Entorhinal Cortex Volume Research Articles

Automatic MRI volumetry in asymptomatic cases at risk for normal pressure hydrocephalus.

The occurrence of significant Alzheimer's disease (AD) pathology was described in approximately 30% of normal pressure hydrocephalus (NPH) cases, leading to the distinction between neurodegenerative and idiopathic forms of this disorder. Whether or not there is a specific MRI signature of NPH remains a matter of debate. The present study focuses on asymptomatic cases at risk for NPH as defined with automatic machine learning tools and combines automatic MRI assessment of cortical and white matter volumetry, risk of AD (AD-RAI), and brain age gap estimation (BrainAge). Our hypothesis was that brain aging and AD process-independent volumetric changes occur in asymptomatic NPH-positive cases. We explored the volumetric changes in normal aging-sensitive (entorhinal cortex and parahippocampal gyrus/PHG) and AD-signature areas (hippocampus), four control cortical areas (frontal, parietal, occipital, and temporal), and cerebral and cerebellar white matter in 30 asymptomatic cases at risk for NPH (NPH probability >30) compared to 30 NPH-negative cases (NPH probability <5) with preserved cognition. In univariate regression models, NPH positivity was associated with decreased volumes in the hippocampus, parahippocampal gyrus (PHG), and entorhinal cortex bilaterally. The strongest negative association was found in the left hippocampus that persisted when adjusting for AD-RAI and Brain Age values. A combined model including the three parameters explained 36.5% of the variance, left hippocampal volumes, and BrainAge values, which remained independent predictors of the NPH status. Bilateral PHG and entorhinal cortex volumes were negatively associated with NPH-positive status in univariate models but this relationship did not persist when adjusting for BrainAge, the latter remaining the only predictor of the NPH status. We also found a negative association between bilateral cerebral and cerebellar white matter volumes and NPH status that persisted after controlling for AD-RAI or Brain Age values, explaining between 50 and 65% of its variance. These observations support the idea that in cases at risk for NPH, as defined by support vector machine assessment of NPH-related MRI markers, brain aging-related and brain aging and AD-independent volumetric changes coexist. The latter concerns volume loss in restricted hippocampal and white matter areas that could be considered as the MRI signature of idiopathic forms of NPH.

42 Cognitive and Neuroanatomic Correlates of Olfactory Function in Cognitively Unimpaired and Impaired Older Adults

Objective:Olfactory function declines during normal aging; however, accelerated olfactory decline is observed in neurodegenerative diseases, such as Alzheimer’s disease (AD). Moreover, olfactory deficits in pre-clinical AD are associated with future cognitive decline. Odor identification and memory deficits have been consistently reported in early stage AD indicating its potential sensitivity to AD pathophysiology in olfactory and limbic structures, yet few studies of olfaction have incorporated structural measures in a well-characterized cohort of older adults. In the current study we examined the association between odor identification impairment, cognition, and medial temporal lobe (MTL) sub-regions in cognitively unimpaired and impaired older adults.Participants and Methods:We enrolled 140 participants (age=72.25±6.54, 56% female, years of education=16.30±2.63, 82% Caucasian, 15% Black/AA, 3% Multiracial) from the Penn Alzheimer’s Disease Research Center Clinical Cohort. Participants completed the Sniffin’ Sticks Odor Identification Test (SS-OIT), cognitive testing (NACC UDS2 or UDS3 and additional cognitive tests), and MRI scans (3T Siemens MAGNETOM Prisma MRI scanner). For the SS-OIT, participants were presented with 16 odorants using felt-tipped pen dispensers and asked to identify each odor from four multiple-choice options. Scores range from 0 to 16. Additionally, cognitive domains were created by averaging z-scores from tests within each domain: attention, memory, language, executive function, and visuospatial. This cohort was divided into participants with unimpaired cognition (n=96) and impaired cognition (MCI, dementia; n=44) using established normative data and consensus diagnosis. Linear regressions were performed to examine the association between SS-OIT score, each cognitive domain, and MTL measurements for unimpaired and impaired groups. For all analyses, we controlled for age, race, sex, education, smoking status, and hypertension and additionally for MOCA score and intracranial volume with MTL measurements.Results:In the unimpaired group, SS-OIT significantly associated with language (p&lt;.05). In the impaired group, SS-OIT significantly associated with language and memory (p&lt;.05). In the unimpaired group, SS-OIT significantly associated with right anterior hippocampal volume (p&lt;.05). In the impaired group, significant associations were found between SS-OIT and right anterior hippocampal volume (p&lt;.05) and left hippocampal mean thickness (p&lt;.05). Additionally, SS-OIT significantly associated with left and right entorhinal cortex volume (p&lt;.05) and mean thickness (p&lt;.05).Conclusions:This study reveals that lower odor identification performance is related to lower performance on measures of cognition and atrophy in MTL sub-regions in unimpaired and impaired older adults. Our findings support prior results demonstrating relationships between olfactory function, cognition, and MTL sub-regions. Specifically, olfactory function and episodic memory have been shown to follow similar patterns of decline in the course of AD, potentially reflecting AD pathology in shared regions of the MTL subserving episodic memory and olfactory function. Our findings demonstrate that reductions in both cortical thickness and grey matter volume of MTL regions are linked to olfactory deficits in individuals at risk for Alzheimer’s dementia. Future steps will include the analysis of longitudinal cognitive and imaging indices and the incorporation of fluid biomarker data.

66 Omega-3 Fatty Acids, Cognition, and Brain Volume in Healthy Elderly Adults

Objective:One common concern amongst the aging population is that of worsening memory. Speed of processing and executive functions are also areas of age-related decline that affect daily living. Lifestyle modifications such as diet, exercise, and sleep have garnered intense interest as potential methods to prevent or delay cognitive decline. Among dietary factors, omega-3 fatty acids (FAs) have been documented as containing a myriad of health benefits, including neuroprotective effects. The aim of this study is to examine the associations between omega-3 FAs, cognitive function, and neuroanatomical regions of interest in a healthy aging population.Participants and Methods:Adults aged 65 and older (n=40, 48.9% Female) were recruited for the Loma Linda University Adventist Health Study-2 Cognitive and Neuroimaging Substudy. Participants had a mean age of 76.25 years (SD=8.29), 16.78 years of education (SD=2.53), and were predominantly White (85.0%). Participants received a two-hour neurocognitive battery, including measures of immediate and delayed memory (Rey Auditory Verbal Learning Test, RAVLT; WMS-IV Logical Memory, LM), processing speed (Stroop), and executive functions (Stroop Color/Word). Participants underwent brain imaging on a 3T Siemens MRI, including a 3D T1-weighted MPRAGE sequence. Cortical reconstruction and volumetric segmentation were performed using FreeSurfer software. Blood samples were collected for fatty acid analysis. Individual FAs were expressed as a percent of total FAs. An omega-3 index was constructed as the sum of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) FAs. Correlational analyses, controlling for age, sex, and education, investigated relationships between omega-3 levels (individual and index) and (a) cognitive function (immediate and delayed memory, processing speed, executive functions), and (b) brain volumes in specific regions of interest (hippocampus, entorhinal cortex, frontal pole, white matter).Results:EPA was significantly positively correlated with Stroop Color (r=.34, p=.048). Although not statistically significant, trends were observed between the omega-3 index and Stroop Color (r=.30, p=.08), and between both DHA and the omega-3 index with RAVLT – delayed recall (r=.29, p=.095; r=.30, p=.08, respectively). With regards to regional brain volumes, EPA and the omega-3 index were both significantly positively correlated with the entorhinal cortex (r=.34, p=.041; r=.41, p=.01, respectively) and white matter volume (r=.36, p=.028; r=.34, p=.038, respectively). DHA was significantly positively correlated with white matter volume (r=.34, p=.044).Conclusions:Blood levels of EPA were positively correlated with a measure of processing speed, and trends were observed between DHA, the omega-3 index and[GN1] verbal memory, and between the omega-3 index and processing speed. We also found that omega-3 FA values were associated with greater brain volume in the entorhinal cortex and white matter in our sample of healthy older adults. Atrophy of the entorhinal cortex has been associated with pathological processes. Additionally, white matter is known to effect processing speed. These findings may offer support for the idea that omega-3 FAs exert their neuroprotective effects by fortifying areas of the brain, specifically the entorhinal cortex and white matter, that promote maintenance of cognitive function in late life.

37 Perceived Financial Exploitation Vulnerability is Associated with Morphometry of the Parahippocampal Gyrus and Entorhinal Cortex in Cognitively Normal Older Adults

Objective:Prior work suggests financial exploitation vulnerability may be an early behavioral manifestation of Alzheimer’s disease (AD). Brain morphometric measures of the parahippocampal gyrus and entorhinal cortex have been shown to be sensitive to early AD progression. We hypothesized that perceived financial exploitation vulnerability may be associated with morphometric measures of the parahippocampal gyrus and entorhinal cortex in cognitively unimpaired older adults. We secondarily investigated the association of morphometric measures with neuropsychological measures.Participants and Methods:The sample consisted of 39 cognitively unimpaired older adults (mean age = 68.74 ± 6.43, mean education = 16.87 ± 2.35, 77% female). Cognitive impairment was screened using the telephone version of the Montreal Cognitive Assessment (MoCA) and the cut-off was 21 for study participation. Perceived financial exploitation vulnerability was characterized using a 6-item self-report measure derived from the contextual items of the Lichtenberg Financial Rating Scale. Neuropsychological measures included the CVLT-II Long Delay Free Recall (verbal memory), Benson Complex Figure Recall (visual memory), and Verbal Fluency: Phonemic Test from the Alzheimer’s Disease Centers’ Uniform Data Set (UDS) version 3. Brain images were collected on a 7 Tesla Siemens Magnetom with the following parameters: TE=2.95ms, TR=2200ms, 240 sagittal slices, acquired voxel size (avs)=0.7mm x 0.7mm x 0.7mm. Structural brain images were processed using FreeSurfer version 7.2.0. Cortical thickness and volume measures were generated using the Killiany/Desikian parcellation atlas. Regions were averaged across hemispheres to obtain a single value for each region. Volume measures were adjusted for intracranial volume. Bivariate analyses were conducted to assess relationships between each outcome variable and potential confounders (age, sex, and education). Linear regression models were adjusted for any covariates significantly associated with the outcome variable (none for perceived financial exploitation vulnerability; sex and age for verbal memory; education for visual memory; sex for verbal fluency).Results:Smaller entorhinal cortex volume (β = -1275.14, SE = 582.79, p &lt; 0.05) and lower parahippocampal gyrus thickness (β = -3.37, SE = 1.57, p &lt; 0.05) were significantly associated with greater perceived financial exploitation vulnerability. Lower entorhinal cortex thickness was marginally associated with greater perceived financial exploitation vulnerability (β = -2.03, SE = 1.11, p = 0.08). Higher parahippocampal gyrus thickness was associated with better verbal fluency (β = 17.66, SE = 7.01, p &lt; 0.05). Higher entorhinal cortex thickness was associated with better visual memory (β = 4.71, SE = 1.73, p &lt; 0.05). No significant associations were observed between structural brain measures and verbal memory.Conclusions:These results suggest smaller entorhinal cortex volume and lower parahippocampal gyrus thickness are associated with higher perceived financial exploitation vulnerability in cognitively normal older adults. Additionally, parahippocampal gyrus thickness appears to be associated with verbal fluency abilities while entorhinal cortex thickness appears to be associated with visual memory. Taken together, these findings lend support to the notion that financial exploitation vulnerability may serve as an early behavioral manifestation of preclinical AD. Longitudinal studies are needed to better understand the temporal nature of these relationships.

11 Contributions of Cardiovascular Burden, Peripheral Inflammation, and Brain Integrity on Digital Clock Drawing Performance in Non-Demented Older Adults

Objective:Higher cardiovascular burden and peripheral inflammation are associated with small vessel vascular disease, a predominantly dysexecutive cognitive profile, and a higher likelihood of conversion to vascular dementia. The digital clock drawing test, a digitized version of a standard neuropsychological tool, is useful in identifying cognitive dysfunction related to vascular etiology. However, little is known about the specific cognitive implications of vascular risk, peripheral inflammation, and varying levels of overall brain integrity. The current study aimed to examine the role of cardiovascular burden, peripheral inflammation, and brain integrity on digitally acquired clock drawing latency and graphomotor metrics in non-demented older adults.Participants and Methods:The final prospectively recruited IRB-consented participant sample included 184 non-demented older adults (age: 69±6 years, education: 16±3 years, 46% female, 94% white) who completed digital clock drawing, vascular assessment, blood draw, and brain MRI. Digital clock drawing variables of interest included: total completion time (TCT), pre-first hand latency (PFHL), digit misplacement, hour hand distance from center, and clock face area (CFA). Cardiovascular burden was calculated using the revised version of the Framingham Stroke Risk Profile (FSRP-10). Peripheral inflammation was operationalized using interleukin (IL)-6, IL-8, IL-10, tumor necrosis factor alpha (TNF-a), and high sensitivity C-reactive protein (hsCRP). The brain integrity composite was comprised of bilateral entorhinal cortex volume, bilateral ventricular volume, and whole brain leukoaraiosis.Results:Over and above age and cognitive reserve, hierarchical regressions showed FSRP-10, inflammatory markers, and brain integrity explained an additional 13.3% of the variance in command TCT (p&lt; 0.001), with FSRP-10 (p=0.001), IL-10 (p= 0.019), and hsCRP (p= 0.019) as the main predictors in the model. FSRP-10, inflammatory markers, and brain integrity explained an additional 11.7% of the variance in command digit misplacement (p= 0.009), with findings largely driven by FSRP-10 (p&lt; 0.001).Conclusions:Overall, in non-demented older adults, subtle behavioral nuances seen in digital clock drawing metrics (i.e., total completion time and digit misplacement) are partly explained by cardiovascular burden, peripheral inflammation, and brain integrity over and above age and cognitive reserve. These nuanced behaviors on digitally acquired clock drawing may associate with an emergent disease process or overall vulnerability.Funding sources: Barber Fellowship; K07AG066813; R01 AG055337; R01 NR014810; American Psychological Foundation Dissertation Award; APA Dissertation Research Award

Correlation of metal ions with specific brain region volumes in neurodegenerative diseases.

There are reports stating that deteriorations in metal homeostasis in neurodegenerative diseases promote abnormal protein accumulation. In this study, the serum metal levels in Alzheimer's disease (AD) and Parkinson's disease (PD) and its relationship with the cortical regions of the brain were investigated. The patients were divided into 3 groups consisting of the AD group, PD group, and healthy control group (n = 15 for each). The volumes of specific brain regions were measured over the participants' 3-dimensional magnetic resonance images, and they were compared across the groups. Copper, zinc, iron, and ferritin levels in the serums were determined, and their correlations with the brain region volumes were examined. The volumes of left hippocampus and right substantia nigra were lower in the AD and PD groups, while the volume of the left nucleus caudatus (CdN) and bilateral insula were lower in the AD group compared to the control group. Serum zinc levels were lower in the AD and PD groups, while the iron level was lower in the PD group in comparison to the control group. In addition, the serum ferritin level was higher in the AD group than in the control group. Serum zinc and copper levels in the AD group were positively correlated with the volumes of the right entorhinal cortex, thalamus, CdN, and insula. Serum zinc and copper levels in the PD group showed a negative correlation with the left nucleus accumbens (NAc), right putamen, and right insula volumes. While the serum ferritin level in the PD group displayed a positive correlation with the bilateral CdN, putamen, and NAc, as well as the right hippocampus and insula volumes, no area was detected that showed a correlation with the serum ferritin level in the AD group. A relationship was determined between the serum metal levels in the AD and PD groups and certain brain cortical regions that showed volumetric changes, which can be important for the early diagnosis of neurodegenerative diseases.

Disturbed sleep is associated with reduced verbal episodic memory and entorhinal cortex volume in younger middle-aged women with risk-reducing early ovarian removal.

Women with early ovarian removal (<48 years) have an elevated risk for both late-life Alzheimer's disease (AD) and insomnia, a modifiable risk factor. In early midlife, they also show reduced verbal episodic memory and hippocampal volume. Whether these reductions correlate with a sleep phenotype consistent with insomnia risk remains unexplored. We recruited thirty-one younger middleaged women with risk-reducing early bilateral salpingo-oophorectomy (BSO), fifteen of whom were taking estradiol-based hormone replacement therapy (BSO+ERT) and sixteen who were not (BSO). Fourteen age-matched premenopausal (AMC) and seventeen spontaneously peri-postmenopausal (SM) women who were ~10y older and not taking ERT were also enrolled. Overnight polysomnography recordings were collected at participants' home across multiple nights (M=2.38 SEM=0.19), along with subjective sleep quality and hot flash ratings. In addition to group comparisons on sleep measures, associations with verbal episodic memory and medial temporal lobe volume were assessed. Increased sleep latency and decreased sleep efficiency were observed on polysomnography recordings of those not taking ERT, consistent with insomnia symptoms. This phenotype was also observed in the older women in SM, implicating ovarian hormone loss. Further, sleep latency was associated with more forgetting on the paragraph recall task, previously shown to be altered in women with early BSO. Both increased sleep latency and reduced sleep efficiency were associated with smaller anterolateral entorhinal cortex volume. Together, these findings confirm an association between ovarian hormone loss and insomnia symptoms, and importantly, identify an younger onset age in women with early ovarian removal, which may contribute to poorer cognitive and brain outcomes in these women.

Are demographic factors, masticatory performance and structural brain signatures associated with cognitive impairment in older people? A pilot study of cross-sectional neuroimaging data.

The occurrence of cognitive impairment (CI) is expected to increase within an ageing population. CI is associated with tooth loss, which influences masticatory performance. A decrease in masticatory performance may cause functional and morphological changes in the brain. However, whether CI is associated with masticatory performance, demographics, and structural brain signatures has not been studied yet. To assess the associations between CI on the one hand, and masticatory performance, demographic factors, and structural brain signatures (i.e. cortical volume and thickness) on the other hand. In total, 18 older adults with CI (mean ± SD age = 72.2 ± 9.5 years) and 68 older adults without CI (65.7 ± 7.5 years) were included in this study. Masticatory performance was quantified using a colour-changeable chewing gum. A Magnetic Resonance Imaging (MRI) scan was used to map structural brain signatures. To study our aim, a multivariate binary logistic regression analysis with backward selection was performed. The cortical volume of the right entorhinal cortex was negatively associated with CI (p < .01). However, demographic factors, masticatory performance, and the other structural brain signatures under investigation were not associated with CI. A decrease in the volume of the right entorhinal cortex is associated with CI in older people.

Contributions of Cardiovascular Burden, Peripheral Inflammation, and Brain Integrity on Digital Clock Drawing Performance in Non-Demented Older Adults.

Greater cardiovascular burden and peripheral inflammation are associated with dysexecutive neuropsychological profiles and a higher likelihood of conversion to vascular dementia. The digital clock drawing test (dCDT) is useful in identifying neuropsychological dysfunction related to vascular etiology. However, the specific cognitive implications of the combination of cardiovascular risk, peripheral inflammation, and brain integrity remain unknown. We aimed to examine the role of cardiovascular burden, inflammation, and MRI-defined brain integrity on dCDT latency and graphomotor metrics in older adults. 184 non-demented older adults (age 69±6, 16±3 education years, 46% female, 94% white) completed dCDT, vascular assessment, blood draw, and brain MRI. dCDT variables of interest: total completion time (TCT), pre-first hand latency, digit misplacement, hour hand distance from center, and clock face area. Cardiovascular burden was calculated using the Framingham Stroke Risk Profile (FSRP-10). Peripheral inflammation markers included interleukin (IL)-6, IL-8, IL-10, tumor necrosis factor-alpha, and high sensitivity C-reactive protein. Brain integrity included bilateral entorhinal cortex volume, lateral ventricular volume, and whole brain leukoaraiosis. FSRP-10, peripheral inflammation, and brain integrity explained an additional 14.6% of the variance in command TCT, where FSRP-10 was the main predictor. FSRP-10, inflammatory markers, and brain integrity explained an additional 17.0% in command digit misplacement variance, with findings largely driven by FSRP-10. Subtle graphomotor behavior operationalized using dCDT metrics (i.e., TCT and digit misplacement) is partly explained by cardiovascular burden, peripheral inflammation, and brain integrity and may indicate vulnerability to a disease process.

Association of anosmia with mild cognitive impairment and biomarkers of brain aging

AbstractBackgroundOlfactory impairment has been associated with neurodegenerative disorders such as Parkinson’s disease and Alzheimer’s disease (AD). We seek to investigate the relationships of impaired olfaction with mild cognitive impairment (MCI), plasma biomarkers of AD and neurodegeneration, and neuroimaging markers of microvascular lesions and neurodegeneration among Chinese older adults.MethodThis population‐based cross‐sectional study included 4214 participants (age ≥65 years; 56.0% women) from MIND‐China who were free of dementia and examined in March‐September 2018. Olfactory function was assessed using the 16‐item Sniffin’ Sticks identification test (SSIT). In the subsamples, we measured plasma concentrations of amyloid‐β40 (Aβ40), Aβ42, total‐tau, and neurofilament light chain (NfL) using the Simoa technology (n = 1054); and quantified hippocampal volume, entorhinal cortex volume, Alzheimer’s disease‐signature cortical thickness, and white matter hyperintensities (WMHs) volume on MRI scans (n = 917). The neuropsychological test battery was used to assess memory, verbal fluence, attention, and executive function. MCI and subtypes of MCI were defined according to the Petersen’s criteria that integrated clinical judgement by neurologists and neuropsychological tests. Data were analyzed with logistic and general linear regression models.ResultOf the 4214 participants, MCI was diagnosed in 1102 persons (26.2%), including 931 with amnestic MCI (aMCI) and 171 with non‐amnestic MCI (naMCI). Olfactory impairment (SSIT score 0‐10) was associated with an increased likelihood of MCI, aMCI, and naMCI in a dose‐response manner (p for trend&lt;.001). In the plasma biomarker or MRI subsample, anosmia (SSIT score 0‐7) was significantly associated with plasma total‐tau (demographic‐adjusted β = 0.26; 95% CI = 0.12‐0.41), NfL (0.12; 0.04‐0.19) and MRI biomarkers of hippocampal volume (‐0.13; ‐0.22‐ ‐0.04), entorhinal cortex volume (‐0.08; ‐0.13‐ ‐0.02), and WMHs volume (0.19; 0.08‐0.30), and marginally associated with Alzheimer‐signature cortical thickness (‐0.02; ‐0.05‐0.00, p = 0.08), but not with plasma Aβ concentrations (P&gt;0.05).ConclusionAnosmia may be a clinical marker for preclinical dementia and neurodegeneration among older adults. Microvascular and neurodegenerative lesions in the brain may be the common neuropathological pathways linking anosmia with cognitive impairment.

Measuring olfactory‐related brain region volume loss in MCI and AD using structural MRI

AbstractBackgroundAlzheimer disease (AD) is a chronic disorder that affects millions of individuals worldwide. Olfactory dysfunction is a common symptom of several neurological disorders including AD. Olfactory dysfunction can be an early alteration heralding the presence of AD. Studying the pattern of alterations in olfaction‐related brain regions might help detection of neurodegenerative diseases at an earlier stage. Objectives of this study are to assess the volume of olfactory areas associated with odour processing in healthy elderly, MCI and AD populations using structural MRI scans. To test whether there are any differences in the volume of olfactory related regions between patients and healthy controls. To determine whether there is an effect of sex on olfactory‐related brain regions’ volume loss.MethodNeurologically healthy participants aged 66‐85 (n = 95), MCI aged 58‐86 (n = 81) and mild probable AD aged 55‐88 (n = 37) participants were recruited. T1‐ weighted MRI scans acquired at 1.5T were processed using SPM12. Smoothed images were used to extract the volume of olfactory cortex, hippocampus, parahippocampus, amygdala, orbitofrontal cortex and entorhinal cortex.ResultOne‐way ANOVA analyses showed a significant reduction in all olfaction‐related brain regions (p≤0.0001). Post‐hoc multiple comparison tests showed a significant reduction in volume in the AD group in all olfaction‐related brain regions. In the MCI group, a significantly smaller volume than the healthy controls was found in four of the selected olfactory‐related brain regions (namely, hippocampus, parahippocampus, amygdala and entorhinal cortex) for the total and left volume in the female group only. Additionally in the female MCI, the volume of the right entorhinal cortex however, was also significantly smaller than that of the control group. When adjusting for MMSE, however, between group differences in all olfaction‐related brain regions were no longer significant.ConclusionThese preliminary data show a significant reduction in grey matter volume in all olfaction‐related brain regions. Grey matter volume loss in these regions appears to be a good proxy of disease severity.

Tau burden is associated with cross‐sectional and longitudinal neurodegeneration in the medial temporal lobe in cognitively normal individuals

AbstractBackgroundNeurofibrillary tangle pathology is thought to drive neurodegeneration in beta‐amyloid positive (A+) cognitively normal (CN) individuals, i.e., preclinical Alzheimer’s disease (AD). However, in beta‐amyloid negative (A‐) CN, the contribution of tau pathology [primary age‐related tauopathy (PART)] to neurodegeneration remains uncertain. We investigate the correlation between tau burden measured by PET in the medial temporal lobe (MTL) and MRI‐derived cross‐sectional and longitudinal structural atrophy in these cohorts.Methods420 CN (A‐/A+: 294/101, Table 1) individuals from ADNI with AV1451 PET and T1‐weighted MRI acquired within one year were included. Bilateral anterior/posterior hippocampal volume and thickness of entorhinal cortex (ERC), Brodmann areas 35/36 (BA35/BA36) and parahipocampal cortex (PHC) were obtained from baseline MRI scans. Bilateral MTL tau burden was computed as AV1451 uptake across ERC and BA35. Beta‐amyloid status was determined with PET by standard cut‐offs (Florbetapir: 1.11; Florbetaben: 1.08). In a subset of participants with prospective longitudinal MRI scans (up to 4.5 years), annualized volume change rate of each MTL subregion was estimated. Partial Pearson’s correlation, controlling for age, sex, and MRI‐PET date difference, was performed between MTL tau burden and structural atrophy measurements. Intracranial volume and MRI follow‐up time were additional covariates for cross‐sectional and longitudinal analysis respectively. We performed the analysis separately for each hemisphere in the whole CN cohort and its A+ and A‐ subgroups.ResultsTau burden was significantly associated with cross‐sectional left BA35/36 thickness in the whole cohort and bilateral posterior hippocampus volume in both A+ CN and the whole cohort (Table 2, Figure 1), but not in in A‐ CN. Stronger correlations between MTL tau burden and longitudinal atrophy, despite smaller sample size, was observed in almost all the MTL subregions regardless of amyloid status (Table 3, Figure 1). In general, effects from the left hemisphere were stronger than those from the right hemisphere. All significant correlations were maintained when corrected for beta‐amyloid PET SUVR.ConclusionsThe results demonstrated that elevated tau predicts subsequent neurodegeneration in early Braak regions in CN subjects regardless of amyloid status. This indicates that PART may be an important driver of neurodegeneration already during normal ageing in cognitively normal individuals.

Association Between False Memories and Delusions in Alzheimer Disease

Understanding the mechanisms of delusion formation in Alzheimer disease (AD) could inform the development of therapeutic interventions. It has been suggested that delusions arise as a consequence of false memories. To investigate whether delusions in AD are associated with false recognition, and whether higher rates of false recognition and the presence of delusions are associated with lower regional brain volumes in the same brain regions. Since the Alzheimer's Disease Neuroimaging Initiative (ADNI) launched in 2004, it has amassed an archive of longitudinal behavioral and biomarker data. This cross-sectional study used data downloaded in 2020 from ADNI participants with an AD diagnosis at baseline or follow-up. Data analysis was performed between June 24, 2020, and September 21, 2021. Enrollment in the ADNI. The main outcomes included false recognition, measured with the 13-item Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog 13) and the Rey Auditory Verbal Learning Test (RAVLT) and volume of brain regions corrected for total intracranial volume. Behavioral data were compared for individuals with delusions in AD and those without using independent-samples t tests or Mann-Whitney nonparametric tests. Significant findings were further explored using binary logistic regression modeling. For neuroimaging data region of interest analyses using t tests, Poisson regression modeling or binary logistic regression modeling and further exploratory, whole-brain voxel-based morphometry analyses were carried out to explore the association between regional brain volume and false recognition or presence of delusions. Of the 2248 individuals in the ADNI database, 728 met the inclusion criteria and were included in this study. There were 317 (43.5%) women and 411 (56.5%) men. Their mean (SD) age was 74.8 (7.4) years. The 42 participants with delusions at baseline had higher rates of false recognition on the ADAS-Cog 13 (median score, 3; IQR, 1 to 6) compared with the 549 control participants (median score, 2; IQR, 0 to 4; U = 9398.5; P = .04). False recognition was not associated with the presence of delusions when confounding variables were included in binary logistic regression models. An ADAS-Cog 13 false recognition score was inversely associated with left hippocampal volume (odds ratio [OR], 0.91 [95% CI, 0.88-0.94], P < .001), right hippocampal volume (0.94 [0.92-0.97], P < .001), left entorhinal cortex volume (0.94 [0.91-0.97], P < .001), left parahippocampal gyrus volume (0.93 [0.91-0.96], P < .001), and left fusiform gyrus volume (0.97 [0.96-0.99], P < .001). There was no overlap between locations associated with false recognition and those associated with delusions. In this cross-sectional study, false memories were not associated with the presence of delusions after accounting for confounding variables, and no indication for overlap of neural networks for false memories and delusions was observed on volumetric neuroimaging. These findings suggest that delusions in AD do not arise as a direct consequence of misremembering, lending weight to ongoing attempts to delineate specific therapeutic targets for treatment of psychosis.

Prediction of Amyloid β-Positivity with both MRI Parameters and Cognitive Function Using Machine Learning.

To investigate the MRI markers for the prediction of amyloid β (Aβ)-positivity in mild cognitive impairment (MCI) and Alzheimer's disease (AD), and to evaluate the differences in MRI markers between Aβ-positive (Aβ [+]) and -negative groups using the machine learning (ML) method. This study included 139 patients with MCI and AD who underwent amyloid PET-CT and brain MRI. Patients were divided into Aβ (+) (n = 84) and Aβ-negative (n = 55) groups. Visual analysis was performed with the Fazekas scale of white matter hyperintensity (WMH) and cerebral microbleeds (CMB) scores. The WMH volume and regional brain volume were quantitatively measured. The multivariable logistic regression and ML using support vector machine, and logistic regression were used to identify the best MRI predictors of Aβ-positivity. The Fazekas scale of WMH (p = 0.02) and CMB scores (p = 0.04) were higher in Aβ (+). The volumes of hippocampus, entorhinal cortex, and precuneus were smaller in Aβ (+) (p < 0.05). The third ventricle volume was larger in Aβ (+) (p = 0.002). The logistic regression of ML showed a good accuracy (81.1%) with mini-mental state examination (MMSE) and regional brain volumes. The application of ML using the MMSE, third ventricle, and hippocampal volume is helpful in predicting Aβ-positivity with a good accuracy.

TAR DNA‐binding protein 43 (TDP‐43) contributes to the mismatch between medial temporal volumes and flortaucipir uptake in elderly patients with Alzheimer’s disease neuropathologic changes

AbstractBackgroundWe previously demonstrated that Alzheimer’s disease (AD) patients ≥70 y/o tend to have smaller medial temporal volumes in the presence of relatively less medial temporal 18F‐flortaucipir‐PET uptake compared to young AD patients. TAR DNA‐binding protein 43 (TDP‐43) is frequently found in the brains of AD patients and is associated with old age and medial temporal atrophy. In this study, we aimed to determine whether TDP‐43 could be contributing to the mismatch between medial temporal volumes and flortaucipir‐PET uptake in older AD patients.MethodWe identified 77 participants (median age at death 79 years [range: 51‐99]) who had been enrolled into the Mayo Clinic Alzheimer’s Disease Research Center or Neurodegenerative Research Group (NRG), had undergone flortaucipir‐PET and volumetric MRI scans close to death, and autopsy confirmed AD neuropathological changes, as well as TDP‐43 assessments. Grey matter volumes and flortaucipir standard uptake value ratios (SUVRs) were calculated for hippocampus, amygdala, entorhinal, inferior temporal, and midfrontal cortices. We used bivariate‐response linear regression modelling, adjusting for Braak neurofibrillary tangle stage, to estimate the effect of TDP‐43 and age on gray matter volume and flortaucipir uptake, and tested whether TDP‐43 effect sizes varied according to age.ResultAfter accounting for Braak stage, older individuals tended to have significantly lower flortaucipir uptake across regions and lower hippocampal and entorhinal cortex (ERC) volumes. TDP‐43 was associated with reduced hippocampus and ERC volumes but was unrelated to flortaucipir SUVRs (Figure 1). Notably, the TDP‐43 effect size for the hippocampus and ERC was largely consistent across age, i.e., at any age, TDP‐43‐positive participants had significantly smaller hippocampal (∼12% decrease) and ERC (13% decrease) volumes than TDP‐43‐negative participants. However, at older ages, the mean volumes in the whole cohort and, more evidently, in those with dementia moved closer towards the mean of those with TDP‐43 (Figure 1), likely attributable to the increasing frequency of TDP‐43 with age.ConclusionTDP‐43 is a major contributor to the mismatch between flortaucipir uptake and medial temporal lobe volumes in older AD patients where lower medial temporal regional volumes are observed in the presence of less flortaucipir uptake.

Predicting Amyloid Positivity from Hippocampal and Entorhinal Cortex Volume and APOE Genotype

AbstractBackgroundAccumulation of brain amyloid – an early indicator of AD – is assessed using PET or CSF samples, but such procedures are highly invasive. There is interest in using less invasive data, such as brain MRI, to predict β‐amyloid (Aβ) positivity, as a precursor to more invasive screening.Here we assessed different predictive models based on logistic regression, using readily measured indices from T1‐weighted MRI (T1w). We hypothesized that entorhinal cortex measures would outperform hippocampal measures in predicting amyloid positivity, given its role as a cortical area with early amyloid accumulation.MethodWe analyzed T1w from 724 subjects (Table 1) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). One cut‐off, for determining amyloid levels, was used based on PET cortical SUVR uptake (Αβ_1) determined by either mean 18F‐florbetapir (Aβ+ defined as &gt;1.11) or florbetaben (Aβ+ defined as &gt;1.20), normalized by using whole cerebellum reference region. After registering the T1w image to a common template, we split the data into independent training and testing sets. A logistic regression classifier was used, and test performance was assessed using balanced accuracy to compare the different predictive models.ResultFigure 1 shows classification results from the models. The balanced accuracy was highest (74.9%) for the logistic regression model including both left and right entorhinal cortex volumes, APOE status, age, and sex. This model outperformed models using hippocampal volume as the main imaging predictor (balanced accuracy 70.8%).ConclusionOptimal accuracy was obtained when predicting Aβ positivity from brain MRI using entorhinal cortical measures. Future work will test deep learning methods for Aβ prediction based on paired training data, and will use voxel‐based data and features from other imaging modalities, such as diffusion MRI, to predict amyloid status.

The role of IGFBP2 in pre‐symptomatic Alzheimer's disease: a multimodal longitudinal study of cognitively unaffected individuals with a family history of sporadic Alzheimer’s disease

AbstractBackgroundInsulin‐like growth factors (IGF) play pivotal roles in neurogenesis, neuronal survival, synaptogenesis and compensatory repair mechanisms following injury. Insulin‐like growth factor binding proteins (IGFBP) bind to IGFs, and regulate interactions between IGFs and their cell surface receptors. In the brain, IGFBP2 is the most abundant IGFBP. Several studies have observed altered IGFBP2 levels in Alzheimer’s disease (AD) patients. However, the role of IGFBP2 during pre‐symptomatic AD remains unknown. Thus, we used longitudinal data acquired from the pre‐symptomatic PREVENT‐AD cohort to examine its possible contributions to AD pathophysiology.MethodFor initial cross‐sectional analyses, the Mini‐Mental State Examination was used to stage the participants (PREVENT‐AD, CCNA and Douglas cohorts) across the AD spectrum. Olink’s primer extension assay was used to measure cerebrospinal fluid (CSF) IGFBP2 levels. PREVENT‐AD participants were followed longitudinally for 6‐8 years. Annual visits included cognitive performance assessments, lumbar punctures and neuroimaging. The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) evaluated five cognitive domains (immediate memory, delayed memory, attention, language and visuospatial abilities) and included a total summary score.ResultCSF IGFBP2 levels were significantly reduced in MCI (p &lt; 0.001) and AD participants (p = 0.027 and p &lt; 0.001 respectively), relative to controls (Figure 1). In the PREVENT‐AD cohort, baseline CSF IGFBP2 levels were negatively correlated with RBANS cognitive performance trajectory slopes estimated over the course of 6 to 8 years, for the delayed memory (p = 0.003), visuospatial (p = 0.008) and total scale indices (p = 0.021) (Figure 2). However, baseline CSF IGFBP2 levels were not associated with cognitive decline for the immediate memory (p = 0.162), attention (p = 0.890) and language (p = 0.841) indices (Figure 3). Finally, in the PREVENT‐AD cohort, baseline CSF IGFBP2 levels were negatively correlated with baseline left entorhinal cortex volume (p = 0.011), but were not correlated with right entorhinal cortex volume (p = 0.868)(Figure 4).ConclusionOur results suggest that IGFBP2 may exhibit a bi‐directional association with AD stage pathology. Our findings revealed that IGFBP2 is strongly correlated with early cognitive decline in the delayed memory and visuospatial domains, in pre‐symptomatic individuals.

Tau burden is associated with cross‐sectional and longitudinal neurodegeneration in the medial temporal lobe in cognitively normal individuals

AbstractBackgroundNeurofibrillary tangle pathology is thought to drive neurodegeneration in beta‐amyloid positive (A+) cognitively normal (CN) individuals, i.e., preclinical Alzheimer’s disease (AD).However, in beta‐amyloid negative (A‐) CN, the contribution of tau pathology [primary age‐related tauopathy (PART)] to neurodegeneration remains uncertain. We investigate the correlation between tau burden measured by PET in the medial temporal lobe (MTL) and MRI‐derived cross‐sectional and longitudinal structural atrophy in these cohorts.Methods420 CN (A‐/A+: 294/101, Table 1) individuals from ADNI with AV1451 PET and T1‐weighted MRI acquired within one year were included. Bilateral anterior/posterior hippocampal volume and thickness of entorhinal cortex (ERC), Brodmann areas 35/36 (BA35/BA36) and parahipocampal cortex (PHC) were obtained from baseline MRI scans. Bilateral MTL tau burden was computed as AV1451 uptake across ERC and BA35. Beta‐amyloid status was determined with PET by standard cut‐offs (Florbetapir: 1.11; Florbetaben: 1.08). In a subset of participants with prospective longitudinal MRI scans (up to 4.5 years), annualized volume change rate of each MTL subregion was estimated. Intracranial volume and MRI follow‐up time were additional covariates for cross‐sectional and longitudinal analysis respectively. We performed the analysis separately for each hemisphere in the whole CN cohort and its A+ and A‐ subgroups.ResultsTau burden was significantly associated with cross‐sectional left BA35/36 thickness in the whole cohort and bilateral volume in both A+ CN and the whole cohort (Table 2, Figure 1), but not in in A‐ CN. Stronger correlations between MTL tau burden and longitudinal atrophy, despite smaller sample size, was observed in almost all the MTL subregions regardless of amyloid status (Table 3, Figure 1). In general, effects from the left hemisphere were stronger than those from the right hemisphere. All significant correlations were maintained when corrected for beta‐amyloid PET SUVR.ConclusionsThe results demonstrated that elevated tau predicts subsequent neurodegeneration in early Braak regions in CN subjects regardless of amyloid status. This indicates that PART may be an important driver of neurodegeneration already during normal ageing in cognitively normal individuals.

Activation of the RMTg Nucleus by Chemogenetic Techniques Alleviates the Learning and Memory Impairment in APP/PS1 Mice.

There is a relationship between non-rapid eye movement (NREM) sleep and Alzheimer's disease (AD). The rostromedial tegmental nucleus (RMTg) is activated can enhance NREM. Therefore, our experiment was designed to investigate the effects of activation of RMTg by chemical genetic techniques on APP/PS1 mice learning and memory. After the AAV-hSyn-hM3Dq-mCherry virus was injected into the RMTg nucleus, CNO solution was intraperitoneally injected to activate RMTg. The new object test and Morris water maze were used to determine the learning and memory level; T2-weighted imaging (T2WI) scanning was performed to analyze the volume of hippocampus and entorhinal cortex of each group; The virus transfection status was determined by laser confocal microscope and use immunohistochemical detection to observe the deposition of Beta Amyloid 1-42 (Aβ42). Activation of RMTg by chemical genetic techniques can reduce the escape latency and increase discrimination index (RI) and the number of crossing platform; Activation of RMTg by chemical genetic techniques reduced the atrophy of the entorhinal cortex. Aβ42 deposition in the brain was decreased after activation of RMTg. Activation of the RMTg nucleus by chemogenetic techniques can improve the learning and memory impairment in APP/PS1 mice.

CSF biomarkers for Alzheimer Disease are associated with spatial cognition in cognitively normal older adults

AbstractBackgroundSpatial cognition has emerged as a promising cognitive fingerprint for the detection of Alzheimer’s disease (AD). Despite evidence that spatial cognition is highly sensitive to AD dementia and is apparent even in adults at‐genetic‐risk of AD, the association between spatial cognition and AD biomarkers in cognitively normal adults is unknown.MethodThis study leverages data from the European Prevention of Alzheimer’s Dementia Consortium, a multinational observational study of clinically normal adults initiated in 2016 that includes two digital spatial paradigms: The Supermarket Task (SMT)and the Four Mountains Task (4MT;Fig1). Using a mixed model approach with random intercepts, we investigated cross‐sectional associations between cerebrospinal fluid (CSF) β‐amyloid1‐42 (Aβ1‐42) and phosphorylated tau (p‐tau181) with task performance (N = 1672; mean age = 68.08[SD = 6.96]).ResultFive hundred and forty‐nine (32.8%) participants had abnormal levels of CSF Aβ1‐42 and p‐tau181. Across the whole sample, higher p‐tau181 concentrations were associated with greater spatial disorientation from the starting location on the SMT (r = ‐0.449, p = &lt;0.001). There was a small association with CSF Aβ1‐42(r = 1.984, p = 0.003; Fig2A‐B). Higher levels of CSF p‐tau181 were associated with more 4MT feature memory errors (r = ‐0.570, p&lt;0.001). There was also a main effect of Aβ1‐42 on 4MT performance (r = 0.301, p = &lt;0.001; Fig2C‐D). Entorhinal cortex and hippocampal volumes both predicted better performance on both tasks (r’s = 0.37‐0.57; Fig3). Post hoc analyses revealed a significant interaction between sex and hippocampal volume, indicating that the association between hippocampal volume and recall of environmental features was stronger in males than females. Finally, volume of the entorhinal cortex, but not the hippocampus, mediated the relationship between p‐tau181 and performance on both spatial tasks (Fig4).ConclusionOur results suggest that spatial tasks are sensitive to CSF p‐tau181 and to a lesser extent Aβ1‐42 in preclinical AD. Given the well‐validated digital platform that these tasks are founded on, these tools provide access to racially and ethnically diverse individuals for preclinical AD trial registries via unsupervised assessment.