Temporal Lobe Regions Research Articles

Taking it to the extreme: The search for determinants of cognitive vulnerability and resilience in children with autosomal dominant Alzheimer’s disease

Abstract:Presenilin-1 (PSEN1) mutations predispose individuals to develop autosomal-dominant Alzheimer's disease (ADAD) in middle adulthood. While the pathogenesis of ADAD may be different from late-onset sporadic AD (e.g., differences in disease etiology, age of disease onset, etc), these conditions share many characteristics, including similar abnormalities in amyloid and tau biomarkers, brain structure and brain activity, and clinical features (Quiroz et al., 2010, Quiroz et al., 2011, Quiroz et al. 2018). Biomarker investigations of families with ADAD have already shed light on the trajectory of some AD-related brain changes, especially prior to the onset of clinical symptoms.We have been studying a Colombian kindred with a genetic form of AD caused by a single genetic mutation in the PSEN1 (E280A), which serves as a unique model for preclinical AD. Because of a well-defined age at clinical onset, and near 100% penetrance, this kindred provides important information about the time course and relationships between physiological mechanisms and cognitive changes, and in so doing, it has yielded new insights about presymptomatic AD that will enhance future prevention trials for AD, including primary prevention trials.The well-characterized clinical trajectory of these PSEN1 E280A mutation carriers allow us to examine brain function in children, more than three decades before the average age of onset of mild cognitive impairment (MCI) and dementia in this cohort (45 years for MCI, 50 years for dementia). This is giving us the unique opportunity to characterize the cognitive and behavioral profiles of children genetically determined to develop dementia in their forties, and is helping us improve our understanding of the impact of ADAD mutations in early life cognitive and brain functioning, as well as its potential impact on learning, academic performance and educational attainment. We previously studied 20 PSEN1 E280A carriers and 20 non-carriers aged 9 to 17 years from the Colombian ADAD cohort and showed that mutation-carrying children were distinguished from non-carriers by plasma biomarker findings consistent with Aß1-42 overproduction, as well as by increased functional connectivity of the posterior cingulate cortex with medial temporal lobe regions (Quiroz et al 2015). More recently, we used the WISC-IV, a measure of general intellectual abilities to examine cognitive abilities in these children. We reported in 265 children with the E280A mutation and 1089 non-carriers that they did not differ on any of the WISC-IV indices. Surprisingly, male carriers performed slightly worse than female carriers on working memory (mean difference = -4.97; P = .001) (Fox-Fuller et al., 2021). Some of our ongoing work includes comprehensive examinations of social, educational and developmental histories along with functional brain networks, as markers of synaptic dysfunction in individuals with ADAD, as this is particularly relevant to understanding the impact of PSEN1 mutations on the developing brain and subsequent neurodegenerative changes seen later in life, without the confounds of aging and age-related comorbidities that often exist in late-onset sporadic AD.Disclosures: Financial: Dr. Quiroz receives a consulting fee from Biogen. Non-Financial: Dr. Quiroz is a Hispanic Neuropsychological Society Member-At-Large and serves as the INS Teleneuropsychology Special Interest Group Chair

6 Posterior cerebral artery-defined white matter hyperintensities are associated with object domain memory and transentorhinal volume independently of global beta-amyloid burden

Objective:White matter hyperintensities (WMH) are a radiological marker of small vessel cerebrovascular disease that are related to cognition and memory decline in aging and Alzheimer’s disease (AD). However, the mechanisms that link WMH to memory impairment and whether they interact with or act independently of AD pathophysiology are unclear. The transentorhinal cortex (BA35) is among the earliest anatomical regions to show tau deposition and subsequent atrophy, and baseline posterior WMH is related to longitudinal cortical thinning of the entorhinal cortex. However, it is unclear whether regional WMH are related to BA35 volume specifically, and whether this relationship is influenced by amyloid-β (Aβ) burden. We hypothesized that WMH in the vascular territory of the posterior cerebral artery (PCA), which perfuses both posterior and medial temporal lobe regions, would be associated with reduced BA35 volume and with lower memory in older adults independently of Aβ.Participants and Methods:114 older adults without dementia, aged 60 to 98 years (mean (SD) = 78.31 (11.02), 71 (62.8%) women), were included. Regional WMH volumes were derived from T2-FLAIR images using ANTs, a vascular territory atlas and manual editing. Global Aβ was assessed with 18F-florbetapir PET, using SUVR of a cortical composite region (FBP mean SUVR) with a cerebellar reference region. Total transentorhinal (BA35) volume was derived using T1 and T2-weighted images using ASHS. To assess hippocampal pattern separation ability, an index of episodic memory, participants completed both object (MDT-O) and spatial (MDT-S) versions of a mnemonic discrimination task, with the lure discrimination index as the outcome. Using linear regressions, we first tested for associations among PCA-defined WMH, Aβ, BA35 volume, and MDT-S and MDT-O scores. We then tested whether the relationship between PCA-defined WMH and MDT-O performance was mediated by BA35 volume and whether this mediation was moderated by Aβ. All models adjusted for age, sex, and education.Results:PCA-defined WMH were related to higher FBP mean SUVR (b=0.287, p=0.042) and lower BA35 volume (b=-0.222, p=0.038). PCA-defined WMH were also negatively related to MDT-O performance (b=-0.229, p=0.044), but not to MDT-S (b=-0.171, p=0.118). FBP mean SUVR was not related to BA35 volume (b=-0.131, p=0.344) or MDT performance (MDT-S: b=-0.138, p=0.348; MDT-O: b=0.059, p=0.690). Furthermore, FBP mean SUVR did not interact with PCA-defined WMH to predict memory performance (interaction b=-0.039, p=0.973), nor BA35 volume (interaction b=-0.140, p=0.894). The association of PCA-defined WMH to MDT-O was fully mediated by BA35 volume (indirect effect b=-0.0005, 95% CI (-0.0014, -0.0003)). This mediation was not moderated by FBP mean SUVR (indirect effect b=-0.00001, 95% CI (-0.001, 0.001)).Conclusions:We found that PCA-defined WMH were related to memory performance in older adults, and this association is fully mediated by transentorhinal volume. While PCA-defined WMH are related to higher global Aβ burden, there is no interaction between PCA-defined WMH and Aβ on BA35 volume. These findings point to an amyloid-independent vascular pathway towards memory decline in aging and AD. Future work should examine whether the pathway linking PCA-defined WMH to transentorhinal cortex atrophy and subsequent memory decline is mediated by regional tau pathology.

Grammatical Parallelism in Aphasia: A Lesion-Symptom Mapping Study.

Sentence structure, or syntax, is potentially a uniquely creative aspect of the human mind. Neuropsychological experiments in the 1970s suggested parallel syntactic production and comprehension deficits in agrammatic Broca's aphasia, thought to result from damage to syntactic mechanisms in Broca's area in the left frontal lobe. This hypothesis was sometimes termed overarching agrammatism, converging with developments in linguistic theory concerning central syntactic mechanisms supporting language production and comprehension. However, the evidence supporting an association among receptive syntactic deficits, expressive agrammatism, and damage to frontal cortex is equivocal. In addition, the relationship among a distinct grammatical production deficit in aphasia, paragrammatism, and receptive syntax has not been assessed. We used lesion-symptom mapping in three partially overlapping groups of left-hemisphere stroke patients to investigate these issues: grammatical production deficits in a primary group of 53 subjects and syntactic comprehension in larger sample sizes (N = 130, 218) that overlapped with the primary group. Paragrammatic production deficits were significantly associated with multiple analyses of syntactic comprehension, particularly when incorporating lesion volume as a covariate, but agrammatic production deficits were not. The lesion correlates of impaired performance of syntactic comprehension were significantly associated with damage to temporal lobe regions, which were also implicated in paragrammatism, but not with the inferior and middle frontal regions implicated in expressive agrammatism. Our results provide strong evidence against the overarching agrammatism hypothesis. By contrast, our results suggest the possibility of an alternative grammatical parallelism hypothesis rooted in paragrammatism and a central syntactic system in the posterior temporal lobe.

Association Between Hippocampal Volume and African Neuropsychology Memory Tests in Adult Individuals with Probable Alzheimer's Disease in Democratic Republic of Congo.

Western studies indicate potential associations between hippocampal volume and memory in the trajectory of Alzheimer's disease (AD). However, limited availability of neuroimaging technology and neuropsychological tests appropriate for sub-Saharan African (SSA) countries makes it difficult to establish neuroanatomical associations of hippocampus and memory in this locale. This study examined hippocampal volumes and memory in healthy control (HC) and probable AD groups in the Democratic Republic of Congo (DRC). Forty-six subjects with probable AD and 29 HC subjects were screened using the Community Instrument for Dementia and the Alzheimer Questionnaire. Participants underwent neuroimaging in Kinshasa, DRC, and memory was evaluated using the African Neuropsychology Battery (ANB). Multiple linear regression was used to determine associations between hippocampal volumes and memory. Patients with probable AD performed significantly worse than HCs on ANB memory measures, and exhibited greater cerebral atrophy, which was significantly pronounced in the medial temporal lobe region (hippocampus, entorhinal cortex). Both AD and HC subjects exhibited high rates of white matter hyperintensities compared to international base rate prevalence, which was significantly worse for probable AD. Both also exhibited elevated rates of microhemorrhages. Regression analysis demonstrated a significant association between hippocampal volume and ANB memory tests. Hippocampal atrophy discriminated probable AD from the HC group. This study establishes the feasibility of conducting neuroimaging research in the SSA, demonstrates many known neuroimaging findings in probable AD patients hold up using culturally appropriate memory tasks, and suggest cardiovascular problems are a greater issue in SSA than in Western countries.

Resolving heterogeneity in Alzheimer's disease based on individualized structural covariance network

The heterogeneity of Alzheimer's disease (AD) poses a challenge to precision medicine. We aimed to identify distinct subtypes of AD based on the individualized structural covariance network (IDSCN) analysis and to research the underlying neurobiology mechanisms. In this study, 187 patients with AD (age = 73.57 ± 6.00, 50% female) and 143 matched normal controls (age = 74.30 ± 7.80, 44% female) were recruited from the Alzheimer's Disease Neuroimaging Initiative (ADNI) project database, and T1 images were acquired. We utilized the IDSCN analysis to generate individual-level altered structural covariance network and performed k-means clustering to subtype AD based on structural covariance network. Cognition, disease progression, morphological features, and gene expression profiles were further compared between subtypes, to characterize the heterogeneity in AD. Two distinct AD subtypes were identified in a reproducible manner, and we named the two subtypes as slow progression type (subtype 1, n = 104, age = 76.15 ± 6.44, 42% female) and rapid progression type (subtype 2, n = 83, age = 71.98 ± 8.72, 47% female), separately. Subtype 1 had better baseline visuospatial function than subtype 2 (p < 0.05), whereas subtype 2 had better baseline memory function than subtype 1 (p < 0.05). Subtype 2 showed worse progression in memory (p = 0.003), language (p = 0.003), visuospatial function (p = 0.020), and mental state (p = 0.038) than subtype 1. Subtype 1 often shared increased structural covariance network, mainly in the frontal lobe and temporal lobe regions, whereas subtype 2 often shared increased structural covariance network, mainly in occipital lobe regions and temporal lobe regions. Functional annotation further revealed that all differential structural covariance network between the two AD subtypes were mainly implicated in memory, learning, emotion, and cognition. Additionally, differences in gray matter volume (GMV) between AD subtypes were identified, and genes associated with GMV differences were found to be enriched in the terms potassium ion transport, synapse organization, and histone modification and the pathways viral infection, neurodegeneration-multiple diseases, and long-term depression. The two distinct AD subtypes were identified and characterized with neuroanatomy, cognitive trajectories, and gene expression profiles. These comprehensive results have implications for neurobiology mechanisms and precision medicine.

A - 34 A Suspected Case of Early-Onset Frontal Variant of Alzheimer's Disease in a 64-Year-Old Male.

Early-onset frontal variant of Alzheimer's disease (fvAD) is characterized by apathy, disinhibition, and executive dysfunction. As such, fvAD is often difficult to clinically distinguish from behavioral variant frontotemporal dementia (bvFTD). However, research suggests that a differentiating feature among the two conditions is that fvAD typically presents with more pronounced memory impairment. Therefore, neuropsychological testing in the context of a comprehensive multidisciplinary assessment can be a valuable tool to aid with differential diagnosis. A 64-year-old male with gradually progressive difficulties in cognition and behavioral-emotional functioning over the past 8-9years presented to a multidisciplinary neurology clinic. MRI showed mild atrophy in the frontal, temporal, and parietal lobe regions. Concerns were raised by his neurologist for early-onset ad versus bvFTD so the patient was referred for neuropsychological evaluation. Neuropsychological testing showed a largely amnestic memory profile along with deficits in executive functioning and semantic fluency. His spouse endorsed concerns for apathy and executive dysfunction on a frontal system rating questionnaire in addition to concerns for disinhibition during the clinical interview. Taken together, the patient's profile appeared to be consistent with early-onset fvAD. Follow-up FDG-PET scan showed decreased uptake in the anteromesial temporal lobes, posterior cingulate cortices, and posterior temporoparietal regions which was consistent with an ad profile. Early-onset fvAD and bvFTD are often difficult to clinically distinguish from each other. However, neuropsychological testing in conjunction with comprehensive multidisciplinary assessment can serve an important role in helping to facilitate differential diagnosis for these two neurodegenerative disorders with overlapping features.

Association of Olfaction and Microstructural Integrity of Brain Tissue in Community-Dwelling Adults: Atherosclerosis Risk in Communities Neurocognitive Study.

Research on olfaction and brain neuropathology may help understand brain regions associated with normal olfaction and dementia pathophysiology. To identify early regional brain structures affected in poor olfaction, we examined cross-sectional associations of microstructural integrity of the brain with olfaction in the Atherosclerosis Risk in Communities Neurocognitive Study. Participants were selected from a prospective cohort study of community-dwelling adults; selection criteria included the following: evidence of cognitive impairment, participation in a previous MRI study, and a random sample of cognitively normal participants. Microstructural integrity was measured by 2 diffusion tensor imaging (DTI) measures, fractional anisotropy (FA) and mean diffusivity (MD), and olfaction by a 12-item odor identification test at the same visit. Higher FA and MD values indicate better and worse microstructural integrity, respectively, and higher odor identification scores indicate better olfaction. We used brain region-specific linear regression models to examine associations between DTI measures and olfaction, adjusting for potential confounders. Among 1,418 participants (mean age 76 ± 5 years, 41% male, 21% Black race, 59% with normal cognition), the mean olfaction score was 9 ± 2.3. Relevant to olfaction, higher MD in the medial temporal lobe (MTL) regions, namely the hippocampus (β -0.79 [95% CI -0.94 to -0.65] units lower olfaction score per 1 SD higher MD), amygdala, entorhinal area, and some white matter (WM) tracts connecting to these regions, was associated with olfaction. We also observed associations with MD and WM FA in multiple atlas regions that were not previously implicated in olfaction. The associations between MD and olfaction were particularly stronger in the MTL regions among individuals with mild cognitive impairment (MCI) compared with those with normal cognition (e.g., βhippocampus -0.75 [95% CI -1.02 to -0.49] and -0.44 [95% CI -0.63 to -0.26] for MCI and normal cognition, respectively, p interaction = 0.004). Neuronal microstructural integrity in multiple brain regions, particularly the MTL (the regions known to be affected in early Alzheimer disease), is associated with odor identification ability. Differential associations in the MTL regions among cognitively normal individuals compared with those with MCI may reflect the earlier vs later effects of the dementia pathogenesis. It is likely that some of the associated regions may not have any functional relevance to olfaction.

Hierarchical organization of the human ventral visual streams revealed with magnetoencephalography.

The hierarchical organization between 25 ventral stream visual cortical regions and 180 cortical regions was measured with magnetoencephalography using the Human Connectome Project Multimodal Parcellation atlas in 83 Human Connectome Project participants performing a visual memory task. The aim was to reveal the hierarchical organization using a whole-brain model based on generative effective connectivity with this fast neuroimaging method. V1-V4 formed a first group of interconnected regions. Especially V4 had connectivity to a ventrolateral visual stream: V8, the fusiform face cortex, and posterior inferior temporal cortex PIT. These regions in turn had effectivity connectivity to inferior temporal cortex visual regions TE2p and TE1p. TE2p and TE1p then have connectivity to anterior temporal lobe regions TE1a, TE1m, TE2a, and TGv, which are multimodal. In a ventromedial visual stream, V1-V4 connect to ventromedial regions VMV1-3 and VVC. VMV1-3 and VVC connect to the medial parahippocampal gyrus PHA1-3, which, with the VMV regions, include the parahippocampal scene area. The medial parahippocampal PHA1-3 regions have connectivity to the hippocampal system regions the perirhinal cortex, entorhinal cortex, and hippocampus. These effective connectivities of two ventral visual cortical streams measured with magnetoencephalography provide support to the hierarchical organization of brain systems measured with fMRI, and new evidence on directionality.

Aging and Alzheimer's disease have dissociable effects on local and regional medial temporal lobe connectivity.

Functional disruption of the medial temporal lobe-dependent networks is thought to underlie episodic memory deficits in aging and Alzheimer's disease. Previous studies revealed that the anterior medial temporal lobe is more vulnerable to pathological and neurodegenerative processes in Alzheimer's disease. In contrast, cognitive and structural imaging literature indicates posterior, as opposed to anterior, medial temporal lobe vulnerability in normal aging. However, the extent to which Alzheimer's and aging-related pathological processes relate to functional disruption of the medial temporal lobe-dependent brain networks is poorly understood. To address this knowledge gap, we examined functional connectivity alterations in the medial temporal lobe and its immediate functional neighbourhood-the Anterior-Temporal and Posterior-Medial brain networks-in normal agers, individuals with preclinical Alzheimer's disease and patients with Mild Cognitive Impairment or mild dementia due to Alzheimer's disease. In the Anterior-Temporal network and in the perirhinal cortex, in particular, we observed an inverted 'U-shaped' relationship between functional connectivity and Alzheimer's stage. According to our results, the preclinical phase of Alzheimer's disease is characterized by increased functional connectivity between the perirhinal cortex and other regions of the medial temporal lobe, as well as between the anterior medial temporal lobe and its one-hop neighbours in the Anterior-Temporal system. This effect is no longer present in symptomatic Alzheimer's disease. Instead, patients with symptomatic Alzheimer's disease displayed reduced hippocampal connectivity within the medial temporal lobe as well as hypoconnectivity within the Posterior-Medial system. For normal aging, our results led to three main conclusions: (i) intra-network connectivity of both the Anterior-Temporal and Posterior-Medial networks declines with age; (ii) the anterior and posterior segments of the medial temporal lobe become increasingly decoupled from each other with advancing age; and (iii) the posterior subregions of the medial temporal lobe, especially the parahippocampal cortex, are more vulnerable to age-associated loss of function than their anterior counterparts. Together, the current results highlight evolving medial temporal lobe dysfunction in Alzheimer's disease and indicate different neurobiological mechanisms of the medial temporal lobe network disruption in aging versus Alzheimer's disease.

Acute stress impairs visual path integration

Acute stress exerts substantial effects on episodic memory, which are often mediated by glucocorticoids, the end-product of the hypothalamic-pituitary-adrenal axis. Surprisingly little is known, however, about the influence of acute stress on human spatial navigation. One specific navigational strategy is path integration, which is linked to the medial entorhinal cortex, a region harboring glucocorticoid receptors and thus susceptible for stress effects. Here, we investigated effects of acute stress on path integration performance using a virtual homing task. We divided a sample of healthy young male participants into a stress group (nstress = 32) and a control group (ncontrol = 34). The stress group underwent the socially evaluated cold-pressor test, while the control group underwent a non-stressful control procedure. Stress induction was confirmed via physiological and subjective markers, including an increase of salivary cortisol concentrations. We applied linear mixed models to investigate the effect of acute stress on path integration depending on task difficulty and the presence or absence of spatial cues. These analyses revealed that stress impaired path integration especially in trials with high difficulty and led to greater decline of performance upon removal of spatial cues. Stress-induced deficits were strongly related to impaired distance estimation, and to a lesser extent to compromised rotation estimation. These behavioral findings are in accordance with the hypothesis that acute stress impairs path integration processes, potentially by affecting the entorhinal grid cell system. More generally, the current data suggests acute stress to impair cognitive functions mediated by medial temporal lobe regions outside the hippocampus.

Anatomical predictors of need for decompressive craniectomy after stroke using voxel-based lesion symptom mapping.

Malignant cerebral edema (MCE) secondary to ischemic stroke is a highly morbid condition. Decompressive craniectomy (DC) is the only treatment for MCE that has been shown to reduce mortality. We examined whether early infarction and/or hypoperfusion in specific topographic regions was predictive of the need for later DC. A retrospective database of patients evaluated for large vessel occlusion (LVO) stroke at Stanford between 2010 and 2019 was used. Thirty patients with LVO and baseline perfusion MRI who underwent DC were evaluated. Propensity matching based on age, lesion size, and recanalization status was performed on the remaining cohort. Baseline masks of apparent diffusion coefficient (ADC)+Tmax >6seconds lesions were generated using automated perfusion software. Voxel-based lesion symptom maping was used to perform logistic regression at each voxel to generate statistical maps of lesion location associated with DC. Hemispheres were combined to increase statistical power. Sixty patients were analyzed. After adjusting for age, lesion size, and recanalization status as covariates, scattered cortical regions, predominately within the temporal and frontal lobe, were mildly to moderately predictive of the need for DC (z-scores: 2.4-6.74, p<.01). Scattered temporal and frontal lobe regions on baseline diffusion and perfusion MRI were found to be mildly to moderately predictive of the need for subsequent DC in patients with LVO stroke.

Altered resting-state functional connectivity patterns in late middle-aged and older adults with obstructive sleep apnea.

Obstructive sleep apnea (OSA) is increasingly recognized as a risk factor for cognitive decline, and has been associated with structural brain alterations in regions relevant to memory processes and Alzheimer's disease. However, it is unclear whether OSA is associated with disrupted functional connectivity (FC) patterns between these regions in late middle-aged and older populations. Thus, we characterized the associations between OSA severity and resting-state FC between the default mode network (DMN) and medial temporal lobe (MTL) regions. Second, we explored whether significant FC changes differed depending on cognitive status and were associated with cognitive performance. Ninety-four participants [24 women, 65.7 ± 6.9 years old, 41% with Mild Cognitive Impairment (MCI)] underwent a polysomnography, a comprehensive neuropsychological assessment and a resting-state functional magnetic resonance imaging (MRI). General linear models were conducted between OSA severity markers (i.e., the apnea-hypopnea, oxygen desaturation and microarousal indices) and FC values between DMN and MTL regions using CONN toolbox. Partial correlations were then performed between OSA-related FC patterns and (i) OSA severity markers in subgroups stratified by cognitive status (i.e., cognitively unimpaired versus MCI) and (ii) cognitive scores in the whole sample. All analyzes were controlled for age, sex and education, and considered significant at a p < 0.05 threshold corrected for false discovery rate. In the whole sample, a higher apnea-hypopnea index was significantly associated with lower FC between (i) the medial prefrontal cortex and bilateral hippocampi, and (ii) the left hippocampus and both the posterior cingulate cortex and precuneus. FC patterns were not associated with the oxygen desaturation index, or micro-arousal index. When stratifying the sample according to cognitive status, all associations remained significant in cognitively unimpaired individuals but not in the MCI group. No significant associations were observed between cognition and OSA severity or OSA-related FC patterns. OSA severity was associated with patterns of lower FC in regions relevant to memory processes and Alzheimer's disease. Since no associations were found with cognitive performance, these FC changes could precede detectable cognitive deficits. Whether these FC patterns predict future cognitive decline over the long-term needs to be investigated.

Perirhinal cortex automatically tracks multiple types of familiarity regardless of task-relevance

Perirhinal cortex (PrC) has long been implicated in familiarity assessment for objects and corresponding concepts. However, extant studies have focused mainly on changes in familiarity induced by recent exposure in laboratory settings. There is an increasing appreciation of other types of familiarity signals, in particular graded familiarity accumulated throughout one's lifetime. In prior work (Duke et al., 2017, Cortex, 89, 61–70), PrC has been shown to track lifetime familiarity ratings when participants make related judgements. A theoretically important characteristic of familiarity is its proposed automaticity. Support for automaticity comes from a documented impact of recent stimulus exposure on behavioral performance, and on PrC signals, under conditions in which this exposure is not task relevant. In the current fMRI study, we tested whether PrC also tracks lifetime familiarity of object concepts automatically, and whether this type of familiarity influences behavior even when it is not task relevant. During scanning, neurotypical participants (N = 30, age range 18–40, 7 males) provided animacy judgements about concrete object concepts presented at differing frequencies in an initial study phase. In a subsequent test phase, they made graded judgements of recent or lifetime familiarity. Behavioral performance showed sensitivity to lifetime familiarity even when it was not relevant for the task at hand. Across five sets of fMRI analyses, we found that PrC consistently tracked recent and lifetime familiarity of object concepts regardless of the task performed. Critically, while several other temporal-lobe regions also showed isolated familiarity effects, none of them tracked familiarity with the same consistency. These findings demonstrate that PrC automatically tracks multiple types of familiarity. They support models that assign a broad role in the representation of information about object concepts to this structure.

The radiomics features of the temporal lobe region related to menopause based on MR-T2WI can be used as potential biomarkers for AD.

Menopause may be an important pathogenic factor for Alzheimer's disease (AD). The M1 polarization of microglia and neuroinflammatory responses occur in the early pathogenetic stages of AD. Currently, no effective monitoring markers are available for AD's early pathological manifestations. Radiomics is an automated feature generation method for the extraction of hundreds of quantitative phenotypes (radiomics features) from radiology images. In this study, we retrospectively analyzed the magnetic resonance T2-weighted imaging (MR-T2WI) on the temporal lobe region and clinical data of both premenopausal and postmenopausal women. There were three significant differences were identified for select radiomic features in the temporal lobe between premenopausal and postmenopausal women, i.e. the texture feature Original-glcm-Idn (OI) based on the Original image, the filter-based first-order feature Log-firstorder-Mean (LM), and the texture feature Wavelet-LHH-glrlm-Run Length Nonuniformity (WLR). In humans, these three features were significantly correlated with the timing of menopause. In mice, these features were also different between the sham and ovariectomy (OVX) groups and were significantly associated with neuronal damage, microglial M1 polarization, neuroinflammation, and cognitive decline in the OVX groups. In AD patients, OI was significantly associated with cognitive decline, while LM was associated with anxiety and depression. OI and WLR could distinguish AD from healthy controls. In conclusion, radiomics features based on brain MR-T2WI scans have the potential to serve as biomarkers for AD and noninvasive monitoring of pathological progression in the temporal lobe of the brain in women undergoing menopause.

Traumatic brain injury alters the relationship between brain structure and episodic memory.

Focal and diffuse pathology resulting from traumatic brain injury (TBI) often disrupts brain circuitry that is critical for episodic memory, including medial temporal lobe and prefrontal regions. Prior studies have focused on unitary accounts of temporal lobe function, associating verbally learned material and brain morphology. Medial temporal lobe structures, however, are domain-sensitive, preferentially supporting different visual stimuli. There has been little consideration of whether TBI preferentially disrupts the type of visually learned material and its association with cortical morphology following injury. Here, we investigated whether (1) episodic memory deficits differ according to the stimulus type, and (2) the pattern in memory performance can be linked to changes in cortical thickness. Forty-three individuals with moderate-severe TBI and 38 demographically similar healthy controls completed a recognition task in which memory was assessed for three categories of stimuli: faces, scenes, and animals. The association between episodic memory accuracy on this task and cortical thickness was subsequently examined within and between groups. Our behavioral results support the notion of category-specific impairments: the TBI group had significantly impaired accuracy for memory for faces and scenes, but not animals. Moreover, the association between cortical thickness and behavioral performance was only significant for faces between groups. Taken together, these behavioral and structural findings provide support for an emergent memory account, and highlight that cortical thickness differentially affects episodic memory for specific categories of stimuli.

Adolescent brain development in girls with Turner syndrome.

Turner syndrome (TS) is a common sex chromosome aneuploidy in females associated with various physical, cognitive, and socio-emotional phenotypes. However, few studies have examined TS-associated alterations in the development of cortical gray matter volume and the two components that comprise this measure-surface area and thickness. Moreover, the longitudinal direct (i.e., genetic) and indirect (i.e., hormonal) effects of X-monosomy on the brain are unclear. Brain structure was assessed in 61 girls with TS (11.3 ± 2.8 years) and 55 typically developing girls (10.8 ± 2.3 years) for up to 4 timepoints. Surface-based analyses of cortical gray matter volume, thickness, and surface area were conducted to examine the direct effects of X-monosomy present before pubertal onset and indirect hormonal effects of estrogen deficiency/X-monosomy emerging after pubertal onset. Longitudinal analyses revealed that, whereas typically developing girls exhibited normative declines in gray matter structure during adolescence, this pattern was reduced or inverted in TS. Further, girls with TS demonstrated smaller total surface area and larger average cortical thickness overall. Regionally, the TS group exhibited decreased volume and surface area in the pericalcarine, postcentral, and parietal regions relative to typically developing girls, as well as larger volume in the caudate, amygdala, and temporal lobe regions and increased thickness in parietal and temporal regions. Surface area alterations were predominant by age 8, while maturational differences in thickness emerged by age 10 or later. Taken together, these results suggest the involvement of both direct and indirect effects of X-chromosome haploinsufficiency on brain development in TS.

Associations of category fluency clustering performance with in vivo brain pathology in autosomal dominant Alzheimer's disease.

Alzheimer's disease (AD) is known to impact semantic access, which is frequently evaluated using the Category Fluency (Animals) test. Recent studies have suggested that in addition to overall category fluency scores (total number of words produced over time), poor clustering could signal AD-related cognitive difficulties. In this study, we examined the association between category fluency clustering performance (i.e., stating words sequentially that are all contained within a subcategory, such as domestic animals) and brain pathology in individuals with autosomal dominant Alzheimer's disease (ADAD). A total of 29 non-demented carriers of the Presenilin1 E280A ADAD mutation and 32 noncarrier family members completed the category fluency test (Animals) and the Mini-Mental State Examination (MMSE). The participants also underwent positron emission tomography (PET) scans to evaluate in vivo amyloid-beta in the neocortex and tau in medial temporal lobe regions. Differences between carriers and noncarriers on cognitive tests were assessed with Mann-Whitney tests; associations between cognitive test performance and brain pathology were assessed with Spearman correlations. Animal fluency scores did not differ between carriers and noncarriers. Carriers, however, showed a stronger association between animal fluency clustering and in vivo AD brain pathology (neocortical amyloid and entorhinal tau) relative to noncarriers. This study indicates that using category fluency clustering, but not total score, is related to AD pathophysiology in the preclinical and early stages of the disease.

Remote effects of temporal lobe epilepsy surgery: Long-term morphological changes after surgical resection.

Epilepsy surgery is an effective treatment for drug-resistant patients. However, how different surgical approaches affect long-term brain structure remains poorly characterized. Here, we present a semiautomated method for quantifying structural changes after epilepsy surgery and compare the remote structural effects of two approaches, anterior temporal lobectomy (ATL), and selective amygdalohippocampectomy (SAH). We studied 36 temporal lobe epilepsy patients who underwent resective surgery (ATL = 22, SAH = 14). All patients received same-scanner MR imaging preoperatively and postoperatively (mean 2 years). To analyze postoperative structural changes, we segmented the resection zone and modified the Advanced Normalization Tools (ANTs) longitudinal cortical pipeline to account for resections. We compared global and regional annualized cortical thinning between surgical treatments. Across procedures, there was significant cortical thinning in the ipsilateral insula, fusiform, pericalcarine, and several temporal lobe regions outside the resection zone as well as the contralateral hippocampus. Additionally, increased postoperative cortical thickness was seen in the supramarginal gyrus. Patients treated with ATL exhibited greater annualized cortical thinning compared with SAH cases (ATL: -0.08 ± 0.11 mm per year, SAH: -0.01 ± 0.02 mm per year, t = 2.99, P = 0.006). There were focal postoperative differences between the two treatment groups in the ipsilateral insula (P = 0.039, corrected). Annualized cortical thinning rates correlated with preoperative cortical thickness (r = 0.60, P < 0.001) and had weaker associations with age at surgery (r = -0.33, P = 0.051) and disease duration (r = -0.42, P = 0.058). Our evidence suggests that selective procedures are associated with less cortical thinning and that earlier surgical intervention may reduce long-term impacts on brain structure.

Metabolic Changes in Medial Temporal Lobe Epilepsy Compared to Healthy Controls Using Advanced [18F] FDG PET SPM Analysis Techniques

Objectives: [18F] FDG PET imaging has emerged as an established modality in the evaluation of medically refractory temporal lobe epilepsy. Advanced techniques improve the sensitivity and detection of abnormalities. We sought to measure changes in metabolic activity using [18F] FDG PET in Medial Temporal Lobe Epilepsy (MTLE) patients compared to healthy controls and evaluate changes in the Seizure Onset Zone (SOZ) and remote areas. Methods: We evaluated a cohort of 14 MTLE patients. Following a standard brain [18F] FDG PET acquisition, images were co-registered to a healthy control database using the Neuro-MIM software. Z scores were generated for different temporal and extra-temporal lobe structures for significant p values &lt;0.05. Seizure laterality was determined by experienced epileptologists (&gt;10 years) using intracranial or surface depth electrodes. Results: The mean age of our patient cohort was 33.9 years (range: 9-52 years). We evaluated 7 left MTLE, 1 bilateral MTLE, and 6 right MTLE patients. Significant hypometabolic changes were seen in the amygdala, the hippocampus, and overall, the medial temporal lobe region (Z score of -2.2, -2.3, and -2.1 respectively). There was a smaller decrease in metabolic activity observed in the parahippocampal gyrus, fusiform gyrus, and the lateral temporal lobe (Z score of -1.4, -1.2, and -1.1 respectively). There were no significant differences in the basal ganglia, thalamus, prefrontal cortex, or cingulate gyrus. Conclusions: Measurable significant differences in FDG brain metabolic activity exist in medial temporal lobe epilepsy patients compared to healthy controls. Our study shows the most significant changes are hypometabolism in the amygdala, hippocampus, and overall, the medial temporal lobe region compared to the lateral temporal lobe.

A Learned Map for Places and Concepts in the Human Medial Temporal Lobe.

Distinct lines of research in both humans and animals point to a specific role of the hippocampus in both spatial and episodic memory function. The discovery of concept cells in the hippocampus and surrounding medial temporal lobe (MTL) regions suggests that the MTL maps physical and semantic spaces with a similar neural architecture. Here, we studied the emergence of such maps using MTL microwire recordings from 20 patients (9 female, 11 male) navigating a virtual environment featuring salient landmarks with established semantic meaning. We present several key findings. The array of local field potentials in the MTL contains sufficient information for above-chance decoding of subjects' instantaneous location in the environment. Closer examination revealed that as subjects gain experience with the environment the field potentials come to represent both the subjects' locations in virtual space and in high-dimensional semantic space. Similarly, we observe a learning effect on temporal sequence coding. Over time, field potentials come to represent future locations, even after controlling for spatial proximity. This predictive coding of future states, more so than the strength of spatial representations per se, is linked to variability in subjects' navigation performance. Our results thus support the conceptualization of the MTL as a memory space, representing both spatial- and nonspatial information to plan future actions and predict their outcomes.SIGNIFICANCE STATEMENT Using rare microwire recordings, we studied the representation of spatial, semantic, and temporal information in the human MTL. Our findings demonstrate that subjects acquire a cognitive map that simultaneously represents the spatial and semantic relations between landmarks. We further show that the same learned representation is used to predict future states, implicating MTL cell assemblies as the building blocks of prospective memory functions.