Citations

AbstractIntroductionHarboring two copies of the apolipoprotein E (APOE) ε2 allele strongly protects against Alzheimer's disease (AD). However, the effect of this genotype on gray matter (GM) volume in cognitively unimpaired individuals has not yet been described.MethodsMulticenter brain magnetic resonance images (MRIs) from cognitively unimpaired ε2 homozygotes were matched (1:1) against all other APOE genotypes for relevant confounders (n = 223). GM volumes of ε2 genotypic groups were compared to each other and to the reference group (APOE ε3/ε3).ResultsCarrying at least one ε2 allele was associated with larger GM volumes in brain areas typically affected by AD and also in areas associated with cognitive resilience. APOE ε2 homozygotes, but not APOE ε2 heterozygotes, showed larger GM volumes in areas related to successful aging.DiscussionIn addition to the known resistance against amyloid‐β deposition, the larger GM volumes in key brain regions may confer APOE ε2 homozygotes additional protection against AD‐related cognitive decline.

Background: The modifying effect of sex on the relation between marital status and dementia has yet to be determined. Objective: To examine if sex modifies the association between marital status and incident dementia. Methods: Population-based samples from the Mayo Clinic Study of Aging (MCSA, N = 3,471) and the Gothenburg H70 Birth Cohort Study (H70-study, N = 913) were used. A multiplicative interaction term was used to analyze the modifying effect of sex on the relation between marital status (married versus not married) and incident dementia using Cox regression models. Further, risk of dementia by marital status was also evaluated in models separated by sex. Results: In the MCSA, there was an interaction between marital status and sex in relation to dementia (p = 0.015). In contrast, in the H70-study, no significant interaction was observed (p = 0.28). Nevertheless, in both studies, not married men had increased risk of dementia compared to married men in models adjusted for age, education, and number of children (H70-study: 1.99; 1.06–3.76, MCSA: 1.43; 1.08–1.89). Associations remained similar after additional adjustment for depression, BMI, hypertension, dyslipidemia, and diabetes mellitus (H70-study: 2.00; 1.05–3.82, MCSA: 1.32; 0.99–1.76). Further, no significant association was observed between marital status and dementia in women (H70-study: 1.24; 0.82–1.89, MCSA: 0.82; 0.64–1.04). Conclusion: Sex had a modifying effect on the association between marital status and incident dementia. In analyses separated by sex, not married men had an increased risk of dementia compared to married men, while no significant association was observed between marital status and risk of dementia in women.

Abstract Introduction As cerebrospinal fluid (CSF) neurofilament light protein (NfL) and the CSF/serum albumin ratio (Q Alb ) are used in the clinical routine, the impact of demographic factors on these biomarkers is important to understand. Methods Participants were derived from two Swedish samples: the population‐based H70 Study (n = 308, age 70) and a clinical routine cohort (CSF NfL, n = 8995, Q Alb , n = 39252, age 0 to 95). In the population‐based study, Q Alb and NfL were examined in relation to sex, cardiovascular risk factors, and cerebral white matter lesions (WMLs). In the clinical cohort, Q Alb and NfL sex differences were tested in relation to age. Results Men had higher Q Alb and NfL concentrations and had higher Q Alb and NfL concentrations from adolescence throughout life. NfL was not related to WML, but Q Alb correlated positively with WMLs. Discussion The CSF NfL sex difference could not be explained by vascular pathology. Future studies should consider using different reference limits for men and women.

AbstractIntroductionWe determined whether cerebrospinal fluid (CSF) neurofilament light (NfL), neurogranin (Ng), and total‐tau (t‐tau) differentially mapped to magnetic resonance imaging (MRI) measures of cortical thickness, microstructural integrity (corpus callosum and cingulum fractional anisotropy [FA]), and white matter hyperintensities (WMH).MethodsAnalyses included 536 non‐demented Mayo Clinic Study of Aging participants with CSF NfL, Ng, t‐tau, amyloid beta (Aβ)42 and longitudinal MRI scans. Linear mixed models assessed longitudinal associations between CSF markers and MRI changes.ResultsHigher CSF NfL was associated with decreasing microstructural integrity and WMH. Higher t‐tau was associated with decreasing temporal lobe and Alzheimer's disease (AD) meta region of interest (ROI) cortical thickness. There was no association between Ng and any MRI measure. CSF Aβ42 interacted with Ng for declines in temporal lobe and AD meta ROI cortical thickness and cingulum FA.DiscussionCSF NfL predicts changes in white matter integrity, t‐tau reflects non‐specific changes in cortical thickness, and Ng reflects AD‐specific synaptic and neuronal degeneration.

AbstractBackgroundComputed tomography (CT) is the most commonly used brain examination tool for the initial assessment of neurodegenerative diseases such as dementia disorders. It is widely available, affordable and provides short scan times, however, it is mainly used for visual assessment of brain integrity and exclusion of co‐pathologies while magnetic resonance imaging (MRI) is the preferred modality for the extraction of regional brain volumetric measures, obtained by brain segmentation into tissue classes and anatomical regions. We developed an automated, deep learning‐based approach to segment CT scans into intracranial volume (ICV), grey matter (GM), white matter (WM) and cerebrospinal fluid (CSF).Method139 CT and T1‐weighted MRI scans acquired on the same day in participants of the Gothenburg H70 Birth Cohort Study (70% female) were included in this study. SPM12 was used to extract GM, WM and CSF tissue class labels and Pincram for creating ICV masks from the MRIs. These labels were used as training input and as the reference criteria for subsequent volumetric and similarity comparisons. In a training subcohort (n=120), CT scans were co‐registered to their corresponding MRI. A U‐Net deep learning model was developed using the Keras software package which underwent two training sessions: 1. Predict ICVs in CT and extract brain; 2. Predict GM, WM and CSF volumes with extracted CT images as input, preserving the predictions in individual space. MRI labels were incorporated during the training sessions including 120 datasets.ResultNineteen validation datasets which were not included in the training were used for the prediction process without MRI intervention. Continuous Dice scores between ICV, GM, WM and CSF predictions from the model in the validation datasets and independently MRI‐derived labels were 0.97, 0.79, 0.81 and 0.72 with a volumetric Pearson correlation coefficient, r of 0.93, 0.84, 0.73 and 0.71, respectively.ConclusionOur pilot study developed a deep learning model that enables the automated segmentation and volumetric measure extraction from cranial CT. With further optimization, training on larger and more diverse datasets, we aim at improving the model to execute predictions comparable to MRI‐based approaches, thus, developing a diagnostic support tool based on routinely acquired CT scans.

AbstractBackgroundCSF neurofilament light protein (NfL) is an important biomarker in several neurologic diseases. CSF NfL concentrations are known to increase with age, but sex differences have been less examined. The CSF/serum albumin ratio (QAlb) is a biomarker for blood‐brain barrier integrity, which has previously been found to be higher in men. As NfL and QAlb are used in clinical routine, the impact of demographic factors on these biomarkers is important to understand.MethodParticipants were derived from two samples. The first was a population‐based cohort of 308 70‐year olds from the Gothenburg H70 Birth Cohort Study, Sweden. The second data set comprised CSF NfL and QAlb results from 8995 and 39252 subjects respectively, generated in clinical practice between 2005‐2012 in Gothenburg, Sweden. In the population‐based study, QAlb and NfL concentrations were examined in relation to sex, cardiovascular risk factors, and MRI signs of cerebral white matter lesions. In the clinical routine cohort, sex differences in QAlb and NfL were tested in relation to age.ResultIn the population‐based sample, men had higher QAlb and NfL concentrations than women. NfL was not related to cerebral vascular pathology, but QAlb correlated positively with several measures of white matter lesions. In the clinical routine cohort, men also had higher QAlb and NfL concentrations from adolescence and throughout life.ConclusionQAlb ratios and CSF NfL levels are higher in men throughout life. The CSF NfL sex difference could not be explained by vascular pathology. Future studies should consider using different reference limits for men and women.

Abstract Introduction Three cerebrospinal fluid (CSF) markers of neurodegeneration (N) (neurofilament light [NfL], total‐tau [T‐tau], and neurogranin [Ng]) have been proposed under the AT(N) scheme of the National Institute on Aging–Alzheimer's Association Research Framework. Methods We examined, in a community‐based population (N = 777, aged 50–95) (1) what variables were associated with each of the CSF (N) markers, and (2) whether the variables associated with each marker differed by increased brain amyloid. CSF T‐tau was measured with an automated electrochemiluminescence Elecsys immunoassay; NfL and Ng were measured with in‐house enzyme‐linked immunosorbent assays. Results Multiple variables were differentially associated with CSF NfL and T‐tau levels, but not Ng. Most associations were attenuated after adjustment for age and sex. T‐tau had the strongest association with cognition in the presence of amyloidosis, followed by Ng. Variables associations with NfL did not differ by amyloid status. Discussion Understanding factors that influence CSF (N) markers will assist in the interpretation and utility of these markers in clinical practice.

Abstract White matter hyperintensities (WMHs) are frequently seen on brain magnetic resonance imaging scans of older people. Usually interpreted clinically as a surrogate for cerebral small vessel disease, WMHs are associated with increased likelihood of cognitive impairment and dementia (including Alzheimer's disease [AD]). WMHs are also seen in cognitively healthy people. In this collaboration of academic, clinical, and pharmaceutical industry perspectives, we identify outstanding questions about WMHs and their relation to cognition, dementia, and AD. What molecular and cellular changes underlie WMHs? What are the neuropathological correlates of WMHs? To what extent are demyelination and inflammation present? Is it helpful to subdivide into periventricular and subcortical WMHs? What do WMHs signify in people diagnosed with AD? What are the risk factors for developing WMHs? What preventive and therapeutic strategies target WMHs? Answering these questions will improve prevention and treatment of WMHs and dementia.