Mapping the Degradable Kinome Provides a Resource for Expedited Degrader Development.

Targeted protein degradation (TPD) refers to the use of small molecules to induce ubiquitin-dependent degradation of proteins. TPD is of interest in drug development, as it can address previously inaccessible targets. However, degrader discovery and optimization remains an inefficient process due to a lack of understanding of the relative importance of the key molecular events required to induce target degradation. Here, we use chemo-proteomics to annotate the degradable kinome. Our expansive dataset provides chemical leads for ∼200 kinases and demonstrates that the current practice of starting from the highest potency binder is an ineffective method for discovering active compounds. We develop multitargeted degraders to answer fundamental questions about the ubiquitin proteasome system, uncovering that kinase degradation is p97 dependent. This work will not only fuel kinase degrader discovery, but also provides a blueprint for evaluating targeted degradation across entire gene families to accelerate understanding of TPD beyond the kinome.

Proteome-scale discovery of protein degradation and stabilization effectors.

Targeted protein degradation and stabilization are promising therapeutic modalities because of their potency, versatility and their potential to expand the druggable target space1,2. However, only a few of the hundreds of E3 ligases and deubiquitinases in the human proteome have been harnessed for this purpose, which substantially limits the potential of the approach. Moreover, there may be other protein classes that could be exploited for protein stabilization or degradation3-5, but there are currently no methods that can identify such effector proteins in a scalable and unbiased manner. Here we established a synthetic proteome-scale platform to functionally identify human proteins that can promote the degradation or stabilization of a target protein in a proximity-dependent manner. Our results reveal that the human proteome contains a large cache of effectors of protein stability. The approach further enabled us to comprehensively compare the activities of human E3 ligases and deubiquitinases, identify and characterize non-canonical protein degraders and stabilizers and establish that effectors have vastly different activities against diverse targets. Notably, the top degraders were more potent against multiple therapeutically relevant targets than the currently used E3 ligases cereblon and VHL. Our study provides a functional catalogue of stability effectors for targeted protein degradation and stabilization and highlights the potential of induced proximity screens for the discovery of new proximity-dependent protein modulators.

The N-terminal methionine of cellular proteins as a degradation signal.

The Arg/N-end rule pathway targets for degradation proteins that bear specific unacetylated N-terminal residues while the Ac/N-end rule pathway targets proteins through their N(α)-terminally acetylated (Nt-acetylated) residues. Here, we show that Ubr1, the ubiquitin ligase of the Arg/N-end rule pathway, recognizes unacetylated N-terminal methionine if it is followed by a hydrophobic residue. This capability of Ubr1 expands the range of substrates that can be targeted for degradation by the Arg/N-end rule pathway because virtually all nascent cellular proteins bear N-terminal methionine. We identified Msn4, Sry1, Arl3, and Pre5 as examples of normal or misfolded proteins that can be destroyed through the recognition of their unacetylated N-terminal methionine. Inasmuch as proteins bearing the Nt-acetylated N-terminal methionine residue are substrates of the Ac/N-end rule pathway, the resulting complementarity of the Arg/N-end rule and Ac/N-end rule pathways enables the elimination of protein substrates regardless of acetylation state of N-terminal methionine in these substrates.

Head-to-Head Comparison of Tau and Amyloid Positron Emission Tomography Visual Reads for Differential Diagnosis of Neurodegenerative Disorders: An International, Multicenter Study.

OBJECTIVE: We compared the accuracy of amyloid and [18F]Flortaucipir (FTP) tau positron emission tomography (PET) visual reads for distinguishing patients with mild cognitive impairment (MCI) or dementia with fluid biomarker support of Alzheimer's disease (AD). METHODS: Participants with FTP-PET, amyloid-PET, and diagnosis of dementia-AD (n = 102), MCI-AD (n = 41), non-AD diseases (n = 76), and controls (n = 20) were included. AD status was determined independent of PET by cerebrospinal fluid or plasma biomarkers. The mean age was 66.9 years, and 44.8% were women. Three readers interpreted scans blindly and independently. Amyloid-PET was classified as positive/negative using tracer-specific criteria. FTP-PET was classified as positive with medial temporal lobe (MTL) binding as the minimum uptake indicating AD tau (tau-MTL+), positive with posterolateral temporal or extratemporal cortical binding in an AD-like pattern (tau-CTX+), or negative. The majority of scan interpretations were used to calculate diagnostic accuracy of visual reads in detecting MCI/dementia with fluid biomarker support for AD (MCI/dementia-AD). RESULTS: Sensitivity of amyloid-PET for MCI/dementia-AD was 95.8% (95% confidence interval 91.1-98.4%), which was comparable to tau-CTX+ 92.3% (86.7-96.1%, p = 0.67) and tau-MTL+ 97.2% (93.0-99.2%, p = 0.27). Specificity of amyloid-PET for biomarker-negative healthy and disease controls was 84.4% (75.5-91.0%), which was like tau-CTX+ 88.5% (80.4-94.1%, p = 0.34), and trended toward being higher than tau-MTL+ 75.0% (65.1-83.3%, p = 0.08). Tau-CTX+ had higher specificity than tau-MTL+ (p = 0.0002), but sensitivity was lower (p = 0.02), driven by decreased sensitivity for MCI-AD (80.5% [65.1-91.2] vs. 95.1% [83.5-99.4], p = 0.03). INTERPRETATION: Amyloid- and tau-PET visual reads have similar sensitivity/specificity for detecting AD in cognitively impaired patients. Visual tau-PET interpretations requiring cortical binding outside MTL increase specificity, but lower sensitivity for MCI-AD. ANN NEUROL 2024;96:476-487.

Role of Enlarged Perivascular Space in the Temporal Lobe in Cerebral Amyloidosis.

OBJECTIVE: Although growing evidence suggests that perivascular space (PVS) serves as a clearance route for amyloid and tau, the association between enlarged PVS (EPVS) and Alzheimer disease is highly inconsistent across studies. As the conventional visual rating systems for EPVS were insufficient to predict amyloid/tau/neurodegeneration (A/T/N) status, we developed a new rating scale for EPVS located in the temporal lobe (T-EPVS). METHODS: EPVS located in the basal ganglia (BG-EPVS), centrum semiovale (CS-EPVS), and T-EPVS was visually rated in 272 individuals (healthy controls, n = 96; mild cognitive impairment, n = 106; dementia, n = 70) who underwent structural magnetic resonance imaging (MRI) and dual positron emission tomography scans (18 F-flortaucipir and 18 F-florbetaben). T-EPVS and BG-EPVS were defined as high degree when the counts in any hemisphere were >10, and the CS-EPVS cutoff was >20. Logistic regression models were constructed to investigate whether the regional EPVS burden was predictive of A/T/N status. The derived models were externally validated in a temporal validation cohort (n = 195) that underwent MRI studies using a different scanner. RESULTS: Compared with those with low-degree T-EPVS (23/136, 16.9%), individuals with high-degree T-EPVS/CS-EPVS but low-degree BG-EPVS were more likely to exhibit amyloid positivity (46/56, 82.1%). High-degree T-EPVS burden (odds ratio [OR] = 7.251, 95% confidence interval [CI] = 3.296-15.952) and low-degree BG-EPVS (OR = 0.241, 95% CI = 0.109-0.530) were predictive of amyloid positivity. Although high-degree T-EPVS was associated with tau positivity, the association was no longer significant after adjusting for amyloid and neurodegeneration status. INTERPRETATION: Investigating the burden and topographic distribution of EPVS including T-EPVS may be useful for predicting amyloid status, indicating that impaired perivascular drainage may contribute to cerebral amyloidosis. ANN NEUROL 2023;93:965-978.

Bickerstaff's brainstem encephalitis: a rare case of neurologic complication in Ulcerative Colitis.

Bickerstaff's brainstem encephalitis is a rare autoimmune disorder that presents with ataxia, ophthalmoplegia, disturbance of consciousness and quadriplegia. A 45-year-old man with a history of ulcerative colitis (UC) taking mesalazine (5-aminosalicylic acid) visited the emergency room presenting with ataxia, ophthalmoplegia and a progressively worsening cognitive impairment. Cerebrospinal fluid analysis showed mild elevation in protein and white blood cell count and increased intracranial pressure. Anti-GQ1b autoantibodies were found positive in the patient's serum and contrast-enhanced brain magnetic resonance imaging showed diffuse leptomeningeal enhancement and pontine lesions. Based on these findings and the patient's clinical course and history, he was diagnosed with Bickerstaff's brainstem encephalitis. Mesalazine was discontinued and high-dose steroid pulse therapy was started, followed by intravenous immunoglobulin, which resulted in gradual improvement of the neurologic symptoms. When an ulcerative colitis patient presents with progressive cognitive impairment, quadriplegia and disturbance of consciousness and gait, Bickerstaff brainstem encephalitis should be considered in the differential diagnosis and prompt immunotherapy may lead to favorable prognosis.

Amyloid and tau-PET in early-onset AD: Baseline data from the Longitudinal Early-onset Alzheimer's Disease Study (LEADS).

INTRODUCTION: We aimed to describe baseline amyloid-beta (Aß) and tau-positron emission tomograrphy (PET) from Longitudinal Early-onset Alzheimer's Disease Study (LEADS), a prospective multi-site observational study of sporadic early-onset Alzheimer's disease (EOAD). METHODS: We analyzed baseline [18F]Florbetaben (Aß) and [18F]Flortaucipir (tau)-PET from cognitively impaired participants with a clinical diagnosis of mild cognitive impairment (MCI) or AD dementia aged < 65 years. Florbetaben scans were used to distinguish cognitively impaired participants with EOAD (Aß+) from EOnonAD (Aß-) based on the combination of visual read by expert reader and image quantification. RESULTS: 243/321 (75.7%) of participants were assigned to the EOAD group based on amyloid-PET; 231 (95.1%) of them were tau-PET positive (A+T+). Tau-PET signal was elevated across cortical regions with a parietal-predominant pattern, and higher burden was observed in younger and female EOAD participants. DISCUSSION: LEADS data emphasizes the importance of biomarkers to enhance diagnostic accuracy in EOAD. The advanced tau-PET binding at baseline might have implications for therapeutic strategies in patients with EOAD. HIGHLIGHTS: 72% of patients with clinical EOAD were positive on both amyloid- and tau-PET. Amyloid-positive patients with EOAD had high tau-PET signal across cortical regions. In EOAD, tau-PET mediated the relationship between amyloid-PET and MMSE. Among EOAD patients, younger onset and female sex were associated with higher tau-PET.

The impact of demographic, clinical, genetic, and imaging variables on tau PET status.

PURPOSE: A substantial proportion of amyloid-ß (Aß)+ patients with clinically diagnosed Alzheimer's disease (AD) dementia and mild cognitive impairment (MCI) are tau PET-negative, while some clinically diagnosed non-AD neurodegenerative disorder (non-AD) patients or cognitively unimpaired (CU) subjects are tau PET-positive. We investigated which demographic, clinical, genetic, and imaging variables contributed to tau PET status. METHODS: We included 2338 participants (430 Aß+ AD dementia, 381 Aß+ MCI, 370 non-AD, and 1157 CU) who underwent [18F]flortaucipir (n = 1944) or [18F]RO948 (n = 719) PET. Tau PET positivity was determined in the entorhinal cortex, temporal meta-ROI, and Braak V-VI regions using previously established cutoffs. We performed bivariate binary logistic regression models with tau PET status (positive/negative) as dependent variable and age, sex, APOEε4, Aß status (only in CU and non-AD analyses), MMSE, global white matter hyperintensities (WMH), and AD-signature cortical thickness as predictors. Additionally, we performed multivariable binary logistic regression models to account for all other predictors in the same model. RESULTS: Tau PET positivity in the temporal meta-ROI was 88.6% for AD dementia, 46.5% for MCI, 9.5% for non-AD, and 6.1% for CU. Among Aß+ participants with AD dementia and MCI, lower age, MMSE score, and AD-signature cortical thickness showed the strongest associations with tau PET positivity. In non-AD and CU participants, presence of Aß was the strongest predictor of a positive tau PET scan. CONCLUSION: We identified several demographic, clinical, and neurobiological factors that are important to explain the variance in tau PET retention observed across the AD pathological continuum, non-AD neurodegenerative disorders, and cognitively unimpaired persons.

Etch characteristics of magnetic tunnel junction materials using H2/NH3 reactive ion beam.

Magnetic tunneling junction (MTJ) materials such as CoFeB, Co, Pt, MgO, and the hard mask material such as W and TiN were etched with a reactive ion beam etching (RIBE) system using H2/NH3. By using gas mixtures of H2 and NH3, especially with the H2/NH3( 2:1) ratio, higher etch rates of MTJ related materials and higher etch selectivities over mask materials (>30) could be observed compared to those etching using pure H2( no etching) and NH3. In addition, no significant chemical and physical damages were observed on etched magnetic materials surfaces and, for CoPt and MTJ nanoscale patterns etched by the H2/NH3( 2:1) ion beam, highly anisotropic etch profiles >83° with no sidewall redeposition could be observed. The higher etch rates of magnetic materials such as CoFeB by the H2/NH3( 2:1) ion beam compared to those by H2 ion beam or NH3 ion beam are believed to be related to the formation of volatile metal hydrides (MH, M = Co, Fe, etc) through the reduction of M-NHx( x = 1 ∼ 3) formed in the CoFeB surface by the exposure to NH3 ion beam. It is believed that the H2/NH3 RIBE is a suitable technique in the etching of MTJ materials for the next generation nanoscale spin transfer torque magnetic random access memory (STT-MRAM) devices.

RAF inhibitors that evade paradoxical MAPK pathway activation.

Oncogenic activation of BRAF fuels cancer growth by constitutively promoting RAS-independent mitogen-activated protein kinase (MAPK) pathway signalling. Accordingly, RAF inhibitors have brought substantially improved personalized treatment of metastatic melanoma. However, these targeted agents have also revealed an unexpected consequence: stimulated growth of certain cancers. Structurally diverse ATP-competitive RAF inhibitors can either inhibit or paradoxically activate the MAPK pathway, depending whether activation is by BRAF mutation or by an upstream event, such as RAS mutation or receptor tyrosine kinase activation. Here we have identified next-generation RAF inhibitors (dubbed 'paradox breakers') that suppress mutant BRAF cells without activating the MAPK pathway in cells bearing upstream activation. In cells that express the same HRAS mutation prevalent in squamous tumours from patients treated with RAF inhibitors, the first-generation RAF inhibitor vemurafenib stimulated in vitro and in vivo growth and induced expression of MAPK pathway response genes; by contrast the paradox breakers PLX7904 and PLX8394 had no effect. Paradox breakers also overcame several known mechanisms of resistance to first-generation RAF inhibitors. Dissociating MAPK pathway inhibition from paradoxical activation might yield both improved safety and more durable efficacy than first-generation RAF inhibitors, a concept currently undergoing human clinical evaluation with PLX8394.

Temporal trajectories of in vivo tau and amyloid-ß accumulation in Alzheimer's disease.

PURPOSE: To investigate the temporal trajectories of tau and amyloid-ß (Aß) accumulation in Alzheimer's disease (AD) by using the longitudinal positron emission tomography (PET) study. METHODS: A total of 132 participants, who were healthy volunteers or recruited in our memory disorder clinic, completed longitudinal 18F-flortaucipir and 18F-florbetaben PET studies with a mean follow-up time of 2 years. Referencing baseline data from 57 Aß-negative cognitively unimpaired individuals, Z-scores and their annual changes were calculated with the global cortical or regional standardized uptake value ratios measured at baseline and follow-up after correcting for partial volume effect. The temporal trajectories of tau and Aß burden as a function of time were obtained based on the spline models from the annual changes and baseline Z-score data. RESULTS: Tau burden first emerged in the Braak's stage I-II regions, followed by stage III-IV regions, and finally in the stage V-VI regions. Time intervals between two time points at which Z-score curves rose above 2 were 17.3 years for the stages I-II and III-IV and 15.2 years for the stages III-IV and V-VI. Rise in the tau curve for stages I-II preceded that for global cortical Aß, while the rise in global cortical Aß curve preceded that for global cortical tau. Aß accumulation rate was attenuated during the surge in tau burden in the global cortex and reached a plateau. CONCLUSION: Sequential appearance of Aß and tau accumulation supports a hypothetical dynamic biomarker model and Braak's hierarchical tau spreading model in AD.

Application of an amyloid and tau classification system in subcortical vascular cognitive impairment patients.

OBJECTIVE: To apply an AT (Aß/tau) classification system to subcortical vascular cognitive impairment (SVCI) patients following recently developed biomarker-based criteria of Alzheimer's disease (AD), and to investigate its clinical significance. METHODS: We recruited 60 SVCI patients who underwent the neuropsychological tests, brain MRI, and 18F-florbetaben and 18F-AV1451 PET at baseline. As a control group, we further recruited 27 patients with AD cognitive impairment (ADCI; eight Aß PET-positive AD dementia and 19 amnestic mild cognitive impairment). ADCI and SVCI patients were classified as having normal or abnormal Aß (A-/A+) and tau (T-/T+) based on PET results. Across the three SVCI groups (A-, A+T-, and A+T+SVCI), we compared longitudinal changes in cognition, hippocampal volume (HV), and cortical thickness using linear mixed models. RESULTS: Among SVCI patients, 33 (55%), 20 (33.3%), and seven (11.7%) patients were A-, A+T-, and A+T+, respectively. The frequency of T+ was lower in A+SVCI (7/27, 25.9%) than in A+ADCI (14/20, 70.0%, p = 0.003) which suggested that cerebral small vessel disease affected cognitive impairments independently of A+. A+T-SVCI had steeper cognitive decline than A-SVCI. A+T+SVCI also showed steeper cognitive decline than A+T-SVCI. Also, A+T-SVCI had steeper decrease in HV than A-SVCI, while cortical thinning did not differ between the two groups. A+T+SVCI had greater global cortical thinning compared with A+T-SVCI, while declines in HV did not differ between the two groups. CONCLUSION: This study showed that the AT system successfully characterized SVCI patients, suggesting that the AT system may be usefully applied in a research framework for clinically diagnosed SVCI.

Distinct tau PET patterns in atrophy-defined subtypes of Alzheimer's disease.

INTRODUCTION: Differential patterns of brain atrophy on structural magnetic resonance imaging (MRI) revealed four reproducible subtypes of Alzheimer's disease (AD): (1) "typical", (2) "limbic-predominant", (3) "hippocampal-sparing", and (4) "mild atrophy". We examined the neurobiological characteristics and clinical progression of these atrophy-defined subtypes. METHODS: The four subtypes were replicated using a clustering method on MRI data in 260 amyloid-ß-positive patients with mild cognitive impairment or AD dementia, and we subsequently tested whether the subtypes differed on [18 F]flortaucipir (tau) positron emission tomography, white matter hyperintensity burden, and rate of global cognitive decline. RESULTS: Voxel-wise and region-of-interest analyses revealed the greatest neocortical tau load in hippocampal-sparing (frontoparietal-predominant) and typical (temporal-predominant) patients, while limbic-predominant patients showed particularly high entorhinal tau. Typical patients with AD had the most pronounced white matter hyperintensity load, and hippocampal-sparing patients showed the most rapid global cognitive decline. DISCUSSION: Our data suggest that structural MRI can be used to identify biologically and clinically meaningful subtypes of AD.

Modeling of Frontotemporal Dementia Using iPSC Technology.

Frontotemporal dementia (FTD) is caused by the progressive degeneration of the frontal and temporal lobes of the brain. Behavioral variant FTD (bvFTD) is the most common clinical subtype of FTD and pathological subtypes of bvFTD are known as FTD-tau, transactive response (TAR) DNA-binding protein 43 (TDP-43), and fused in sarcoma (FUS). Pathological mechanisms of bvFTD are largely unknown. In this study, we investigated the expression of pathological markers, such as p-Tau, TDP-43, and FUS, in the induced pluripotent stem-cell-derived neurons (iPSN) from two sporadic bvFTD patients and one normal subject. We also used an FTD-patient-derived iPSC-line-carrying microtubule-associated protein tau (MAPT) P301L point mutation as positive control for p-Tau expression. Staurosporine (STS) was used to induce cellular stress in order to investigate dynamic cellular responses related to the cell death pathway. As a result, the expression of active caspase-3 was highly increased in the bvFTD-iPSNs compared with control iPSNs in the STS-treated conditions. Other cell-death-related proteins, including Bcl-2-associated X protein (Bax)/Bcl-2 and cytochrome C, were also increased in the bvFTD-iPSNs. Moreover, we observed abnormal expression patterns of TDP-43 and FUS in the bvFTD-iPSNs compared with control iPSNs. We suggest that the iPSC technology might serve as a potential tool to demonstrate neurodegenerative phenotypes of bvFTD, which will be useful for studying pathological mechanisms for FTD as well as related drug screening in the future.

THK5351 and flortaucipir PET with pathological correlation in a Creutzfeldt-Jakob disease patient: a case report.

BACKGROUND: THK5351 and flortaucipir tau ligands have high affinity for paired helical filament tau, yet diverse off-target bindings have been reported. Recent data support the hypothesis that THK5351 binds to monoamine oxidase B (MAO-B) expressed from reactive astrocytes and that flortaucipir has an affinity toward MAO-A and B; however, pathological evidence is lacking. We performed a head-to-head comparison of the two tau ligands in a sporadic Creutzfeldt-Jakob disease (CJD) patient and performed an imaging-pathological correlation study. CASE PRESENTATION: A 67-year-old man visited our clinic a history of 6 months of rapidly progressive dementia, visual disturbance, and akinetic mutism. Diffusion-weighted imaging showed cortical diffusion restrictions in the left temporo-parieto-occipital regions. 18F-THK5351 PET, but not 18F-flortaucipir PET showed high uptake in the left temporo-parieto-occipital regions, largely overlapping with the diffusion restricted areas. Cerebrospinal fluid analysis was weakly positive for 14-3-3 protein and pathogenic prion protein was found. The patient showed rapid cognitive decline along with myoclonic seizures and died 13 months after his first visit. A post-mortem study revealed immunoreactivity for PrPsc, no evidence of neurofibrillary tangles, and abundant astrocytosis which was reactive for MAO-B antibody. CONCLUSIONS: Our findings add pathological evidence that increased THK5351 uptake in sporadic CJD patients might be caused by an off-target binding driven by its high affinity for MAO-B.

Head to head comparison of [18F] AV-1451 and [18F] THK5351 for tau imaging in Alzheimer's disease and frontotemporal dementia.

PURPOSE: Tau accumulation is a core pathologic change in various neurodegenerative diseases including Alzheimer's disease and frontotemporal lobar degeneration-tau. Recently, tau positron emission tomography tracers such as [18F] AV-1451 and [18F] THK5351 have been developed to detect tau deposition in vivo. In the present study, we performed a head to head comparison of these two tracers in Alzheimer's disease and frontotemporal dementia cases and aimed to investigate which tracers are better suited to image tau in these disorders. METHODS: A cross-sectional study was conducted using a hospital-based sample at a tertiary referral center. We recruited eight participants (two Alzheimer's disease, four frontotemporal dementia and two normal controls) who underwent magnetic resonance image, amyloid positron emission tomography with [18F]-Florbetaben and tau positron emission tomography with both THK5351 and AV-1451. To measure regional AV1451 and THK5351 uptakes, we used the standardized uptake value ratios by dividing mean activity in target volume of interest by mean activity in the cerebellar hemispheric gray matter. RESULTS: Although THK5351 and AV-1451 uptakes were highly correlated, cortical uptake of AV-1451 was more striking in Alzheimer's disease, while cortical uptake of THK5351 was more prominent in frontotemporal dementia. THK5351 showed higher off-target binding than AV-1451 in the white matter, midbrain, thalamus, and basal ganglia. CONCLUSIONS: AV-1451 is more sensitive and specific to Alzheimer's disease type tau and shows lower off-target binding, while THK5351 may mirror non-specific neurodegeneration.

Distinct patterns of amyloid-dependent tau accumulation in Lewy body diseases.

BACKGROUND: In addition to Lewy body pathology, amyloid-ß plaques and neurofibrillary tangles that are characteristic for Alzheimer's disease are also frequently found in Lewy body diseases. OBJECTIVES: The objective of this study was to investigate tau accumulation patterns in dementia with Lewy bodies and other Lewy body diseases using in vivo 18 F-AV-1451 PET. METHODS: The study included 12 Parkinson's disease (PD) patients with normal cognition, 22 PD patients with cognitive impairment, and 18 dementia with Lewy bodies patients. In addition, 25 Alzheimer's disease patients and 25 healthy controls were included for comparison. All participants underwent 18 F-AV-1451 and 18 F-florbetaben PET scans, and cortical binding values were compared between the controls and each disease group. RESULTS: When compared with the controls, dementia with Lewy bodies patients showed slightly increased 18 F-AV-1451 binding in the primary sensorimotor and visual cortices and the parieto-temporal cortices, which failed to survive multiple comparisons. Amyloid-positive dementia with Lewy bodies patients showed significantly increased binding in the same regions when compared with controls, and even greater binding in the primary sensorimotor and visual cortices than Alzheimer's disease. Meanwhile, binding in the lateral and medial temporal cortices was less prominent than in Alzheimer's disease. In dementia with Lewy bodies, 18 F-AV-1451 binding in the occipital cortex correlated with 18 F-florbetaben binding. Amyloid-negative patients with normal cognition, patients with cognitive impairment, and dementia with Lewy bodies patients did not show increased 18 F-AV-1451 binding. CONCLUSIONS: Dementia with Lewy bodies patients may harbor 18 F-AV-1451 binding patterns distinct from Alzheimer's disease, with greater involvement of the primary cortices and less involvement of the temporal cortex. Tau burden increases in the Lewy body disease spectrum, and amyloid may play an important role in the accumulation of neocortical tau in Lewy body diseases. © 2017 International Parkinson and Movement Disorder Society.

Nonlinear couplings and energy transfers in micro- and nano-mechanical resonators: intermodal coupling, internal resonance and synchronization.

Extensive development of micro/nano-electromechanical systems (MEMS/NEMS) has resulted in technologies that exhibit excellent performance over a wide range of applications in both applied (e.g. sensing, imaging, timing and signal processing) and fundamental sciences (e.g. quantum-level problems). Many of these outstanding applications benefit from resonance phenomena by employing micro/nanoscale mechanical resonators often fabricated into a beam-, membrane- or plate-type structure. During the early development stage, one of the vibrational modes (typically the fundamental mode) of a resonator is considered in the design and application. In the past decade, however, there has been a growing interest in using more than one vibrational mode for the enhanced functionality of MEMS/NEMS. In this paper, we review recent research efforts to investigate the nonlinear coupling and energy transfers between multiple modes in micro/nano-mechanical resonators, focusing especially on intermodal coupling, internal resonance and synchronization.This article is part of the theme issue 'Nonlinear energy transfer in dynamical and acoustical systems'.

Discriminative Accuracy of [18F]flortaucipir Positron Emission Tomography for Alzheimer Disease vs Other Neurodegenerative Disorders.

Importance: The positron emission tomography (PET) tracer [18F]flortaucipir allows in vivo quantification of paired helical filament tau, a core neuropathological feature of Alzheimer disease (AD), but its diagnostic utility is unclear. Objective: To examine the discriminative accuracy of [18F]flortaucipir for AD vs non-AD neurodegenerative disorders. Design, Setting, and Participants: In this cross-sectional study, 719 participants were recruited from 3 dementia centers in South Korea, Sweden, and the United States between June 2014 and November 2017 (160 cognitively normal controls, 126 patients with mild cognitive impairment [MCI], of whom 65.9% were amyloid-ß [Aß] positive [ie, MCI due to AD], 179 patients with AD dementia, and 254 patients with various non-AD neurodegenerative disorders). Exposures: The index test was the [18F]flortaucipir PET standardized uptake value ratio (SUVR) in 5 predefined regions of interest (ROIs). Cut points for tau positivity were determined using the mean +2 SDs observed in controls and Youden Index for the contrast AD dementia vs controls. Main Outcomes and Measures: The reference standard was the clinical diagnosis determined at the specialized memory centers. In the primary analysis, the discriminative accuracy (ie, sensitivity and specificity) of [18F]flortaucipir was examined for AD dementia vs all non-AD neurodegenerative disorders. In secondary analyses, the area under the curve (AUC) of [18F]flortaucipir SUVR was compared with 3 established magnetic resonance imaging measures (hippocampal volumes and AD signature and whole-brain cortical thickness), and sensitivity and specificity of [18F]flortaucipir in MCI due to AD vs non-AD neurodegenerative disorders were determined. Results: Among 719 participants, the overall mean (SD) age was 68.8 (9.2) years and 48.4% were male. The proportions of patients who were amyloid-ß positive were 26.3%, 65.9%, 100%, and 23.8% among cognitively normal controls, patients with MCI, patients with AD dementia, and patients with non-AD neurodegenerative disorders, respectively. [18F]flortaucipir uptake in the medial-basal and lateral temporal cortex showed 89.9% (95% CI, 84.6%-93.9%) sensitivity and 90.6% (95% CI, 86.3%-93.9%) specificity using the threshold based on controls (SUVR, 1.34), and 96.8% (95% CI, 92.0%-99.1%) sensitivity and 87.9% (95% CI, 81.9%-92.4%) specificity using the Youden Index-derived cutoff (SUVR, 1.27) for distinguishing AD dementia from all non-AD neurodegenerative disorders. The AUCs for all 5 [18F]flortaucipir ROIs were higher (AUC range, 0.92-0.95) compared with the 3 volumetric MRI measures (AUC range, 0.63-0.75; all ROIs P < .001). Diagnostic performance of the 5 [18F]flortaucipir ROIs were lower in MCI due to AD (AUC range, 0.75-0.84). Conclusions and Relevance: Among patients with established diagnoses at a memory disorder clinic, [18F]flortaucipir PET was able to discriminate AD from other neurodegenerative diseases. The accuracy and potential utility of this test in patient care require further research in clinically more representative populations.

In vivo cortical spreading pattern of tau and amyloid in the Alzheimer disease spectrum.

OBJECTIVE: To determine the in vivo cortical spreading pattern of tau and amyloid and to establish positron emission tomography (PET) image-based tau staging in the Alzheimer disease (AD) spectrum. METHODS: We included 195 participants (53 AD, 52 amnestic mild cognitive impairment [MCI], 23 nonamnestic MCI, and 67 healthy controls) who underwent 2 PET scans ((18) F-florbetaben for amyloid-ß and (18) F-AV-1451 for tau). We assumed that regions with earlier appearances of pathology may show increased binding in a greater number of participants and acquired spreading order of tau accumulation by sorting the regional frequencies of involvement. We classified each participant into image-based tau stage based on the Z score of the composite region for each stage. RESULTS: Tau accumulation was most frequently observed in the medial temporal regions and spread stepwise to the basal and lateral temporal, inferior parietal, posterior cingulate, and other association cortices, and then ultimately to the primary cortical regions. In contrast, amyloid accumulation was found with similar frequency in the diffuse neocortical areas and then finally spread to the medial temporal regions. The image-based tau stage correlated with the general cognitive status, whereas cortical thinning was found only in the advanced tau stages: medial temporal region in stage V and widespread cortex in stage VI. INTERPRETATION: Our PET study replicated postmortem spreading patterns of tau and amyloid-ß pathologies. Unlike the diffuse accumulation of amyloid throughout the neocortex, tau spreading occurred in a stepwise fashion through the networks. Image-based tau staging may be useful for the objective assessment of AD progression. Ann Neurol 2016;80:247-258.