Medial Temporal Lobe Volume Research Articles

Automated Quantification of Lateral and Medial Temporal Lobe Volumes for Improved Diagnosis of Early Alzheimer’s Disease

Automated Quantification of Lateral and Medial Temporal Lobe Volumes for Improved Diagnosis of Early Alzheimer’s Disease

Associations of brain morphology with cortical proteins of cognitive resilience

In a recent proteome-wide study, we identified several candidate proteins for drug discovery whose cortical abundance was associated with cognitive resilience to late-life brain pathologies. This study examines the extent to which these proteins are associated with the brain structures of cognitive resilience in decedents from the Religious Orders Study and Memory and Aging Project. Six proteins were associated with brain morphometric characteristics related to higher resilience (i.e., larger anterior and medial temporal lobe volumes), and five were associated with morphometric characteristics related to lower resilience (i.e., enlarged ventricles). Two synaptic proteins, RPH3A and CPLX1, remained inversely associated with the lower resilience signature, after further controlling for 10 neuropathologic indices. These findings suggest preserved brain structure in periventricular regions as a potential mechanism by which RPH3A and CPLX1 are associated with cognitive resilience. Further work is needed to elucidate other mechanisms by which targeting these proteins can circumvent the effects of pathology on individuals at risk for cognitive decline.

Utility of accessible neuroimaging markers of cerebrovascular disease in identifying cerebral amyloidosis across the Alzheimer’s disease spectrum

AbstractBackgroundAlzheimer’s disease (AD) is defined by the presence of cognitive impairment and cerebral amyloidosis and is associated with several cerebrovascular disease (CVD) risk factors including age, apolipoprotein‐E ε4 (APOE‐ε4) genotype, hypertension, diabetes and hyperlipidemia. Despite this association, the clinical utility of individual CVD biomarkers in screening for AD pathology is understudied. Therefore, we sought to examine the relationship between cerebral amyloidosis and magnetic resonance imaging (MRI)‐based CVD measures, including cerebral microbleeds, ischemic infarction, and white matter hyperintensities (WMH). We hypothesized that CVD biomarker burden would be positively associated with amyloidosis. Given recent studies have shown plasma phospho‐tau181 (P‐tau181) is a promising early biomarker of amyloidosis, we further hypothesized that combining P‐tau181 with CVD biomarkers would predict amyloid status in cognitively unimpaired and impaired persons.MethodParticipant data were extracted from the Alzheimer’s Disease Neuroimaging Initiative database (N = 1,430). Volumetric data (WMH volume [WMHv], medial temporal lobe volume [MTLv]) were normalized and log‐transformed. Adjusted odds ratio (OR) was calculated using logistic regression with dichotomized amyloid‐PET status as the outcome. Area under the curve (AUC) was compared by the likelihood ratio test.ResultAfter adjustment for age, sex, APOE‐ε4 status, MTLv, cognition (MoCA), and other CVD biomarkers of interest, we found that WMHv alone was significantly associated with amyloidosis in both cognitively impaired (OR = 1.21) and unimpaired (OR = 1.25) persons. We then developed an accessible diagnostic model incorporating WMHv, significant covariates and plasma P‐tau181. Addition of P‐tau181 to the model improved diagnostic accuracy in cognitively impaired persons (AUC = 0.85 to 0.87, p < 0.001), and did not attenuate the relationship between WMHv and amyloidosis.ConclusionWe newly identify WMH, but not other CVD lesions, as predictive of amyloidosis in both preclinical and symptomatic AD. The current study adds to the literature regarding which CVD biomarkers are most predictive of AD pathology. Measurement of WMH alongside P‐tau181 and other biomarkers may produce an accessible screening algorithm for AD. Study generalizability is limited by ascertainment bias and lack of diversity. Future research will compare the performance of WMH to standard AD biomarkers in a more diverse, community‐based sample.

Relationship of structural and functional visual biomarkers with measures of amyloid, tau, and neurodegeneration across the AD continuum

AbstractBackgroundThe eye often reflects changes seen in the brain in neurodegenerative diseases. This study sought to examine the relationship of contrast sensitivity measured using frequency doubling technology (FDT) and retinal thickness measured using optical coherence tomography (OCT) with temporal lobe neurodegeneration, cerebral tau deposition, and mean plasma ptau181 in older adults along the Alzheimer’s disease (AD) continuum.MethodParticipants included 28 individuals with subjective cognitive decline (SCD), 18 mild cognitive impairment (MCI), 4 with AD, and 30 age‐matched cognitive normal (CN) from the Indiana Memory and Aging Study at the Indiana ADRC. Participants were excluded from the study if they had significant eye disease determined to interfere with OCT, FDT, non‐AD dementia, or exclusion for MRI or PET. Mean deviation (MD) and pattern standard deviation (PSD) from FDT were used as measures of contrast sensitivity. OCT scans from each eye to measure retinal thickness in the retinal nerve fiber layer (RNFL) and macula. MRI scans were processed using Freesurfer v6 to measure medial (MTL) and lateral temporal lobe (LTL) volumes. LTL SUVR values were extracted from [18F]flortaucipir PET scans. Plasma ptau 181 was measured using a SIMOA assay. Finally, the association between contrast sensitivity, average RNFL thickness, macular volumes with temporal lobe volumes, LTL tau, and mean plasma ptau181 was assessed using a partial Pearson correlation, covaried for age, sex, and diagnosis. p<0.05 was considered significant.ResultRNFL thickness was decreased in patients with AD. Hippocampal volume correlated with RNFL thickness and macular volume in both eyes and with PSD in the left eye. The inferior temporal volume correlated with MD in both eyes, while mean plasma ptau181 with PSD in both eyes. Finally, lateral temporal lobe tau was correlated with the inner retinal layers of ganglion cell layer plus inner plexiform layer thickness.ConclusionContrast sensitivity correlates with temporal lobe volumes and mean plasma ptau181. RNFL thinning and macular volumes are associated with hippocampal atrophy, and inner retinal nuclear layers correlate with lateral temporal tau. Imaging of the eye may represent a useful biomarker to screen patients at risk for AD prior to more invasive and prolonged testing.

Medial temporal lobe gray matter microstructure alterations provide improved sensitivity to detect neurodegeneration associated with Alzheimer’s disease biomarkers

AbstractBackgroundDespite the strengths conventional structural imaging measures to detect atrophy, cross‐sectional relationships between neurodegeneration and Alzheimer’s disease (AD) biomarkers in early stages is limited. Neurite orientation dispersion and density imaging (NODDI) measures microstructural alterations that are unique from conventional structural metrics. Alterations in microstructure have been detected in individuals with AD compared to cognitively normal individuals, but there is sparse data regarding the relationship between these metrics and AD biomarkers. Here we sought to characterize how NODDI metrics in the medial temporal lobe (MTL) are associated with plasma AD biomarkers.MethodOne‐hundred and sixty‐seven cognitively normal (CN) individuals, 47 individuals with mild cognitive impairment, and 16 individuals with AD underwent diffusion and T1w imaging. T1w images were segmented using the ASHS‐T1 protocol to form anterior and posterior MTL ROIs. Multi‐shell DTI data were collected in 113 non‐collinear directions with 1.5mm isotropic voxels, were pre‐processed using a custom pipeline, and fit with voxel‐wise NODDI models. ANTs was used to linearly register NODDI and T1w images to allow transformation of MTL ROIs to diffusion space. Stepwise‐regression models examined relationships between anterior and posterior MTL NODDI metrics with plasma biomarkers in CN and impaired (MCI/AD) groups after accounting for MTL volume.ResultNODDI metrics of intracellular volume fraction (icVf) and orientation dispersion index (ODI) were decreased, and isometric volume fraction (isoVf) was increased in cognitively impaired compared to CN. Amyloid positivity was associated with decreased ODI and increased isoVf in cognitively impaired individuals. While posterior MTL volume predicted plasma p‐Tau‐181, inclusion of NODDI metrics subsumed this effect (F‐change>7.54, p<0.0067), and reduced ODI was the best predictor of plasma pTau‐181 within cognitively impaired individuals, while isoVf best predicted pTau‐181 across all individuals. Posterior MTL volume did not predict plasma GFAP, but inclusion of ODI and icVf both significantly predicted plasma GFAP in both CN and impaired individuals (F‐change>12.68, p<.001). Anterior MTL icVf predicted both pTau‐181 and GFAP.ConclusionMicrostructural alterations measured by NODDI appear more closely linked to AD‐related molecular measures and, thus, may provide a more sensitive cross‐sectional measure of neurodegeneration of the MTL compared to conventional macrostructural metrics.

Association between basal forebrain and medial temporal lobe tau, and gray matter volume

AbstractBackgroundTau pathology is a hallmark of Alzheimer’s disease (AD). The basal forebrain (BF) is a significant cholinergic projection site with cholinergic groups 1‐3 (Ch1‐3) projecting to the hippocampus, hypothalamus, and olfactory bulb, and group 4 (Ch4) projecting to the cortical mantle and amygdala. Braak stage 1 includes BF tau and recent literature suggests BF degeneration precedes medial temporal lobe (MTL) degeneration, thus implicating early involvement of the BF in AD. This study examines BF 18F‐flortaucipir (FTP) retention and gray matter (GM) volume, and their associations with MTL FTP retention and GM volume.MethodData were acquired for 111 older adults (Table 1) in the Baltimore Longitudinal Study of Aging. Binary masks for BF subregions Ch1‐3 and Ch4 were generated using a probabilistic atlas (Figure 1). We computed mean standardized uptake value ratio (SUVR) using an inferior cerebellar GM reference region and mean GM volume using average voxel‐based morphometry values for each BF subregion. Colocalized relationships between BF tau and volume were assessed using Pearson correlations. Proximal relationships between BF tau/GM and MTL tau/GM were assessed at the voxel level controlling for age, sex, and intracranial volume and corrected for multiple comparisons using non‐parametric permutations.ResultsWithin the BF, FTP‐SUVR in Ch1‐3 was strongly related to FTP‐SUVR in Ch4, and FTP‐SUVR was associated with larger volume in Ch1‐3, but not Ch4 (Figure 2). Voxelwise analyses showed strong BF‐MTL associations with higher Ch1‐3 and Ch4 FTP‐SUVR associated with higher FTP‐SUVR throughout the MTL. The strongest associations were observed anteriorly (amygdala, peri/entorhinal cortices) and medially along the longitudinal axis of the hippocampus/parahippocampal gyrus. Moreover, for both BF Ch groups, larger volume was associated with larger MTL volume. This association was strongest in the amygdala and hippocampal head and body.ConclusionAs expected, BF FTP‐SUVR was positively associated with MTL FTP‐SUVR, and BF volume was positively associated with MTL GM volume, supporting the use of these BF measures. Further analysis is necessary to better understand the positive associations between BF FTP‐SUVR and GM volume and to assess the temporal ordering of FTP‐SUVR accumulation in the BF and MTL.

Medial temporal lobe gray matter microstructure alterations provide improved sensitivity to detect neurodegeneration associated with Alzheimer’s disease biomarkers

AbstractBackgroundDespite the strengths conventional structural imaging measures to detect atrophy, cross‐sectional relationships between neurodegeneration and Alzheimer’s disease (AD) biomarkers in early stages is limited. Neurite orientation dispersion and density imaging (NODDI) measures microstructural alterations that are unique from conventional structural metrics. Alterations in microstructure have been detected in individuals with AD compared to cognitively normal individuals, but there is sparse data regarding the relationship between these metrics and AD biomarkers. Here we sought to characterize how NODDI metrics in the medial temporal lobe (MTL) are associated with plasma AD biomarkers.MethodOne‐hundred and sixty‐seven cognitively normal (CN) individuals, 47 individuals with mild cognitive impairment, and 16 individuals with AD underwent diffusion and T1w imaging. T1w images were segmented using the ASHS‐T1 protocol to form anterior and posterior MTL ROIs. Multi‐shell DTI data were collected in 113 non‐collinear directions with 1.5mm isotropic voxels, were pre‐processed using a custom pipeline, and fit with voxel‐wise NODDI models. ANTs was used to linearly register NODDI and T1w images to allow transformation of MTL ROIs to diffusion space. Stepwise‐regression models examined relationships between anterior and posterior MTL NODDI metrics with plasma biomarkers in CN and impaired (MCI/AD) groups after accounting for MTL volume.ResultNODDI metrics of intracellular volume fraction (icVf) and orientation dispersion index (ODI) were decreased, and isometric volume fraction (isoVf) was increased in cognitively impaired compared to CN. Amyloid positivity was associated with decreased ODI and increased isoVf in cognitively impaired individuals. While posterior MTL volume predicted plasma p‐Tau‐181, inclusion of NODDI metrics subsumed this effect (F‐change>7.54, p<0.0067), and reduced ODI was the best predictor of plasma pTau‐181 within cognitively impaired individuals, while isoVf best predicted pTau‐181 across all individuals. Posterior MTL volume did not predict plasma GFAP, but inclusion of ODI and icVf both significantly predicted plasma GFAP in both CN and impaired individuals (F‐change>12.68, p<.001). Anterior MTL icVf predicted both pTau‐181 and GFAP.ConclusionMicrostructural alterations measured by NODDI appear more closely linked to AD‐related molecular measures and, thus, may provide a more sensitive cross‐sectional measure of neurodegeneration of the MTL compared to conventional macrostructural metrics.

Volumetric brain correlates of gait associated with cognitive decline in community-dwelling older adults.

To determine the extent to which the regional brain volumes associated with slow gait speed can inform subsequent cognitive decline in older adults from the Rush Memory and Aging Project. We utilized deformation-based morphometry (DBM) in a whole-brain exploratory approach to identify the regional brain volumes associated with gait speed assessed over a short distance during an in-home assessment. We created deformation scores to summarize the gait-associated regions and entered the scores into a series of longitudinal mixed effects models to determine the extent to which deformation predicted change in cognition over time, controlling for associations between gait and cognition. In 438 older adults (81 ± 7; 76% female), DBM revealed that slower gait speed was associated with smaller volumes across frontal white matter, temporal grey matter, and subcortical areas and larger volumes in the ventricles during the same testing cycle. When a subset was followed over multiple (5 ± 2) years, slower gait speed was also associated with annual declines in global cognition, executive functioning, and memory abilities. Several of the gait-related brain structures were associated with these declines in cognition; however, larger ventricles and smaller medial temporal lobe volumes proved most robust and attenuated the association between slow gait and cognitive decline. Regional brain volumes in the ventricles and temporal lobe associated with both slow gait speed and faster cognitive decline have potential to improve risk stratification for cognitive decline in older adults.

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.

Ultra-high-field 7T MRI reveals changes in human medial temporal lobe volume in female adults during menstrual cycle

Ovarian hormones have substantial effects on the brain, and early menopause has been associated with increased risk of accelerated brain aging and dementia later in life. However, the impact of ovarian hormone fluctuations on brain structure earlier in life is less understood. Here we show that ovarian hormone fluctuations shape structural brain plasticity during the reproductive years. We use longitudinal ultra-high field neuroimaging across the menstrual cycle to map the morphology of medial temporal lobe subregions in 27 participants. Controlling for water content and blood flow, our findings reveal positive associations between estradiol and parahippocampal cortex volume, progesterone and subiculum and perirhinal area 35 volumes, and an estradiol*progesterone interaction with CA1 volume. This research offers a blueprint for future studies on the shared dynamics of the brain and ovarian function and a fundamental stepping stone towards developing sex-specific strategies to improve brain health and mental health.

Menopause age, reproductive span and hormone therapy duration predict the volume of medial temporal lobe brain structures in postmenopausal women

Medial temporal lobe (MTL) atrophy is correlated with risk and severity of Alzheimer disease (AD) pathology and cognitive decline. Increasing evidence suggest that oestrogens affect the aging of MTL structures. Here we investigate the relationship between reproductive hormone exposure, polygenic scores for AD risk and oestradiol concentration, MTL anatomy and cognitive performance in postmenopausal women. To this end, we used data from 10,924 female participants in the UK Biobank from whom brain MRI and genetic data were available. We fitted linear regression models to test whether the volume of structures comprising the MTL were predicted by a) timing related to menopause, b) the use and timing of hormone replacement therapy (HRT) and c) polygenic scores for AD risk and oestradiol concentration. Results showed that longer use of HRT was associated with larger parahippocampal volumes (2.53 mm3/year, p = 0.042). A later age of natural menopause, and a longer reproductive span, was associated with larger hippocampal (6.08 and 5.72 mm3/year, p = 0.0006 and 0.0005), parahippocampal (4.17 mm3 and 4.19 mm3/year, p = 0.00006 and 0.00001), amygdala (2.10 and 2.22 mm3/year, p = 0.028 and 0.01) and perirhinal cortical (2.56 and 2.95 mm3/year, p = 0.028 and 0.008) volumes. Superior prospective memory performance was associated with later age at natural menopause, and a longer reproductive span (ß = 0.05 and 0.05 respectively, p = 0.019 and 0.019). Polygenic scores for AD risk and for oestradiol concentration were not associated with MTL volume and did not interact with menopause-related factors to affect MTL structure. Our results suggest that HRT use did not have any detrimental effects on cognition or brain structure, whilst greater exposure to reproductive hormones across time is associated both with slightly larger volumes of specific MTL structures and marginally superior memory performance, independent of genetic risk for AD and genetic predisposition for higher oestradiol levels. However, the clinical utility of maintenance of oestrogens post-menopause for brain health and protection against cognitive decline is curtailed by the small effect sizes observed.

Dairy products and brain structure in French older adults.

Among food groups with putative benefits for brain structures, dairy products (DP) have been poorly studied. The sample included participants without dementia from the ancillary brain imaging study of the Three-City cohort who were aged 65+ years, had their DP intake assessed with a FFQ at baseline and underwent an anatomical scan 3 years (n 343) or 9 years (n 195) after completing the dietary survey. The frequencies of consumption of total DP, milk and cheese were not associated with brain structure. Compared with the lowest frequency, the highest frequency of fresh DP (F-DP) consumption (< 0·5 v. > 1·5 times/d) was significantly associated with a lower medial temporal lobe volume (MTLV) (β = -1·09 cm3, 95 % CI - 1·83, -0·36) 9 years later. In this population-based study of older adults, the consumption of F-DP more than 1·5 times/d was associated with a lower MTLV, which is considered an early biomarker of Alzheimer's disease, 9 years later. This original study should be replicated in different settings before conclusions are drawn.

P11.01.A BASELINE TOTAL BRAIN VOLUME PREDICTS FOR POORER QUALITY OF LIFE AND REDUCED OVERALL SURVIVAL AFTER CRANIAL RADIOTHERAPY IN OLDER PATIENTS WITH GLIOBLASTOMA (GBM): RESULTS FROM THE PROSPECTIVE BRITER STUDY

Abstract BACKGROUND GBM incidence peaks in the 7th and 8th decades, with median life expectancy of 3-6 months. Treatment decisions finely balance benefit to side-effects and worsening quality of life (QoL). Short-course partial brain radiotherapy, +/- chemotherapy, extends survival compared to supportive care but there is no validated evidence for prediction of individual risk of acute radiotherapy related side effects. We aimed to consider putative MRI markers of brain resilience and their relationship to change in QoL amongst older patients being treated for GBM with cranial radiotherapy. MATERIAL AND METHODS BRITER, a prospective multicentre observational trial, recruited patients with newly diagnosed GBM aged ≥ 65 planned for cranial radiotherapy. Baseline MRI scans were analysed for: relative total brain volume (ratio of cerebrospinal fluid (CSF) volume to total intracranial volume (TIV)), contralateral medial temporal lobe volume, number and volume of T1 white matter hypointensities, and Fazekas' scale of white matter change. Radiotherapy treatment volumes were obtained from planning software. RESULTS 126 patients were enrolled from 12 UK centres; mean age 72 years (range 65-83); 67% men, 33% women. 4% had a radiological diagnosis, 19% biopsy and 77% had debulking surgery. 21% received palliative radiotherapy alone (25% 30Gy/6#, 75% 40Gy/15#), 79% received radiotherapy with concurrent TMZ (47% 40Gy/15#, 53% 60Gy/30#). Median OS was 11.3 months. 56 participants completed all MRI sequences and QoL data points. After accounting for age, sex, treatment and baseline MoCA score, there was a significant relationship between baseline CSF:TIV ratio and change in QoL score. For each unit point of increase in CSF:TIV ratio, there was a corresponding decrease in EORTC QLC C30 QoL score by a factor of 1.27 (coefficient -1.27, 95% CI -3.24 to -0.19 p=0.02). 35 participants were too unwell to complete questionnaires or had died by the 8 week follow up visit. In this subgroup, post hoc logistic regression showed baseline CSF:TIV ratio was related to risk of non-attendance (OR 1.35, 95% CI 1.01-1.80, p=0.04). Cox regression models were fitted for time to death in 88 participants who had analysable baseline MRI sequences. Baseline CSF:TIV was associated with worsened OS (HR 1.41, 95% CI 1.19-1.66, p&amp;lt;0.001). CONCLUSION This unique prospective study indicates that baseline imaging parameters can predict the impact of cranial radiotherapy on QoL and OS. Due to frailty, there was a significant attrition rate in data return. 29% of participants were too unwell by 8 weeks post treatment to attend hospital, also predicted by baseline imaging. These results promote and enable discussion of individualised treatment options with older patients with GBM, differentiating those who are likely to suffer reduced QoL and short survival rather than benefit from radiotherapy

Alzheimer’s pathology is associated with altered cognition, brain volume, and plasma biomarker patterns in traumatic encephalopathy syndrome

BackgroundTraumatic encephalopathy syndrome (TES) is a clinical phenotype sensitive but non-specific to underlying chronic traumatic encephalopathy (CTE) neuropathology. However, cognitive symptoms of TES overlap with Alzheimer’s disease (AD), and features of AD pathology like beta-amyloid (Aβ) plaques often co-occur with CTE, making clinical-to-pathological conclusions of TES diagnoses challenging. We investigated how Alzheimer’s neuropathological changes associated with cognition, brain volume, and plasma biomarkers in patients with repetitive head impacts (RHI)/TES, clinical AD, or typically aging controls.MethodsWe studied 154 participants including 33 with RHI/TES (age 61.5 ± 11.5, 100% male, 11/33 Aβ[ +]), 62 with AD and no known prior RHI (age 67.1 ± 10.2, 48% male, 62/62 Aβ[ +]), and 59 healthy controls without RHI (HC; age 73.0 ± 6.2, 40% male, 0/59 Aβ[ +]). Patients completed neuropsychological testing (memory, executive functioning, language, visuospatial) and structural MRI (voxel-based morphometry analysis), and provided plasma samples analyzed for GFAP, NfL, IL-6, IFN-γ, and YKL-40. For cognition and plasma biomarkers, patients with RHI/TES were stratified as Aβ[ +] or Aβ[ −] and compared to each other plus the AD and HC groups (ANCOVA adjusting for age and sex). Differences with at least a medium effect size (Cohen’s d > 0.50) were interpreted as potentially meaningful.ResultsCognitively, within the TES group, Aβ[ +] RHI/TES performed worse than Aβ[-] RHI/TES on visuospatial (p = .04, d = 0.86) and memory testing (p = .07, d = 0.74). Comparing voxel-wise brain volume, both Aβ[ +] and Aβ[ −] RHI/TES had lower medial and anterior temporal lobe volume than HC and did not significantly differ from AD. Comparing plasma biomarkers, Aβ[ +] RHI/TES had higher plasma GFAP than HC (p = .01, d = 0.88) and did not significantly differ from AD. Conversely, Aβ[ −] RHI/TES had higher NfL than HC (p = .004, d = 0.93) and higher IL-6 than all other groups (p’s ≤ .004, d’s > 1.0).ConclusionsPresence of Alzheimer’s pathology in patients with RHI/TES is associated with altered cognitive and biomarker profiles. Patients with RHI/TES and positive Aβ-PET have cognitive and plasma biomarker changes that are more like patients with AD than patients with Aβ[ −] RHI/TES. Measuring well-validated Alzheimer’s biomarkers in patients with RHI/TES could improve interpretation of research findings and heighten precision in clinical management.

Age-related and amyloid-beta-independent tau deposition and its downstream effects.

Amyloid-β (Aβ) is hypothesized to facilitate the spread of tau pathology beyond the medial temporal lobe. However, there is evidence that, independently of Aβ, age-related tau pathology might be present outside of the medial temporal lobe. We therefore aimed to study age-related Aβ-independent tau deposition outside the medial temporal lobe in two large cohorts and to investigate potential downstream effects of this on cognition and structural measures. We included 545 cognitively unimpaired adults (40-92 years) from the BioFINDER-2 study (in vivo) and 639 (64-108 years) from the Rush Alzheimer's Disease Center cohorts (ex vivo). 18F-RO948- and 18F-flutemetamol-PET standardized uptake value ratios were calculated for regional tau and global/regional Aβ in vivo. Immunohistochemistry was used to estimate Aβ load and tangle density ex vivo. In vivo medial temporal lobe volumes (subiculum, cornu ammonis 1) and cortical thickness (entorhinal cortex, Brodmann area 35) were obtained using Automated Segmentation for Hippocampal Subfields packages. Thickness of early and late neocortical Alzheimer's disease regions was determined using FreeSurfer. Global cognition and episodic memory were estimated to quantify cognitive functioning. In vivo age-related tau deposition was observed in the medial temporal lobe and in frontal and parietal cortical regions, which was statistically significant when adjusting for Aβ. This was also observed in individuals with low Aβ load. Tau deposition was negatively associated with cortical volumes and thickness in temporal and parietal regions independently of Aβ. The associations between age and cortical volume or thickness were partially mediated via tau in regions with early Alzheimer's disease pathology, i.e. early tau and/or Aβ pathology (subiculum/Brodmann area 35/precuneus/posterior cingulate). Finally, the associations between age and cognition were partially mediated via tau in Brodmann area 35, even when including Aβ-PET as covariate. Results were validated in the ex vivo cohort showing age-related and Aβ-independent increases in tau aggregates in and outside the medial temporal lobe. Ex vivo age-cognition associations were mediated by medial and inferior temporal tau tangle density, while correcting for Aβ density. Taken together, our study provides support for primary age-related tauopathy even outside the medial temporal lobe in vivo and ex vivo, with downstream effects on structure and cognition. These results have implications for our understanding of the spreading of tau outside the medial temporal lobe, also in the context of Alzheimer's disease. Moreover, this study suggests the potential utility of tau-targeting treatments in primary age-related tauopathy, likely already in preclinical stages in individuals with low Aβ pathology.

Olfactory function reflects episodic memory performance and atrophy in the medial temporal lobe in individuals at risk for Alzheimer’s disease

We examined cognitive domains and brain regions associated with olfactory performance in cognitively unimpaired older adults (CU-OAs) and individuals with or at risk for Alzheimer’s Disease (AD). We compared CU-OAs (N = 55), individuals with subjective cognitive decline (SCD, N = 55), mild cognitive impairment (MCI, N = 101), and AD (N = 45) on measures of olfactory function (Brief Smell Identification Test), cognition (episodic and semantic memory), and medial temporal lobe thickness and volume. Analyses controlled for age, sex, education, and total intracranial volume. Olfactory function decreased from SCD to MCI to AD. CU-OAs outperformed all groups except SCDs on tests of cognition and olfaction. Although these measures did not differ between the CU-OAs and SCDs, olfactory function correlated with episodic memory tests and with entorhinal cortex atrophy only in the SCD group. Olfactory function also correlated with hippocampal volume and right-hemisphere entorhinal cortex thickness in the MCI group. Olfactory dysfunction reflects medial temporal lobe integrity and memory performance in a group at risk for AD with normal cognition and olfaction.

Computer assisted diagnosis of Alzheimer's disease using statistical likelihood-ratio test.

The purpose of this work is to present a computer assisted diagnostic tool for radiologists in their diagnosis of Alzheimer's disease. A statistical likelihood-ratio procedure from signal detection theory was implemented in the detection of Alzheimer's disease. The probability density functions of the likelihood ratio were constructed by using medial temporal lobe (MTL) volumes of patients with Alzheimer's disease (AD) and normal controls (NC). The volumes of MTL as well as other anatomical regions of the brains were calculated by the FreeSurfer software using T1 weighted MRI images. The MRI images of AD and NC were downloaded from the database of Alzheimer's disease neuroimaging initiative (ADNI). A separate dataset of minimal interval resonance imaging in Alzheimer's disease (MIRIAD) was used for diagnostic testing. A sensitivity of 89.1% and specificity of 87.0% were achieved for the MIRIAD dataset which are better than the 85% sensitivity and specificity achieved by the best radiologists without input of other patient information.

Longitudinal medial temporal lobe gray matter volume and cognitive changes in late middle‐aged and older adults with treated and non‐treated obstructive sleep apnea

AbstractBackgroundNeuroimaging studies in obstructive sleep apnea (OSA) have found both gray matter atrophy and hypertrophy in medial temporal lobe subregions, the latter probably reflecting edema. Whether and how these changes progress over time when OSA is treated or untreated remains unclear. Here, we investigated gray matter volume changes in medial temporal lobe subregions in treated OSA, untreated OSA and control participants aged &gt; 55 years. We also explored whether the medial temporal lobe volume at baseline could predict cognitive decline.MethodTwenty‐three non‐treated OSA participants (65.8 ±5.4 years) and twenty controls (64.0 ±6.4 years) were evaluated with overnight polysomnography, MRI session and neuropsychological assessment. Twelve OSA participants then started continuous positive airway pressure (CPAP) therapy and used it at least 4 hours per night, 4 nights per week. Eleven participants refused treatment. Participants were evaluated again with MRI and neuropsychology after 18 months. We extracted the entorhinal, hippocampal and parahippocampal volumes using FreeSurfer 7.1. We performed repeated‐measure ANOVAs with Group (treated OSA, untreated OSA and controls) and Time (baseline and follow‐up) on bilateral volumes. We also performed partial correlations between bilateral medial temporal volumes at baseline and changes in cognition (Montreal Cognitive Assessment, score at follow‐up – baseline) in each group separately. Analyses were corrected for age, sex, and total intracranial volume.ResultWe found a significant Group X Time interaction for bilateral parahippocampal volumes (F = 7.2; p = 0.002) where treated OSA participants showed a decreased volume over time (p tukey&lt;0.001), while no changes occurred in the two other groups. Regarding the predictive value of medial temporal lobe volume, in untreated participants, higher bilateral hippocampal volume at baseline was associated with more severe cognitive decline over time (r = ‐0.77; p = 0.01). In treated participants, higher bilateral entorhinal cortex volume at baseline was associated with more cognitive decline (r = ‐0.74; p = 0.035). No associations were found in controls.ConclusionThese preliminary results showed that presenting hypertrophy of the medial temporal lobe subregions at baseline is associated with worse cognitive outcome at 18‐month follow‐up in OSA participants. In the CPAP group, the decrease in parahippocampal volume might represent a reduction in hypertrophy, possibly by limiting edema.

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.

MRI‐guided Clustering of Alzheimer’s Disease patients: A post‐hoc analysis of Phase 3 Trial of Solanezumab for Mild Dementia Due to Alzheimer’s Disease

AbstractBackgroundAlzheimer’s disease (AD) is a phenotypically and pathologically heterogenous disorder. We used MRI in amyloid positive patients enrolled in the placebo arm of the Phase 3 Trial of solanezumab for mild dementia due to AD (EXPEDITION3) to identify more homogeneous subgroups based on variation in volumetrics.MethodsWe implemented the self‐organizing map algorithm on baseline volumetric MRI measures from nine brain regions of interest (ROIs) to cluster 1041 individuals enrolled in the placebo arm of the EXPEDITION3 trial. Volumetric MRI differences were compared among clusters. Demographics as well as baseline and longitudinal cognitive performance metrics were used to evaluate cluster characteristics.ResultsThree distinct clusters, with an overall silhouette coefficient of 0.383, were identified based on MRI volumetrics. Cluster 1 (N=400) had the largest baseline volumetric measures across all ROIs and the best cognitive performance at baseline (Table 1). Cluster 2 (N=269) had larger hippocampal and medial temporal lobe volumes, but smaller parietal lobe volumes in comparison with the third cluster (N=372) (Figure 1). Spider plots show the normalized test performance at baseline and follow‐up with larger values corresponding to worse test performance; Cluster 1 shows relatively little cognitive change (Figure 2). Spider plots of regional MRI volumes show smaller volumes for Clusters 2 and 3 relative to Cluster 1 and asymmetries that reflect regional differences in atrophy (Figure 2). The mean change from baseline to week 80 in the ADAS‐cog14 score for Clusters 1, 2, and 3 were 4.28 (SE=0.35), 10.14 (SE=0.51), and 7.90 (SE=0.43), respectively. Significant between‐group mean differences were observed between Clusters 1 and 2 (difference, 2.38; 95% CI, 1.85 to 2.91; P&lt;0.001), Clusters 1 and 3 (difference, 1.93; 95% CI, 1.41 to 2.44; P&lt;0.001), but not between Clusters 2 and 3 (difference, 0.45; 95% CI, ‐0.11 to 1.02; P=0.146) in ADAS‐cog14 (Figure 3).ConclusionsVolumetric MRI can be used to identify homogenous clusters of amyloid positive individuals with mild dementia. The groups identified differ in baseline and longitudinal characteristics. Cluster 1 shows little ADAS‐cog14 change over the first 40 weeks of study on placebo treatment and may be unsuitable for identifying early benefits of treatment.