistic regression models did not show any association between SUVr and daytime sleep duration, 24-h sleep duration, naps, RLS, daytime sleepiness, insomnia symptoms, and sleep apnea risk (before and after adjustment for APOEε4 and depressive symptoms). Conclusion: Our study did not confirm the association between amyloid-PET burden, poor sleep quantity/quality in elderly population, suggesting that the interplay between sleep, and amyloid is more complex than described.

Diagnostic performance of 18F-FDG PET-CT for large vessel involvement assessment in patients with suspected giant cell arteritis and negative temporal artery biopsy.

OBJECTIVE: The purpose of our study was to assess the diagnostic performance of 18F-FDG PET-CT for large vessel involvement in patients with suspected giant cells arteritis (GCA) and a negative temporal artery biopsy (TAB). METHODS: We conducted a retrospective study in a cohort of patients with suspected GCA and negative TAB who underwent an 18F-FDG PET-CT. Ten vascular segments were studied using a visual score and a semi-quantitative method based on SUVmax ratio with respect to liver uptake. The diagnosis of GCA was established during a mean follow-up of 42 months, based on the presence of clinical symptoms, laboratory results, and imaging data compatible with GCA, good response to corticosteroid therapy, and no differential diagnosis after a follow-up of at least 18 months. RESULTS: We included 63 patients (30 men and 33 women, aged 67 ± 12 years). 18F-FDG PET-CT showed large vessel involvement in 22 patients, 14 of whom were finally diagnosed with GCA. Forty-one patients were 18F-FDG PET-CT negative, 9 of whom were finally diagnosed with GCA. Overall, 18F-FDG uptake by large vessel yielded 61% sensitivity, 80% specificity, 64% positive predictive value, 78% negative predictive value, and 73% diagnostic accuracy. A significant number of patients were treated by corticosteroids before 18F-FDG PET-CT. However, corticosteroid therapy did not impact significantly the diagnostic performance, although there was a trend to a lower sensitivity in patients receiving corticosteroid therapy for more than 3 days. CONCLUSIONS: 18F-FDG PET-CT is a useful imaging technique to assess large vessel involvement in patients with suspected GCA and negative TAB.

Reduced brain amyloid burden in elderly patients with narcolepsy type 1.

OBJECTIVE: To determine whether brain amyloid burden in elderly patients with narcolepsy type 1 (NT1) is lower than in controls, and to assess in patients with NT1 the relationships between amyloid burden, cerebral spinal fluid (CSF) markers of Alzheimer disease (AD), CSF orexin-A, and cognitive profile. METHODS: Cognitive and 18 F-florbetapir positron emission tomography (PET) data were compared in patients with NT1 aged ≥ 65 years (n = 23) and in age- and sex-matched controls free of clinical dementia selected from the Alzheimer's Disease Neuroimaging Initiative (ADNI; n = 69) and the Multi-Domain Intervention Alzheimer's Prevention Trial (MAPT-18F AV45-PET; n = 23) cohorts. The standardized uptake values (SUVs) of the cortical retention index for 6 regions of interest were computed and averaged to create a mean SUV ratio normalized to 3 subcortical reference regions (cerebellum, pons, and a composite region). A cortical/cerebellum SUV ratio ≥ 1.17 defined positive PET amyloid. RESULTS: Lower cortical amyloid burden was observed in the NT1 than in the ADNI and MAPT-AV45 groups (mean cortical/cerebellum SUV ratios = 0.95 ± 0.15, 1.11 ± 0.18 [p < 0.0001], and 1.14 ± 0.17 [p = 0.0005], respectively). Similar results were obtained with all subcortical reference regions and for all cortical regions of interest, except cingulum. Only 1 patient with NT1 (4.4%) had positive PET amyloid compared with 27.5% in the ADNI and 30.4% in the MAPT-AV45 group. In the NT1 group, cortical or regional amyloid load was not associated with CSF orexin-A, CSF AD biomarkers, or neuropsychological profile. INTERPRETATION: Lower brain amyloid burden, assessed by 18 F-florbetapir PET, in patients with NT1 suggests delayed appearance of amyloid plaques. ANN NEUROL 2019;85:74-83.

[18F]Fludeoxyglucose-Positron Emission Tomography Evidence for Cerebral Hypermetabolism in the Awake State in Narcolepsy and Idiopathic Hypersomnia.

BACKGROUND: Changes in structural and functional central nervous system have been reported in narcolepsy, with large discrepancies between studies. No study has investigated yet spontaneous brain activity at wake in idiopathic hypersomnia (IH). We compared relative changes in regional brain metabolism in two central hypersomnia conditions with different clinical features, namely narcolepsy type 1 (NT1) and IH, and in healthy controls. METHODS: Sixteen patients [12 males, median age 30 years (17-78)] with NT1, nine patients [2 males, median age 27 years (20-60)] with IH and 19 healthy controls [16 males, median age 36 years (17-78)] were included. 18F-fludeoxyglucose positron emission tomography (PET) was performed in all drug-free subjects under similar conditions and instructions to stay in a wake resting state. RESULTS: We found increased metabolism in the anterior and middle cingulate and the insula in the two pathological conditions as compared to healthy controls. The reverse contrast failed to evidence hypometabolism in patients vs. controls. Comparisons between patient groups were non-significant. At sub-statistical threshold, we found higher right superior occipital gyrus glucose metabolism in narcolepsy and higher middle orbital cortex and supplementary motor area metabolism in IH, findings that require further confirmation. CONCLUSION: There is significant hypermetabolism in narcolepsy and IH in the wake resting state in a set of brain regions constitutive of the salience cortical network that may reflect a compensatory neurocircuitry activity secondary to sleepiness. Metabolic differences between the two disorders within the executive-control network may be a signature of abnormally functioning neural system leading to persistent drowsiness typical of IH.

Cognitive Event-Related Potential, an Early Diagnosis Biomarker in Frail Elderly Subjects: The ERP-MAPT-PLUS Ancillary Study.

BACKGROUND: By analyzing brain synaptic function, cognitive event-related potentials (ERPs) could provide powerful and innovative tools for early Alzheimer's disease (AD) diagnosis. OBJECTIVE: We investigated the relevance of the ERP-P300 component as a potential diagnosis marker in elderly subjects at risk of developing AD. METHODS: ERP-P300 was analyzed on 85 subjects recruited from the Multidomain Alzheimer Preventive Trial (MAPT). PET-AV45 brain imaging was available from 36 subjects. RESULTS: Two ERP-P300 subgroups were identified according to their PET-AV45 status: PET-Aß positive (n = 15) and PET-Aß negative (n = 21). In the amyloid positive group, we observed a highly significant increase in P3b latency in parietal brain regions (p = 0.0052). P3b in parietal regions correctly categorized 69.4% elderly subjects from the P300-PET Aß positive group. Combined analysis of parietal P3b latencies and category fluency correctly classified 75% subjects from the P300-PET Aß positive group. CONCLUSIONS: The P300 ERP presents good predictive measure of brain amyloid load and has the potential to be used as a screening instrument for preclinical AD. The incorporation of P3b latency may be used as an adjunctive tool with neuropsychological assessment (i.e., verbal category fluency) as a specific and sensitive method for preclinical assessment of AD.

Late-onset behavioral variant of frontotemporal lobar degeneration versus Alzheimer's disease: Interest of cerebrospinal fluid biomarker ratios.

INTRODUCTION: Cerebrospinal fluid (CSF) biomarker ratios were never evaluated in late-onset (>65 years) behavioral variant of frontotemporal lobar degeneration (bvFTLD) versus Alzheimer's disease (AD). METHODS: A retrospective monocentric study on 44 clinically suspected amnestic AD or bvFTLD patients with onset after 65 years and available CSF and clinical data. RESULTS: The final clinical diagnosis was AD (n = 28; 64%), late-onset bvFTLD (n = 14; 32%), and others (n = 2; 4%). Applying the CSF cutoff total-tau/Aß1-42 of 1.06, all the bvFTLD were in the FTLD range (<1.06, bvFTLD/FTLD), whereas the AD patients were either in the AD (>1.06, AD/AD) or in the FTLD range (<1.06, AD/FTLD); CSF biomarkers were significantly different in these three groups, but not neuroradiological features or presence of episodic memory deficit. DISCUSSION: Late-onset bvFTLD is underdiagnosed. The available CSF biomarker ratio cutoff need further improvement and overestimated late-onset bvFTLD but could potentially differentiate it from AD, notably in case of conflicting results.

Neck restaging with sentinel node biopsy in T1-T2N0 oral and oropharyngeal cancer: Why and how?

OBJECTIVE: To evaluate the lack of accuracy in neck staging with the classical technique (i.e., neck dissection and routine histopathology) with the sentinel node (SN) biopsy in oral and oropharyngeal T1-T2N0 cancer. STUDY DESIGN: Cross-sectional study with planned data collection. SETTING: Tertiary center care. SUBJECTS AND METHODS: In 50 consecutive patients, the pathological stage of sentinel node (pSN) was established after analyzing SN biopsies (n = 148) using serial sectioning and immunohistochemistry. Systematic selective neck dissection was performed. The pN stage was established with routine histopathologic analysis of both the non-SN (n = 1075) and the 148 SN biopsies. RESULTS: The sensitivity and negative predictive value of pSN staging were 100 percent. Conversely, if one considers pSN staging procedure as the reference test for micro- and macro-metastasis diagnosis, the sensitivity of the classical pN staging procedure was 50 percent (9/1; 95% CI 26.9-73.1) and its negative predictive value was 78 percent (95% CI 61.9-88.8). Fifteen patients (30%) were upstaged, including nine cases from pN0 to pSN >or= 1 and six cases from pN1 to pSN2. Two of the pN0-pSN1 upstaged patients died with relapsed neck disease. CONCLUSION: The SN biopsy technique appeared to be the best staging method in cN0 patients and provided evidence that routinely undiagnosed lymph node invasion may have clinical significance.