A spontaneous hyperglycaemic cynomolgus monkey presents cognitive deficits, neurological dysfunction and cataract.

Chronic hyperglycaemia is a chief feature of diabetes mellitus and complicates with many systematic anomalies. Non-human primates (NHPs) are excellent for studying hyperglycaemia or diabetes and associated comorbidities, but lack behavioural observation. In the study, behavioural, brain imaging and histological analysis were performed in a case of spontaneously hyperglycaemic (HGM) Macaca fascicularis. The results were shown that the HGM monkey had persistent body weight loss, long-term hyperglycaemia, insulin resistance, dyslipidemia, but normal concentrations of insulin, C-peptide, insulin autoantibody, islet cell antibody and glutamic acid decarboxylase antibody. Importantly, an impaired working memory in a delayed response task and neurological dysfunctions were found in the HGM monkey. The tendency for atrophy in hippocampus was observed by magnetic resonance imaging. Lenticular opacification, lens fibres disruptions and vacuole formation also occurred to the HGM monkey. The data suggested that the spontaneous HGM monkey might present diabetes-like characteristics and associated neurobehavioral anomalies in this case. This study first reported cognitive deficits in a spontaneous hyperglycaemia NHPs, which might provide evidence to use macaque as a promising model for translational research in diabetes and neurological complications.

Lost in space(s): Multimodal neuroimaging of disorientation along the Alzheimer's disease continuum.

Orientation is a fundamental cognitive faculty and the bedrock of the neurologic examination. Orientation is defined as the alignment between an individual's internal representation and the external world in the spatial, temporal, and social domains. While spatial disorientation is a recognized hallmark of Alzheimer's disease (AD), little is known about disorientation beyond space in AD. This study aimed to explore disorientation in spatial, temporal, and social domains along the AD continuum. Fifty-one participants along the AD continuum performed an ecological orientation task in the spatial, temporal, and social domains while undergoing functional MRI. Disorientation in AD followed a three-way association between orientation domain, brain region, and disease stage. Specifically, patients with early amnestic mild cognitive impairment exhibited spatio-temporal disorientation and reduced brain activity in temporoparietal regions, while patients with AD dementia showed additional social disorientation and reduced brain activity in frontoparietal regions. Furthermore, patterns of hypoactivation overlapped different subnetworks of the default mode network, patterns of fluorodeoxyglucose hypometabolism, and cortical atrophy characteristic of AD. Our results suggest that AD may encompass a disorder of orientation, characterized by a biphasic process manifesting as early spatio-temporal and late social disorientation. As such, disorientation may offer a unique window into the clinicopathological progression of AD. SIGNIFICANCE STATEMENT: Despite extensive research into Alzheimer's disease (AD), its core cognitive deficit remains a matter of debate. In this study, we investigated whether orientation, defined as the ability to align internal representations with the external world in spatial, temporal, and social domains, constitutes a core cognitive deficit in AD. To do so, we used PET-fMRI imaging to collect behavioral, functional, and metabolic data from 51 participants along the AD continuum. Our findings suggest that AD may constitute a disorder of orientation, characterized by an early spatio-temporal disorientation and followed by late social disorientation, manifesting in task-evoked and neurodegenerative changes. We propose that a profile of disorientation across multiple domains offers a unique window into the progression of AD and as such could greatly benefit disease diagnosis, monitoring, and evaluation of treatment response.

Amyloid deposition and small vessel disease are associated with cognitive function in older adults with type 2 diabetes.

Diabetes is associated with cognitive decline, but the underlying mechanisms are complex and their relationship with Alzheimer's Disease biomarkers is not fully understood. We assessed the association of small vessel disease (SVD) and amyloid burden with cognitive functioning in 47 non-demented older adults with type-2 diabetes from the Israel Diabetes and Cognitive Decline Study (mean age 78Y, 64% females). FLAIR-MRI, Vizamyl amyloid-PET, and T1W-MRI quantified white matter hyperintensities as a measure of SVD, amyloid burden, and gray matter (GM) volume, respectively. Mean hemoglobin A1c levels and duration of type-2 diabetes were used as measures of diabetic control. Cholesterol level and blood pressure were used as measures of cardiovascular risk. A broad neuropsychological battery assessed cognition. Linear regression models revealed that both higher SVD and amyloid burden were associated with lower cognitive functioning. Additional adjustments for type-2 diabetes-related characteristics, GM volume, and cardiovascular risk did not alter the results. The association of amyloid with cognition remained unchanged after further adjustment for SVD, and the association of SVD with cognition remained unchanged after further adjustment for amyloid burden. Our findings suggest that SVD and amyloid pathology may independently contribute to lower cognitive functioning in non-demented older adults with type-2 diabetes, supporting a multimodal approach for diagnosing, preventing, and treating cognitive decline in this population.

A multiple hits hypothesis for memory dysfunction in Parkinson disease.

Cognitive disorders are increasingly recognized in Parkinson disease (PD), even in early disease stages, and memory is one of the most affected cognitive domains. Classically, hippocampal cholinergic system dysfunction was associated with memory disorders, whereas nigrostriatal dopaminergic system impairment was considered responsible for executive deficits. Evidence from PD studies now supports involvement of the amygdala, which modulates emotional attribution to experiences. Here, we propose a tripartite model including the hippocampus, striatum and amygdala as key structures for cognitive disorders in PD. First, the anatomo-functional relationships of these structures are explored and experimental evidence supporting their role in cognitive dysfunction in PD is summarized. We then discuss the potential role of α-synuclein, a pathological hallmark of PD, in the tripartite memory system as a key mechanism in the pathogenesis of memory disorders in the disease.

The role of the thalamus in modular functional networks in temporal lobe epilepsy with cognitive impairment.

OBJECTIVE: Cognitive deficit is common in patients with temporal lobe epilepsy (TLE). Here, we aimed to investigate the modular architecture of functional networks associated with distinct cognitive states in TLE patients together with the role of the thalamus in modular networks. METHODS: Resting-state functional magnetic resonance imaging scans were acquired from 53 TLE patients and 37 matched healthy controls. All patients received the Montreal Cognitive Assessment test and accordingly were divided into TLE patients with normal cognition (TLE-CN, n = 35) and TLE patients with cognitive impairment (TLE-CI, n = 18) groups. The modular properties of functional networks were calculated and compared including global modularity Q, modular segregation index, intramodular connections, and intermodular connections. Thalamic subdivisions corresponding to the modular networks were generated by applying a 'winner-take-all' strategy before analyzing the modular properties (participation coefficient and within-module degree z-score) of each thalamic subdivision to assess the contribution of the thalamus to modular functional networks. Relationships between network properties and cognitive performance were then further explored. RESULTS: Both TLE-CN and TLE-CI patients showed lower global modularity, as well as lower modular segregation index values for the ventral attention network and the default mode network. However, different patterns of intramodular and intermodular connections existed for different cognitive states. In addition, both TLE-CN and TLE-CI patients exhibited anomalous modular properties of functional thalamic subdivisions, with TLE-CI patients presenting a broader range of abnormalities. Cognitive performance in TLE-CI patients was not related to the modular properties of functional network but rather to the modular properties of functional thalamic subdivisions. CONCLUSIONS: The thalamus plays a prominent role in modular networks and potentially represents a key neural mechanism underlying cognitive impairment in TLE.

Inhibiting CSF1R alleviates cerebrovascular white matter disease and cognitive impairment.

White matter abnormalities, related to poor cerebral perfusion, are a core feature of small vessel cerebrovascular disease, and critical determinants of vascular cognitive impairment and dementia. Despite this importance there is a lack of treatment options. Proliferation of microglia producing an expanded, reactive population and associated neuroinflammatory alterations have been implicated in the onset and progression of cerebrovascular white matter disease, in patients and in animal models, suggesting that targeting microglial proliferation may exert protection. Colony-stimulating factor-1 receptor (CSF1R) is a key regulator of microglial proliferation. We found that the expression of CSF1R/Csf1r and other markers indicative of increased microglial abundance are significantly elevated in damaged white matter in human cerebrovascular disease and in a clinically relevant mouse model of chronic cerebral hypoperfusion and vascular cognitive impairment. Using the mouse model, we investigated long-term pharmacological CSF1R inhibition, via GW2580, and demonstrated that the expansion of microglial numbers in chronic hypoperfused white matter is prevented. Transcriptomic analysis of hypoperfused white matter tissue showed enrichment of microglial and inflammatory gene sets, including phagocytic genes that were the predominant expression modules modified by CSF1R inhibition. Further, CSF1R inhibition attenuated hypoperfusion-induced white matter pathology and rescued spatial learning impairments and to a lesser extent cognitive flexibility. Overall, this work suggests that inhibition of CSF1R and microglial proliferation mediates protection against chronic cerebrovascular white matter pathology and cognitive deficits. Our study nominates CSF1R as a target for the treatment of vascular cognitive disorders with broader implications for treatment of other chronic white matter diseases.

Huntington disease-like 2: insight into neurodegeneration from an African disease.

Huntington disease (HD)-like 2 (HDL2) is a rare genetic disease caused by an expanded trinucleotide repeat in the JPH3 gene (encoding junctophilin 3) that shows remarkable clinical similarity to HD. To date, HDL2 has been reported only in patients with definite or probable African ancestry. A single haplotype background is shared by patients with HDL2 from different populations, supporting a common African origin for the expansion mutation. Nevertheless, outside South Africa, reports of patients with HDL2 in Africa are scarce, probably owing to limited clinical services across the continent. Systematic comparisons of HDL2 and HD have revealed closely overlapping motor, cognitive and psychiatric features and similar patterns of cerebral and striatal atrophy. The pathogenesis of HDL2 remains unclear but it is proposed to occur through several mechanisms, including loss of protein function and RNA and/or protein toxicity. This Review summarizes our current knowledge of this African-specific HD phenocopy and highlights key areas of overlap between HDL2 and HD. Given the aforementioned similarities in clinical phenotype and pathology, an improved understanding of HDL2 could provide novel insights into HD and other neurodegenerative and/or trinucleotide repeat expansion disorders.

Cross-Sectional Analysis of Periodontal Disease and Cognitive Impairment Conducted in a Memory Clinic: The Pearl Study.

BACKGROUND: Periodontal disease (PeD) is a risk factor of Alzheimer's disease and is associated with cognitive decline in older adults. However, the relationships between subitems of neuropsychological tests and PeD have not been fully clarified. OBJECTIVE: To evaluate associations between PeD and subitems of neuropsychological tests. METHODS: We performed a cross-sectional analysis of data of 183 participants (women: 50%, mean age: 79 years) from a clinical study. We enrolled patients who visited our memory clinic and assessed demographics, dementia-related risk factors, neuropsychological tests, brain magnetic resonance images, and a dental screening check. We evaluated the relationships between cognitive function and PeD using multivariable logistic regression analyses. RESULTS: Participants with dementia were less likely to make periodical visits to the dentist, had fewer teeth, had less frequent tooth brushing habits, and were more likely to have PeD. Impaired cognitive function was significantly associated with an increasing degree of PeD. In multivariable logistic regression analyses, impaired visuospatial function and attention were associated with twice the risk of moderate or severe PeD compared with individuals with preserved visuospatial function and attention (odds ratio: 2.11, 95% confidence interval: 1.04-4.29, p = 0.037). Impaired word recall and recognition and following commands were associated with increased risk of PeD (odds ratio: 2.80, 95% confidence interval: 1.41-5.32, p = 0.003). CONCLUSIONS: Cognitive decline, such as impaired visuospatial function, attention, word recall and recognition, and inability to follow commands were independently and strongly associated with PeD. These items can be assessed easily on a daily basis.

The Spectrum of Cognitive Dysfunction in Amyotrophic Lateral Sclerosis: An Update.

Cognitive dysfunction is an important non-motor symptom in amyotrophic lateral sclerosis (ALS) that has a negative impact on survival and caregiver burden. It shows a wide spectrum ranging from subjective cognitive decline to frontotemporal dementia (FTD) and covers various cognitive domains, mainly executive/attention, language and verbal memory deficits. The frequency of cognitive impairment across the different ALS phenotypes ranges from 30% to 75%, with up to 45% fulfilling the criteria of FTD. Significant genetic, clinical, and pathological heterogeneity reflects deficits in various cognitive domains. Modern neuroimaging studies revealed frontotemporal degeneration and widespread involvement of limbic and white matter systems, with hypometabolism of the relevant areas. Morphological substrates are frontotemporal and hippocampal atrophy with synaptic loss, associated with TDP-43 and other co-pathologies, including tau deposition. Widespread functional disruptions of motor and extramotor networks, as well as of frontoparietal, frontostriatal and other connectivities, are markers for cognitive deficits in ALS. Cognitive reserve may moderate the effect of brain damage but is not protective against cognitive decline. The natural history of cognitive dysfunction in ALS and its relationship to FTD are not fully understood, although there is an overlap between the ALS variants and ALS-related frontotemporal syndromes, suggesting a differential vulnerability of motor and non-motor networks. An assessment of risks or the early detection of brain connectivity signatures before structural changes may be helpful in investigating the pathophysiological mechanisms of cognitive impairment in ALS, which might even serve as novel targets for effective disease-modifying therapies.

Association of Motor Function With Cognitive Trajectories and Structural Brain Differences: A Community-Based Cohort Study.

BACKGROUND AND OBJECTIVES: The association of motor function with cognitive health remains controversial, and the mechanisms underlying this relationship are unclear. We aimed to examine the association between motor function and long-term cognitive trajectories and further explore the underlying mechanisms using brain MRI. METHODS: In the Rush Memory and Aging Project, a prospective cohort study, a total of 2,192 volunteers were recruited from the communities in northeastern Illinois and followed up for up to 22 years (from 1997 to 2020). Individuals with dementia, disability, missing data on motor function at baseline, and missing follow-up data on cognitive function were excluded. At baseline, global motor function was evaluated using the averaged z scores of 10 motor tests covering dexterity, gait, and hand strength; the composite score was tertiled as low, moderate, or high. Global and domain-specific cognitive functions-including episodic memory, semantic memory, working memory, visuospatial ability, and perceptual speed-were measured annually through 19 cognitive tests. A subsample (n = 401) underwent brain MRI scans and regional brain volumes were measured. Data were analyzed using linear mixed-effects models and linear regression. RESULTS: Among the 1,618 participants (mean age 79.45 ± 7.32 years) included in this study, baseline global motor function score ranged from 0.36 to 1.82 (mean 1.03 ± 0.22). Over the follow-up (median 6.03 years, interquartile range 3.00-10.01 years), low global motor function and its subcomponents were related to significantly faster declines in global cognitive function (ß = -0.005, 95% CI -0.006 to -0.005) and each of the 5 cognitive domains. Of the 344 participants with available MRI data, low motor function was also associated with smaller total brain (ß = -25.848, 95% CI -44.902 to -6.795), total white matter (ß = -18.252, 95% CI -33.277 to -3.226), and cortical white matter (ß = -17.503, 95% CI -32.215 to -2.792) volumes, but a larger volume of white matter hyperintensities (ß = 0.257, 95% CI 0.118-0.397). DISCUSSION: Low motor function is associated with an accelerated decline in global and domain-specific cognitive functions. Both neurodegenerative and cerebrovascular pathologies might contribute to this association.

Preoperative thalamus volume is not associated with preoperative cognitive impairment (preCI) or postoperative cognitive dysfunction (POCD).

A growing body of literature suggests the important role of the thalamus in cognition and neurodegenerative diseases. This study aims to elucidate whether the preoperative thalamic volume is associated with preoperative cognitive impairment (preCI) and whether it is predictive for postoperative cognitive dysfunction at 3 months (POCD). We enrolled 301 patients aged 65 or older and without signs of dementia who were undergoing elective surgery. Magnetic resonance imaging was conducted prior to surgery. Freesurfer (version 5.3.) was used to automatically segment the thalamus volume. A neuropsychological test battery was administered before surgery and at a 3 month follow-up. It included the computerized tests Paired Associate Learning (PAL), Verbal Recognition Memory (VRM), Spatial Span Length (SSP), Simple Reaction Time (SRT), the pen-and-paper Trail-Making-Test (TMT) and the manual Grooved Pegboard Test (GPT). Using a reliable change index, preCI and POCD were defined as total Z-score > 1.96 (sum score over all tests) and/or Z-scores > 1.96 in ≥ 2 individual cognitive test parameters. For statistical analyses, multivariable logistic regression models were applied. Age, sex and intracranial volume were covariates in the models. Of 301 patients who received a presurgical neuropsychological testing and MRI, 34 (11.3%) had preCI. 89 patients (29.5%) were lost to follow-up. The remaining 212 patients received a follow-up cognitive test after 3 months, of whom 25 (8.3%) presented with POCD. Independently of age, sex and intracranial volume, neither preCI (OR per cm3 increment 0.81 [95% CI 0.60-1.07] p = 0.14) nor POCD (OR 1.02 per cm3 increment [95% CI 0.75-1.40] p = 0.87) were statistically significantly associated with patients' preoperative thalamus volume. In this cohort we could not show an association of presurgical thalamus volume with preCI or POCD.Clinical Trial Number: NCT02265263 ( https://clinicaltrials.gov/ct2/show/results/NCT02265263 ).

Repeated mild closed head injury in neonatal rats results in sustained cognitive deficits associated with chronic microglial activation and neurodegeneration.

Abusive head trauma in infants is a consequence of multiple episodes of abuse and results in axonal injury, brain atrophy, and chronic cognitive deficits. Anesthetized 11-day-old rats, neurologically equivalent to infants, were subjected to 1 impact/day to the intact skull for 3 successive days. Repeated, but not single impact(s) resulted in spatial learning deficits (p < 0.05 compared to sham-injured animals) up to 5 weeks postinjury. In the first week following single or repetitive brain injury, axonal and neuronal degeneration, and microglial activation were observed in the cortex, white matter, thalamus, and subiculum; the extent of the histopathologic damage was significantly greater in the repetitive-injured animals compared to single-injured animals. At 40 days postinjury, loss of cortical, white matter and hippocampal tissue was evident only in the repetitive-injured animals, along with evidence of microglial activation in the white matter tracts and thalamus. Axonal injury and neurodegeneration were evident in the thalamus up to 40 days postinjury in the repetitive-injured rats. These data demonstrate that while single closed head injury in the neonate rat is associated with pathologic alterations in the acute post-traumatic period, repetitive closed head injury results in sustained behavioral and pathologic deficits reminiscent of infants with abusive head trauma.

The multifactorial etiology of cognitive deficits in epilepsy and the neuropathology of mesial temporal lobe epilepsy beyond hyperphosphorylated tau.

In response to the recent review by Zawar and Kapur on the overlap between mesial temporal lobe epilepsy (MTLE) and Alzheimer's disease (AD), we (1) underscore that the bidirectionality between epilepsy and dementia is of high interest, also from the epileptological perspective; (2) outline the multifactorial etiology of cognitive deficits in epilepsy; (3) emphasize that the most prevalent neuropathological findings in MTLE comprise hippocampal sclerosis, dysplastic lesions, and neurodevelopmental neoplasm; and (4) state that anti-seizure medication can also have adverse effects on cognition. We conclude that the neuropsychology and neuropathology of MTLE is actually more complex than implicated in the review by Zawar and Kapur. Their suggested model may be valid for a small specific subgroup of cases. However, more studies are needed to confirm the role of hyperphosphorylated tau in epilepsy patients with and without AD considering age and age at epilepsy onset as potential moderator variables.

Abnormal Structural Network Communication Reflects Cognitive Deficits in Schizophrenia.

Schizophrenia has long been thought to be a disconnection syndrome and several previous studies have reported widespread abnormalities in white matter tracts in individuals with schizophrenia. Furthermore, reductions in structural connectivity may also impair communication between anatomically unconnected pairs of brain regions, potentially impacting global signal traffic in the brain. Therefore, we used different communication models to examine direct and indirect structural connections (polysynaptic) communication in large-scale brain networks in schizophrenia. Diffusion-weighted magnetic resonance imaging scans were acquired from 62 patients diagnosed with schizophrenia and 35 controls. In this study, we used five network communication models including, shortest paths, navigation, diffusion, search information and communicability to examine polysynaptic communication in large-scale brain networks in schizophrenia. We showed less efficient communication between spatially widespread brain regions particulary encompassing cortico-subcortical basal ganglia network in schizophrenia group relative to controls. Then, we also examined whether reduced communication efficiency was related to clinical symptoms in schizophrenia group. Among different measures of communication efficiency, only navigation efficiency was associated with global cognitive impairment across multiple cognitive domains including verbal learning, processing speed, executive functions and working memory, in individuals with schizophrenia. We did not find any association between communication efficiency measures and positive or negative symptoms within the schizophrenia group. Our findings are important for improving our mechanistic understanding of neurobiological process underlying cognitive symptoms in schizophrenia.

Shared and distinct structural brain alterations and cognitive features in drug-naïve schizophrenia and bipolar disorder.

Our study aimed to examine the shared and distinct structural brain alterations, including cortical thickness(CT) and local gyrification index(LGI), and cognitive impairments between the early course stage of drug-naïve schizophrenia(SZ) and bipolar disorder(BD) patients when compared to healthy controls(HCs), and to further explore the correlation between altered brain structure and cognitive impairments. We included 72 SZ patients, 35 BD patients and 43 HCs. The cognitive function was assessed using the MATRICS Consensus Cognitive Battery. Cerebral cortex analyses were performed with FreeSurfer. Furthermore, any structural aberrations related to cognition impairments were examined. Cognitive impairments existed in SZ and BD patients and were much more severe and widespread in SZ patients, compared to HCs. There were no significant differences in LGI among three groups. Compared to HCs, SZ had thicker cortex in left pars triangularis, and BD showed thinner CT in left postcentral gyrus. In addition, BD showed thinner cortex in left pars triangularis, left pars opercularis, left insula and right fusiform gyrus compared to SZ. Moreover, our results indicated that CT in many brain areas were significantly correlated with cognitive function in HCs, but only CT of left pars triangularis was correlated with impaired social cognition found in SZ. The findings suggest that changes of CT in the left pars triangularis and left postcentral gyrus may be potential pathophysiological mechanisms of the cognition impairments in SZ and BD, respectively, and the divergent CT of partly brain areas in BD vs. SZ may help distinguish them in early phases.

Association of regional white matter hyperintensities with hypertension and cognition in the population-based 1000BRAINS study.

BACKGROUND: White matter hyperintensities of presumed vascular origin (WMH) are frequent in cerebral magnetic resonance imaging of older people. They are promoted by vascular risk factors, especially hypertension, and are associated with cognitive deficits at the group level. It has been suggested that not only the severity, but also the location, of lesions might critically influence cognitive deficits and represent different pathologies. METHODS: In 560 participants (65.2 ± 7.5 years, 51.4% males) of the population-based 1000BRAINS study, we analyzed the association of regional WMH using Fazekas scoring separately for cerebral lobes, with hypertension and cognition. RESULTS: WMH most often affected the frontal lobe (83.7% score >0), followed by the parietal (75.8%), temporal (32.7%), and occipital lobe (7.3%). Higher Fazekas scores in the frontal, parietal, and temporal lobe were associated with higher blood pressure and antihypertensive treatment in unadjusted ordinal regression models and in models adjusted for age, sex, and vascular risk factors (e.g., age- and sex-adjusted odds ratio = 1.14, 95% confidence interval = 1.03-1.25 for the association of frontal lobe WMH Fazekas score with systolic blood pressure [SBP] [per 10 mm Hg]; 1.13 [1.02-1.23] for the association of parietal lobe score with SBP; 1.72 [1.19-2.48] for the association of temporal lobe score with antihypertensive medications). In linear regressions, higher frontal lobe scores were associated with lower performance in executive function and non-verbal memory, and higher parietal lobe scores were associated with lower performance in executive function, verbal-, and non-verbal memory. CONCLUSIONS: Hypertension promotes WMH in the frontal, parietal, and temporal lobe. WMH in the frontal and parietal lobe are associated with reduced executive function and memory.

The role of genetic risk factors of Alzheimer's disease in synaptic dysfunction.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by the progressive deterioration of cognitive functions. Due to the extended global life expectancy, the prevalence of AD is increasing among aging populations worldwide. While AD is a multifactorial disease, synaptic dysfunction is one of the major neuropathological changes that occur early in AD, before clinical symptoms appear, and is associated with the progression of cognitive deterioration. However, the underlying pathological mechanisms leading to this synaptic dysfunction remains unclear. Recent large-scale genomic analyses have identified more than 40 genetic risk factors that are associated with AD. In this review, we discuss the functional roles of these genes in synaptogenesis and synaptic functions under physiological conditions, and how their functions are dysregulated in AD. This will provide insights into the contributions of these encoded proteins to synaptic dysfunction during AD pathogenesis.

Paired associates learning is disrupted after unilateral parietal lobe controlled cortical impact in rats: A trial-by-trial behavioral analysis.

Approximately 60-70 million people suffer from traumatic brain injury (TBI) each year. Animal models continue to be paramount in understanding mechanisms of cellular dysfunction and testing new treatments for TBI. Enhancing the translational potential of novel interventions therefore necessitates testing pre-clinical intervention strategies with clinically relevant cognitive assays. This study used a unilateral parietal lobe controlled cortical impact (CCI) model of TBI and tested rats on a touchscreen-based Paired Associates Learning (PAL) task, which is part of the Cambridge Neuropsychological Test Automated Battery. In humans, the PAL task has been used to assess cognitive deficits in the ability to form stimulus-location associations in a multitude of disease states, including TBI. Although the use of PAL in animal models could be important for understanding the clinical severity of cognitive impairment post-injury and throughout intervention, to date, the extent to which a rat model of TBI produces deficits in PAL task performance has not yet been reported. This study details the behavioral consequences of the CCI injury model with a Trial-by-Trial analysis of PAL performance that enables behavioral strategy use to be inferred. Following behavior, the extent of the injury was quantified with histology and staining for the presence of glial fibrillary acid protein and ionized calcium-binding adapter molecule 1. Rats that received unilateral CCI were impaired on the PAL task and showed more aberrant response-driven behavior. The magnitude of PAL impairment was also correlated with Iba1 staining in the thalamus. These observations suggest that PAL could be useful for pre-clinical assessments of novel interventions for treating TBI.

Prediction of the information processing speed performance in multiple sclerosis using a machine learning approach in a large multicenter magnetic resonance imaging data set.

Many patients with multiple sclerosis (MS) experience information processing speed (IPS) deficits, and the Symbol Digit Modalities Test (SDMT) has been recommended as a valid screening test. Magnetic resonance imaging (MRI) has markedly improved the understanding of the mechanisms associated with cognitive deficits in MS. However, which structural MRI markers are the most closely related to cognitive performance is still unclear. We used the multicenter 3T-MRI data set of the Italian Neuroimaging Network Initiative to extract multimodal data (i.e., demographic, clinical, neuropsychological, and structural MRIs) of 540 MS patients. We aimed to assess, through machine learning techniques, the contribution of brain MRI structural volumes in the prediction of IPS deficits when combined with demographic and clinical features. We trained and tested the eXtreme Gradient Boosting (XGBoost) model following a rigorous validation scheme to obtain reliable generalization performance. We carried out a classification and a regression task based on SDMT scores feeding each model with different combinations of features. For the classification task, the model trained with thalamus, cortical gray matter, hippocampus, and lesions volumes achieved an area under the receiver operating characteristic curve of 0.74. For the regression task, the model trained with cortical gray matter and thalamus volumes, EDSS, nucleus accumbens, lesions, and putamen volumes, and age reached a mean absolute error of 0.95. In conclusion, our results confirmed that damage to cortical gray matter and relevant deep and archaic gray matter structures, such as the thalamus and hippocampus, is among the most relevant predictors of cognitive performance in MS.

History of Traumatic Brain Injury in Relation to Cognitive Functioning, Memory Complaints, and Brain Structure in Mid-Life.

In this study, we investigated history of traumatic brain injury with loss of consciousness in relation to cognitive functioning, subjective memory complaints, and brain structure in mid-life. This study included 2005 participants (mean age: 47.6 years, standard deviation: 5.0, women: 65%) from the Origins of Alzheimer's Disease Across the Life Course (ORACLE) study between 2017 and 2020. History of traumatic brain injury was defined as at least one lifetime self-reported brain injury with loss of consciousness. Associations of history of traumatic brain injury with (1) cognitive functioning (measured with the 15-Word Learning Test, Stroop Task, Letter-Digit Substitution Test, Word Fluency Test, Purdue Pegboard Test, and Design Organization Test), (2) current subjective memory complaints (present/absent, measured with a survey), and (3) brain structure (total brain volume, frontal and temporal lobe volume, gray matter volume, white matter volume, white matter hyperintensities volume, infarcts, and microbleeds, measured with brain magnetic resonance imaging [MRI]) were assessed using linear or logistical regression models and adjusted for relevant confounders. In total, 250 of 2005 (12%) participants reported a history of traumatic brain injury. Of those who reported the time post-injury (n = 173), most participants (n = 151, 87%) reported that it had occurred >10 years ago. We found no associations between history of traumatic brain injury and any of the cognitive tests. We did find that a history of traumatic brain injury was associated with having mid-life subjective memory complaints (odds ratio [OR]: 1.87; 95% confidence interval [CI]: 1.35, 2.58). This association was also present when investigating only those who reported an injury >10 years ago (OR:1.69; 95% CI: 1.15, 2.50). Additionally, the association was stronger in those with >30 min loss of consciousness (OR: 3.57; 95% CI: 1.48, 8.59) than in those with <30 min loss of consciousness (OR: 1.85; 95% CI: 1.25, 2.74), when compared with those without history of traumatic brain injury. Lastly, we found no associations between history of traumatic brain injury and any of the structural brain MRI outcomes. In conclusion, our study suggests that at least one lifetime traumatic brain injury with loss of consciousness in mid-life is associated with long-term subjective memory complaints, but not with cognitive functioning or brain structure.