Amyloid-ß and tau pathologies relate to distinctive brain dysconnectomics in preclinical autosomal-dominant Alzheimer's disease.

The human brain is composed of functional networks that have a modular topology, where brain regions are organized into communities that form internally dense (segregated) and externally sparse (integrated) subnetworks that underlie higher-order cognitive functioning. It is hypothesized that amyloid-ß and tau pathology in preclinical Alzheimer's disease (AD) spread through functional networks, disrupting neural communication that results in cognitive dysfunction. We used high-resolution (voxel-level) graph-based network analyses to test whether in vivo amyloid-ß and tau burden was associated with the segregation and integration of brain functional connections, and episodic memory, in cognitively unimpaired Presenilin-1 E280A carriers who are expected to develop early-onset AD dementia in ∼13 y on average. Compared to noncarriers, mutation carriers exhibited less functional segregation and integration in posterior default-mode network (DMN) regions, particularly the precuneus, and in the retrospenial cortex, which has been shown to link medial temporal regions and cortical regions of the DMN. Mutation carriers also showed greater functional segregation and integration in regions connected to the salience network, including the striatum and thalamus. Greater tau burden was associated with lower segregated and integrated functional connectivity of DMN regions, particularly the precuneus and medial prefrontal cortex. In turn, greater tau pathology was related to higher segregated and integrated functional connectivity in the retrospenial cortex and the anterior cingulate cortex, a hub of the salience network. These findings enlighten our understanding of how AD-related pathology distinctly alters the brain's functional architecture in the preclinical stage, possibly contributing to pathology propagation and ultimately resulting in dementia.

Peak Width of Skeletonized Mean Diffusivity: A Neuroimaging Marker for White Matter Injury.

A leading cause of white matter (WM) injury in older individuals is cerebral small vessel disease (SVD). Cerebral SVD is the most prevalent vascular contributor to cognitive impairment and dementia. Therapeutic progress for cerebral SVD and other WM disorders depends on the development and validation of neuroimaging markers suitable as outcome measures in future interventional trials. Diffusion-tensor imaging (DTI) is one of the best-suited MRI techniques for assessing the extent of WM damage in the brain. But the optimal method to analyze individual DTI data remains hindered by labor-intensive and time-consuming processes. Peak width of skeletonized mean diffusivity (PSMD), a recently developed fast, fully automated DTI marker, was designed to quantify the WM damage secondary to cerebral SVD and reflect related cognitive impairment. Despite its promising results, knowledge about PSMD is still limited in the radiologic community. This focused review provides an overview of the technical details of PSMD while synthesizing the available data on its clinical and neuroimaging associations. From a critical expert viewpoint, the authors discuss the limitations of PSMD and its current validation status as a neuroimaging marker for vascular cognitive impairment. Finally, they point out the gaps to be addressed to further advance the field.

Notch3 Signaling and Aggregation as Targets for the Treatment of CADASIL and Other NOTCH3-Associated Small-Vessel Diseases.

Mutations in the NOTCH3 gene can lead to small-vessel disease in humans, including the well-characterized cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a condition caused by NOTCH3 mutations altering the number of cysteine residues in the extracellular domain of Notch3. Growing evidence indicates that other types of mutations in NOTCH3, including cysteine-sparing missense mutations or frameshift and premature stop codons, can lead to small-vessel disease phenotypes of variable severity or penetrance. There are currently no disease-modifying therapies for small-vessel disease, including those associated with NOTCH3 mutations. A deeper understanding of underlying molecular mechanisms and clearly defined targets are needed to promote the development of therapies. This review discusses two key pathophysiological mechanisms believed to contribute to the emergence and progression of small-vessel disease associated with NOTCH3 mutations: abnormal Notch3 aggregation and aberrant Notch3 signaling. This review offers a summary of the literature supporting and challenging the relevance of these mechanisms, together with an overview of available preclinical experiments derived from these mechanisms. It highlights knowledge gaps and future research directions. In view of recent evidence demonstrating the relatively high frequency of NOTCH3 mutations in the population, and their potential role in promoting small-vessel disease, progress in the development of therapies for NOTCH3-associated small-vessel disease is urgently needed.

The INECO Frontal Screening for the Evaluation of Executive Dysfunction in Cerebral Small Vessel Disease: Evidence from Quantitative MRI in a CADASIL Cohort from Colombia.

OBJECTIVES: Executive dysfunction is a predominant cognitive symptom in cerebral small vessel disease (SVD). The Institute of Cognitive Neurology Frontal Screening (IFS) is a well-validated screening tool allowing the rapid assessment of multiple components of executive function in Spanish-speaking individuals. In this study, we examined performance on the IFS in subjects with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), an inherited condition leading to the early onset of SVD. We further explored associations between performance on the IFS and magnetic resonance imaging (MRI) markers of SVD. METHODS: We recruited 24 asymptomatic CADASIL subjects and 23 noncarriers from Colombia. All subjects underwent a research MRI and a neuropsychological evaluation, including the IFS. Structural MRI markers of SVD were quantified in each subject, together with an SVD Sum Score representing the overall burden of cerebrovascular alterations. General linear model, correlation, and receiver operating characteristic curve analyses were used to explore group differences on the IFS and relationships with MRI markers of SVD. RESULTS: CADASIL subjects had a significantly reduced performance on the IFS Total Score. Performance on the IFS correlated with all quantified markers of SVD, except for brain atrophy and perivascular spaces enlargement. Finally, while the IFS Total Score was not able to accurately discriminate between carriers and noncarriers, it showed adequate sensitivity and specificity in detecting the presence of multiple MRI markers of SVD. CONCLUSIONS: These results suggest that the IFS may be a useful screening tool to assess executive function and disease severity in the context of SVD.

The hippocampal-to-ventricle ratio (HVR): Presentation of a manual segmentation protocol and preliminary evidence.

Disentangling age-related changes from developmental variations in hippocampal volume has proven challenging. This article presents a manual segmentation protocol for the hippocampal-to-ventricle ratio (HVR), a measure combining the assessment of hippocampal volume with surrounding ventricular volume. By providing in a single measure both a standard volumetric assessment of the hippocampus and an approximation of volume loss, based on ventricular enlargement, we believe the HVR provides a superior cross-sectional estimation of hippocampal structural integrity. In a first attempt to validate this measure, we contrasted the HVR and standard hippocampal volume in their associations with age and memory performance in two independent cohorts of healthy aging individuals. The first cohort consisted in 50 cognitively normal subjects (mean age: 66.8 years, SD: 4.96, range: 60-75 years), while the second cohort included 88 cognitively normal subjects (mean age: 65.06 years, SD: 6.42, range: 55-80 years). We showed that the manual segmentation protocol for the HVR can be implemented with high reliability. In both cohorts, the HVR showed stronger negative associations with age than standard hippocampal volume. Correlations with memory performance were also numerically superior with the HVR than standard hippocampal volume, across the two cohorts. These findings support an added benefit of using the HVR over standard hippocampal volume when examining relationships with age or memory function in aging individuals. Although further validation is required, we propose that the computation of the HVR is a promising method to improve the evaluation of hippocampal integrity from cross-sectional MR images.

Recollection and familiarity in aging individuals: Gaining insight into relationships with medial temporal lobe structural integrity.

Dual-process theories posit that two separate processes are involved in recognition, namely recollection and familiarity. Studies investigating the neuroanatomical substrates of these two processes have frequently revealed that, while recollection is functionally linked with the hippocampus, familiarity appears to be associated with perirhinal and/or entorhinal cortices integrity. Interestingly these regions are known to be sensitive to normal and neuropathological aging processes. The objective of this study was to examine the effects of aging on recollection and familiarity performance, as well as to investigate associations with the rate of false alarms. In older individuals, we further aimed to explore relationships between these recognition variables and structural integrity of the hippocampus and the entorhinal and perirhinal cortices. Younger (N = 56) and older (N = 59) adults were tested on a computerized recollection and familiarity task. In a separate session, older adults (N = 56) underwent a structural MRI. Hippocampal, entorhinal and perihinal cortices volumes were automatically segmented and then manually corrected to ensure validity of the volumetric assessment. Regional volumes were normalized for total intracranial volume. While the overall recognition performance did not significantly differ across groups, our results reveal a decrease in recollection, together with an increase in familiarity in older adults. The increase reliance on familiarity was significantly and positively associated with the rate of false alarms. In the older adult sample, significant positive associations were found between recollection estimates and normalized hippocampal volumes. The normalized total hippocampal volume accounted for 25% of the variance in recollection performance. No correlation was found between any recognition variables and perirhinal or entorhinal cortices volumes. Overall, our results suggest that the age-related impairment in recollection is linked with reduced hippocampal structural integrity.

A harmonized segmentation protocol for hippocampal and parahippocampal subregions: Why do we need one and what are the key goals?

The advent of high-resolution magnetic resonance imaging (MRI) has enabled in vivo research in a variety of populations and diseases on the structure and function of hippocampal subfields and subdivisions of the parahippocampal gyrus. Because of the many extant and highly discrepant segmentation protocols, comparing results across studies is difficult. To overcome this barrier, the Hippocampal Subfields Group was formed as an international collaboration with the aim of developing a harmonized protocol for manual segmentation of hippocampal and parahippocampal subregions on high-resolution MRI. In this commentary we discuss the goals for this protocol and the associated key challenges involved in its development. These include differences among existing anatomical reference materials, striking the right balance between reliability of measurements and anatomical validity, and the development of a versatile protocol that can be adopted for the study of populations varying in age and health. The commentary outlines these key challenges, as well as the proposed solution of each, with concrete examples from our working plan. Finally, with two examples, we illustrate how the harmonized protocol, once completed, is expected to impact the field by producing measurements that are quantitatively comparable across labs and by facilitating the synthesis of findings across different studies. © 2016 Wiley Periodicals, Inc.

Frequency of Penile-Vaginal Intercourse is Associated with Verbal Recognition Performance in Adult Women.

Previous studies have identified a number of factors that contribute to improved cognitive function, and to memory function specifically, in cognitively normal individuals. One such factor, frequency of penile-vaginal intercourse (PVI), has been reported in a number of animal studies to be advantageous to memory for previously presented objects by increasing neurogenesis in the dentate gyrus of the hippocampus. However, studies investigating the potential benefits of frequent PVI on memory function in young women are to the best of our knowledge absent from the literature. The current study thus investigated whether the self-reported frequency of sexual intercourse was related to memory function in healthy female college students. To determine whether variation in PVI would be associated with memory performance, we asked 78 heterosexual women aged 18-29 years to complete a computerized memory paradigm consisting of abstract words and neutral faces. Results showed that frequency of PVI was positively associated with memory scores for abstract words, but not faces. Because memory for words depends to a large extent on the hippocampus, whereas memory for faces may rely to a greater extent on surrounding extra-hippocampal structures, our results appear to be specific for memory believed to rely on hippocampal function. This may suggest that neurogenesis in the hippocampus is higher in those women with a higher frequency of PVI, in line with previous animal research. Taken together, these results suggest that PVI may indeed have beneficial effects on memory function in healthy young women.

Hippocampus and amygdala volumes from magnetic resonance images in children: Assessing accuracy of FreeSurfer and FSL against manual segmentation.

The volumetric quantification of brain structures is of great interest in pediatric populations because it allows the investigation of different factors influencing neurodevelopment. FreeSurfer and FSL both provide frequently used packages for automatic segmentation of brain structures. In this study, we examined the accuracy and consistency of those two automated protocols relative to manual segmentation, commonly considered as the "gold standard" technique, for estimating hippocampus and amygdala volumes in a sample of preadolescent children aged between 6 to 11 years. The volumes obtained with FreeSurfer and FSL-FIRST were evaluated and compared with manual segmentations with respect to volume difference, spatial agreement and between- and within-method correlations. Results highlighted a tendency for both automated techniques to overestimate hippocampus and amygdala volumes, in comparison to manual segmentation. This was more pronounced when using FreeSurfer than FSL-FIRST and, for both techniques, the overestimation was more marked for the amygdala than the hippocampus. Pearson correlations support moderate associations between manual tracing and FreeSurfer for hippocampus (right r=0.69, p<0.001; left r=0.77, p<0.001) and amygdala (right r=0.61, p<0.001; left r=0.67, p<0.001) volumes. Correlation coefficients between manual segmentation and FSL-FIRST were statistically significant (right hippocampus r=0.59, p<0.001; left hippocampus r=0.51, p<0.001; right amygdala r=0.35, p<0.001; left amygdala r=0.31, p<0.001) but were significantly weaker, for all investigated structures. When computing intraclass correlation coefficients between manual tracing and automatic segmentation, all comparisons, except for left hippocampus volume estimated with FreeSurfer, failed to reach 0.70. When looking at each method separately, correlations between left and right hemispheric volumes showed strong associations between bilateral hippocampus and bilateral amygdala volumes when assessed using manual segmentation or FreeSurfer. These correlations were significantly weaker when volumes were assessed with FSL-FIRST. Finally, Bland-Altman plots suggest that the difference between manual and automatic segmentation might be influenced by the volume of the structure, because smaller volumes were associated with larger volume differences between techniques. These results demonstrate that, at least in a pediatric population, the agreement between amygdala and hippocampus volumes obtained with automated FSL-FIRST and FreeSurfer protocols and those obtained with manual segmentation is not strong. Visual inspection by an informed individual and, if necessary, manual correction of automated segmentation outputs are important to ensure validity of volumetric results and interpretation of related findings.

Quantitative comparison of 21 protocols for labeling hippocampal subfields and parahippocampal subregions in in vivo MRI: towards a harmonized segmentation protocol.

OBJECTIVE: An increasing number of human in vivo magnetic resonance imaging (MRI) studies have focused on examining the structure and function of the subfields of the hippocampal formation (the dentate gyrus, CA fields 1-3, and the subiculum) and subregions of the parahippocampal gyrus (entorhinal, perirhinal, and parahippocampal cortices). The ability to interpret the results of such studies and to relate them to each other would be improved if a common standard existed for labeling hippocampal subfields and parahippocampal subregions. Currently, research groups label different subsets of structures and use different rules, landmarks, and cues to define their anatomical extents. This paper characterizes, both qualitatively and quantitatively, the variability in the existing manual segmentation protocols for labeling hippocampal and parahippocampal substructures in MRI, with the goal of guiding subsequent work on developing a harmonized substructure segmentation protocol. METHOD: MRI scans of a single healthy adult human subject were acquired both at 3 T and 7 T. Representatives from 21 research groups applied their respective manual segmentation protocols to the MRI modalities of their choice. The resulting set of 21 segmentations was analyzed in a common anatomical space to quantify similarity and identify areas of agreement. RESULTS: The differences between the 21 protocols include the region within which segmentation is performed, the set of anatomical labels used, and the extents of specific anatomical labels. The greatest overall disagreement among the protocols is at the CA1/subiculum boundary, and disagreement across all structures is greatest in the anterior portion of the hippocampal formation relative to the body and tail. CONCLUSIONS: The combined examination of the 21 protocols in the same dataset suggests possible strategies towards developing a harmonized subfield segmentation protocol and facilitates comparison between published studies.

Recollection and familiarity in aging individuals with mild cognitive impairment and Alzheimer's disease: a literature review.

Memory impairment is a central cognitive symptom in mild cognitive impairment (MCI) and Alzheimer Disease (AD). Recognition tasks are often used to characterize and define the nature of memory deficits. Dual-process theories posit that familiarity and recollection are independently involved in the recognition of previously encountered material and both contribute to successful recognition. Recent evidence indicates that there is a double dissociation in the neuronal substrates of those two processes. More precisely, it has been suggested that perirhinal and entorhinal areas are selectively involved in familiarity-based recognition, while the hippocampus is associated with recollection. Interestingly, these regions are among the first to be targeted by neurofibrillary tangles, one of AD's neuropathological hallmarks. Impairment in recognition performance can occur in the very early stages of AD, such as MCI. To define the nature of recognition impairment in these clinical populations, we reviewed the current literature on familiarity and recollection performance in individuals with MCI and AD. Together with clinical features, methodological factors are taken into consideration in the interpretation of findings.

Association Between Hippocampal Volumes and Cognition in Cerebral Amyloid Angiopathy.

BACKGROUND AND OBJECTIVES: Accumulating evidence suggests that gray matter atrophy, often considered a marker of Alzheimer disease (AD), can also result from cerebral small vessel disease (CSVD). Cerebral amyloid angiopathy (CAA) is a form of sporadic CSVD, diagnosed through neuroimaging criteria, that often co-occurs with AD pathology and leads to cognitive impairment. We sought to identify the role of hippocampal integrity in the development of cognitive impairment in a cohort of patients with possible and probable CAA. METHODS: Patients were recruited from an ongoing CAA study at Massachusetts General Hospital. Composite scores defined performance in the cognitive domains of memory, language, executive function, and processing speed. Hippocampal subfields' volumes were measured from 3T MRI, using an automated method, and multivariate linear regression models were used to estimate their association with each cognitive domain and relationship to CAA-related neuroimaging markers. RESULTS: One hundred twenty patients, 36 with possible (age mean [range]: 75.6 [65.6-88.9]), 67 with probable CAA (75.9 [59.0-94.0]), and 17 controls without cognitive impairment and CSVD (72.4 [62.5-82.7]; 76.4% female patients), were included in this study. We found a positive association between all investigated hippocampal subfields and memory and language, whereas specific subfields accounted for executive function (CA4 [Estimate = 5.43; 95% CI 1.26-9.61; p = 0.020], subiculum [Estimate = 2.85; 95% CI 0.67-5.02; p = 0.022]), and processing speed (subiculum [Estimate = 1.99; 95% CI 0.13-3.85; p = 0.036]). These findings were independent of other CAA-related markers, which did not have an influence on cognition in this cohort. Peak width of skeletonized mean diffusivity (PSMD), a measure of white matter integrity, was negatively associated with hippocampal subfields' volumes (CA3 [Estimate = -0.012; 95% CI -0.020 to -0.004; p = 0.034], CA4 [Estimate = -0.010; 95% CI -0.020 to -0.0007; p = 0.037], subiculum [Estimate = -0.019; 95% CI -0.042 to -0.0001; p = 0.003]). DISCUSSION: These results suggest that hippocampal integrity is an independent contributor to cognitive impairment in patients with CAA and that it might be related to loss of integrity in the white matter. Further studies exploring potential causes and directionality of the relationship between white matter and hippocampal integrity may be warranted.

Association of Long-Term Blood Pressure Variability with Cerebral Amyloid Angiopathy-related Brain Injury and Cognitive Decline.

Introduction: Long-term systolic blood pressure variability (BPV) has been proposed as a novel risk factor for dementia, but the underlying mechanisms are largely unknown. We aimed to investigate the association between long-term blood pressure variability (BPV), brain injury, and cognitive decline in patients with mild cognitive symptoms and cerebral amyloid angiopathy (CAA), a well-characterized small-vessel disease that causes cognitive decline in older adults. Methods: Using a prospective memory clinic cohort, we enrolled 102 participants, of whom 52 with probable CAA. All underwent a 3-tesla research MRI at baseline and annual neuropsychological evaluation over 2 years, for which standardized z-scores for four cognitive domains were calculated. BPV was assessed using a coefficient of variation derived from serial outpatient BP measurements (median 12) over five years. We measured the peak width of skeletonized mean diffusivity (PSMD) as a marker of white matter integrity, and other neuroimaging markers of CAA, including lacunes and cortical cerebral microinfarcts. Using regression models, we evaluated the association of BPV with microstructural brain injury and whether CAA modified this association. We also examined the association of BPV with subsequent cognitive decline. Results: Systolic BPV was dose-dependently associated with PSMD (estimate=0.22, 95% CI: 0.06, 0.39, p=0.010), independent of age, sex, mean BP, common vascular risk factors, brain atrophy, and CAA severity. The presence of probable CAA strengthened the association between BPV and PSMD (estimate=9.33, 95% CI: 1.32, 17.34, p for interaction = 0.023). Higher BPV correlated with greater ischemic injury (lobar lacunes and cortical cerebral microinfarcts) and a decline in global cognition and processing speed (estimate=-0.30, 95% CI: -0.55, -0.04, p=0.022). Discussion: Long-term BPV has a dose-dependent association with alterations in white matter integrity, lobar lacunes, and cortical cerebral microinfarcts, and predicts cognitive decline. Controlling BPV is a potential strategic approach to prevent cognitive decline, especially in early-stage CAA.

Apathy in Patients With Cerebral Amyloid Angiopathy: A Multimodal Neuroimaging Study.

BACKGROUND AND OBJECTIVE: To analyze the prevalence and associated clinical characteristics of apathy in sporadic cerebral amyloid angiopathy and investigate whether apathy was associated with disease burden and disconnections of key structures in the reward circuit through a structural and functional multimodal neuroimaging approach. METHODS: Thirty-seven participants with probable sporadic cerebral amyloid angiopathy without symptomatic intracranial hemorrhage or dementia (mean age, 73.3 ± 7.2 years, % male = 59.5%) underwent a detailed neuropsychological evaluation, including measures of apathy and depression, and a multimodal MR neuroimaging study. A multiple linear regression analysis was used to assess the association of apathy with conventional small vessel disease neuroimaging markers. A voxel-based morphometry with a small volume correction within regions previously associated with apathy and a whole-brain tract-based spatial statistics were performed to identify differences in the gray matter and white matter between the apathetic and nonapathetic groups. Gray matter regions significantly associated with apathy were further evaluated for their functional alterations as seeds in the seed-based resting-state functional connectivity analysis. Potential confounders, namely, age, sex, and measures of depression, were entered as covariates in all analyses. RESULTS: A higher composite small vessel disease marker score (CAA-SVD) was associated with a higher degree of apathy (standardized coefficient = 1.35 (0.07-2.62), adjusted R2 = 27.90, p = 0.04). Lower gray matter volume of the bilateral orbitofrontal cortices was observed in the apathetic group than in the nonapathetic group (F = 13.20, family-wise error-corrected p = 0.028). The apathetic group demonstrated a widespread decrease in white matter microstructural integrity compared with the nonapathetic group. These tracts connect key regions within and between related reward circuits. Finally, there were no significant functional alterations between the apathetic and nonapathetic groups. DISCUSSION: Our findings revealed the orbitofrontal cortex as a key region in the reward circuit associated with apathy in sporadic cerebral amyloid angiopathy, independent from depression. Apathy was shown to be associated with a higher CAA-SVD score and an extensive disruption of white matter tracts, which suggested that a higher burden of CAA pathology and the disruption in large-scale white matter networks may underlie manifestations of apathy.

Verbal memory formation across PET-based Braak stages of tau accumulation in Alzheimer's disease.

A classical early sign of typical Alzheimer's disease is memory decline, which has been linked to the aggregation of tau in the medial temporal lobe. Verbal delayed free recall and recognition tests have consistently probed useful to detect early memory decline, and there is substantial debate on how performance, particularly in recognition tests, is differentially affected through health and disease in older adults. Using in vivo PET-Braak staging, we investigated delayed recall and recognition memory dysfunction across the Alzheimer's disease spectrum. Our cross-sectional study included 144 cognitively unimpaired elderly, 39 amyloid-ß+ individuals with mild cognitive impairment and 29 amyloid-ß+ Alzheimer's disease patients from the Translational Biomarkers in Aging and Dementia cohort, who underwent [18F]MK6240 tau and [18F]AZD4694 amyloid PET imaging, structural MRI and memory assessments. We applied non-parametric comparisons, correlation analyses, regression models and voxel-wise analyses. In comparison with PET-Braak Stage 0, we found that reduced, but not clinically significant, delayed recall starts at PET-Braak Stage II (adjusted P < 0.0015), and that recognition (adjusted P = 0.011) displayed a significant decline starting at PET-Braak Stage IV. While performance in both delayed recall and recognition related to tau in nearly the same cortical areas, further analyses showed that delayed recall rendered stronger associations in areas of early tau accumulation, whereas recognition displayed stronger correlations in mostly posterior neocortical regions. Our results support the notion that delayed recall and recognition deficits are predominantly associated with tau load in allocortical and neocortical areas, respectively. Overall, delayed recall seems to be more dependent on the integrity of anterior medial temporal lobe structures, while recognition appears to be more affected by tau accumulation in cortices beyond medial temporal regions.

Resilience to autosomal dominant Alzheimer's disease in a Reelin-COLBOS heterozygous man.

We characterized the world's second case with ascertained extreme resilience to autosomal dominant Alzheimer's disease (ADAD). Side-by-side comparisons of this male case and the previously reported female case with ADAD homozygote for the APOE3 Christchurch (APOECh) variant allowed us to discern common features. The male remained cognitively intact until 67 years of age despite carrying a PSEN1-E280A mutation. Like the APOECh carrier, he had extremely elevated amyloid plaque burden and limited entorhinal Tau tangle burden. He did not carry the APOECh variant but was heterozygous for a rare variant in RELN (H3447R, termed COLBOS after the Colombia-Boston biomarker research study), a ligand that like apolipoprotein E binds to the VLDLr and APOEr2 receptors. RELN-COLBOS is a gain-of-function variant showing stronger ability to activate its canonical protein target Dab1 and reduce human Tau phosphorylation in a knockin mouse. A genetic variant in a case protected from ADAD suggests a role for RELN signaling in resilience to dementia.

A cultural approach to dementia - insights from US Latino and other minoritized groups.

Alzheimer disease and related dementias present considerable challenges to health-care and medical systems worldwide. In the USA, older Black and Latino individuals are more likely than older white individuals to have Alzheimer disease and related dementias. In this Perspective, we leverage our experience and expertise with older US Latino groups to review and discuss the need to integrate cultural factors into dementia research and care. We examine the importance of considering the effects of cultural factors on clinical presentation and diagnosis, dementia risk, clinical research and recruitment, and caregiving practices, with a focus on minoritized groups in the USA. We highlight critical gaps in the literature to stimulate future research aimed at improving the prevention and early detection of Alzheimer disease and related dementias and developing novel treatments and interventions across ethnoracially diverse populations. In addition, we briefly discuss some of our own initiatives to promote research and clinical care among Latino populations living in the USA.

White matter hyperintensities are a prominent feature of autosomal dominant Alzheimer's disease that emerge prior to dementia.

BACKGROUND: To promote the development of effective therapies, there is an important need to characterize the full spectrum of neuropathological changes associated with Alzheimer's disease. In line with this need, this study examined white matter abnormalities in individuals with early-onset autosomal dominant Alzheimer's disease, in relation to age and symptom severity. METHODS: This is a cross-sectional analysis of data collected in members of a large kindred with a PSEN1 E280A mutation. Participants were recruited between September 2011 and July 2012 from the Colombian Alzheimer's Prevention Initiative registry. The studied cohort comprised 50 participants aged between 20 and 55 years, including 20 cognitively unimpaired mutation carriers, 9 cognitively impaired mutation carriers, and 21 non-carriers. Participants completed an MRI, a lumbar puncture for cerebrospinal fluid collection, a florbetapir PET scan, and neurological and neuropsychological examinations. The volume of white matter hyperintensities (WMH) was compared between cognitively unimpaired carriers, cognitively impaired carriers, and non-carriers. Relationships between WMH, age, and cognitive performance were further examined in mutation carriers. RESULTS: The mean (SD) age of participants was 35.8 (9.6) years and 64% were women. Cardiovascular risk factors were uncommon and did not differ across groups. Cognitively impaired carriers [median, 6.37; interquartile range (IQR), 9.15] had an increased volume of WMH compared to both cognitively unimpaired carriers [median, 0.85; IQR, 0.79] and non-carriers [median, 1.07; IQR, 0.71]. In mutation carriers, the volume of WMH strongly correlated with cognition and age, with evidence for an accelerated rate of changes after the age of 43 years, 1 year earlier than the estimated median age of symptom onset. In multivariable regression models including cortical amyloid retention, superior parietal lobe cortical thickness, and cerebrospinal fluid phospho-tau, the volume of WMH was the only biomarker independently and significantly contributing to the total explained variance in cognitive performance. CONCLUSIONS: The volume of WMH is increased among individuals with symptomatic autosomal-dominant Alzheimer's disease, begins to increase prior to clinical symptom onset, and is an independent determinant of cognitive performance in this group. These findings suggest that WMH are a key component of autosomal-dominant Alzheimer's disease that is closely related to the progression of clinical symptoms.