Absence Of Amyloid Research Articles

Familial Alzheimer's Disease Neurons Bearing Mutations in PSEN1 Display Increased Calcium Responses to AMPA as an Early Calcium Dysregulation Phenotype.

Familial Alzheimer's disease (FAD) can be caused by mutations in PSEN1 that encode presenilin-1, a component of the gamma-secretase complex that cleaves amyloid precursor protein. Alterations in calcium (Ca2+) homeostasis and glutamate signaling are implicated in the pathogenesis of FAD; however, it has been difficult to assess in humans whether or not these phenotypes are the result of amyloid or tau pathology. This study aimed to assess the early calcium and glutamate phenotypes of FAD by measuring the Ca2+ response of induced pluripotent stem cell (iPSC)-derived neurons bearing PSEN1 mutations to glutamate and the ionotropic glutamate receptor agonists NMDA, AMPA, and kainate compared to isogenic control and healthy lines. The data show that in early neurons, even in the absence of amyloid and tau phenotypes, FAD neurons exhibit increased Ca2+ responses to glutamate and AMPA, but not NMDA or kainate. Together, this suggests that PSEN1 mutations alter Ca2+ and glutamate signaling as an early phenotype of FAD.

APOE3ch alters microglial response and suppresses Aβ-induced tau seeding and spread

A recent case report described an individual who was a homozygous carrier of the APOE3 Christchurch (APOE3ch) mutation and resistant to autosomal dominant Alzheimer's Disease (AD) caused by a PSEN1-E280A mutation. Whether APOE3ch contributed to the protective effect remains unclear. We generated a humanized APOE3ch knock-in mouse and crossed it to an amyloid-β (Aβ) plaque-depositing model. We injected AD-tau brain extract to investigate tau seeding and spreading in the presence or absence of amyloid. Similar to the case report, APOE3ch expression resulted in peripheral dyslipidemia and a marked reduction in plaque-associated tau pathology. Additionally, we observed decreased amyloid response and enhanced microglial response around plaques. We also demonstrate increased myeloid cell phagocytosis and degradation of tau aggregates linked to weaker APOE3ch binding to heparin sulfate proteoglycans. APOE3ch influences the microglial response to Aβ plaques, which suppresses Aβ-induced tau seeding and spreading. The results reveal new possibilities to target Aβ-induced tauopathy.

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

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

Posterior Primary Progressive Prosopagnosia: Imaging and Neuropathology

AbstractBackgroundProsopagnosia is common with right temporal lesions, often in the fusiform gyrus when caused by vascular pathology. When caused by frontotemporal dementia, the lesion typically begins in the temporal tip. We are reporting advanced imaging, including tau and inflammation, as well as neuropathology in a patient with pathology centered at the posterior extent of the fusiform gyrus.MethodA 69‐year‐old man with apperceptive prosopagnosia and a negative amyloid positron emission tomogram (PET) underwent MRI and PET using 11C‐PBR28, an inflammation tracer, and 18F‐flortaucipir. V T values for 11C‐PBR28 were calculated with the Logan plot and a metabolite‐corrected arterial input function. For 18F‐flortaucipir, the SUV ratio over the cerebellar gray matter was calculated for t = 80‐100 min. A neuropathological examination was conducted using standard procedures as well as phospho‐tau histochemistry.ResultAtrophy and 18F‐flortaucipir uptake involved a similar region at the posterior extent of the right fusiform gyrus and, minimally, a symmetrical region of the left fusiform gyrus and an area in right premotor cortex. Involving the same regions, the 11C‐PBR28 signal was however more extensive than atrophy or 18F‐flortaucipir signal. At autopsy, the patient had corticobasal degeneration (CBD), with severe 4R tau involvement of temporo‐occipital, inferior parietal, and frontal cortices, as well as limbic regions and subcortical nuclei. The location of CBD pathology in this patient was highly atypical, as shown by comparing the neuropathological findings with the findings in two typical CBD patients.ConclusionAlthough prosopagnosia from ischemic and other lesions in the right posterior temporo‐occipital region is common, primary progressive prosopagnosia in the absence of amyloid has been described mostly with involvement of the right anterior temporal region. As exemplified by our patient, it can rarely happen with posterior temporal involvement and in this case the pathology was not TDP‐43 type C, as present in most patients with anterior temporal involvement, but corticobasal degeneration, a 4R tauopathy.

Posterior Primary Progressive Prosopagnosia: Imaging and Neuropathology

AbstractBackgroundProsopagnosia is common with right temporal lesions, often in the fusiform gyrus when caused by vascular pathology. When caused by frontotemporal dementia, the lesion typically begins in the temporal tip. We are reporting advanced imaging, including tau and inflammation, as well as neuropathology in a patient with pathology centered at the posterior extent of the fusiform gyrus.MethodA 69‐year‐old man with apperceptive prosopagnosia and a negative amyloid positron emission tomogram (PET) underwent MRI and PET using 11C‐PBR28, an inflammation tracer, and 18F‐flortaucipir. VT values for 11C‐PBR28 were calculated with the Logan plot and a metabolite‐corrected arterial input function. For 18F‐flortaucipir, the SUV ratio over the cerebellar gray matter was calculated for t = 80‐100 min. A neuropathological examination was conducted using standard procedures as well as phospho‐tau histochemistry.ResultAtrophy and 18F‐flortaucipir uptake involved a similar region at the posterior extent of the right fusiform gyrus and, minimally, a symmetrical region of the left fusiform gyrus and an area in right premotor cortex. Involving the same regions, the 11C‐PBR28 signal was however more extensive than atrophy or 18F‐flortaucipir signal. At autopsy, the patient had corticobasal degeneration (CBD), with severe 4R tau involvement of temporo‐occipital, inferior parietal, and frontal cortices, as well as limbic regions and subcortical nuclei. The location of CBD pathology in this patient was highly atypical, as shown by comparing the neuropathological findings with the findings in two typical CBD patients.ConclusionAlthough prosopagnosia from ischemic and other lesions in the right posterior temporo‐occipital region is common, primary progressive prosopagnosia in the absence of amyloid has been described mostly with involvement of the right anterior temporal region. As exemplified by our patient, it can rarely happen with posterior temporal involvement and in this case the pathology was not TDP‐43 type C, as present in most patients with anterior temporal involvement, but corticobasal degeneration, a 4R tauopathy.

A more natural context: Variation in mouse background improves models of vascular contributions to Alzheimer’s disease

AbstractBackgroundInitial research focused on vascular contributions to dementia often categorized these pathologies as not relevant to Alzheimer’s disease (AD). Patients that presented with vascular pathologies would commonly be excluded from clinical studies and trials of AD. Recently, these vascular contributions have become more appreciated. A number of studies have identified vascular factors either contribute to, or result from central AD hallmarks such as amyloid and tau pathology, and glial cell dysregulation. A number of genetic risk factors for AD are also centered on vascular cells and function. Unfortunately, current mouse models are limited in their presentation of vascular pathologies, and require introduction of other interventions such as diet‐induced obesity or middle cerebral artery occlusion.MethodOur group performed a strain survey using amyloid drivers. APP/PS1 transgenes were backcrossed from C57BL/6J to nine strains including wild‐derived WSB/EiJ, PWK/PhJ and CAST/EiJ. All strains were assessed for cerebral amyloid angiopathy (CAA) as this vascular pathology is common in AD cases.ResultWSB/EiJ showed the highest incidence of CAA, accompanied by indications of vascular leakage and damage. Male and female WSB.APP/PS1 and WSB mice were then aged from 4 to 18 months. Amyloid deposits co‐localized with astrocyte processes, but were devoid of microglia and collagen. Brain transcriptional profiling comparing differences between WSB and B6 context identified significant differences in gene expression relating to vascular health including basement membrane, endothelial function and blood vessel formation. Furthermore, upon examination of aged WSB, microbleeds were present even in the absence of amyloid. Single‐cell sequencing of WSB‐microglia states identified a signification proportion of homeostatic microglia enriched for expression of P2ry12 present in WSB but not WSB.APP/PS1. As P2RY12‐mediated chemotaxis is critical for closure of the blood brain barrier (BBB) after injury, these microglia may be central to BBB health in the WSB context. Further work is being performed to determine whether differences in microglia states, vascular integrity or metabolic dysfunction contribute to significant development of CAA present in WSB/EiJ.ConclusionThe WSB genetic context provides a new platform to dissect vascular contributions to AD. Other factors such as humanized amyloid, tau, and apolipoprotein E are also being examined.

Characteristics of primary age‐related tauopathy defined by neuroimaging biomarkers

AbstractBackgroundPrimary age‐related tauopathy (PART) is a neuropathological entity with neurofibrillary tangles (NFTs) in the absence of amyloid (Aβ) plaques in the brain. Recent advance of neuroimaging makes it possible to identify PART in living human brain. We tried to investigate the frequency and clinical characteristics including rate of cognitive decline of non‐demented older adults with PART defined by neuroimaging biomarkers.MethodA total of 113 non‐demented older individuals recruited from the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer’s Disease (KBASE) were included in the analysis. All participants underwent [11C] PiB PET and [18F] AV‐1451 PET with comprehensive clinical assessment. Global cognition was measured annually using MMSE, from 2 years before to 2 years after the PET scans. PART was defined when beta‐amyloid deposition is negative and tau burden corresponds to Braak stage I‐IV.ResultAmong 113 participants, 40 (35.4%) were classified as PART, 29 (25.7%) as no Alzheimer's disease (AD)‐ pathology (amyloid‐negative, Tau Braak stage 0), and 44 (38.9%) as AD (amyloid‐positive). Compared to PART and no‐AD associated pathology group, AD group had higher apolipoprotein E ε4 positivity (13.8%, 12.5%, and 59.1% for PART, no‐AD pathology, and AD, respectively). In regard of cognitive decline rate over 4 years, PART was similar to no‐AD pathology, but significantly slower than AD.ConclusionOur findings indicate that PART is relatively common in non‐demented older adults. In regard of genetic risk and progression rate, PART appears closer to no‐AD pathology condition rather than AD.

Modeling functional and structural brain‐predicted age in relation to Alzheimer disease and cognition

AbstractBackgroundEstimates of “brain‐predicted age” quantify apparent brain age compared to normative trajectories of neuroimaging features. Brain‐predicted age is elevated in symptomatic Alzheimer disease (AD), but is underexplored in preclinical AD. Prior studies have typically modeled brain‐predicted age with volumetric magnetic resonance imaging (MRI), but other modalities, including resting‐state functional connectivity (FC) and multimodal MRI, have more recently been explored. In the present study, we tested the sensitivity of brain‐age predictions derived from volumetric, FC, and multimodal MRI to group differences in AD status and individual differences in cognition.MethodWe trained three Gaussian process regression models to predict age from (1) FC, (2) regional brain volumes, and (3) multimodal MRI (FC+volumetric) in 493 control participants (cognitively normal, amyloid‐negative [A‐], 18‐89 years old). We applied the trained models to independent samples staged by the presence or absence of amyloid (A+/A‐) and tau (T+/T‐) using PET (Centiloid) and CSF (amyloid β‐42/40 ratio, phosphorylated tau 181): 122 A‐T‐, 62 A+T‐, 62 A+T+, as well as 154 symptomatic AD participants. Global cognition was assessed using an established composite of cognitive tests across multiple domains.ResultAll models successfully predicted age in the control training set, with the multimodal model (mean absolute error [MAE]=5.3 years) outperforming the unimodal volumetric (MAE=6.0 years) and FC models (MAE=8.3 years) (Figure 1). In all three models, the brain age gap (BAG) was significantly elevated in symptomatic AD compared to cognitively normal controls. In the FC and multimodal models, the BAG was significantly reduced in A+T+ participants compared to T‐ controls (Figure 2). In symptomatic AD, lower global cognitive composite scores were associated with elevated volumetric and multimodal BAGs (Figure 3).ConclusionBoth FC and volumetric estimates of brain age are sensitive to symptomatic AD, consistent with previous reports. Additionally, FC‐based brain age may exhibit a biphasic response to preclinical AD pathology while volumetric brain age may be sensitive to cognitive decline in the symptomatic stage. Multimodal estimates of brain age capture each of these modality‐specific relationships, and further, improve sensitivity to healthy age differences. Hence, multimodal neuroimaging models may be useful in staging early symptomatic and preclinical AD.

Incorporation of plasma biomarkers for screening and diagnosis in primary care

AbstractBackgroundPlasma biomarkers that reflect Alzheimer’s neuropathological changes are under FDA consideration for approval as diagnostic tests. Their use in primary care will become feasible, and it will be difficult to limit biomarker screening to symptomatic or high risk individuals, especially as symptoms of cognitive decline are often nonspecific.MethodsAs members of the NIA Advisory Group on Risk Evidence Education for Dementia (AGREED), we have examined analytics of AD biomarkers in asymptomatic and symptomatic contexts, as well as language used in disclosure of biomarker results in research studies. We review recent data and describe key issues in plasma screening for Alzheimer’s Disease in primary care and propose directions for future research.ResultsCritical issues include: 1. Assessing accuracy of biomarker(s) measurement, and sensitivity and specificity of cutoffs to determine presence or absence of amyloid or other AD pathology. 2. Recognizing the critical need to study biomarkers in population‐based settings and among under‐represented individuals to understand factors that may modify cutoffs and normative data, e.g., age, sex, ethnicity, renal and hepatic function. 3. Data and models regarding the value of amyloid positivity to predict the development of Mild Cognitive Impairment (MCI) or dementia in asymptomatic individuals, and for progression of MCI to dementia. 4. Disclosure of APOE genotype if it is part of a biomarker risk algorithm. 5. Selecting nuanced language for describing positive, negative or indeterminate biomarker results, with clear explanations of what the tests measure, and risks associated with positive or negative results. 6. Current plasma biomarkers do not measure other pathologies and cognitions that may contribute to MCI and dementia, e.g., a‐synuclein, TDP43 or vascular pathology; depression, medical comorbidities, sleep disorders or medications that may adversely impact cognition. Together with biomarker results, the impact of these factors on cognition should be considered and discussed. 7. Screening for cognition is underdeveloped, limited by the types of tests currently used for screening and the time typically available to assess patients in primary care.ConclusionsFurther research on these topics and support and education of primary care providers is essential for the deployment of blood‐based biomarkers in primary care.

A-252 A Suspected Case Of Limbic-Predominant Age-Related TDP-43 Encephalopathy (LATE) in an Older Adult

Abstract Objective: LATE is a common but underrecognized neuropathology that causes a progressive amnestic syndrome in older adults which mimics an Alzheimer’s disease (AD) clinical profile. Method: A 75-year-old female with a history of progressive cognitive impairment presented to a multidisciplinary neurology clinic. Neurocognitive screening during her neurological exam showed an amnestic memory profile. A work-up for medical causes for her cognitive impairment was negative. She had prominent hippocampal atrophy on MRI with a negative amyloid PET scan, raising concerns for LATE. She was referred for a comprehensive neuropsychological evaluation. Results: Neuropsychological testing confirmed an amnestic mild dementia profile in the context of her other cognitive skills (e.g., attention, executive functioning, processing speed, word finding, and visuospatial abilities) being largely preserved. On self-report questionnaires, the patient denied having any significant symptoms of depression or anxiety. Conclusions: LATE is described as causing a primarily amnestic neurocognitive profile with associated hippocampal atrophy and this was well demonstrated in our patient. While the diagnosis of LATE cannot be definitively made until autopsy, the absence of amyloid on her PET scan highly suggests a non-AD pathology like LATE. A limitation of the evaluation is that tau biomarker tests were not performed, making primary age-related tauopathy (PART) another possible pathology or co-pathology. Overall, this case study illustrates the importance of multidisciplinary assessment to help facilitate differential diagnosis for neurodegenerative conditions associated with amnestic cognitive impairment, especially when a non-AD pathology is suspected.

Application of histopathologically derived 3D tau burden map as in‐vivo region of interest for biomarker analysis

AbstractBackgroundQuantitative three‐dimensional maps of tau neurofibrillary tangles (NFT) burden derived from dense serial histology have potential application for in‐vivo biomarker studies. We constructed a group‐level NFT burden map from 15 medial temporal lobe (MTL) specimens, majority with Primary Age‐Related Tauopathy (PART) or low‐level Alzheimer’s disease neuropathologic change, and showed relatively greater NFT burden in the anterior vs. posterior MTL. We investigated whether in‐vivo MRI and PET measures in ROIs derived from this map show meaningful biological relationships.MethodMultimodal in‐vivo imaging data from 292 participants in the Aging Brain Cohort were used. The group‐level NFT burden map was mapped to each participant’s MRI to define an ROI mask, further divided into anterior (aMTL) and posterior (pMTL) ROIs. Cortical thickness (N=292) and 18F‐Flortaucipir SUVR maps (N=86) were computed. Participants’ age was correlated with average thickness in the aMTL, pMTL, and anatomically defined MTL ROIs. 18F‐Flortaucipir uptake was compared between aMTL and pMTL. The analyses were repeated in subsets of cognitive normal participants, and those with negative amyloid PET scans.ResultCortical thickness in the aMTL ROI showed stronger correlation with age than pMTL and anatomically defined MTL subregional thickness. A polynomial fit provided the best age regression, with older participants showing a parabolic decline in thickness around age 60, when substantial NFT accumulation begins in MTL. Further, tau tracer uptake in aMTL was slightly but significantly higher than in pMTL (SUVR 1.19 vs. 1.18, p=0.02).ConclusionWe demonstrate the potential use of ex‐vivo NFT burden maps for in‐vivo image analysis. NFT deposition is particularly prominent in the anterior MTL in cases without or with low amyloid burden and at early Braak stage. Prior work suggests that even in the absence of amyloid, this tangle pathology may drive neurodegeneration in the aging population. Here we show that cortical thickness, a biormarker for neurodegeneration, when measured within a histopathologically‐defined region enriched for PART NFTs in the aMTL, is better correlated with age than when measured within anatomically defined subregions, suggesting that the relationship may be driven by PART. Greater tau tracer uptake in the aMTL ROI further supports this notion.

Evidence for the progression of tau and neurodegeneration beyond the medial temporal lobe in amyloid-negative older adults.

Despite the important role of tau in Alzheimer's disease (AD), tau in the absence of amyloid (Aβ) is typically considered as separable from the AD continuum. Our previous research demonstrated a high proportion of elevated tau PET (Braak stage I/II) in the context of normal Aβ PET, and that this group exhibited subtle cognitive deficits. Here we extend these findings to investigate whether there also exists a subset of amyloid negative individuals who have progressed in their tauopathy to Braak stage III/IV. A sample of 467 older adults across the AD clinical spectrum from the Alzheimer's Disease Neuroimaging Initiative who had concurrent Aβ and tau PET data were included. Participants were categorized as positive or negative for cortical Aβ (A) and tau Braak stage III/IV (T34) PET and fell into one of four groups: A-/T34-, A+/T34-, A-/T34+, A+/T34+. Resultant groups were compared on demographic factors, apolipoprotein E (APOE) genetic risk, vascular risk (i.e., pulse pressure), and volume/cortical thickness (n = 300) of the hippocampus, inferior temporal gyrus, and inferior parietal lobe. The following proportions were observed: 54% A-/T34-, 19% A+/T34-, 5% A-/T34+, and 22% A+/T34+. Specifically, 23 individuals had elevated Braak III/IV tau PET in the absence of cortical Ab. This A-/T34+ group did not differ from other groups in age, sex, or pulse pressure, but did have a lower proportion of APOE ε4 carriers. Further, the A-/T34+ group did not differ from the A+/T34+ group on any measures of volume/cortical thickness but had lower volume/thickness than both T34- groups. These findings suggest that tau pathology can extend beyond the medial temporal lobe in the continued absence of Aβ and exert the same degree of neurodegenerative effects as if Aβ were present. Regardless of the classification of these individuals in relation to current definitional nosologies for AD (see Jack et al. 2020), tau appears capable of progressing through Braak stages I-IV in a malignant manner independent of Aβ, exerting similar neurodegenerative effects observed as one advances along the AD continuum. Results highlight the need to target tau-only individuals in clinical treatment trials and the deleterious consequences of excluding such individuals.

Downstream effects of polypathology on neurodegeneration of medial temporal lobe subregions

The medial temporal lobe (MTL) is a nidus for neurodegenerative pathologies and therefore an important region in which to study polypathology. We investigated associations between neurodegenerative pathologies and the thickness of different MTL subregions measured using high-resolution post-mortem MRI. Tau, TAR DNA-binding protein 43 (TDP-43), amyloid-β and α-synuclein pathology were rated on a scale of 0 (absent)—3 (severe) in the hippocampus and entorhinal cortex (ERC) of 58 individuals with and without neurodegenerative diseases (median age 75.0 years, 60.3% male). Thickness measurements in ERC, Brodmann Area (BA) 35 and 36, parahippocampal cortex, subiculum, cornu ammonis (CA)1 and the stratum radiatum lacunosum moleculare (SRLM) were derived from 0.2 × 0.2 × 0.2 mm3 post-mortem MRI scans of excised MTL specimens from the contralateral hemisphere using a semi-automated approach. Spearman’s rank correlations were performed between neurodegenerative pathologies and thickness, correcting for age, sex and hemisphere, including all four proteinopathies in the model. We found significant associations of (1) TDP-43 with thickness in all subregions (r = − 0.27 to r = − 0.46), and (2) tau with BA35 (r = − 0.31) and SRLM thickness (r = − 0.33). In amyloid-β and TDP-43 negative cases, we found strong significant associations of tau with ERC (r = − 0.40), BA35 (r = − 0.55), subiculum (r = − 0.42) and CA1 thickness (r = − 0.47). This unique dataset shows widespread MTL atrophy in relation to TDP-43 pathology and atrophy in regions affected early in Braak stageing and tau pathology. Moreover, the strong association of tau with thickness in early Braak regions in the absence of amyloid-β suggests a role of Primary Age-Related Tauopathy in neurodegeneration.

Opposing Roles of apolipoprotein E in aging and neurodegeneration.

Apolipoprotein E (APOE) effects on brain function remain controversial. Removal of APOE not only impairs cognitive functions but also reduces neuritic amyloid plaques in mouse models of Alzheimer's disease (AD). Can APOE simultaneously protect and impair neural circuits? Here, we dissociated the role of APOE in AD versus aging to determine its effects on neuronal function and synaptic integrity. Using two-photon calcium imaging in awake mice to record visually evoked responses, we found that genetic removal of APOE improved neuronal responses in adult APP/PSEN1 mice (8-10 mo). These animals also exhibited fewer neuritic plaques with less surrounding synapse loss, fewer neuritic dystrophies, and reactive glia. Surprisingly, the lack of APOE in aged mice (18-20 mo), even in the absence of amyloid, disrupted visually evoked responses. These results suggest a dissociation in APOE's role in AD versus aging: APOE may be neurotoxic during early stages of amyloid deposition, although being neuroprotective in latter stages of aging.

Disease-related patterns of in vivo pathology in Corticobasal syndrome

PurposeTo assess disease-related patterns of in vivo pathology in 11 patients with Corticobasal Syndrome (CBS) compared to 20 healthy controls and 33 mild cognitive impairment (MCI) patients due to Alzheimer’s disease.MethodsWe assessed tau aggregates with [18F]AV1451 PET, amyloid-β depositions with [18F]AV45 PET, and volumetric microstructural changes with MRI. We validated for [18F]AV1451 standardised uptake value ratio (SUVRs) against input functions from arterial metabolites and found that SUVRs and arterial-derived distribution volume ratio (DVRs) provide equally robust measures of [18F]AV1451 binding.ResultsCBS patients showed increases in [18F]AV1451 SUVRs in parietal (P < 0.05) and frontal (P < 0.05) cortices in the affected hemisphere compared to healthy controls and in precentral (P = 0.008) and postcentral (P = 0.034) gyrus in the affected hemisphere compared to MCI patients. Our data were confirmed at the histopathological level in one CBS patient who underwent brain biopsy and showed sparse tau pathology in the parietal cortex co-localizing with increased [18F]AV1451 signal. Cortical and subcortical [18F]AV45 uptake was within normal levels in CBS patients. In parietal and frontal cortices of the most affected hemisphere we found also grey matter loss (P < 0.05), increased mean diffusivity (P < 0.05) and decreased fractional anisotropy (P < 0.05) in CBS patients compared to healthy controls and MCI patients. Grey matter loss and white matter changes in the precentral gyrus of CBS patients were associated with worse motor symptoms.ConclusionsOur findings demonstrate disease-related patterns of in vivo tau and microstructural pathology in the absence of amyloid-β, which distinguish CBS from non-affected individuals and MCI patients.

AV1451 TAU TRACER UPTAKE CORRELATES WITH HIPPOCAMPAL CA1 SUBFIELD ATROPHY IN AMYLOID-NEGATIVE INDIVIDUALS

We present novel preliminary data demonstrating relationships between the amount of tau binding measured by AV1451 PET imaging and atrophy within hippocampal subfields measured by hippocampus-focused high-resolution structural MRI in individuals classified as either Amyloid-β positive or negative based on Florbetapir-PET imaging. While the cornu ammonis 1 (CA1) subfield is known to be an early site of tau pathology in Alzheimer's disease (AD) and Primary Age Related Tauopathy (PART, defined by the presence of tau-based neurofibrillary tangles in the absence of amyloid), it is unclear how tau pathology in PART relates to subfield structure. The dataset included 80 participants (27 Aβ positive: 9 controls, 13 Mild Cognitive Impairment (MCI), 5 AD; 53 Aβ negative: 37 controls, 14 MCI, 2 AD) in the ADNI study. Normalized tau tracer uptake in the medial temporal lobe (MTL) was measured from AV1451 PET within a composite cortical ROI consisting of Brodmann area 35 (BA35) region of perirhinal cortex and entorhinal cortex. Hippocampus wasn't included to avoid a known confound of high choroid plexus uptake. Hippocampal subfield volumes (CA1, CA4 and dentate gyrus (DG), subiculum (SUB)) were measured from high-resolution T2-weighted structural MRI using a joint label fusion technique implemented in the ASHS software. Both PET and atrophy measures were averaged across the hemispheres. We correlated a summary measure of MTL tau tracer uptake with hippocampal subfield volumes, with age and intracranial volume as covariates. In the Aβ positive group, CA1 had the strongest correlation with tracer uptake, followed by CA4DG, and SUB being marginally significant. In the Aβ negative group, all three subfields had significant correlation with tracer uptake, with CA1 marginally stronger than SUB (Figures 1 and 2, note different axes limits; Table 1). Amyloid positive. Amyloid negative. This is the first report relating AV1451 to high-resolution MRI specifically targeted for hippocampal subfield morphometry. The strong relationship between AV1451 tau uptake and CA1 atrophy in Aβ negative individuals suggests that AV1451 PET may be sensitive to the tau pathology of PART, which, in turn, drives MTL neurodegeneration and perhaps the cognitive symptoms of those in this group with MCI/AD designations.

Role of presynaptic calcium stores for neural network dysfunction in Alzheimer's disease.

Role of presynaptic calcium stores for neural network dysfunction in Alzheimer's disease.

TDP-43 Depletion in Microglia Promotes Amyloid Clearance but Also Induces Synapse Loss

SummaryMicroglia coordinate various functions in the central nervous system ranging from removing synaptic connections, to maintaining brain homeostasis by monitoring neuronal function, and clearing protein aggregates across the lifespan. Here we investigated whether increased microglial phagocytic activity that clears amyloid can also cause pathological synapse loss. We identified TDP-43, a DNA-RNA binding protein encoded by the Tardbp gene, as a strong regulator of microglial phagocytosis. Mice lacking TDP-43 in microglia exhibit reduced amyloid load in a model of Alzheimer’s disease (AD) but at the same time display drastic synapse loss, even in the absence of amyloid. Clinical examination from TDP-43 pathology cases reveal a considerably reduced prevalence of AD and decreased amyloid pathology compared to age-matched healthy controls, confirming our experimental results. Overall, our data suggest that dysfunctional microglia might play a causative role in the pathogenesis of neurodegenerative disorders, critically modulating the early stages of cognitive decline.

Schwann cell and endothelial cell damage in transthyretin familial amyloid polyneuropathy.

To examine the morphology of Schwann cells and endoneurial microvessels with electron microscopy. Sural nerve biopsy specimens from 49 patients with familial amyloid polyneuropathy (FAP) with transthyretin Val30Met mutation were assessed. Patients included 11 early-onset cases from endemic foci and 38 late-onset cases from nonendemic areas. Loss of nerve fibers with or without neighboring amyloid deposition was a common feature. The amount of amyloid deposition was greater relative to the extent of nerve fiber loss in early-onset cases than in late-onset cases. The atrophy of Schwann cells, particularly nonmyelinating Schwann cells, that were apposed to amyloid fibrils was more conspicuous in early-onset cases than in late-onset cases. The numbers of endothelial cell nuclei, endothelial cell profiles, and occluded microvessels were significantly increased in the patients with FAP compared with 37 patients with nutritional/alcoholic neuropathies (p < 0.05, 0.01, and 0.01, respectively). Findings suggestive of the disruption of blood-nerve barriers such as the loss of tight junctions and the fenestration of endothelial cells were also found more frequently in the patients with FAP (p < 0.001), regardless of the presence or absence of amyloid deposition. These findings suggest that direct insult of amyloid fibrils causes Schwann cell damage, resulting in the predominant loss of small-fiber axons characteristic of early-onset cases. In addition, vasculopathy may participate in the pathogenesis of neuropathy, particularly in late-onset cases.

Data on thrombotic ischemic lesions in the presence or absence of amyloid ß-protein precursor or its homolog amyloid precursor-like protein-2 in mice.

Amyloid ß-protein precursor (AßPP) and amyloid precursor-like protein-2 (APLP2) are potent inhibitors of thrombosis, see related article “The influence of the amyloid ß-protein and its precursor in modulating cerebral thrombosis” (Van Nostrand, 2016) [1]. Datapresented are images of photo-induced thrombotic ischemic stroke in wild-type mice, AßPP−/− mice and APLP2−/− mice, and the calculated infarct volume show approximately 40% and 33%, respectively, larger cerebral infarcts compared to wild-type mice.