Markers Of Brain Pathology Research Articles

Cerebral-cognitive reserve: concept and functions of the cerebral-cognitive reserve

IntroductionThe modern understanding of AD allows us to consider it through the constructs of “vulnerability” and “stability” of the brain as a dynamic system of dialectical interaction between the pathogenic process and the protective process that prevents neurodegeneration. The concept of cognitive reserve (CR) is based on observations of discrepancy between the degree of brain pathology and the severity of clinical manifestations. The concept of “reserve” was proposed to describe the resistance of the brain to a developing damage caused by a pathological process. Stern (2002) considered CR as a protective factor that modifies the impact of brain pathology on cognitive function. The researchers have defined CR as an ability to optimize cognitive function through differential involvement of structures or neural networks of the brain into brain activity.ObjectivesA systematic review of scientific studies has been conductedMethodsThe review includes an analysis of full-text literature sources.ResultsSeveral possible directions of CR influence on cognitive functions have been described:1)CR may reduce the risk of MCI or dementia through mechanisms, which do not depend on the level of neurodegenerative pathological changes in the brain.2)CR can interact with the markers of brain pathology or healthaffectingthe future cognitive decline or risk of progression. It has been found that smaller volumes or thickness in some AD vulnerable areas of the brain represent a stronger risk factor for cognitive impairment in people with low CR than in people with higher CR. CR protective effects on clinical outcomes reduce as the number of damaged neurons increases.3)The protective effect of CR increasesduring late AD onset and at a low rate of the damaged substrate accumulation.4)CR changes the relationship between genetic factors and aging withclinical and cognitive outcomes. The relationship between age and AD pathology level or age-related structural changes in the brain may weaken in people with higher CR ConclusionsThe concept of cerebral-cognitive reserve actualizes the problem of the search for compensatory mechanisms of cognitive deficit in AD, the assessmentof the structure of the reserve, the development and implementationof programs to maintain the reserve, the preventionof its depletion, starting from the preclinical stage of the disease, which can prevent the transformation of preclinical manifestations of AD into cognitive disordersDisclosure of InterestNone Declared

Associations between metabolic syndrome and markers of brain pathology: the role of sex- differences

Associations between metabolic syndrome and markers of brain pathology: the role of sex- differences

LAS‐Face‐ Name Associative Memory Exam: Discriminant validity for the detection of associative memory disorders in people with mild cognitive impairment in Argentina

AbstractBackgroundThe Latin American Spanish version of the Face‐Name Associative Memory Exam (LAS‐FNAME) is a validated version of the test that has been used to detect subtle cognitive changes in cognitively unimpaired adults at increased risk for Alzheimer’s disease (AD). Performance in this test has also been associated with markers of brain pathology in cognitively unimpaired older adults at increased risk for AD due to genetic factors or subjective cognitive decline (Papp et al., 2014;Vila‐Castelar et al., 2020). However, this test has not yet been used for the detection of Mild Cognitive Impairment (MCI) in the Latin American population. This study aims to analyze the discriminative validity and diagnostic performance of the LAS FNAME for the detection of verbal associative memory disorders in patients with MCI.MethodWe recruited 30 patients with MCI according to Petersen’s criteria (2010) and 20 healthy controls matched by age, sex and educational level. All participants completed the LAS‐FNAME, which consists of 12 learning trials of novel pairs of face‐names (immediate learning), followed by a delayed recall condition, and a neuropsychological assessment that included: Montreal Cognitive Assessment (MoCA), Craft Story 21, Multifactorial Memory Questionnaire (MMQ‐S) and a Functional Activity Questionnaire (FAQ).ResultThe groups did not differ in age, sex or education (p = 0.25, p = 0.54, p = 0.54). The age range was 61 to 86 years (M = 74.66; SD = 6.65) and the education range was 7 to 18 years (M = 14.63; SD = 3.41). The LAS‐FNAME showed an ability to discriminate against healthy controls from patients with MCI, both in its immediate (AUC = 0.81) and delayed (AUC = 0.79) conditions. The predictive ability was superior than a screening measure (MoCA, AUC = 0.74). The sensitivity and specificity was 68.4% and 89.3%, respectively. The LAS‐FNAME also showed evidence of concurrent validity with a standard memory test (Craft Story 21) in both immediate (r = 0.52, p<0.01) and delayed (r = 0.63, p<0.01) conditions, and reliability was excellent (α = 0.91).ConclusionPerformance on the LAS‐FNAME was able to distinguish MCI patients from healthy controls, suggesting that the LAS‐FNAME can detect early cognitive changes in prodromal stages of Alzheimer’s disease in Spanish‐speaking individuals.

Symposium 04: Innovative Ways of Applying Digital Technology in Neuropsychology - A Sneak Peak into the Future

Summary Abstract:The explosion of digital technology in the past decade has led to unprecedented possibilities towards improving cognitive assessment and understanding brain health. Digital technology encompasses using a multitude of devices, such as laptops, smartphones, etc, to collect health-related data. The settings can be varied to include in-clinic, remote/virtual, or a combination of hybrid models for data collection. Data can be collected at a single time point or over a continued period of time. Furthermore, the unique combination of devices used, settings, and methods of collecting digital data can become even more exclusive against the backdrop of the 'purpose’ for conducting the digital study. This symposium, consisting of four abstracts, brings together the unique combination of digital studies with exclusive devices, methodologies, settings, and purposes. The topics range from how smartphone-based assessments can be applied to understand the interaction between day-to-day variability in sleep and cognition, to the use of computerized testing to investigate the associations between cognitive performance and markers of brain pathology (e.g. amyloid and tau status), to understanding cognition from an open-source smartphone application to passively and continuously capture sensor data including global positioning system trajectories, to the development and validation of an online simulated money management credit card task, and to determining the effects of cognitive rehabilitation via digital technology on cognition, neuropsychiatric symptoms, and memory strategies.

Long‐term memory over 1‐week and markers of brain pathology in cognitively unimpaired individuals from a Colombian cohort with autosomal dominant Alzheimer’s disease

AbstractBackgroundLong‐term forgetting (LTF) over days or weeks may be a sensitive early marker of Alzheimer’s disease (AD), useful for preclinical AD trials. We examined associations between LTF and markers of brain pathology in individuals from the world’s largest kindred with autosomal dominant AD due to the Presenilin‐1 (PSEN1) E280A mutation.MethodsA total of 14 cognitively unimpaired PSEN1 mutation carriers (mean age: 35.9 years) and 16 matched non‐carriers (mean age: 32.8 years) from the Colombia‐Boston Biomarker Study of autosomal dominant AD were included. Participants underwent amyloid (11‐C Pittsburgh compound B) and tau (Flortaucipir) PET imaging, and memory tasks (NEUROPSI word list, stories and semi‐complex figure). We examined performance on learning and delayed recall after a 20‐min, 1‐day and 7‐day interval. LTF was calculated for the three tasks as the proportion of material retained at 20 min that was recalled 7 days later. Mann‐Whitney tests were conducted to compare memory performance and LTF between PSEN1 mutation carriers and non‐carriers. Spearman’s correlations were used to examine the association between LTF and brain pathology markers of amyloid burden and regional tau (entorhinal and inferior temporal cortices). Fisher’s exact tests were used to compare correlation coefficients between groups.ResultsLearning did not differ between carriers and non‐carriers. Compared to non‐carriers, carriers had lower 20‐min recall in all three tasks (p<0.05), and lower 1‐day and 7‐day recall of word list and stories. There were no group differences in word list, stories or figure LTF. Further, no group differences were observed in the association of amyloid burden and LTF on any of the tasks. Lower word list LTF was associated with greater entorhinal burden among carriers, and the strength of this association was significantly different between carriers and non‐carriers (p = 0.046; carriers: r = 0.73, p = 0.003; non‐carriers: r = 0.43, p = 0.094).ConclusionsOur preliminary findings show that, while rates of LTF over 7 days did not differ between PSEN1 carriers and non‐carriers, carriers had lower verbal memory recall over 1 and 7 days. Further, LTF was associated with early tau accumulation, suggesting that longer recall intervals may be more sensitive to detect subtle memory changes in cognitively unimpaired individuals at risk for AD.

Associations between subregional thalamic volume and brain pathology in autosomal dominant Alzheimer's disease.

Histopathological reports suggest that subregions of the thalamus, which regulates multiple physiological and cognitive processes, are not uniformly affected by Alzheimer’s disease. Despite this, structural neuroimaging studies often consider the thalamus as a single region. Identification of in vivo Alzheimer’s-dependent volumetric changes in thalamic subregions may aid the characterization of early nuclei-specific neurodegeneration in Alzheimer’s disease. Here, we leveraged access to the largest single-mutation cohort of autosomal-dominant Alzheimer’s disease to test whether cross-sectional abnormalities in subregional thalamic volumes are evident in non-demented mutation carriers (n = 31), compared to non-carriers (n = 36), and whether subregional thalamic volume is associated with age, markers of brain pathology and cognitive performance. Using automatic parcellation we examined the thalamus in six subregions (anterior, lateral, ventral, intralaminar, medial, and posterior) and their relation to age and brain pathology (amyloid and tau), as measured by PET imaging. No between-group differences were observed in the volume of the thalamic subregions. In carriers, lower volume in the medial subregion was related to increased cortical amyloid and entorhinal tau burden. These findings suggest that thalamic Alzheimer’s-related volumetric reductions are not uniform even in preclinical and prodromal stages of autosomal-dominant Alzheimer’s disease and therefore, this structure should not be considered as a single, unitary structure in Alzheimer’s disease research.

Good News for Dementia Prevention: Multiple Behavioral Features Are Associated With Markers of Brain Pathology in the Preclinical Phase of Sporadic and Autosomal Dominant Alzheimer’s Disease

In the last decade, there has been growing interest and investment in dementia prevention. Pharmacologic clinical trials in preclinical Alzheimer’s disease (AD) have shown limited efficacy, contributing to the interest in identifying factors that might prevent or postpone disease onset to aid in the development of disease-related interventions (1,2). Modifiable risk factors may account for 35% to 40% of sporadic AD risk (1,3) (e.g., education, cognitive lifestyle, physical exercise, psychosocial factors, and general health behaviors), but few studies have examined these factors in autosomal dominant AD (ADAD), likely given the causative genetic mutations.

Associations between physical activity and markers of brain pathology in autosomal dominant Alzheimer’s disease: A preliminary report

AbstractBackgroundPhysical activity is a promising lifestyle factor that could protect against memory decline in preclinical Alzheimer’s disease (AD). Greater physical activity has been shown to attenuate the relationship between amyloid‐b and cognitive decline and neurodegeneration in individuals at risk for dementia. Yet, little is known about the relation of physical activity with tau pathology, a strong predictor of cognitive decline. Autosomal dominant Alzheimer’s disease (ADAD) provides a unique opportunity to study preclinical AD since carriers of ADAD mutations are destined to develop dementia at early age, have a well‐characterized disease trajectory, and do not present age‐related comorbidities. We examined physical activity levels in young mutation carriers and non‐carriers from a Colombian kindred with ADAD, and explored the associations among physical activity, brain pathology (amyloid and tau), hippocampus volume, and memory performance.MethodsTen Presenilin‐1 E280A cognitively unimpaired mutation carriers and 23 matched non‐carriers (ages: μ=37.46, σ:6.01) traveled from Colombia to Boston for 11C Pittsburgh compound B‐PET (amyloid), Flortaucipir‐PET (tau), MRI and cognitive testing. All completed the 7‐day Physical Activity Recall questionnaire, which provides a measure of metabolic equivalents (METS) based on an estimate of the energy expenditure for common physical activities. Group differences were tested using the Mann Whitney U test. Linear regressions were used to examine associations between METS, imaging markers, and memory.ResultsCompared to non‐carriers, mutation carriers had greater cortical amyloid (non‐carriers: μ=1.05, σ=0.03, carriers: μ=1.26, σ=0.20, p<.001), and performed worse on the CERAD word list recall test (non‐carriers: μ=7.96, σ=1.24, carriers: μ=5.83, σ=2.75, p=.012). Groups did not differ in age, sex, education or METS (non‐carriers: μ=248.89, σ:27.53; carriers: μ=249., σ:20.81). Further, METS were not significantly associated with pathology levels, age, hippocampus volume or memory. However, those carriers (n=4) with the highest entorhinal and inferior temporal tau burden also had the lowest METS.ConclusionPreliminary findings of this ongoing study suggest that physical activity levels may not be associated with markers of neurodegeneration or memory performance in early preclinical ADAD. Future studies with larger samples and longitudinal follow‐up are needed to better understand the role of physical activity in the risk and progression of AD.

A systematic review on the potential role of APOE genotype as a moderator in the relationship between physical activity, brain health and dementia risk

AbstractBackgroundPhysical activity (PA) has been associated with decreased dementia risk, reduced Alzheimer’s disease (AD) neuropathological burden, and cognitive decline. On the other hand, the strongest genetic risk factor for AD is the Apolipoprotein E (APOE) ε4 allele, which increases AD‐risk in a dose‐dependent manner. Over the past two decades, researchers around the world have tried to unveil whether APOE ε4 carriage moderates the relationship between PA, brain health and dementia risk (Figure 1). Nevertheless, at present, this findings within this field remain inconsistent.MethodPubmed and Web of Science were searched for entries following the criteria specified in Table 1. The PRISMA guidelines for systematic reviews were followed throughout the process. A final set of 33 studies were considered after abstracts and full‐text articles were screened by two independent researchers. These included studies addressing the protective effect of PA on dementia risk (19 publications) and different markers of brain pathology (14 publications, see Figure 2).ResultStudies with shorter follow‐up periods found PA reduced dementia risk generally found that in both genotype groups; however, studies with longer follow‐ups showed varying results. Midlife PA seems to exert a greater impact on ε4 non‐carriers. Conversely, in neuroimaging studies, mainly ε4 carriers or both groups showed benefits, particularly when group sizes were large. Additionally, the association between PA and amyloid burden is stronger among ε4 carriers.ConclusionAlthough available data appears inconclusive, a close‐up look into the different study designs, methodologies and outcomes utilized can clarify the relationship between dementia and PA. More randomized clinical trials as well as longitudinal neuroimaging studies are need in order to fully elucidate relationship between PA, brain health and dementia risk.

Reduced thalamic volume is associated with early brain pathology in preclinical autosomal dominant Alzheimer’s disease

AbstractBackgroundSleep‐wake dysregulation may increase the risk of developing Alzheimer’s Disease (AD). In turn, AD pathology in sleep/wake regulatory brain regions may exacerbate sleep disturbances. It is unclear whether sleep dysregulation occurs before or after the onset of clinical symptoms in AD. In this study, we aimed to investigate whether the volume of brain regions known to regulate sleep/wake cycles (thalamus, brainstem sub‐regions) was different between carriers and non‐carriers of autosomal dominant AD (ADAD); and whether volume of such brain regions is associated with markers of brain pathology (amyloid and tau) and memory performance.MethodsA total of 36 non‐demented Presenilin‐1 mutation carriers and 32 age‐matched non‐carrier family members (mean age=36.3, SD=6.1) from the Colombia‐Boston (COLBOS) study underwent memory testing, and MRI and PET scanning. The CERAD word list delayed recall was used to assess memory; FreeSurfer was used to analyze bilateral volumes of the thalamus and sub‐regions of the brainstem (medulla, pons, superior cerebellar peduncle, midbrain); Pittsburgh compound‐B and flortaucipir (FTP) were used to assess cortical amyloid and entorhinal tau levels, respectively. Non‐parametric tests were used to assess group differences and correlations between brain volume, brain pathology, and memory.ResultsNo MRI volumetric differences were found between groups. In carriers, reduced thalamic volume was associated with greater mean cortical amyloid (r= ‐0.48, p=0.006) and entorhinal tau (r= ‐0.46, p=0.008). Reduced thalamic volume was also associated with worse memory performance (r= 0.38, p=0.03). When controlling for age, which is a proxy for clinical progression in this population, these associations were no longer significant. No associations were observed between memory, pathology, and any of the brainstem sub‐regions .ConclusionFindings suggest that brain regions important for sleep‐wake regulation do not show early signs of degeneration in preclinical ADAD. The association between reduced thalamic volume with both cortical amyloid and entorhinal tau supports previous work suggesting that thalamic structures are affected early in the preclinical stage of ADAD. Future research should focus on the functional abnormalities and AD‐related pathology in specific thalamic nuclei during preclinical ADAD, and their potential associations with sleep physiological features, such as thalamic spindles.

Diabetes, markers of brain pathology and cognitive function

We investigated whether, and the extent to which, vascular and degenerative lesions in the brain mediate the association of diabetes with poor cognitive performance. This cross-sectional study included 4,206 participants (age > 65 years; 57.8% women) of the Age, Gene/Environment Susceptibility-Reykjavik Study. Data were collected through interview, clinical examination, psychological testing, and laboratory tests. The composite scores on memory, information-processing speed, and executive function were derived from a cognitive test battery. Markers of cerebral macrovascular (cortical infarcts), microvascular (subcortical infarcts, cerebral microbleeds, and higher white matter lesion volume), and neurodegenerative (lower gray matter, normal white matter, and total brain tissue volumes) processes were assessed on magnetic resonance images. Mediation models were employed to test the mediating effect of brain lesions on the association of diabetes with cognitive performance controlling for potential confounders. There were 462 (11.0%) persons with diabetes. Diabetes was significantly associated with lower scores on processing speed and executive function, but not with memory function. Diabetes was significantly associated with all markers of brain pathology. All of these markers were significantly associated with lower scores on memory, processing speed, and executive function. Formal mediation tests suggested that markers of cerebrovascular and degenerative pathology significantly mediated the associations of diabetes with processing speed and executive function. Diabetes is associated with poor performance on cognitive tests of information-processing speed and executive function. The association is largely mediated by markers of both neurodegeneration and cerebrovascular disease. Older people with diabetes should be monitored for cognitive problems and brain lesions.

The Relationship Between Cerebrospinal Fluid Biomarkers and Depression in Elderly Women

Cerebrospinal fluid (CSF) biomarkers including the 42 amino-acid form of beta-amyloid (Abeta42), total tau protein (T-tau), and the CSF/serum albumin ratio are markers of brain pathology and metabolism. Abeta42 and T-tau are sometimes used to discriminate geriatric depression from mild forms of Alzheimer disease (AD) in clinical studies. However, studies focusing on the relationship between these CSF biomarkers and geriatric depression are lacking. This was a cross-sectional study with a population-based sample of 84 nondemented elderly women in Sweden. Measurements included neuropsychiatric, physical, and lumbar puncture examinations, with Diagnostic and Statistical Manual of Mental Disorders, Third Revision-based depression diagnoses and measurement of CSF levels of Abeta42, T-tau, albumin, and serum albumin. Fourteen women (mean age: 72.6 years) had any depression (11 with major depressive disorder [MDD]). Compared to women without depression, women with MDD had higher levels of Abeta42 and the CSF/serum albumin ratio. The CSF/serum albumin ratio was also higher in women with any depression. No differences in T-tau were observed; however, T-tau increased with age. Higher levels of CSF Abeta42 were observed among elderly depressed women, in contrast to lower levels usually observed in AD, indicating potential neuropathological differences between the two disorders. Higher CSF/serum albumin ratios observed in depressed women point to potential vascular processes.