Age-related constraints on the spatial geometry of the brain.

Age-related structural brain changes may be better captured by assessing complex spatial geometric differences rather than isolated changes to individual regions. We applied a novel analytic method to quantify age-related changes to the spatial anatomy of the brain by measuring expansion and compression of global brain shape and the distance between cross-hemisphere homologous regions. To test how global brain shape and regional distances are affected by aging, we analyzed 2,603 structural MRIs (range: 30-97 years). Increasing age was associated with global shape expansion across inferior-anterior gradients, global compression across superior-posterior gradients, and regional expansion between frontotemporal homologues. Specific patterns of global and regional expansion and compression were further associated with clinical impairment and distinctly related to deficits in various cognitive domains. These findings suggest that changes to the complex spatial anatomy and geometry of the aging brain may be associated with reduced efficiency and cognitive dysfunction in older adults.

Behaviorally meaningful functional networks mediate the effect of Alzheimer's pathology on cognition.

Tau pathology is associated with cognitive impairment in both aging and Alzheimer's disease, but the functional and structural bases of this relationship remain unclear. We hypothesized that the integrity of behaviorally meaningful functional networks would help explain the relationship between tau and cognitive performance. Using resting state fMRI, we identified unique networks related to episodic memory and executive function cognitive domains. The episodic memory network was particularly related to tau pathology measured with positron emission tomography in the entorhinal and temporal cortices. Further, episodic memory network strength mediated the relationship between tau pathology and cognitive performance above and beyond neurodegeneration. We replicated the association between these networks and tau pathology in a separate cohort of older adults, including both cognitively unimpaired and mildly impaired individuals. Together, these results suggest that behaviorally meaningful functional brain networks represent a functional mechanism linking tau pathology and cognition.

Comparison of histological delineations of medial temporal lobe cortices by four independent neuroanatomy laboratories.

The medial temporal lobe (MTL) cortex, located adjacent to the hippocampus, is crucial for memory and prone to the accumulation of certain neuropathologies such as Alzheimer's disease neurofibrillary tau tangles. The MTL cortex is composed of several subregions which differ in their functional and cytoarchitectonic features. As neuroanatomical schools rely on different cytoarchitectonic definitions of these subregions, it is unclear to what extent their delineations of MTL cortex subregions overlap. Here, we provide an overview of cytoarchitectonic definitions of the entorhinal and parahippocampal cortices as well as Brodmann areas (BA) 35 and 36, as provided by four neuroanatomists from different laboratories, aiming to identify the rationale for overlapping and diverging delineations. Nissl-stained series were acquired from the temporal lobes of three human specimens (two right and one left hemisphere). Slices (50 µm thick) were prepared perpendicular to the long axis of the hippocampus spanning the entire longitudinal extent of the MTL cortex. Four neuroanatomists annotated MTL cortex subregions on digitized slices spaced 5 mm apart (pixel size 0.4 µm at 20× magnification). Parcellations, terminology, and border placement were compared among neuroanatomists. Cytoarchitectonic features of each subregion are described in detail. Qualitative analysis of the annotations showed higher agreement in the definitions of the entorhinal cortex and BA35, while the definitions of BA36 and the parahippocampal cortex exhibited less overlap among neuroanatomists. The degree of overlap of cytoarchitectonic definitions was partially reflected in the neuroanatomists' agreement on the respective delineations. Lower agreement in annotations was observed in transitional zones between structures where seminal cytoarchitectonic features are expressed less saliently. The results highlight that definitions and parcellations of the MTL cortex differ among neuroanatomical schools and thereby increase understanding of why these differences may arise. This work sets a crucial foundation to further advance anatomically-informed neuroimaging research on the human MTL cortex.

Evaluation of Antibiotic Allergy in the Ambulatory Setting Using a Standardized Questionnaire.

Patients are sometimes mislabeled as having an immune-mediated antibiotic allergy in their medical records. Therefore, the aim of this study was to investigate the prevalence of subjects with non-immune mediated reactions to antibiotics using a standardized questionnaire. Subjects aged 18 years and older with a documented antibiotic allergy were identified and recruited from 2 outpatient clinics in the greater Chicago area. Subjects completed a standardized questionnaire during a single visit regarding their previous adverse reaction to an antibiotic. For subjects with multiple documented antibiotic allergies, 1 questionnaire was filled out for each antibiotic allergy. Investigators subsequently evaluated the questionnaire responses to determine whether the adverse reaction was a true immune-mediated allergic reaction or an adverse drug reaction. A total of 98 subjects were recruited with completion of 159 questionnaires. Eighteen subjects (18.37%, 95% CI: 10.7%, 26.3%) had antibiotic allergy labels with no corresponding immune-mediated reaction history. There were 35 allergy labels (22.0%, 95% CI: 14.7%, 29.4%) that were unlikely to be immune-mediated. Antibiotics with the highest percentage of clinical histories that were unlikely to be immune-mediated were macrolides (8 of 11 subjects), nitrofurantoin (1 of 2 subjects), and amoxicillin/clavulanate (2 of 8 subjects). The most common antibiotic allergy labels were penicillin (43 of 159 subjects), sulfonamides (25 of 159 subjects), and fluoroquinolones (21 of 159 subjects). Identification of adverse reactions to antibiotics that are unlikely to be immune-mediated can be accomplished using a standardized questionnaire in the outpatient setting. Improved identification of low-risk antibiotic allergy labels can guide de-labeling initiatives to improve antibiotic prescribing.

Comparison of histological delineations of medial temporal lobe cortices by four independent neuroanatomy laboratories.

The medial temporal lobe (MTL) cortex, located adjacent to the hippocampus, is crucial for memory and prone to the accumulation of certain neuropathologies such as Alzheimer's disease neurofibrillary tau tangles. The MTL cortex is composed of several subregions which differ in their functional and cytoarchitectonic features. As neuroanatomical schools rely on different cytoarchitectonic definitions of these subregions, it is unclear to what extent their delineations of MTL cortex subregions overlap. Here, we provide an overview of cytoarchitectonic definitions of the cortices that make up the parahippocampal gyrus (entorhinal and parahippocampal cortices) and the adjacent Brodmann areas (BA) 35 and 36, as provided by four neuroanatomists from different laboratories, aiming to identify the rationale for overlapping and diverging delineations. Nissl-stained series were acquired from the temporal lobes of three human specimens (two right and one left hemisphere). Slices (50 µm thick) were prepared perpendicular to the long axis of the hippocampus spanning the entire longitudinal extent of the MTL cortex. Four neuroanatomists annotated MTL cortex subregions on digitized (20X resolution) slices with 5 mm spacing. Parcellations, terminology, and border placement were compared among neuroanatomists. Cytoarchitectonic features of each subregion are described in detail. Qualitative analysis of the annotations showed higher agreement in the definitions of the entorhinal cortex and BA35, while definitions of BA36 and the parahippocampal cortex exhibited less overlap among neuroanatomists. The degree of overlap of cytoarchitectonic definitions was partially reflected in the neuroanatomists' agreement on the respective delineations. Lower agreement in annotations was observed in transitional zones between structures where seminal cytoarchitectonic features are expressed more gradually. The results highlight that definitions and parcellations of the MTL cortex differ among neuroanatomical schools and thereby increase understanding of why these differences may arise. This work sets a crucial foundation to further advance anatomically-informed human neuroimaging research on the MTL cortex.

Amyloid induced hyperexcitability in default mode network drives medial temporal hyperactivity and early tau accumulation.

In early Alzheimer's disease (AD) ß-amyloid (Aß) deposits throughout association cortex and tau appears in the entorhinal cortex (EC). Why these initially appear in disparate locations is not understood. Using task-based fMRI and multimodal PET imaging, we assess the impact of local AD pathology on network-to-network interactions. We show that AD pathologies flip interactions between the default mode network (DMN) and the medial temporal lobe (MTL) from inhibitory to excitatory. The DMN is hyperexcited with increasing levels of Aß, which drives hyperexcitability within the MTL and this directed hyperexcitation of the MTL by the DMN predicts the rate of tau accumulation within the EC. Our results support a model whereby Aß induces disruptions to local excitatory-inhibitory balance in the DMN, driving hyperexcitability in the MTL, leading to tau accumulation. We propose that Aß-induced disruptions to excitatory-inhibitory balance is a candidate causal route between Aß and remote EC-tau accumulation.

Medial temporal lobe functional network architecture supports sleep-related emotional memory processing in older adults.

Memory consolidation occurs via reactivation of a hippocampal index during non-rapid eye movement slow-wave sleep (NREM SWS) which binds attributes of an experience existing within cortical modules. For memories containing emotional content, hippocampal-amygdala dynamics facilitate consolidation over a sleep bout. This study tested if modularity and centrality-graph theoretical measures that index the level of segregation/integration in a system and the relative import of its nodes-map onto central tenets of memory consolidation theory and sleep-related processing. Findings indicate that greater network integration is tied to overnight emotional memory retention via NREM SWS expression. Greater hippocampal and amygdala influence over network organization supports emotional memory retention, and hippocampal or amygdala control over information flow are differentially associated with distinct stages of memory processing. These centrality measures are also tied to the local expression and coupling of key sleep oscillations tied to sleep-dependent memory consolidation. These findings suggest that measures of intrinsic network connectivity may predict the capacity of brain functional networks to acquire, consolidate, and retrieve emotional memories.

Examining the diagnostic value of the mnemonic discrimination task for classification of cognitive status and amyloid-beta burden.

Alzheimer's disease (AD) is the most common type of dementia, characterized by early memory impairments and gradual worsening of daily functions. AD-related pathology, such as amyloid-beta (Aß) plaques, begins to accumulate many years before the onset of clinical symptoms. Predicting risk for AD via related pathology is critical as the preclinical stage could serve as a therapeutic time window, allowing for early management of the disease and reducing health and economic costs. Current methods for detecting AD pathology, however, are often expensive and invasive, limiting wide and easy access to a clinical setting. A non-invasive, cost-efficient platform, such as computerized cognitive tests, could be potentially useful to identify at-risk individuals as early as possible. In this study, we examined the diagnostic value of an episodic memory task, the mnemonic discrimination task (MDT), for predicting risk of cognitive impairment or Aß burden. We constructed a random forest classification algorithm, utilizing MDT performance metrics and various neuropsychological test scores as input features, and assessed model performance using area under the curve (AUC). Models based on MDT performance metrics achieved classification results with an AUC of 0.83 for cognitive status and an AUC of 0.64 for Aß status. Our findings suggest that mnemonic discrimination function may be a useful predictor of progression to prodromal AD or increased risk of Aß load, which could be a cost-efficient, noninvasive cognitive testing solution for potentially wide-scale assessment of AD pathological and cognitive risk.

NODDI-derived measures of microstructural integrity in medial temporal lobe white matter pathways are associated with Alzheimer's disease pathology and cognitive outcomes.

INTRODUCTION: Diffusion tensor imaging has been used to assess white matter (WM) changes in the early stages of Alzheimer's disease (AD). However, the tensor model is necessarily limited by its assumptions. Neurite Orientation Dispersion and Density Imaging (NODDI) can offer insights into microstructural features of WM change. We assessed whether NODDI more sensitively detects AD-related changes in medial temporal lobe WM than traditional tensor metrics. METHODS: Standard diffusion and NODDI metrics were calculated for medial temporal WM tracts from 199 older adults drawn from ADNI3 who also received PET to measure pathology and neuropsychological testing. RESULTS: NODDI measures in medial temporal tracts were more strongly correlated to cognitive performance and pathology than standard measures. The combination of NODDI and standard metrics exhibited the strongest prediction of cognitive performance in random forest analyses. CONCLUSIONS: NODDI metrics offer additional insights into contributions of WM degeneration to cognitive outcomes in the aging brain.

Functional network structure supports resilience to memory deficits in cognitively normal older adults with amyloid-ß pathology.

Older adults may harbor large amounts of amyloid-ß (Aß) pathology, yet still perform at age-normal levels on memory assessments. We tested whether functional brain networks confer resilience or compensatory mechanisms to support memory in the face of Aß pathology. Sixty-five cognitively normal older adults received high-resolution resting state fMRI to assess functional networks, 18F-florbetapir-PET to measure Aß, and a memory assessment. We characterized functional networks with graph metrics of local efficiency (information transfer), modularity (specialization of functional modules), and small worldness (balance of integration and segregation). There was no difference in functional network measures between older adults with high Aß (Aß+) compared to those with no/low Aß (Aß-). However, in Aß+ older adults, increased local efficiency, modularity, and small worldness were associated with better memory performance, while this relationship did not occur Aß- older adults. Further, the association between increased local efficiency and better memory performance in Aß+ older adults was localized to local efficiency of the default mode network and hippocampus, regions vulnerable to Aß and involved in memory processing. Our results suggest functional networks with modular and efficient structures are associated with resilience to Aß pathology, providing a functional target for intervention.

Effect of Alzheimer's Pathology on Task-Related Brain Network Reconfiguration in Aging.

Large-scale brain networks undergo widespread changes with older age and in neurodegenerative diseases such as Alzheimer's disease (AD). Research in young adults (YA) suggest that the underlying functional architecture of brain networks remains relatively consistent between rest and task states. However, it remains unclear whether the same is true in aging and to what extent any changes may be related to accumulation of AD pathology such as ß-amyloid (Aß) and tau. Here, we examined age-related differences in functional connectivity (FC) between rest and an object-scene mnemonic discrimination task using fMRI in young and older adults (OA; both females and males). We used an a priori episodic memory network (EMN) parcellation scheme associated with object and scene processing, that included anterior-temporal regions and posterior-medial regions. We also used positron emission topography to measure Aß and tau in older adults. The correlation between rest and task FC (i.e., FC similarity) was reduced in older compared with younger adults. Older adults with lower FC similarity in EMN had higher levels of tau in the same EMN regions and performed worse during object, but not scene, trials during the fMRI task. These findings link AD pathology, particularly tau, to a less stable functional architecture in memory networks. They also suggest that smaller changes in FC organization between rest and task states may facilitate better performance in older age. Interpretations are limited by methodological factors related to different acquisition directions and durations between rest and task scans.SIGNIFICANCE STATEMENT The brain's large-scale network organization is relatively consistent between rest and task states in young adults (YA). We found that memory networks in older adults (OA) were less correlated between rest and (memory) task states compared with young adults. Older adults with less correlated brain networks also had higher levels of Alzheimer's disease (AD) pathology in the same regions, suggesting that a less stable network architecture may reflect the early evolution of AD. Older adults with less correlated brain networks also performed worse during the memory task suggesting that more similar network organization between rest and task states may facilitate better performance in older age.

Differential involvement of hippocampal subfields in the relationship between Alzheimer's pathology and memory interference in older adults.

Introduction: We tested whether Alzheimer's disease (AD) pathology predicts memory deficits in non-demented older adults through its effects on medial temporal lobe (MTL) subregional volume. Methods: Thirty-two, non-demented older adults with cerebrospinal fluid (CSF) (amyloid-beta [Aß]42/Aß40, phosphorylated tau [p-tau]181, total tau [t-tau]), positron emission tomography (PET; 18F-florbetapir), high-resolution structural magnetic resonance imaging (MRI), and neuropsychological assessment were analyzed. We examined relationships between biomarkers and a highly granular measure of memory consolidation, retroactive interference (RI). Results: Biomarkers of AD pathology were related to RI. Dentate gyrus (DG) and CA3 volume were uniquely associated with RI, whereas CA1 and BA35 volume were related to both RI and overall memory recall. AD pathology was associated with reduced BA35, CA1, and subiculum volume. DG volume and Aß were independently associated with RI, whereas CA1 volume mediated the relationship between AD pathology and RI. Discussion: Integrity of distinct hippocampal subfields demonstrate differential relationships with pathology and memory function, indicating specificity in vulnerability and contribution to different memory processes.

Antimicrobial Stewardship Techniques for Critically Ill Patients with Pneumonia.

Pneumonia is common in the intensive care unit (ICU), infecting 27% of all critically ill patients. Given the high prevalence of this disease state in the ICU, optimizing antimicrobial therapy while minimizing toxicities is of utmost importance. Inappropriate antimicrobial use can increase the risk of antimicrobial resistance, Clostridiodes difficile infection, allergic reaction, and other complications from antimicrobial use (e.g., QTc prolongation, thrombocytopenia). This review article aims to discuss methods to optimize antimicrobial treatment in patients with pneumonia, including the following: procalcitonin use, utilization of methicillin-resistant Staphylococcus aureus nares testing to determine need for vancomycin therapy, utilization of the Biofire® FilmArray® pneumonia polymerase chain reaction (PCR), and microbiology reporting techniques.

In vitro susceptibility of carbapenem resistant Enterobacterales to meropenem-vaborbactam and ceftazidime-avibactam at a single academic medical centre.

BACKGROUND: Carbapenem-resistant Enterobacterales (CRE) are considered an urgent threat. Ceftazidime-avibactam and meropenem-vaborbactam contain ß-lactamase inhibitors active against CRE isolates including those that produce Klebsiella pneumoniae carbapenemases (KPC). METHODS: Retrospective chart review of CRE isolates from 1 January 2016 to 1 November 2018. Collected data includes a descriptive overview of measured MIC values, resistance mechanism via a polymerase chain reaction test (Xpert Carba-R, Cepheid, Sunnyvale CA), as well as clinical outcomes. RESULTS: Of 106 isolates reviewed, 86 isolates met the inclusion criteria from 85 individual subjects. The breakpoint:MIC ratio for ceftazidime-avibactam overall was 4, while for meropenem-vaborbactam this ratio was 32 (p < 0.0001). For KPC isolates, ceftazidime-avibactam MIC50/MIC90 in 2016, 2017, and 2018 were 2/4 mg/L (n = 32), 2/4 mg/L (n = 17), and 2/8 mg/L (n = 30), respectively. The meropenem-vaborbactam MIC50/MIC90, for KPC isolates in 2016, 2017, and 2018 were 0.06/0.125 mg/L (n = 32), 0.06/0.1 mg/L (n = 17), and 0.06/0.5 mg/L (n = 30), respectively. Microbiologic cure was 75% (n = 16) in ceftazidime-avibactam subjects and 58.3% (n = 12) in subjects treated with alternative agents (p = 0.43). The 14- and 30-day mortality was numerically higher in subjects treated with alternate agents when compared ceftazidime-avibactam 2/9 (22.2%) vs 3/17 (17.6%) (p = 1.00) and 4/9 (44.4%) vs 4/17 (28.6%) (p = 0.38), respectively. For ceftazidime-avibactam, 30-day mortality in 2016, 2017, and 2018 was 0/5 (0%), 0/2 (0%), and 4/10 (40%). CONCLUSION: Selective pressure from the use of ceftazidime-avibactam at our institution may be decreasing its utility as a first-line agent for CRE infections. Meropenem-vaborbactam maintained low MIC values and may be a promising treatment option for CRE.

Locus coeruleus catecholamines link neuroticism and vulnerability to tau pathology in aging.

Higher neuroticism is a risk factor for Alzheimer's disease (AD), and is implicated in disordered stress responses. The locus coeruleus (LC)-catecholamine system is activated during perceived threat and is a centerpiece of developing models of the pathophysiology of AD, as it is the first brain region to develop abnormal tau. We examined relationships among the "Big 5" personality traits, LC catecholamine synthesis capacity measured with [18F]Fluoro-m-tyrosine PET, and tau burden measured with [18F]Flortaucipir PET in cognitively normal older adults (n = 47). ß-amyloid (Aß) status was determined using [11C]Pittsburgh compound B PET (n = 14 Aß positive). Lower LC catecholamine synthesis capacity was associated with higher neuroticism, more depressive symptoms as measured by the Geriatric Depression Scale, and higher amygdala tau-PET binding. Exploratory analyses with other personality traits revealed that low trait conscientiousness was also related to both lower LC catecholamine synthesis capacity, and more depressive symptoms. A significant indirect path linked both high neuroticism and low conscientiousness to greater amygdala tau burden via their mutual association with low LC catecholamine synthesis capacity. Together, these findings reveal LC catecholamine synthesis capacity to be a promising marker of affective health and pathology burden in aging, and identifies candidate neurobiological mechanisms for the effect of personality on increased vulnerability to dementia.

Entorhinal-Hippocampal Circuit Integrity Is Related to Mnemonic Discrimination and Amyloid-ß Pathology in Older Adults.

Mnemonic discrimination, a cognitive process that relies on hippocampal pattern separation, is one of the first memory domains to decline in aging and preclinical Alzheimer's disease. We tested whether functional connectivity (FC) within the entorhinal-hippocampal circuit, measured with high-resolution resting state fMRI, is associated with mnemonic discrimination and amyloid-ß (Aß) pathology in a sample of 64 cognitively normal human older adults (mean age, 71.3 ± 6.4 years; 67% female). FC was measured between entorhinal-hippocampal circuit nodes with known anatomical connectivity, as well as within cortical memory networks. Aß pathology was measured with 18F-florbetapir-PET, and neurodegeneration was assessed with subregional volume from structural MRI. Participants performed both object and spatial versions of a mnemonic discrimination task outside of the scanner and were classified into low-performing and high-performing groups on each task using a median split. Low object mnemonic discrimination performance was specifically associated with increased FC between anterolateral entorhinal cortex (alEC) and dentate gyrus (DG)/CA3, supporting the importance of this connection to object memory. This hyperconnectivity between alEC and DG/CA3 was related to Aß pathology and decreased entorhinal cortex volume. In contrast, spatial mnemonic discrimination was not associated with altered FC. Aß was further associated with dysfunction within hippocampal subfields, particularly with decreased FC between CA1 and subiculum as well as reduced volume in these regions. Our findings suggest that Aß may indirectly lead to memory impairment through entorhinal-hippocampal circuit dysfunction and neurodegeneration and provide a mechanism for increased vulnerability of object mnemonic discrimination.SIGNIFICANCE STATEMENT Mnemonic discrimination is a critical episodic memory process that is performed in the dentate gyrus (DG) and CA3 subfield of the hippocampus, relying on input from entorhinal cortex. Mnemonic discrimination is particularly vulnerable to decline in older adults; however, the mechanisms behind this vulnerability are still unknown. We demonstrate that object mnemonic discrimination impairment is related to hyperconnectivity between the anterolateral entorhinal cortex and DG/CA3. This hyperconnectivity was associated with amyloid-ß pathology and neurodegeneration in entorhinal cortex, suggesting aberrantly increased network activity is a pathological process. Our findings provide a mechanistic explanation of the vulnerability of object compared to spatial mnemonic discrimination in older adults and has translational implications for choice of outcome measures in clinical trials for Alzheimer's disease.

Distinct Factors Drive the Spatiotemporal Progression of Tau Pathology in Older Adults.

Mechanisms underlying the initial accumulation of tau pathology across the human brain are largely unknown. We examined whether baseline factors including age, amyloid-ß (Aß), and neural activity predicted longitudinal tau accumulation in temporal lobe regions that reflect distinct stages of tau pathogenesis. Seventy cognitively normal human older adults (77 ± 6 years, 59% female) received two or more 18F-flortaucipir (FTP) and 11C-Pittsburgh Compound B (PiB) PET scans (mean follow-up, 2.5 ± 1.1 years) to quantify tau and (Aß). Linear mixed-effects models were used to calculate the slopes of FTP change in entorhinal cortex (EC), parahippocampal cortex (PHC), and inferior temporal gyrus (IT), and slopes of global PiB change. Thirty-seven participants underwent functional MRI to measure baseline activation. Older age predicted EC tau accumulation, and baseline EC tau levels predicted subsequent tau accumulation in EC and PHC. In IT, however, baseline EC tau interacted with Aß to predict IT tau accumulation. Higher baseline local activation predicted tau accumulation within EC and PHC, and higher baseline hippocampal activation predicted EC tau accumulation. Our findings indicate that factors predicting tau accumulation vary as tau progresses through the temporal lobe. Older age is associated with initial tau accumulation in EC, while baseline EC tau and neural activity drive tau accumulation within medial temporal lobe. Aß subsequently facilitates tau spread from medial to lateral temporal lobe. Our findings elucidate potential drivers of tau accumulation and spread in aging, which are critical for understanding Alzheimer's disease pathogenesis.SIGNIFICANCE STATEMENT To further understand the mechanisms leading to tau pathogenesis and spread, we tested whether baseline factors such as age, amyloid-ß pathology, and activation predicted longitudinal tau accumulation in cognitively normal older adults. We found that distinct mechanisms contribute to tau accumulation as tau progresses across the temporal lobe, with initial tau accumulation in entorhinal cortex driven by age and subsequent spread driven by neural activity and amyloid-ß. We demonstrate that higher baseline activation predicts increased longitudinal tau accumulation, providing novel evidence that activation-dependent tau production may occur in the human brain. Our findings support major hypotheses generated from preclinical research, and have important translational implications, suggesting that the reduction of hyperactivation may help prevent the development of tau pathology.

Fusiform Gyrus Phospho-Tau is Associated with Failure of Proper Name Retrieval in Aging.

Difficulty retrieving proper names is common in older adults, coinciding with the accumulation of aggregated proteins in mid-life. We investigated the ability of healthy older adults to retrieve the names of famous faces in relation to positron emission tomography measurements of amyloid-ß plaques and tau neurofibrillary tangles. More tau in the left fusiform and parahippocampal gyrus was related to reduced proper name retrieval performance and this effect was potentiated by amyloid-ß. These findings provide an explanation for a common complaint of older adults and link proper name retrieval to neural systems involved in face perception, memory, and naming. ANN NEUROL 2021;90:988-993.

Hippocampal Connectivity with Retrosplenial Cortex is Linked to Neocortical Tau Accumulation and Memory Function.

The mechanisms underlying accumulation of Alzheimer's disease (AD)-related tau pathology outside of the medial temporal lobe (MTL) in older adults are unknown but crucial to understanding cognitive decline. A growing body of evidence from human and animal studies strongly implicates neural connectivity in the propagation of tau in humans, but the pathways of neocortical tau spread and its consequences for cognitive function are not well understood. Using resting state functional magnetic resonance imaging (fMRI) and tau PET imaging from a sample of 97 male and female cognitively normal older adults, we examined MTL structures involved in medial parietal tau accumulation and associations with memory function. Functional connectivity between hippocampus (HC) and retrosplenial cortex (RsC), a key region of the medial parietal lobe, was associated with tau in medial parietal lobe. By contrast, connectivity between entorhinal cortex (EC) and RsC did not correlate with medial parietal lobe tau. Further, greater hippocampal-retrosplenial (HC-RsC) connectivity was associated with a stronger correlation between MTL and medial parietal lobe tau. Finally, an interaction between connectivity strength and medial parietal tau was associated with episodic memory performance, particularly in the visuospatial domain. This pattern of tau accumulation thus appears to reflect pathways of neural connectivity, and propagation of tau from EC to medial parietal lobe via the HC may represent a critical process in the evolution of cognitive dysfunction in aging and AD.SIGNIFICANCE STATEMENT The accumulation of tau pathology in the neocortex is a fundamental process underlying Alzheimer's disease (AD). Here, we use functional connectivity in cognitively normal older adults to track the accumulation of tau in the medial parietal lobe, a key region for memory processing that is affected early in the progression of AD. We show that the strength of connectivity between the hippocampus (HC) and retrosplenial cortex (RsC) is related to medial parietal tau burden, and that these tau and connectivity measures interact to associate with episodic memory performance. These findings establish the HC as the origin of medial parietal tau and implicate tau pathology in this region as a crucial marker of the beginnings of AD.

Alzheimer's Pathology Is Associated with Dedifferentiation of Intrinsic Functional Memory Networks in Aging.

In presymptomatic Alzheimer's disease (AD), beta-amyloid plaques (Aß) and tau tangles accumulate in distinct spatiotemporal patterns within the brain, tracking closely with episodic memory decline. Here, we tested whether age-related changes in the segregation of the brain's intrinsic functional episodic memory networks-anterior-temporal (AT) and posterior-medial (PM) networks-are associated with the accumulation of Aß, tau, and memory decline using fMRI and PET. We found that AT and PM networks were less segregated in older than that in younger adults and this reduced specialization was associated with more tau and Aß in the same regions. The effect of network dedifferentiation on memory depended on the amount of Aß and tau, with low segregation and pathology associated with better performance at baseline and low segregation and high pathology related to worse performance over time. This pattern suggests a compensation phase followed by a degenerative phase in the early, preclinical phase of AD.