Temporal Lobe Volume Research Articles

Validity and Normative Data for the Biber Figure Learning Test: A Visual Supraspan Memory Measure.

The Biber Figure Learning Test (BFLT), a visuospatial serial figure learning test, was evaluated for biological correlates and psychometric properties, and normative data were generated. Nondemented individuals (n = 332, 73 ± 7, 41% female) from the Vanderbilt Memory & Aging Project completed a comprehensive neuropsychological protocol. Adjusted regression models related BFLT indices to structural brain magnetic resonance imaging and cerebrospinal fluid (CSF) markers of brain health. Regression-based normative data were generated. Lower BFLT performances (Total Learning, Delayed Recall, Recognition) related to smaller medial temporal lobe volumes and higher CSF tau concentrations but not CSF amyloid. BFLT indices were most strongly correlated with other measures of verbal and nonverbal memory and visuospatial skills. The BFLT provides a comprehensive assessment of all aspects of visuospatial learning and memory and is sensitive to biomarkers of unhealthy brain aging. Enhanced normative data enriches the clinical utility of this visual serial figure learning test for use with older adults.

Telomere attrition is associated with declines in medial temporal lobe volume and white matter microstructure in functionally independent older adults.

Although leukocyte telomere length (TL) shortens over the lifespan and is associated with diseases of aging, little is known about the relationships between TL, memory, and brain structure. Sixty-nine functionally normal older adults (mean age= 71.7) were assessed at 2 time points (mean interval= 2.9years). Linear mixed models assessed relationships between TL and hippocampal volume, fractional anisotropy, and mean diffusivity (MD) of the fornix and verbal and visual episodic memory. Unstandardized coefficients are reported in the following, and p values are not corrected for multiple comparisons. A negative baseline trend was observed between TL and fornix MD (b=-0.01, p= 0.06), but no other cross-sectional associations were significant (ps > 0.16). Greater TL shortening at follow-up was associated with greater hippocampal volume loss (b= 27.09, p < 0.001), even after controlling for global volume loss (b= 10.83, p= 0.002). Greater telomere attrition was also associated with larger increases in fornix MD (b=-0.01, p= 0.012) and decreases in fornix fractional anisotropy (b= 0.004, p= 0.002). TL was not associated with changes in episodic memory (ps > 0.23). These relationships may reflect neurobiological influences that affect both TL and brain structure, as well as the effect of TL on brain aging via mechanisms such as cellular senescence and inflammation.

Assessing brain volume changes in older women with breast cancer receiving adjuvant chemotherapy: a brain magnetic resonance imaging pilot study

BackgroundCognitive decline is among the most feared treatment-related outcomes of older adults with cancer. The majority of older patients with breast cancer self-report cognitive problems during and after chemotherapy. Prior neuroimaging research has been performed mostly in younger patients with cancer. The purpose of this study was to evaluate longitudinal changes in brain volumes and cognition in older women with breast cancer receiving adjuvant chemotherapy.MethodsWomen aged ≥ 60 years with stage I–III breast cancer receiving adjuvant chemotherapy and age-matched and sex-matched healthy controls were enrolled. All participants underwent neuropsychological testing with the US National Institutes of Health (NIH) Toolbox for Cognition and brain magnetic resonance imaging (MRI) prior to chemotherapy, and again around one month after the last infusion of chemotherapy. Brain volumes were measured using Neuroreader™ software. Longitudinal changes in brain volumes and neuropsychological scores were analyzed utilizing linear mixed models.ResultsA total of 16 patients with breast cancer (mean age 67.0, SD 5.39 years) and 14 age-matched and sex-matched healthy controls (mean age 67.8, SD 5.24 years) were included: 7 patients received docetaxel and cyclophosphamide (TC) and 9 received chemotherapy regimens other than TC (non-TC). There were no significant differences in segmented brain volumes between the healthy control group and the chemotherapy group pre-chemotherapy (p > 0.05). Exploratory hypothesis generating analyses focusing on the effect of the chemotherapy regimen demonstrated that the TC group had greater volume reduction in the temporal lobe (change = − 0.26) compared to the non-TC group (change = 0.04, p for interaction = 0.02) and healthy controls (change = 0.08, p for interaction = 0.004). Similarly, the TC group had a decrease in oral reading recognition scores (change = − 6.94) compared to the non-TC group (change = − 1.21, p for interaction = 0.07) and healthy controls (change = 0.09, p for interaction = 0.02).ConclusionsThere were no significant differences in segmented brain volumes between the healthy control group and the chemotherapy group; however, exploratory analyses demonstrated a reduction in both temporal lobe volume and oral reading recognition scores among patients on the TC regimen. These results suggest that different chemotherapy regimens may have differential effects on brain volume and cognition. Future, larger studies focusing on older adults with cancer on different treatment regimens are needed to confirm these findings.Trial registrationClinicalTrials.gov, NCT01992432. Registered on 25 November 2013. Retrospectively registered.

Anomalous Brain Development Is Evident in Preschoolers With Attention-Deficit/Hyperactivity Disorder.

Attention-deficit/hyperactivity disorder (ADHD) is a common neurological disorder with symptom onset early in childhood. Growing evidence suggests anomalous brain development across multiple brain regions is evident in school-aged children; however, few studies have examined whether such differences are notable in the preschool years when symptom onset typically occurs. High resolution anatomical (MPRAGE) images and cognitive and behavioral measures were analyzed in a total of 90 medication-naïve preschoolers, ages 4-5 years (52 with ADHD, 38 controls; 64.4% boys). Results revealed reductions in bilateral frontal, parietal, and temporal lobe gray matter volumes in children with ADHD relative to typically developing children, with largest effect sizes noted for right frontal and left temporal lobe volumes. Examining frontal lobe sub-regions, the largest between group effect sizes were evident for left orbitofrontal cortex, left primary motor cortex (M1), and left supplementary motor complex (SMC). ADHD-related reductions in specific sub-regions (left prefrontal, left premotor, left frontal eye field, left M1, and right SMC) were significantly correlated with symptom severity, such that higher ratings of hyperactive/impulsive symptoms were associated with reduced cortical volumes. These findings represent the first comprehensive examination of cortical volume in preschool children with ADHD, providing evidence that anomalous brain structure in ADHD is evident very early in development. Furthermore, findings set the stage for developing our understanding of the way in which developmental trajectories of anomalous brain development are associated with the unfolding of symptoms in childhood ADHD. (JINS, 2018, 24, 531-539).

Associations of plasma clusterin and Alzheimer's disease-related MRI markers in adults at mid-life: The CARDIA Brain MRI sub-study.

BackgroundClinical and epidemiological studies of older persons have implicated clusterin in Alzheimer's disease (AD) pathogenesis. In the context of identifying early biomarkers of risk, we examined associations of plasma clusterin and characteristics of AD in middle-aged individuals from the community.Materials and methodsSubjects were 639 cognitively normal individuals (mean age 50 ± 3.5) from the Coronary Artery Risk Development in Young Adults (CARDIA) Brain MRI sub-study. Clusterin was quantified using ELISA (mean 255± 31 ng/ml). Associations were assessed between clusterin and volumes of brain regions known to atrophy in early AD, including entorhinal cortex (ECV), hippocampus (HV), and medial temporal lobe (MTLV) volumes (cm3). Total brain volume (TBV) and volumes of structures affected in later AD were examined for comparison.ResultsIn multivariable models, higher clusterin had a negative non-linear association with ECV (combined left and right hemispheres), and this association was influenced by the highest clusterin levels. Compared to mean clusterin, 1 and 2 standard deviation (SD) level increases in clusterin were associated with -2.1% (95% CI: -3.3,-0.9) and -7.3% (95% CI: -11.3,-3.3) lower ECV, respectively. Similar relationships were observed between clusterin and HV, although the relationship was stronger for left-side HV than the right-side. However, the association was not significant after adjusting for covariates. Negative non-linear associations between clusterin and MTLV were strongest for the left side: compared to mean clusterin, 1 and 2 SD level increases in clusterin were associated with -0.9% (95% CI: -1.9, 0.1) and -3.7% (95% CI: -7.1, -0.3) lower MTLV. There were no significant associations between clusterin and brain structures affected in later AD.ConclusionsIn middle-aged adults unselected for AD, plasma clusterin was associated with lower volume of the entorhinal cortex, an area that atrophies early in AD. Clusterin could be informative as part of a multi-component preclinical marker for AD.

From early stress to 12-month development in very preterm infants: Preliminary findings on epigenetic mechanisms and brain growth.

Very preterm (VPT) infants admitted to Neonatal Intensive Care Unit (NICU) are at risk for altered brain growth and less-than-optimal socio-emotional development. Recent research suggests that early NICU-related stress contributes to socio-emotional impairments in VPT infants at 3 months through epigenetic regulation (i.e., DNA methylation) of the serotonin transporter gene (SLC6A4). In the present longitudinal study we assessed: (a) the effects of NICU-related stress and SLC6A4 methylation variations from birth to discharge on brain development at term equivalent age (TEA); (b) the association between brain volume at TEA and socio-emotional development (i.e., Personal-Social scale of Griffith Mental Development Scales, GMDS) at 12 months corrected age (CA). Twenty-four infants had complete data at 12-month-age. SLC6A4 methylation was measured at a specific CpG previously associated with NICU-related stress and socio-emotional stress. Findings confirmed that higher NICU-related stress associated with greater increase of SLC6A4 methylation at NICU discharge. Moreover, higher SLC6A4 discharge methylation was associated with reduced anterior temporal lobe (ATL) volume at TEA, which in turn was significantly associated with less-than-optimal GMDS Personal-Social scale score at 12 months CA. The reduced ATL volume at TEA mediated the pathway linking stress-related increase in SLC6A4 methylation at NICU discharge and socio-emotional development at 12 months CA. These findings suggest that early adversity-related epigenetic changes might contribute to the long-lasting programming of socio-emotional development in VPT infants through epigenetic regulation and structural modifications of the developing brain.

Hippocampal Atrophy and Psychotic Symptoms in Patients with Alzheimer's Disease

Objectives This study examined the difference in the volume or thickness of the medial temporal lobe between Alzheimer’s disease patients with psychosis (AD+P) and those without psychosis (AD-P). Methods Overall, 31 AD+P patients and 29 AD-P patients were included from the Memory impairment clinics of Pusan National University Hospital in Korea. AD+P was diagnosed according to Jeste and Finkel’s proposed diagnostic criteria for psychosis of Alzheimer’s disease. AD-P included AD patients with no psychotic symptoms during a 5-year follow-up period. Medial temporal volume or thickness was measured by 3-tesla MRI and freesufer analysis. Analysis of variance was used to examine the difference in the volume or thickness of medial temporal lobe between AP+P and AD-P after controlling for age, gender, education years, Clinical Dementia Rating scale-Sum of Box, and total intracranial volume. Results The hippocampal volume in AD+P was smaller than that in AD-P. Conclusion These findings suggest that AD+P is associated with a reduced hippocampal volume.

A Voxel-Based Morphometric Brain Study of Patients with Methamphetamine Dependency: A Case Controlled Study

Methamphetamine (MA) use has been an important health problem in Iran in recent decade. Previous studies have suggested brain structural abnormalities in MA users. Increasing knowledge about the MA induced structurally and functionally brain changes is important for better management of this disorder. The aim of the present study was to investigate the possible structural brain structural changes in MA dependent patients. This was a case-control study, which conducted in Farabi mental hospital in the west of Iran. Voxel-based-mor phometry (VBM) as a whole-brain technique for characterizing regional cerebral volume and tissue concentration differences in structural MRI was administered. We used VBM to assess regional brain differences in 25 MA dependent patients and 20 age, sex matched healthy controls. In MA dependent patients hippocam, parahippocamp, left frontal lobe, right frontal lobe, left temporal lobe, and right temporal lobe volumes were significantly lower than healthy control subjects (P< 0.05). Also caudate and amygdala volume in MA dependent patients were smaller than healthy subjects (P< 0.05). The brain volume reduction of MA dependent patients compared to control subjects may explain the prevalence of psychiatric disorders in these patients, and could help to provide therapeutic strategies for drug-induced brain injury.

The Brain Health Assessment for Detecting and Diagnosing Neurocognitive Disorders.

Brief cognitive screens lack the sensitivity to detect mild cognitive impairment (MCI) or support differential diagnoses. The objective of this study was to validate the 10-minute, tablet-based University of California, San Francisco (UCSF) Brain Health Assessment (BHA) to overcome these limitations. Cross-sectional. UCSF Memory and Aging Center. Older adults (N=347) (neurologically healthy controls (n=185), and individuals diagnosed with MCI (n=99), dementia (n=42), and as normal with concerns (n=21)). The BHA includes subtests of memory, executive function and speed, visuospatial skills, and language and an optional informant survey. Participants completed the Montreal Cognitive Assessment (MoCA) and criterion-standard neuropsychological tests. Standardized structural 3T brain magnetic resonance imaging was performed in 145 participants. At a fixed 85% specificity rate, the BHA had 100% sensitivity to dementia and 84% to MCI; the MoCA had 75% sensitivity to dementia and 25% to MCI. The BHA had 83% sensitivity to MCI likely due to AD and 88% to MCI unlikely due to AD, and the MoCA had 58% sensitivity to MCI likely AD and 24% to MCI unlikely AD. The BHA subtests demonstrated moderate to high correlations with the criterion-standard tests from their respective cognitive domains. Memory test performance correlated with medial temporal lobe volumes; executive and speed with frontal, parietal, and basal ganglia volumes; and visuospatial with right parietal volumes. The BHA had excellent combined sensitivity and specificity to detect dementia and MCI, including MCI due to diverse etiologies. The subtests provide efficient, valid measures of neurocognition that are critical in making a differential diagnosis.

Longitudinal brain structural alterations in patients with nasopharyngeal carcinoma early after radiotherapy.

Background and purposeTo investigate effects of radiotherapy on normal brain tissue using in vivo neuroimaging in patients with nasopharyngeal carcinoma (NPC).Methods and materialsWe used longitudinal MRI to monitor structural brain changes during standard radiotherapy in patients newly diagnosed with NPC. We assessed volumetric measures in 63 patients at 2–3 time points before and after radiotherapy, with 20 NPC-free participants as normal controls. Images were processed using validated software (FreeSurfer). Automated results were inspected visually for accuracy. We examined changes in volume of the whole brain, gray matter, white matter, and ventricles, as well as in cerebral volumes partitioned into temporal, frontal, parietal, and occipital lobes. A linear mixed model was used to evaluate longitudinal changes in these measurements. Statistical significance was evaluated at p < 0.05, which was corrected for multiple comparisons.ResultsVolumes of the gray matter, and bilateral temporal lobes decreased in a time-dependent manner, whereas ventricle volume showed a time-dependent increase after radiotherapy. No volume changes were detected in NPC patients before radiotherapy when compared normal controls. No volume changes were detected in the subcohort of patients after completion of induction chemotherapy but prior to initiation of radiotherapy. Changes of bilateral temporal lobe volume correlated with irradiation dose in this region. Expansion of the ventricles correlated with a reduction in cognition assessment.ConclusionsWe detected significant and progressive radiotherapy-associated structural changes in the brains of patients with NPC who were treated with standard radiotherapy, especially in the bilateral temporal lobe in which the effect was dose-dependent. Expansion of the ventricles can serve as an imaging marker for treatment-related reduction in cognitive function. Future studies with longer follow-ups are needed to evaluate morphometric changes long-term after radiotherapy.

RBFOX1, encoding a splicing regulator, is a candidate gene for aggressive behavior

The RBFOX1 gene (or A2BP1) encodes a splicing factor important for neuronal development that has been related to autism spectrum disorder and other neurodevelopmental phenotypes. Evidence from complementary sources suggests that this gene contributes to aggressive behavior. Suggestive associations with RBFOX1 have been identified in genome-wide association studies (GWAS) of anger, conduct disorder, and aggressive behavior. Nominal association signals in RBFOX1 were also found in an epigenome-wide association study (EWAS) of aggressive behavior. Also, variants in this gene affect temporal lobe volume, a brain area that is altered in several aggression-related phenotypes. In animals, this gene has been shown to modulate aggressive behavior in Drosophila. RBFOX1 has also been associated with canine aggression and is upregulated in mice that show increased aggression after frustration of an expected reward. Associated common genetic variants as well as rare duplications and deletions affecting RBFOX1 have been identified in several psychiatric and neurodevelopmental disorders that are often comorbid with aggressive behaviors. In this paper, we comprehensively review the cumulative evidence linking RBFOX1 to aggression behavior and provide new results implicating RBFOX1 in this phenotype. Most of these studies (genetic and epigenetic analyses in humans, neuroimaging genetics, gene expression and animal models) are hypothesis-free, which strengthens the validity of the findings, although all the evidence is nominal and should therefore be taken with caution. Further studies are required to clarify in detail the role of this gene in this complex phenotype.

Continuous measurement of object location memory is sensitive to effects of age and mild cognitive impairment and related to medial temporal lobe volume

IntroductionWe present findings of a novel and ecologically relevant associative memory test, the Object Location Touchscreen Test (OLTT), which was posited as sensitive to early medial temporal lobe compromise associated with mild cognitive impairment (MCI). MethodsA total of 114 participants, including healthy young and older controls and patients with MCI, completed the OLTT and standard neuropsychological testing. The OLTT required participants to recall the location of objects under free and cued recall conditions, with accuracy evaluated using distance measures (i.e., a continuous error score), and a standard recognition format. Correlations between performance and volumetric data were evaluated from a subset of 77 participants. ResultsSignificant age effects were dwarfed by MCI effects across all test conditions. OLTT Cued Recall was strongly and specifically related to the volume of disease-relevant medial temporal lobe regions, generally more than traditional memory tests. DiscussionThe OLTT may be sensitive to early structural compromise in regions affected by Alzheimer's disease.

The relationship between neuropsychological functioning and mesial temporal lobe volumes determined by mri volumetry in hippocampal sclerosis international league against epilepsy type1

Background: The international consensus classification for hippocampal sclerosis (HS) has been proposed in 2013, but no research has reported the relationship between neuropsychological functioning and brain structural changes in patients with pathologically confirmed HS according to the classification.

Heterogeneity and Homogeneity of Regional Brain Structure in Schizophrenia

Schizophrenia is associated with alterations in mean regional brain volumes. However, it is not known whether the clinical heterogeneity seen in the disorder is reflected at the neurobiological level, for example, in differences in the interindividual variability of these brain volumes relative to control individuals. To investigate whether patients with first-episode schizophrenia exhibit greater variability of regional brain volumes in addition to mean volume differences. Studies that reported regional brain volumetric measures in patients and controls by using magnetic resonance imaging in the MEDLINE, EMBASE, and PsycINFO databases from inception to October 1, 2016, were examined. Case-control studies that reported regional brain volumes in patients with first-episode schizophrenia and healthy controls by using magnetic resonance imaging were selected. Means and variances (SDs) were extracted for each measure to calculate effect sizes, which were combined using multivariate meta-analysis. Relative variability of regional brain volumetric measurements in patients compared with control groups as indexed by the variability ratio (VR) and coefficient of variation ratio (CVR). Hedges g was used to quantify mean differences. A total of 108 studies that reported measurements from 3901 patients (1272 [32.6%] female) with first-episode schizophrenia and 4040 controls (1613 [39.9%] female) were included in the analyses. Variability of putamen (VR, 1.13; 95% CI, 1.03-1.24; P = .01), temporal lobe (VR, 1.12; 95% CI, 1.04-1.21; P = .004), thalamus (VR, 1.16; 95% CI, 1.07-1.26; P < .001), and third ventricle (VR, 1.43; 95% CI, 1.20-1.71; P < 1 × 10-5) volume was significantly greater in patients, whereas variability of anterior cingulate cortex volume was lower (VR, 0.89; 95% CI, 0.81-0.98; P = .02). These findings were robust to choice of outcome measure. There was no evidence of altered variability of caudate nucleus or frontal lobe volumes. Mean volumes of the lateral (g = 0.40; 95% CI, 0.29-0.51; P < .001) and third ventricles (g = 0.43; 95% CI, 0.26-0.59; P < .001) were greater, whereas mean volumes of the amygdala (g = -0.46; -0.65 to -0.26; P < .001), anterior cingulate cortex (g = -0.26; 95% CI, -0.43 to -0.10; P = .005), frontal lobe (g = -0.31; 95% CI, -0.44 to -0.19; P = .001), hippocampus (g = -0.66; 95% CI, -0.84 to -0.47; P < .001), temporal lobe (g = -0.22; 95% CI, -0.36 to -0.09; P = .001), and thalamus (g = -0.36; 95% CI, -0.57 to -0.15; P = .001) were lower in patients. There was no evidence of altered mean volume of caudate nucleus or putamen. In addition to altered mean volume of many brain structures, schizophrenia is associated with significantly greater variability of temporal cortex, thalamus, putamen, and third ventricle volumes, consistent with biological heterogeneity in these regions, but lower variability of anterior cingulate cortex volume. This finding indicates greater homogeneity of anterior cingulate volume and, considered with the significantly lower mean volume of this region, suggests that this is a core region affected by the disorder.

Conceptual elaboration versus direct lexical access in WAIS-similarities: differential effects of white-matter lesions and gray matter volumes

ABSTRACTWechsler Adult Intelligence Scale (WAIS) subscale Similarities have been classified as a test of either verbal comprehension or of inductive reasoning. The reason may be that items divide into two categories. We tested the hypothesis of heterogeneity of items in WAIS-Similarities. Consecutive patients at a memory clinic and healthy controls participated in the study. White-matter hyperintensities (WMHs) and normalized temporal lobe volumes were measured based on Magnetic resonance Imaging (MRI), and tests of verbal memory and attention were used in addition to WAIS-Similarities to collect behavioural data. Factor analysis supported the hypothesis that two factors are involved in the performance of WAIS-similarities: (1) semiautomatic lexical access and (2) conceptual elaboration. These factors were highly correlated but provided discriminative diagnostic information: In logistic regression analyses, scores of the lexical access factor and of the conceptual elaboration factor discriminated patients with mild cognitive impairment from Alzheimer’s disease patients and from healthy controls, respectively. High scores of WMH, indicating periventricular white-matter lesions, predicted factor scores of direct lexical access but not those of conceptual elaboration, which were predicted only by medial and lateral temporal lobe volumes.

BRAIN VOLUME, CEREBRAL β-AMYLOID DEPOSITION, AND AGEING: A STUDY OF OVER 200 INDIVIDUALS BORN IN THE SAME WEEK IN 1946

Ageing is associated with cerebral atrophy and accumulation of cerebral β-amyloid. We examined the relationships between β-amyloid load and brain volume in a large cohort of individuals born in the same week in 1946. We analysed cross-sectional data from Insight 46; a sub-study of the MRC National Survey of Health and Development(NSHD) which includes individuals born in mainland Britain in one week in 1946. Participants had 18F-Florbetapir PET and volumetric T1-weighted MRI on the same 3T-PET/MR unit. β-amyloid load was quantified as a cortical standard uptake value ratios (SUVR) using a cerebellar reference region. The relationship between automated measurements of whole brain, ventricle, hippocampal and lobar volumes, age at time of scan and β-amyloid load was examined using regression models and voxel based morphometry, incorporating total intracranial volume and gender as co-variates. Data from 210 individuals without dementia or significant neurological/psychiatric illness were included. Mean age at scanning was 70.1±0.39 years (range 69.3–70.8). 38 individuals were β-amyloid positive: defined as SUVr=>1.078. Comparison of positive and negative groups revealed no difference in volumetric measurements. However, within β-amyloid-positive individuals, SUVR was negatively associated with total brain volume(p=0.034). There was also evidence of an interaction between β-amyloid status(positive/negative) and SUVR in terms of their effects on total brain volume(p=0.006) across the whole sample. Age at scanning was associated with increased ventricular volume (p=0.014) and with lower total brain(p<0.001), hippocampal(p=0.003), frontal lobe(p=0.023) and temporal lobe(p=0.042) volumes. Whole-brain voxel based morphometry analysis(FWE corrected, p<0.05) revealed age to be associated with volume loss in fronto-temporal regions, thalamus, and cingulate gyri. These preliminary data suggest that there is no significant difference in brain volume between β-amyloid positive and negative individuals aged ∼70 years, but there is some evidence for volume loss once a β-amyloid threshold level is reached. Unexpectedly, there was also a relationship between age and total brain volume independent of β-amyloid load over a very narrow age range. Whether this reflects recruitment bias, non-AD pathologies or ageing effects is unclear. These findings will be examined in a larger sample size utilizing life course and genetic data in the future.

DATA-DRIVEN MODELS OF DISEASE PROGRESSION AND APPLICATIONS TO ALZHEIMER’S DISEASE: EVENT-BASED MODEL AND DIFFERENTIAL EQUATION MODELS OF BIOMARKER CHANGES IN ADNI

Understanding and identifying early pathological changes of neurological diseases is key to realizing disease-modifying treatments, but identifying presymptomatic individuals is challenging. Data-driven disease progression modelling is a family of emerging techniques for achieving this by learning directly from measured data. We considered two such models. The event-based model1,2 (EBM) robustly finds the order in which a set of biomarkers become abnormal, using cross-sectional data, without defined biomarker cut-points, and requiring no prior clinical staging variable. This uniquely fine-grained picture of disease progression is capable of probabilistic, high-resolution patient staging and stratification, useful for clinical trials selection and end-points. However, the EBM doesn't quantify time. Differential equation models3,4 (DEMs) use short-term longitudinal change to find biomarker trajectories that can be used to stage patients temporally, and to predict symptom onset. Both approaches assume monotonic disease progression, and have succeeded in building data-driven models of neurodegenerative disease progression. We present and compare models built on the latest contents of the ADNI data set. Biomarker data is from 1737 ADNI-1/GO/2 participants (417 cognitively normal (CN), 106 significant memory concern (SMC), 310 early mild cognitive impairment (EMCI), 562 late MCI (LMCI), 342 diagnosed Alzheimer's disease (AD)): a multi-modal set of measurements derived from magnetic resonance imaging, positron emission tomography, cerebrospinal fluid, and cognitive test scores. From baseline data we estimated a pathological cascade in ApoE4-positive participants using an EBM. From short-term longitudinal data we estimated probabilistic biomarker trajectories for ApoE4-positive clinical progressors using nonparametric DEMs. The EBM-estimated AD pathological cascade (Figure 1) starts with accumulation of amyloid and tau, followed by cognitive abnormalities and temporal lobe volume reduction, then brain hypometabolism, and broader neurodegeneration. A similar pattern was found by DEMs (Figure 2), with biomarker trajectories accelerating from normal to abnormal levels. Patient staging with both models (Figures 3, 4) provided much finer resolution of AD progression than traditional diagnostic categorization, while remaining consistent with clinical diagnoses. We found a data-driven sequence, and timings, of AD biomarker progression in the ADNI dataset. Our data-driven model-based approaches increase understanding of neurological disease progression with potential utility for patient staging and prognosis. Event-based model of AD progression: probabilistic sequence of biomarker abnormality. Biomarkers (imaging/molecular/cognitive) along the vertical axis are ordered by the maximum likelihood disease progression sequence (from top to bottom). The horizontal axis shows estimated variance in the posterior sequence, with positional likelihood per event given by grayscale intensity. Differential equation model of AD progression: preclinical cumulative probability of biomarker abnormality, increasing from left (dark blue) to right (light yellow) as a function of time to AD diagnosis. Biomarker trajectories estimated from differential data are aligned at the average point of AD diagnosis. Biomarkers along the vertical axis (top to bottom) are ordered by the time where the cumulative abnormality probability equals 50%. Box plots of the interquartile range show the speed of abnormality progression for each biomarker. Event-based model fine-grained probabilistic staging of individuals across clinical groups in ADNI-1/GO/2. Differential equation model probabilistic temporal staging of individuals across clinical groups in ADNI-1/GO/2.

COGNITIVE IMPAIRMENT IN ASSOCIATION WITH AMYLOID DEPOSITION AND MEDIAL TEMPORAL LOBE VOLUME IN DEMENTIA WITH LEWY BODIES

COGNITIVE IMPAIRMENT IN ASSOCIATION WITH AMYLOID DEPOSITION AND MEDIAL TEMPORAL LOBE VOLUME IN DEMENTIA WITH LEWY BODIES

Distinguishing early and late brain aging from the Alzheimer's disease spectrum: consistent morphological patterns across independent samples

Alzheimer's disease (AD) is a debilitating age-related neurodegenerative disorder. Accurate identification of individuals at risk is complicated as AD shares cognitive and brain features with aging. We applied linked independent component analysis (LICA) on three complementary measures of gray matter structure: cortical thickness, area and gray matter density of 137 AD, 78 mild (MCI) and 38 subjective cognitive impairment patients, and 355 healthy adults aged 18–78 years to identify dissociable multivariate morphological patterns sensitive to age and diagnosis. Using the lasso classifier, we performed group classification and prediction of cognition and age at different age ranges to assess the sensitivity and diagnostic accuracy of the LICA patterns in relation to AD, as well as early and late healthy aging. Three components showed high sensitivity to the diagnosis and cognitive status of AD, with different relationships with age: one reflected an anterior-posterior gradient in thickness and gray matter density and was uniquely related to diagnosis, whereas the other two, reflecting widespread cortical thickness and medial temporal lobe volume, respectively, also correlated significantly with age. Repeating the LICA decomposition and between-subject analysis on ADNI data, including 186 AD, 395 MCI and 220 age-matched healthy controls, revealed largely consistent brain patterns and clinical associations across samples. Classification results showed that multivariate LICA-derived brain characteristics could be used to predict AD and age with high accuracy (area under ROC curve up to 0.93 for classification of AD from controls). Comparison between classifiers based on feature ranking and feature selection suggests both common and unique feature sets implicated in AD and aging, and provides evidence of distinct age-related differences in early compared to late aging.

Family History of Alzheimer's Disease is Associated with Impaired Perceptual Discrimination of Novel Objects.

Early detection may be the key to developing therapies that will combat Alzheimer’s disease (AD). It has been consistently demonstrated that one of the main pathologies of AD, tau, is present in the brain decades before a clinical diagnosis. Tau pathology follows a stereotypical route through the medial temporal lobe beginning in the entorhinal and perirhinal cortices. If early pathology leads to very subtle changes in behavior, it may be possible to detect these changes in subjects years before a clinical diagnosis can currently be made. We aimed to discover if cognitively normal middle-aged adults (40–60 years old) at increased risk for AD due to family history would have impaired performance on a cognitive task known to challenge the perirhinal cortex. Using an oddity detection task, we found that subjects with a family history of AD had lowered accuracy without demonstrating differences in rate of acquisition. There were no differences between subjects’ medial temporal lobe volume or cortical thickness, indicating that the changes in behavior were not due to significant atrophy. These results demonstrate that subtle changes in perceptual processing are detectable years before a typical diagnosis even when there are no differences detectable in structural imaging data. Anatomically-targeted cognitive testing may be useful in identifying subjects in the earliest stages of AD.