Characterizing brain tau and cognitive decline along the amyloid timeline in Alzheimer's disease.

Recent longitudinal PET imaging studies have established methods to estimate the age at which amyloid becomes abnormal at the level of the individual. Here we recontextualized amyloid levels into the temporal domain to better understand the downstream Alzheimer's disease processes of tau neurofibrillary tangle (NFT) accumulation and cognitive decline. This cohort study included a total of 601 individuals from the Wisconsin Registry for Alzheimer's Prevention and Wisconsin Alzheimer's Disease Research Center that underwent amyloid and tau PET, longitudinal neuropsychological assessments, and met clinical criteria for three clinical diagnosis groups: cognitively unimpaired (CU; n=537); mild cognitive impairment (MCI; n=48); or dementia (n=16)). Cortical 11C-Pittsburgh compound B (PiB) distribution volume ratio (DVR) and sampled iterative local approximation were used to estimate amyloid positive (A+; global PiB DVR>1.16 equivalent to 17.1 Centiloids) onset age and years of A+ duration at tau PET (i.e., amyloid chronicity). Tau PET burden was quantified using 18F-MK-6240 standardized uptake value ratios (SUVRs; 70-90 min, inferior cerebellar gray matter reference region). Whole-brain and region-specific approaches were used to examine tau PET binding along the amyloid timeline and across the Alzheimer's disease clinical continuum. Voxel-wise 18F-MK-6240 analyses revealed that with each decade of A+, the spatial extent of measurable tau spread (i.e., progressed) from regions associated with early to late NFT tau stages. Regional analyses indicated that tau burden in the entorhinal cortex was detectable, on average, within ten years of A+ onset. Additionally, the entorhinal cortex was the region most sensitive to early amyloid pathology and clinical impairment in this predominantly preclinical sample. Among initially CU (n=472) individuals with longitudinal cognitive follow-up, mixed effects models showed significant linear and non-linear interactions of A+ duration and entorhinal tau on cognitive decline, suggesting a synergistic effect whereby greater A+ duration together with a higher entorhinal tau burden increases the likelihood of cognitive decline beyond their separable effects. Overall, the amyloid time framework enabled a spatiotemporal characterization of tau deposition patterns across the Alzheimer's disease continuum. This approach, which examined cross-sectional tau PET data along the amyloid timeline to make longitudinal disease-course inferences, demonstrated that A+ duration explains a considerable amount of variability in the magnitude and topography of tau spread, which largely recapitulated NFT staging observed in human neuropathological studies. By anchoring disease progression to the onset of amyloid, this study provides a temporal disease context which may help inform disease prognosis and timing windows for anti-amyloid therapies.

Comparison of tau spread in people with Down syndrome versus autosomal-dominant Alzheimer's disease: a cross-sectional study.

BACKGROUND: In people with genetic forms of Alzheimer's disease, such as in Down syndrome and autosomal-dominant Alzheimer's disease, pathological changes specific to Alzheimer's disease (ie, accumulation of amyloid and tau) occur in the brain at a young age, when comorbidities related to ageing are not present. Studies including these cohorts could, therefore, improve our understanding of the early pathogenesis of Alzheimer's disease and be useful when designing preventive interventions targeted at disease pathology or when planning clinical trials. We compared the magnitude, spatial extent, and temporal ordering of tau spread in people with Down syndrome and autosomal-dominant Alzheimer's disease. METHODS: In this cross-sectional observational study, we included participants (aged ≥25 years) from two cohort studies. First, we collected data from the Dominantly Inherited Alzheimer's Network studies (DIAN-OBS and DIAN-TU), which include carriers of autosomal-dominant Alzheimer's disease genetic mutations and non-carrier familial controls recruited in Australia, Europe, and the USA between 2008 and 2022. Second, we collected data from the Alzheimer Biomarkers Consortium-Down Syndrome study, which includes people with Down syndrome and sibling controls recruited from the UK and USA between 2015 and 2021. Controls from the two studies were combined into a single group of familial controls. All participants had completed structural MRI and tau PET (18F-flortaucipir) imaging. We applied Gaussian mixture modelling to identify regions of high tau PET burden and regions with the earliest changes in tau binding for each cohort separately. We estimated regional tau PET burden as a function of cortical amyloid burden for both cohorts. Finally, we compared the temporal pattern of tau PET burden relative to that of amyloid. FINDINGS: We included 137 people with Down syndrome (mean age 38·5 years [SD 8·2], 74 [54%] male, and 63 [46%] female), 49 individuals with autosomal-dominant Alzheimer's disease (mean age 43·9 years [11·2], 22 [45%] male, and 27 [55%] female), and 85 familial controls, pooled from across both studies (mean age 41·5 years [12·1], 28 [33%] male, and 57 [67%] female), who satisfied the PET quality-control procedure for tau-PET imaging processing. 134 (98%) people with Down syndrome, 44 (90%) with autosomal-dominant Alzheimer's disease, and 77 (91%) controls also completed an amyloid PET scan within 3 years of tau PET imaging. Spatially, tau PET burden was observed most frequently in subcortical and medial temporal regions in people with Down syndrome, and within the medial temporal lobe in people with autosomal-dominant Alzheimer's disease. Across the brain, people with Down syndrome had greater concentrations of tau for a given level of amyloid compared with people with autosomal-dominant Alzheimer's disease. Temporally, increases in tau were more strongly associated with increases in amyloid for people with Down syndrome compared with autosomal-dominant Alzheimer's disease. INTERPRETATION: Although the general progression of amyloid followed by tau is similar for people Down syndrome and people with autosomal-dominant Alzheimer's disease, we found subtle differences in the spatial distribution, timing, and magnitude of the tau burden between these two cohorts. These differences might have important implications; differences in the temporal pattern of tau accumulation might influence the timing of drug administration in clinical trials, whereas differences in the spatial pattern and magnitude of tau burden might affect disease progression. FUNDING: None.

AT(N) biomarker profiles and Alzheimer's disease symptomology in Down syndrome.

INTRODUCTION: Down syndrome (DS) is a genetic cause of early-onset Alzheimer's disease (AD). The National Institute on Aging-Alzheimer's Association AT(N) Research Framework is a staging model for AD biomarkers but has not been assessed in DS. METHOD: Data are from the Alzheimer's Biomarker Consortium-Down Syndrome. Positron emission tomography (PET) amyloid beta (Aß; 15 mCi of [11 C]Pittsburgh compound B) and tau (10 mCi of [18 F]AV-1451) were used to classify amyloid (A) -/+ and tau (T) +/-. Hippocampal volume classified neurodegeneration (N) -/+. The modified Cued Recall Test assessed episodic memory. RESULTS: Analyses included 162 adults with DS (aged M = 38.84 years, standard deviation = 8.41). Overall, 69.8% of participants were classified as A-/T-/(N)-, 11.1% were A+/T-/(N)-, 5.6% were A+/T+/(N)-, and 9.3% were A+/T+/(N)+. Participants deemed cognitively stable were most likely to be A-T-(N)- and A+T-(N)-. Tau PET (T+) most closely aligning with memory impairment and AD clinical status. DISCUSSION: Findings add to understanding of AT(N) biomarker profiles in DS. HIGHLIGHTS: Overall, 69.8% of adults with Down syndrome (DS) aged 25 to 61 years were classified as amyloid (A)-/tau (T)-/neurodegeneration (N)-, 11.1% were A+/T-/(N)-, 5.6% were A+/T+/(N)-, and 9.3% were A+/T+/(N)+. The AT(N) profiles were associated with clinical Alzheimer's disease (AD) status and with memory performance, with the presence of T+ aligned with AD clinical symptomology. Findings inform models for predicting the transition to the prodromal stage of AD in DS.

Characterizing the emergence of amyloid and tau burden in Down syndrome.

INTRODUCTION: Almost all individuals with Down syndrome (DS) will develop neuropathological features of Alzheimer's disease (AD). Understanding AD biomarker trajectories is necessary for DS-specific clinical interventions and interpretation of drug-related changes in the disease trajectory. METHODS: A total of 177 adults with DS from the Alzheimer's Biomarker Consortium-Down Syndrome (ABC-DS) underwent positron emission tomography (PET) and MR imaging. Amyloid-beta (Aß) trajectories were modeled to provide individual-level estimates of Aß-positive (A+) chronicity, which were compared against longitudinal tau change. RESULTS: Elevated tau was observed in all NFT regions following A+ and longitudinal tau increased with respect to A+ chronicity. Tau increases in NFT regions I-III was observed 0-2.5 years following A+. Nearly all A+ individuals had tau increases in the medial temporal lobe. DISCUSSION: These findings highlight the rapid accumulation of amyloid and early onset of tau relative to amyloid in DS and provide a strategy for temporally characterizing AD neuropathology progression that is specific to the DS population and independent of chronological age. HIGHLIGHTS: Longitudinal amyloid trajectories reveal rapid Aß accumulation in Down syndrome NFT stage tau was strongly associated with A+ chronicity Early longitudinal tau increases were observed 2.5-5 years after reaching A.

Evaluation of an Image-Derived Input Function for Kinetic Modeling of Nicotinic Acetylcholine Receptor-Binding PET Ligands in Mice.

Positron emission tomography (PET) radioligands that bind with high-affinity to α4ß2-type nicotinic receptors (α4ß2Rs) allow for in vivo investigations of the mechanisms underlying nicotine addiction and smoking cessation. Here, we investigate the use of an image-derived arterial input function and the cerebellum for kinetic analysis of radioligand binding in mice. Two radioligands were explored: 2-[18F]FA85380 (2-FA), displaying similar pKa and binding affinity to the smoking cessation drug varenicline (Chantix), and [18F]Nifene, displaying similar pKa and binding affinity to nicotine. Time-activity curves of the left ventricle of the heart displayed similar distribution across wild type mice, mice lacking the ß2-subunit for ligand binding, and acute nicotine-treated mice, whereas reference tissue binding displayed high variation between groups. Binding potential estimated from a two-tissue compartment model fit of the data with the image-derived input function were higher than estimates from reference tissue-based estimations. Rate constants of radioligand dissociation were very slow for 2-FA and very fast for Nifene. We conclude that using an image-derived input function for kinetic modeling of nicotinic PET ligands provides suitable results compared to reference tissue-based methods and that the chemical properties of 2-FA and Nifene are suitable to study receptor response to nicotine addiction and smoking cessation therapies.

Trapping of Nicotinic Acetylcholine Receptor Ligands Assayed by In Vitro Cellular Studies and In Vivo PET Imaging.

A question relevant to nicotine addiction is how nicotine and other nicotinic receptor membrane-permeant ligands, such as the anti-smoking drug varenicline (Chantix), distribute in brain. Ligands, like varenicline, with high pKa and high affinity for α4ß2-type nicotinic receptors (α4ß2Rs) are trapped in intracellular acidic vesicles containing α4ß2Rs in vitro Nicotine, with lower pKa and α4ß2R affinity, is not trapped. Here, we extend our results by imaging nicotinic PET ligands in vivo in male and female mouse brain and identifying the trapping brain organelle in vitro as Golgi satellites (GSats). Two PET 18F-labeled imaging ligands were chosen: [18F]2-FA85380 (2-FA) with varenicline-like pKa and affinity and [18F]Nifene with nicotine-like pKa and affinity. [18F]2-FA PET-imaging kinetics were very slow consistent with 2-FA trapping in α4ß2R-containing GSats. In contrast, [18F]Nifene kinetics were rapid, consistent with its binding to α4ß2Rs but no trapping. Specific [18F]2-FA and [18F]Nifene signals were eliminated in ß2 subunit knock-out (KO) mice or by acute nicotine (AN) injections demonstrating binding to sites on ß2-containing receptors. Chloroquine (CQ), which dissipates GSat pH gradients, reduced [18F]2-FA distributions while having little effect on [18F]Nifene distributions in vivo consistent with only [18F]2-FA trapping in GSats. These results are further supported by in vitro findings where dissipation of GSat pH gradients blocks 2-FA trapping in GSats without affecting Nifene. By combining in vitro and in vivo imaging, we mapped both the brain-wide and subcellular distributions of weak-base nicotinic receptor ligands. We conclude that ligands, such as varenicline, are trapped in neurons in α4ß2R-containing GSats, which results in very slow release long after nicotine is gone after smoking.SIGNIFICANCE STATEMENT Mechanisms of nicotine addiction remain poorly understood. An earlier study using in vitro methods found that the anti-smoking nicotinic ligand, varenicline (Chantix) was trapped in α4ß2R-containing acidic vesicles. Using a fluorescent-labeled high-affinity nicotinic ligand, this study provided evidence that these intracellular acidic vesicles were α4ß2R-containing Golgi satellites (GSats). In vivo PET imaging with F-18-labeled nicotinic ligands provided additional evidence that differences in PET ligand trapping in acidic vesicles were the cause of differences in PET ligand kinetics and subcellular distributions. These findings combining in vitro and in vivo imaging revealed new mechanistic insights into the kinetics of weak base PET imaging ligands and the subcellular mechanisms underlying nicotine addiction.

Novel Strategies for Managing Retropharyngeal Lymph Node Metastases in Head and Neck and Thyroid Cancer with Transoral Robotic Surgery (TORS).

Retropharyngeal metastases are encountered in a variety of head and neck malignancies, imposing significant surgical challenges owing to their distinct location and proximity to neurovascular structures. Radiotherapy is the recommended treatment in most cases owing to its oncological efficacy. However, retropharyngeal irradiation affects the superior pharyngeal constrictor muscles and parotid glands, with the potential for long-term dysphagia and xerostomia. A younger oropharyngeal and thyroid cancer patient demographic is trending, fueling interest in treatment de-escalation strategies. Consequently, reducing radiotoxicity and its long-term effects is of special relevance in modern head and neck oncology practice. Through its unique ability to safely extirpate these traditionally difficult-to-access retropharyngeal lymph nodes via a natural orifice, TransOral Robotic Surgery (TORS) can considerably lower the surgical morbidity of retropharyngeal lymph node dissection (RPLND), compared with current existing approaches. This review summarizes the latest developments in the field, exposing current research gaps and discusses specific clinical settings where TORS could enable treatment de-escalation. In early-stage node-negative oropharyngeal cancer, single-modality surgical treatment with TORS RPLND may improve risk stratification of metastasis and recurrence in this region. TORS RPLND is also a potentially viable treatment option in salvage of an isolated retropharyngeal node recurrence or in the primary setting of a thyroid malignancy with a single positive retropharyngeal node. In time, TORS RPLND may provide an alternative de-escalation strategy in these three scenarios. However, with the reported morbidities, further prospective trials with long-term follow-up data are required to prove oncological safety and functional benefits over existing strategies.

Role of tau deposition in early cognitive decline in Down syndrome.

Introduction: Drawing on the amyloid/tau/neurodegeneration (AT[N]) model, the study examined whether the tau positron emission tomography (PET) biomarker [18F]AV-1451 was associated with episodic memory problems beyond what was predicted by the amyloid beta (Aß) PET in Down syndrome (DS). Methods: Data from 123 non-demented adults with DS (M  = 47 years, standard deviation = 6.34) were analyzed. The Cued Recall Test assessed episodic memory. Tau PET standardized update value ratio (SUVR) was assessed across Braak regions as continuous and binary (high tau [TH] vs. low tau [TL]) variable. Global PET Aß SUVR was assessed as binary variable (Aß- vs. Aß+). Results: In models adjusting for controls, tau SUVR was negatively associated with episodic memory performance in the Aß+ but not Aß- group. The Aß+/TH group evidenced significantly worse episodic memory than the Aß+/TL group. Discussion: Similar to late-onset and autosomal dominant Alzheimer's disease (AD), high tau was an indicator of early prodromal AD in DS.

Challenging NICE guidelines on parathyroid surgery.

BACKGROUND: National Institute of Clinical Excellence (NICE) recommend against routinely using Intra-Operative Parathyroid Hormone (IOPTH) for first-time parathyroid surgery due to its cost and minimal surgical benefit. The European Society of Endocrine Surgeons differ from this and recommends IOPTH with conflicting pre-operative or single imaging. NICE guidance acknowledged that this may change practice in larger centres. We devised a retrospective single-centre cohort study to analyse the impact of IOPTH on decision-making and cost-effectiveness. METHODOLOGY: First-time parathyroidectomy procedures for primary hyperparathyroidism were assessed between 2017 and 2019. Ultrasound (US) and Sestamibi with parathyroid single-photon emission with computed tomography (SPECT-CT) were compared with IOPTH. The contribution of IOPTH to cure and cost effectiveness ratio was calculated. RESULTS: 114 cases were included, with IOPTH performed in all cases, SPECT-CT in 112 and US in 108 cases. A cure rate of 99.1% (113/114) was achieved. 11.4% (13/114) of the cure rate was influenced by IOPTH (P 0.01), instigating further exploration when its levels didn't decrease. This included 7.1% (4/56) in the concordant-imaging cohort. IOPTH accuracy (96.5%) was significantly superior (P = 0.03) to both US (80%) and SPECT-CT (81%). Comparing the total costs for IOPTH testing over 2 years (£39,721) with 13 potential re-operative procedures in its absence (£63,536), a positive cost-effectiveness ratio of £1832 per re-operative procedure averted was achieved. CONCLUSION: Abandoning IOPTH in first-time parathyroid surgery is too ambitious when weighing the cost of re-operative surgery against cost savings obtained by using routine IOPTH to achieve an improved cure rate, even in concordant imaging.

White matter microstructure associations to amyloid burden in adults with Down syndrome.

INTRODUCTION: Individuals with Down syndrome (DS) are at an increased risk of developing Alzheimer's Disease (AD). One of the early underlying mechanisms in AD pathology is the accumulation of amyloid protein plaques, which are deposited in extracellular gray matter and signify the first stage in the cascade of neurodegenerative events. AD-related neurodegeneration is also evidenced as microstructural changes in white matter. In this work, we explored the correlation of white matter microstructure with amyloid load to assess amyloid-related neurodegeneration in a cohort of adults with DS. METHODS: In this study of 96 adults with DS, the relation of white matter microstructure using diffusion tensor imaging (DTI) and amyloid plaque burden using [11C]PiB PET were examined. The amyloid load (AßL) derived from [11C]PiB was used as a global measure of amyloid burden. AßL and DTI measures were compared using tract-based spatial statistics (TBSS) and corrected for imaging site and chronological age. RESULTS: TBSS of the DTI maps showed widespread age-by-amyloid interaction with both fractional anisotropy (FA) and mean diffusivity (MD). Further, diffuse negative association of FA and positive association of MD with amyloid were observed. DISCUSSION: These findings are consistent with the white matter microstructural changes associated with AD disease progression in late onset AD in non-DS populations.

Sleep and White Matter in Adults with Down Syndrome.

Adults with Down syndrome are at a high risk for disordered sleep. These sleep problems could have marked effects on aging and Alzheimer's disease, potentially altering white matter integrity. This study examined the associations between disordered sleep assessed via an actigraph accelerometer worn on 7 consecutive nights, presence of diagnosis of obstructive sleep apnea, and diffusion tensor imaging indices of white matter integrity in 29 non-demented adults with Down Syndrome (48% female, aged 33-54 years). Average total sleep time was associated with lower mean diffusivity in the left superior longitudinal fasciculus (r = -0.398, p = 0.040). Average sleep efficiency, length of awakenings, and movement index were related to fractional anisotropy in the right inferior longitudinal fasciculus (r = -0.614 to 0.387, p ≤ 0.050). Diagnosis of obstructive sleep apnea was associated with fractional anisotropy in the right inferior longitudinal fasciculus (r = -0.373, p = 0.050). Findings suggest that more disrupted sleep is associated with lower white matter integrity in the major association tracts in middle-aged adults with Down syndrome. Longitudinal work is needed to confirm the directionally of associations. Sleep interventions could be an important component for promoting optimal brain aging in the Down syndrome population.

Corrigendum: Basal Forebrain Cholinergic Neurons: Linking Down Syndrome and Alzheimer's Disease.

[This corrects the article DOI: 10.3389/fnagi.2021.703876.].

Physical activity and cognitive and imaging biomarkers of Alzheimer's disease in down syndrome.

Adults with Down syndrome (DS) are at risk for Alzheimer's disease. Despite sharing trisomy 21, however, there is variability in the age of disease onset. This variability may mean that other factors, such as lifestyle, influence cognitive aging and disease timing. The present study assessed the association between everyday life physical activity using an actigraph accelerometer and cognitive functioning and early Alzheimer's disease pathology via positron emission tomography amyloid-ß and tau and diffusion tension imaging measures of white matter integrity in 61 non-demented adults with DS. Percent time in sedentary behavior and in moderate-to-vigorous activity were associated (negatively and positively, respectively) with cognitive functioning (r = -.472 to .572, p < 0.05). Neither sedentary behavior nor moderate-to-vigorous activity were associated with amyloid-ß or tau, but both were associated with white matter integrity in the superior and inferior longitudinal fasciculus (Fractional Anisotropy: r = -.397 to -.419, p < 0.05; Mean Diffusivity: r = .400, p < 0.05). Longitudinal studies are needed to determine if physical activity promotes healthy aging in DS.

The prevalence of oropharyngeal squamous cell carcinoma in patients admitted with symptoms of peritonsillar abscess or cellulitis: A retrospective multicentre study.

OBJECTIVES: Anecdotal evidence suggests that oropharyngeal squamous cell carcinoma (OPSCC) should be suspected in patients presenting with symptoms of peritonsillar abscess (PTA) or cellulitis (PTC). The aim of this study was to estimate the prevalence of OPSCC in patients presenting with symptoms of PTA/PTC. METHOD, SETTING AND PARTICIPANTS: We retrospectively identified all adults with a coded diagnosis of PTA or PTC who presented between 2012 and 2016 inclusive, across six ENT units in Merseyside. Records were compared to that of the centralised regional head and neck cancer database. The clinical records of a subset of patients were reviewed for the purposes of data validation. RESULTS: A total of 1975 patients with PTA/PTC were identified. Three patients were subsequently diagnosed with OPSCC. None of the three actually had an objective underlying diagnosis of PTA/PTC on the same side. The prevalence of OPSCC in patients admitted with symptoms of PTA/PTC was 0.15% or approximately 1:650 admissions. The records of 510 patients who presented over a one-year period (2016) were reviewed in even greater detail. There were 298 patients with PTA (59.4%) and 151 with PTC (29.1%) and 61 had an alternative diagnosis (11.9%). High-risk features (age ≥40, tonsillar asymmetry or tonsillar lesion) were present in 106 patients (24%). Urgent follow-up was expedited for 77 patients (73%). CONCLUSION: This study estimates the risk of OPSCC in patients with peritonsillar symptoms. The prevalence is low, even in a region with a relatively heavy disease burden. Clinicians should, however, retain a high level of suspicion in patients with persistent symptoms.

Basal Forebrain Cholinergic Neurons: Linking Down Syndrome and Alzheimer's Disease.

Down syndrome (DS, trisomy 21) is characterized by intellectual impairment at birth and Alzheimer's disease (AD) pathology in middle age. As individuals with DS age, their cognitive functions decline as they develop AD pathology. The susceptibility to degeneration of a subset of neurons, known as basal forebrain cholinergic neurons (BFCNs), in DS and AD is a critical link between cognitive impairment and neurodegeneration in both disorders. BFCNs are the primary source of cholinergic innervation to the cerebral cortex and hippocampus, as well as the amygdala. They play a critical role in the processing of information related to cognitive function and are directly engaged in regulating circuits of attention and memory throughout the lifespan. Given the importance of BFCNs in attention and memory, it is not surprising that these neurons contribute to dysfunctional neuronal circuitry in DS and are vulnerable in adults with DS and AD, where their degeneration leads to memory loss and disturbance in language. BFCNs are thus a relevant cell target for therapeutics for both DS and AD but, despite some success, efforts in this area have waned. There are gaps in our knowledge of BFCN vulnerability that preclude our ability to effectively design interventions. Here, we review the role of BFCN function and degeneration in AD and DS and identify under-studied aspects of BFCN biology. The current gaps in BFCN relevant imaging studies, therapeutics, and human models limit our insight into the mechanistic vulnerability of BFCNs in individuals with DS and AD.

Neurofibrillary tau depositions emerge with subthreshold cerebral beta-amyloidosis in down syndrome.

INTRODUCTION: Adults with Down syndrome are genetically predisposed to develop Alzheimer's disease and accumulate beta-amyloid plaques (Aß) early in life. While Aß has been heavily studied in Down syndrome, its relationship with neurofibrillary tau is less understood. The aim of this study was to evaluate neurofibrillary tau deposition in individuals with Down syndrome with varying levels of Aß burden. METHODS: A total of 161 adults with Down syndrome (mean age = 39.2 (8.50) years) and 40 healthy, non-Down syndrome sibling controls (43.2 (12.6) years) underwent T1w-MRI, [C-11]PiB and [F-18]AV-1451 PET scans. PET images were converted to units of standardized uptake value ratios (SUVrs). Aß burden was calculated using the amyloid load metric (AßL); a measure of global Aß burden that improves quantification from SUVrs by suppressing the nonspecific binding signal component and computing the specific Aß signal from all Aß-carrying voxels from the image. Regional tau was assessed using control-standardized AV-1451 SUVr. Control-standardized SUVrs were compared across Down syndrome groups of Aß-negative (A-) (AßL < 13.3), subthreshold A+ (13.3 ≤ AßL < 20) and conventionally A+ (AßL ≥ 20) individuals. The subthreshold A + group was identified as having significantly higher Aß burden compared to the A- group, but not high enough to satisfy a conventional A + classification. RESULTS: A large-sized association that survived adjustment for chronological age, mental age (assessed using the Peabody Picture Vocabulary Test), and imaging site was observed between AßL and AV-1451 within each Braak region (p < .05). The A + group showed significantly higher AV-1451 retention across all Braak regions compared to the A- and subthreshold A + groups (p < .05). The subthreshold A + group showed significantly higher AV-1451 retention in Braak regions I-III compared to an age-matched sample from the A- group (p < .05). DISCUSSION: These results show that even the earliest detectable Aß accumulation in Down syndrome is accompanied by elevated tau in the early Braak stage regions. This early detection of tau can help characterize the tau accumulation phase during preclinical Alzheimer's disease progression in Down syndrome and suggests that there may be a relatively narrow window after Aß accumulation begins to prevent the downstream cascade of events that leads to Alzheimer's disease.

White matter microstructure associations with episodic memory in adults with Down syndrome: a tract-based spatial statistics study.

BACKGROUND: Nearly all persons with Down syndrome will show pathology of Alzheimer's disease in their 40s. There is a critical need for studies to identify early biomarkers of these various pathological changes of Alzheimer's disease in the Down syndrome population and understand the relationship of these biomarkers to cognitive symptoms in order to inform clinical trials. Although Alzheimer's disease is often considered a disease of gray matter, white matter degeneration has been documented during the preclinical stage of Alzheimer's disease. The current study examined the association between diffusion tensor imaging (DTI) measures of white matter microstructure and episodic memory performance in 52 adults with Down syndrome. METHODS: Seventy (N = 70) participants (M = 40.13, SD = 7.77 years) received baseline scans as part of the Neurodegeneration in Aging Down Syndrome (NiAD) study at two imaging facilities (36 at the University of Wisconsin-Madison [UW-Madison] and 34 at the University of Pittsburgh Medical Center [UPMC]). All participants had genetically confirmed trisomy 21. Fifty-two (N = 52) participants remained after QC. The DTI measures, fractional anisotropy (FA) and mean diffusivity (MD), were calculated for each participant. A combined measure of episodic memory was generated by summing the z-scores of (1) Free and Cued Recall test and (2) Rivermead Behavioural Memory Test for Children Picture Recognition. The DTI data were projected onto a population-derived FA skeleton and tract-based spatial statistics analysis was conducted using the FSL tool PALM to calculate Pearson's r values between FA and MD with episodic memory. RESULTS: A positive correlation of episodic memory with FA and a negative correlation of episodic memory and MD in the major association white matter tracts were observed. Results were significant (p < 0.05) after correction for chronological age, imaging site, and premorbid cognitive ability. CONCLUSION: These findings suggest that white matter degeneration may be implicated in early episodic memory declines prior to the onset of dementia in adults with Down syndrome. Further, our findings suggest a coupling of episodic memory and white matter microstructure independent of chronological age.

Autologous transplant therapy alleviates motor and depressive behaviors in parkinsonian monkeys.

Degeneration of dopamine (DA) neurons in the midbrain underlies the pathogenesis of Parkinson's disease (PD). Supplement of DA via L-DOPA alleviates motor symptoms but does not prevent the progressive loss of DA neurons. A large body of experimental studies, including those in nonhuman primates, demonstrates that transplantation of fetal mesencephalic tissues improves motor symptoms in animals, which culminated in open-label and double-blinded clinical trials of fetal tissue transplantation for PD1. Unfortunately, the outcomes are mixed, primarily due to the undefined and unstandardized donor tissues1,2. Generation of induced pluripotent stem cells enables standardized and autologous transplantation therapy for PD. However, its efficacy, especially in primates, remains unclear. Here we show that over a 2-year period without immunosuppression, PD monkeys receiving autologous, but not allogenic, transplantation exhibited recovery from motor and depressive signs. These behavioral improvements were accompanied by robust grafts with extensive DA neuron axon growth as well as strong DA activity in positron emission tomography (PET). Mathematical modeling reveals correlations between the number of surviving DA neurons with PET signal intensity and behavior recovery regardless autologous or allogeneic transplant, suggesting a predictive power of PET and motor behaviors for surviving DA neuron number.