The APOE4 effect: structural brain differences in Alzheimer's disease according to the age at symptom onset.

BACKGROUND AND PURPOSE: How the APOE genotype can differentially affect cortical and subcortical memory structures in biomarker-confirmed early-onset (EOAD) and late-onset (LOAD) Alzheimer's disease (AD) was assessed. METHOD: Eighty-seven cerebrospinal fluid (CSF) biomarker-confirmed AD patients were classified according to their APOE genotype and age at onset. 28 were EOAD APOE4 carriers (+EOAD), 21 EOAD APOE4 non-carriers (-EOAD), 23 LOAD APOE4 carriers (+LOAD) and 15 LOAD APOE4 non-carriers (-LOAD). Grey matter (GM) volume differences were analyzed using voxel-based morphometry in Papez circuit regions. Multiple regression analyses were performed to determine the relation between GM volume loss and cognition. RESULTS: Significantly more mammillary body atrophy in +EOAD compared to -EOAD is reported. The medial temporal and posterior cingulate cortex showed less GM in +LOAD compared to -LOAD. Medial temporal GM volume loss was also found in +EOAD compared to -LOAD. With an exception for +EOAD, medial temporal GM was strongly associated with episodic memory in the three groups, whilst posterior cingulate cortex GM volume was more related with visuospatial abilities. Visuospatial abilities and episodic memory were also associated with the anterior thalamic nucleus in -LOAD. CONCLUSIONS: Our results show that the APOE genotype has a significant effect on GM integrity as a function of age of disease onset. Specifically, whilst LOAD APOE4 genotype is mostly associated with increased medial temporal and parietal atrophy compared to -LOAD, for EOAD APOE4 might have a more specific effect on subcortical (mammillary body) structures. The findings suggest that APOE genotype needs to be taken into account when classifying patients by age at onset.

Multimodal Neurocognitive Markers of Naturalistic Discourse Typify Diverse Neurodegenerative Diseases.

Neurodegeneration has multiscalar impacts, including behavioral, neuroanatomical, and neurofunctional disruptions. Can disease-differential alterations be captured across such dimensions using naturalistic stimuli? To address this question, we assessed comprehension of four naturalistic stories, highlighting action, nonaction, social, and nonsocial events, in Parkinson's disease (PD) and behavioral variant frontotemporal dementia (bvFTD) relative to Alzheimer's disease patients and healthy controls. Text-specific correlates were evaluated via voxel-based morphometry, spatial (fMRI), and temporal (hd-EEG) functional connectivity. PD patients presented action-text deficits related to the volume of action-observation regions, connectivity across motor-related and multimodal-semantic hubs, and frontal hd-EEG hypoconnectivity. BvFTD patients exhibited social-text deficits, associated with atrophy and spatial connectivity patterns along social-network hubs, alongside right frontotemporal hd-EEG hypoconnectivity. Alzheimer's disease patients showed impairments in all stories, widespread atrophy and spatial connectivity patterns, and heightened occipitotemporal hd-EEG connectivity. Our framework revealed disease-specific signatures across behavioral, neuroanatomical, and neurofunctional dimensions, highlighting the sensitivity and specificity of a single naturalistic task. This investigation opens a translational agenda combining ecological approaches and multimodal cognitive neuroscience for the study of neurodegeneration.

Going round in circles-The Papez circuit in Alzheimer's disease.

The hippocampus is regarded as the pivotal structure for episodic memory symptoms associated with Alzheimer's disease (AD) pathophysiology. However, what is often overlooked is that the hippocampus is 'only' one part of a network of memory critical regions, the Papez circuit. Other Papez circuit regions are often regarded as less relevant for AD as they are thought to sit 'downstream' of the hippocampus. However, this notion is oversimplistic, and increasing evidence suggests that other Papez regions might be affected before or concurrently with the hippocampus. In addition, AD research has mostly focused on episodic memory deficits, whereas spatial navigation processes are also subserved by the Papez circuit with increasing evidence supporting its valuable potential as a diagnostic measure of incipient AD pathophysiology. In the current review, we take a step forward analysing recent evidence on the structural and functional integrity of the Papez circuit across AD disease stages. Specifically, we will review the integrity of specific Papez regions from at-genetic-risk (APOE4 carriers), to mild cognitive impairment (MCI), to dementia stage of sporadic AD and autosomal dominant AD (ADAD). We related those changes to episodic memory and spatial navigation/orientation deficits in AD. Finally, we provide an overview of how the Papez circuit is affected in AD diseases and their specific symptomology contributions. This overview strengthened the need for moving away from a hippocampal-centric view to a network approach on how the whole Papez circuit is affected in AD and contributes to its symptomology, informing future research and clinical approaches.

GERO Cohort Protocol, Chile, 2017-2022: Community-based Cohort of Functional Decline in Subjective Cognitive Complaint elderly.

BACKGROUND: With the global population aging and life expectancy increasing, dementia has turned a priority in the health care system. In Chile, dementia is one of the most important causes of disability in the elderly and the most rapidly growing cause of death in the last 20 years. Cognitive complaint is considered a predictor for cognitive and functional decline, incident mild cognitive impairment, and incident dementia. The GERO cohort is the Chilean core clinical project of the Geroscience Center for Brain Health and Metabolism (GERO). The objective of the GERO cohort is to analyze the rate of functional decline and progression to clinical dementia and their associated risk factors in a community-dwelling elderly with subjective cognitive complaint, through a population-based study. We also aim to undertake clinical research on brain ageing and dementia disorders, to create data and biobanks with the appropriate infrastructure to conduct other studies and facilitate to the national and international scientific community access to the data and samples for research. METHODS: The GERO cohort aims the recruitment of 300 elderly subjects (> 70 years) from Santiago (Chile), following them up for at least 3 years. Eligible people are adults not diagnosed with dementia with subjective cognitive complaint, which are reported either by the participant, a proxy or both. Participants are identified through a household census. The protocol for evaluation is based on a multidimensional approach including socio-demographic, biomedical, psychosocial, neuropsychological, neuropsychiatric and motor assessments. Neuroimaging, blood and stool samples are also obtained. This multidimensional evaluation is carried out in a baseline and 2 follow-ups assessments, at 18 and 36 months. In addition, in months 6, 12, 24, and 30, a telephone interview is performed in order to keep contact with the participants and to assess general well-being. DISCUSSION: Our work will allow us to determine multidimensional risks factors associated with functional decline and conversion to dementia in elderly with subjective cognitive complain. The aim of our GERO group is to establish the capacity to foster cutting edge and multidisciplinary research on aging in Chile including basic and clinical research. TRIAL REGISTRATION: NCT04265482 in ClinicalTrials.gov. Registration Date: February 11, 2020. Retrospectively Registered.

Your perspective and my benefit: multiple lesion models of self-other integration strategies during social bargaining.

Recursive social decision-making requires the use of flexible, context-sensitive long-term strategies for negotiation. To succeed in social bargaining, participants' own perspectives must be dynamically integrated with those of interactors to maximize self-benefits and adapt to the other's preferences, respectively. This is a prerequisite to develop a successful long-term self-other integration strategy. While such form of strategic interaction is critical to social decision-making, little is known about its neurocognitive correlates. To bridge this gap, we analysed social bargaining behaviour in relation to its structural neural correlates, ongoing brain dynamics (oscillations and related source space), and functional connectivity signatures in healthy subjects and patients offering contrastive lesion models of neurodegeneration and focal stroke: behavioural variant frontotemporal dementia, Alzheimer's disease, and frontal lesions. All groups showed preserved basic bargaining indexes. However, impaired self-other integration strategy was found in patients with behavioural variant frontotemporal dementia and frontal lesions, suggesting that social bargaining critically depends on the integrity of prefrontal regions. Also, associations between behavioural performance and data from voxel-based morphometry and voxel-based lesion-symptom mapping revealed a critical role of prefrontal regions in value integration and strategic decisions for self-other integration strategy. Furthermore, as shown by measures of brain dynamics and related sources during the task, the self-other integration strategy was predicted by brain anticipatory activity (alpha/beta oscillations with sources in frontotemporal regions) associated with expectations about others' decisions. This pattern was reduced in all clinical groups, with greater impairments in behavioural variant frontotemporal dementia and frontal lesions than Alzheimer's disease. Finally, connectivity analysis from functional magnetic resonance imaging evidenced a fronto-temporo-parietal network involved in successful self-other integration strategy, with selective compromise of long-distance connections in frontal disorders. In sum, this work provides unprecedented evidence of convergent behavioural and neurocognitive signatures of strategic social bargaining in different lesion models. Our findings offer new insights into the critical roles of prefrontal hubs and associated temporo-parietal networks for strategic social negotiation.

Thalamic nuclei changes in early and late onset Alzheimer's disease.

Alzheimer's disease (AD) is the most common cause of dementia worldwide. Increasing evidence points to the thalamus as an important hub in the clinical symptomatology of the disease, with the 'limbic thalamus' been described as especially vulnerable. In this work, we examined thalamic atrophy in early-onset AD (EOAD) and late-onset AD (LOAD) compared to young and old healthy controls (YHC and OHC, respectively) using a recently developed cutting-edge thalamic nuclei segmentation method. A deep learning variant of Thalamus Optimized Multi Atlas Segmentation (THOMAS) was used to parcellate 11 thalamic nuclei per hemisphere from T1-weighted MRI in 88 biomarker-confirmed AD patients (49 EOAD and 39 LOAD) and 58 healthy controls (41 YHC and 17 OHC) with normal AD biomarkers. Nuclei volumes were compared among groups using MANCOVA. Further, Pearson's correlation coefficient was computed between thalamic nuclear volume and cortical-subcortical regions, CSF tau levels, and neuropsychological scores. The results showed widespread thalamic nuclei atrophy in EOAD and LOAD compared to their respective healthy control groups, with EOAD showing additional atrophy in the centromedian and ventral lateral posterior nuclei compared to YHC. In EOAD, increased thalamic nuclei atrophy was associated with posterior parietal atrophy and worse visuospatial abilities, while LOAD thalamic nuclei atrophy was preferentially associated with medial temporal atrophy and worse episodic memory and executive function. Our findings suggest that thalamic nuclei may be differentially affected in AD according to the age at symptoms onset, associated with specific cortical-subcortical regions, CSF total tau and cognition.

The "when" matters: Evidence from memory markers in the clinical continuum of Alzheimer's disease.

OBJECTIVE: Cognitive assessment able to detect impairments in the early neuropathological stages of Alzheimer's disease (AD) is urgently needed. The visual short-term memory binding task (VSTMBT) and the Free and Cued Selective Reminding Test (FCSRT) have been recommended by the neurodegenerative disease working group as promising tests to aid in the early detection of AD. In this study, we investigated their complementary value across the clinical stages of the AD continuum. METHOD: One hundred and seventeen older adults with subjective cognitive complaint (SCC), 79 with mild cognitive impairment (MCI), 31 patients with AD dementia (ADD), and 37 cognitively unimpaired (CU) subjects, underwent assessment with the VSTMBT and the picture version of the Spanish FCSRT. RESULTS: After controlling for multiple comparisons, significant differences were found across groups. The VSTMBT was the only test that "marginally" differentiated between CU and SCC (d = 0.47, p = .052). Moreover, whereas the FCSRT showed a gradient (CU = SCC) > MCI > ADD, the VSTMBT gradient was CU > SCC > (MCI = ADD) suggesting that conjunctive binding deficits assessed by the latter may be sensitive to the very early stages of the disease. CONCLUSIONS: Our results suggest that the VSTMBT and the FCSRT are sensitive to the clinical continuum of AD. Whereas the former detects changes in the early prodromal stages, the latter is more sensitive to the advanced prodromal stages of AD. These novel tests can aid in the early detection, monitor disease progression and response to treatment, and thus support drug development programs. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Moral Emotions and Their Brain Structural Correlates Across Neurodegenerative Disorders.

BACKGROUND: Although social cognition is compromised in patients with neurodegenerative disorders such as behavioral variant frontotemporal dementia (bvFTD) and Alzheimer's disease (AD), research on moral emotions and their neural correlates in these populations is scarce. No previous study has explored the utility of moral emotions, compared to and in combination with classical general cognitive state tools, to discriminate bvFTD from AD patients. OBJECTIVE: To examine self-conscious (guilt and embarrassment) and other-oriented (pity and indignation) moral emotions, their subjective experience, and their structural brain underpinnings in bvFTD (n = 31) and AD (n = 30) patients, compared to healthy controls (n = 37). We also explored the potential utility of moral emotions measures to discriminate bvFTD from AD. METHODS: We used a modified version of the Moral Sentiment Task measuring the participants' accuracy scores and their emotional subjective experiences. RESULTS: bvFTD patients exhibited greater impairments in self-conscious and other-oriented moral emotions as compared with AD patients and healthy controls. Moral emotions combined with general cognitive state tools emerged as useful measures to discriminate bvFTD from AD patients. In bvFTD patients, lower moral emotions scores were associated with lower gray matter volumes in caudate nucleus and inferior and middle temporal gyri. In AD, these scores were associated with lower gray matter volumes in superior and middle frontal gyri, middle temporal gyrus, inferior parietal lobule and supramarginal gyrus. CONCLUSION: These findings contribute to a better understanding of moral emotion deficits across neurodegenerative disorders, highlighting the potential benefits of integrating this domain into the clinical assessment.

Peripubertal soy isoflavone consumption leads to subclinical hypothyroidism in male Wistar rats.

Exposure to endocrine-disrupting chemicals during critical windows of development may lead to functional abnormalities in adulthood. Isoflavones are a flavonoid group of phytoestrogens that are recognized by their estrogenic activity and are highly abundant in soybean. Since the thyroid gland presents estrogen receptors and infants, toddlers and teenagers may consume isoflavones from soy-based infant formula and beverages as alternatives to animal milk, we propose to investigate the potential effects of relevant concentrations of soy isoflavones in the regulation of the hypothalamic-pituitary (HP) thyroid axis using peripubertal male rats as an experimental model. Thirty-two 23-day-old male rats were exposed to 0.5, 5, or 50 mg of soy isoflavones/kg from weaning to 60 days of age, when they were euthanized, and the tissues were collected to evaluate the mRNA expression of genes involved in the regulation of the HP thyroid axis and dosages of thyroid hormones (THs). Serum TSH concentrations were increased, while alterations were not observed in serum concentrations of triiodothyronine and thyroxine. Regarding mRNA gene expression, Mct-8 was increased in the hypothalamus, Mct-8, Thra1, and Thrb2 were decreased in the pituitary, and Nis and Pds were reduced in the thyroid. In the heart, Mct8 and Thrb2 were increased, and Thra1 was decreased. In the liver, Mct8, Thra1, and Thrb2 were decreased. These results suggest that the consumption of relevant doses of soy isoflavones during the peripubertal period in males may induce subclinical hypothyroidism, with alterations in the regulation of the HP thyroid axis, modulation of TH synthesis, and peripheral alterations in TH target organs.

Consumption of soy isoflavones during the prepubertal phase delays puberty and causes hypergonadotropic hypogonadism with disruption of hypothalamic-pituitary gonadotropins regulation in male rats.

Isoflavones are phytoestrogens with recognized estrogenic activity but may also affect testosterone, corticosterone and thyroid hormone levels in experimental models. However, the molecular mechanisms involved in these alterations are still unclear. Isoflavones are present in soy-based infant formula, in breast milk after the consumption of soy by the mother and are widely used for the preparation of beverages consumed by toddlers and teenagers. In this sense, we proposed to investigate the effects of soy isoflavone exposure during the prepubertal period, a recognized window of sensitivity for endocrine disruption, over the hypothalamic-pituitary-testicular (HPT) axis. For this, 42 3-week-old male Wistar rats were exposed to 0.5, 5 or 50 mg of soy isoflavones/kg from postnatal day (PND) 23 to PND60. We evaluated body growth, age at puberty, serum concentrations of LH, FSH, testosterone and estradiol, and the expression of the transcripts (mRNA) of genes encoding key genes controlling the hypothalamic-pituitary-testicular (HPT) axis. In the hypothalamus, we observed an increase in Esr1 mRNA expression (0.5 and 5 mg). In the pituitary, we observed an increase in Gnrhr mRNA expression (50 mg), a reduction in Lhb mRNA expression (0.5 mg), and a reduction in Ar mRNA expression. In the testis, we observed an increase in Lhcgr mRNA expression (50 mg) and a reduction in Star mRNA expression (0.5 and 5 mg). The serum levels of LH (5 and 50 mg) and FSH (0.5 mg) were increased, while testosterone and estradiol were reduced. Puberty was delayed in all groups. Taken together, these results suggest that prepubertal consumption of relevant levels of soy isoflavones disrupts the HPT axis, causing hypergonadotropic hypogonadism and altered expression levels of key genes regulating the axis.

Automated text-level semantic markers of Alzheimer's disease.

INTRODUCTION: Automated speech analysis has emerged as a scalable, cost-effective tool to identify persons with Alzheimer's disease dementia (ADD). Yet, most research is undermined by low interpretability and specificity. METHODS: Combining statistical and machine learning analyses of natural speech data, we aimed to discriminate ADD patients from healthy controls (HCs) based on automated measures of domains typically affected in ADD: semantic granularity (coarseness of concepts) and ongoing semantic variability (conceptual closeness of successive words). To test for specificity, we replicated the analyses on Parkinson's disease (PD) patients. RESULTS: Relative to controls, ADD (but not PD) patients exhibited significant differences in both measures. Also, these features robustly discriminated between ADD patients and HC, while yielding near-chance classification between PD patients and HCs. DISCUSSION: Automated discourse-level semantic analyses can reveal objective, interpretable, and specific markers of ADD, bridging well-established neuropsychological targets with digital assessment tools.

Neurological soft signs (NSS) and cognitive deficits in HIV associated neurocognitive disorder.

Neurological soft signs (NSS) are frequently found in severe mental disorders, such as Alzheimer's disease, schizophrenia or HIV associated neurocognitive disorder (HAND) which includes asymptomatic neurocognitive impairment (ANI), mild neurocognitive disorder (MND) and HIV-associated dementia. To characterize NSS in patients with HIV we examined them with respect to neuropsychological deficits typically found in the disorder. 67 HIV + patients without a history of head trauma, opportunistic infections, severe psychiatric disorders or acute confounding comorbidities of the Central nervous system (CNS) were recruited. NSS and neuropsychological deficits were examined on the Heidelberg scale and the Cambridge Neuropsychological Test Automated Battery (CANTAB), respectively. Semantic and phonemic verbal fluency were additionally established. According to NIMH and NINDS criteria, 18 patients were diagnosed with ANI and 21 with MND, 28 showed no cognitive deficits. NSS total scores were significantly correlated with several cognitive domains and NSS subscales. These correlations were confirmed when motor performance was entered as a covariate. According to our findings, NSS in HIV positive patients are significantly correlated with deficits in a broad range of neuropsychological domains. Similar findings were reported in schizophrenia, emphasizing the transdiagnostic character of NSS and supporting NSS examination in screening HIV patients for HAND.

Mapping the neuroanatomy of functional decline in Alzheimer's disease from basic to advanced activities of daily living.

BACKGROUND: Impairments in activities of daily living (ADL) are a criterion for Alzheimer's disease (AD) dementia. However, ADL gradually decline in AD, impacting on advanced (a-ADL, complex interpersonal or social functioning), instrumental (IADL, maintaining life in community), and finally basic functions (BADL, activities related to physiological and self-maintenance needs). Information and communication technologies (ICT) have become an increasingly important aspect of daily functioning. Yet, the links of ADL, ICT, and neuropathology of AD dementia are poorly understood. Such knowledge is critical as it can provide biomarker evidence of functional decline in AD. METHODS: ADL were evaluated with the Technology-Activities of Daily Living Questionnaire (T-ADLQ) in 33 patients with AD and 30 controls. ADL were divided in BADL, IADL, and a-ADL. The three domain subscores were covaried against gray matter atrophy via voxel-based morphometry. RESULTS: Our results showed that three domain subscores of ADL correlate with several brain structures, with a varying degree of overlap between them. BADL score correlated mostly with frontal atrophy, IADL with more widespread frontal, temporal and occipital atrophy and a-ADL with occipital and temporal atrophy. Finally, ICT subscale was associated with atrophy in the precuneus. CONCLUSIONS: The association between ADL domains and neurodegeneration in AD follows a traceable neuropathological pathway which involves different neural networks. This the first evidence of ADL phenotypes in AD characterised by specific patterns of functional decline and well-defined neuropathological changes. The identification of such phenotypes can yield functional biomarkers for dementias such as AD.

Neurological soft signs as a marker of cognitive impairment severity in people living with HIV.

HIV-associated neurocognitive disorders (HAND) include asymptomatic neurocognitive impairment (ANI), mild neurocognitive disorder (MND) and HIV-associated dementia. Early recognition of HAND is crucial, and usually requires thorough neuropsychological testing. Neurological soft signs (NSS), i.e. minor motor and sensory changes, a common feature in severe psychiatric disorders, may facilitate early diagnosis. NSS were examined using the Heidelberg NSS Scale in 18 patients with ANI, 21 with MND, 28 HIV positive patients without HAND, and 39 healthy controls matched for age, gender, and education. The highest NSS scores were obtained in the MND patients (13.3 ±â€¯10.0, p < 0.0001) followed by those with ANI (11.7 ±â€¯10.6), the HIV positive subjects without neurocognitive deficits (8.0 ±â€¯4.1) and the healthy controls (3.8 ±â€¯3.2). This result was confirmed when age and years of school education were entered as covariates. No significant correlations between NSS and CD4 counts or any other clinical variables were found among the HIV positive groups. Our results demonstrate that NSS are frequently found in both ANI and MND but not HIV positive patients without neurocognitive deficits. NSS may facilitate the screening of HIV positive patients for ANI and MND as an easier and less expensive clinical tool.

Feeling, learning from and being aware of inner states: interoceptive dimensions in neurodegeneration and stroke.

Interoception is a complex process encompassing multiple dimensions, such as accuracy, learning and awareness. Here, we examined whether each of those dimensions relies on specialized neural regions distributed throughout the vast interoceptive network. To this end, we obtained relevant measures of cardiac interoception in healthy subjects and patients offering contrastive lesion models of neurodegeneration and focal brain damage: behavioural variant fronto-temporal dementia (bvFTD), Alzheimer's disease (AD) and fronto-insular stroke. Neural correlates of the three dimensions were examined through structural and functional resting-state imaging, and online measurements of the heart-evoked potential (HEP). The three patient groups presented deficits in interoceptive accuracy, associated with insular damage, connectivity alterations and abnormal HEP modulations. Interoceptive learning was differentially impaired in AD patients, evidencing a key role of memory networks in this skill. Interoceptive awareness results showed that bvFTD and AD patients overestimated their performance; this pattern was related to abnormalities in anterior regions and associated networks sub-serving metacognitive processes, and probably linked to well-established insight deficits in dementia. Our findings indicate how damage to specific hubs in a broad fronto-temporo-insular network differentially compromises interoceptive dimensions, and how such disturbances affect widespread connections beyond those critical hubs. This is the first study in which a multiple lesion model reveals fine-grained alterations of body sensing, offering new theoretical insights into neuroanatomical foundations of interoceptive dimensions.This article is part of the themed issue 'Interoception beyond homeostasis: affect, cognition and mental health'.

Intraperitoneal exposure to nano/microparticles of fullerene (C60) increases acetylcholinesterase activity and lipid peroxidation in adult zebrafish (Danio rerio) brain.

Even though technologies involving nano/microparticles have great potential, it is crucial to determine possible toxicity of these technological products before extensive use. Fullerenes C60 are nanomaterials with unique physicochemical and biological properties that are important for the development of many technological applications. The aim of this study was to evaluate the consequences of nonphotoexcited fullerene C60 exposure in brain acetylcholinesterase expression and activity, antioxidant responses, and oxidative damage using adult zebrafish as an animal model. None of the doses tested (7.5, 15, and 30 mg/kg) altered AChE activity, antioxidant responses, and oxidative damage when zebrafish were exposed to nonphotoexcited C60 nano/microparticles during 6 and 12 hours. However, adult zebrafish exposed to the 30 mg/kg dose for 24 hours have shown enhanced AChE activity and augmented lipid peroxidation (TBARS assays) in brain. In addition, the up-regulation of brain AChE activity was neither related to the transcriptional control (RT-qPCR analysis) nor to the direct action of nonphotoexcited C60 nano/microparticles on the protein (in vitro results) but probably involved a posttranscriptional or posttranslational modulation of this enzymatic activity. Taken together these findings provided further evidence of toxic effects on brain after C60 exposure.