Publications by authors named "Francisco Lopera"

156 Publications

Cortical thickness across the lifespan in a Colombian cohort with autosomal-dominant Alzheimer's disease: A cross-sectional study.

Alzheimers Dement (Amst) 2021 14;13(1):e12233. Epub 2021 Sep 14.

Department of Psychiatry Massachusetts General Hospital Harvard Medical School Boston Massachusetts USA.

Introduction: Cortical thinning is a marker of neurodegeneration in Alzheimer's disease (AD). We investigated the age-related trajectory of cortical thickness across the lifespan (9-59 years) in a Colombian kindred with autosomal dominant AD (ADAD).

Methods: Two hundred eleven participants (105 presenilin-1 [] E280A mutation carriers, 16 with cognitive impairment; 106 non-carriers) underwent magnetic resonance imaging. A piecewise linear regression identified change-points in the age-related trajectory of cortical thickness in carriers and non-carriers.

Results: Unimpaired carriers exhibited elevated cortical thickness compared to non-carriers, and thickness more negatively correlated with age and cognition in carriers relative to non-carriers. We found increased cortical thickness in child carriers, after which thickness steadied compared to non-carriers prior to a rapid reduction in the decade leading up to the expected age at cognitive impairment in carriers.

Discussion: Findings suggest that cortical thickness may fluctuate across the ADAD lifespan, from early-life increased thickness to atrophy proximal to clinical onset.
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http://dx.doi.org/10.1002/dad2.12233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8438687PMC
September 2021

Subjective Cognitive and Communicative Complaints and Health-Related Quality of Life in Parkinson's Disease with and without Mild Cognitive Impairment.

Rev Colomb Psiquiatr (Engl Ed) 2021 Sep 3. Epub 2021 Sep 3.

Grupo de Neurociencias de Antioquia, Universidad de Antioquia, School of Medicine, Medellín, Colombia.

Introduction: Mild Cognitive Impairment (MCI) is common in Parkinson's Disease (PD). Few studies have compared the Health-Related Quality of Life (HRQoL) in patients with and without MCI due to PD (PD-MCI), and its correlation to patients' subjective cognitive and communicative difficulties has not been explored.

Objective: We aimed to compare HRQoL in PD-MCI and PD without MCI (PD-nMCI), and explore its possible relationship to subjective cognitive and communicative complaints.

Methods: We included 29 PD-nMCI and 11 PD-MCI patients. The HRQoL was assessed with the Parkinson's Disease Questionnaire-39 (PDQ-39): its Cognition dimension was used as a measure of subjective cognitive complaints, its Communication dimension for subjective communicative complaints, and the summary index (PDQ-39 SI) as an indicator of HRQoL. Non-parametric partial correlations between the Cognition and Communication dimensions, and the adjusted PDQ-39 SI were conducted.

Results: PD-MCI patients had greater subjective cognitive and communicative complaints and worse HRQoL than PD-nMCI patients. In the PD-MCI group, both subjective cognitive and communicative complaints exhibited significant direct correlations with the adjusted HRQoL scores.

Conclusions: HRQoL seems to be affected in PD-MCI, and it might be influenced by greater subjective cognitive and communicative complaints. Including patient-reported outcome measures of HRQoL, and providing cognitive and speech rehabilitation, as well as psychotherapeutic strategies to face these deficits can enhance the patient-centred approach in PD.
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http://dx.doi.org/10.1016/j.rcp.2021.07.005DOI Listing
September 2021

Sex Differences in Cognitive Abilities Among Children With the Autosomal Dominant Alzheimer Disease Presenilin 1 E280A Variant From a Colombian Cohort.

JAMA Netw Open 2021 Aug 2;4(8):e2121697. Epub 2021 Aug 2.

Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston.

Importance: We previously reported that children with the autosomal dominant Alzheimer disease (ADAD) presenilin 1 (PSEN1) E280A variant had early life plasma biomarker findings consistent with amyloid β overproduction. However, the cognitive functioning of children with this variant has not been characterized vs those without the variant.

Objective: To test whether cognitive functioning of children with and without the PSEN1 E280A variant in the same ADAD cohort differed by genetic status (ie, PSEN1 variant) and sex.

Design, Setting, And Participants: This cohort study was conducted among 1354 children (including 265 children with the variant) aged 6 to 16 years recruited from the Alzheimer Prevention Initiative Colombia Registry. Participants from the city of Medellín and surrounding suburban areas traveled to the University of Antioquia to undergo all procedures. Participants were administered a Spanish version of the Wechsler Intelligence Scale for Children, Fourth Edition (WISC-IV) to measure general cognitive functioning. Data were analyzed from July through November 2020.

Main Outcomes And Measures: Univariate general linear models were used to characterize differences on WISC-IV cognitive performance by genetic status, sex, and the interaction of genetic status with sex. Urbanity, socioeconomic status, and education were entered as covariates.

Results: Among 1354 children with ADAD (695 [51.3%] girls; mean [SD] age, 11.64 [2.64] years), there were 265 children with the variant (19.6%) and 1089 children without the variant (80.4%). Children with and without the variant did not differ by demographic variables or performance on WISC-IV indices. Irrespective of genetic status, boys had statistically significantly decreased mean scores on indices for working memory (90.27 [95% CI, 89.21-91.34] vs 92.99 [95% CI, 91.98-93.99]; mean difference = -2.72; P < .001), perceptual reasoning (91.56 [95% CI, 90.47-92.65] vs. 93.27 [95% CI, 91.23-94.30]; mean difference = -1.71; P = .03), and verbal comprehension (88.69 [95% CI, 87.54-89.84] vs. 90.81 [95% CI, 89.73-91.90]; mean difference = -2.12; P = .009) compared with girls. In the interaction between sex and genetic status, boys with the variant had worse mean working memory index performance (88.78 [95% CI, 86.86-90.70]) than girls with the variant (93.75 [95% CI, 91.95-95.55]; mean difference = -4.97; P = .001), as well as boys (91.77 [95% CI, 90.85-92.70]; mean difference = -2.99; P = .04) and girls (92.22 [95% CI, 91.32-93.13]; mean difference = -3.44; P = .009) without the variant.

Conclusions And Relevance: This study found that boys with the PSEN1 variant had decreased working memory abilities compared with girls with the variant and boys and girls without the variant, suggesting a sex-specific genetic risk in early life cognitive performance among individuals with the PSEN1 variant. This increased risk of future cognitive difficulties among boys with the variant may have important downstream implications for learning and academic achievement and could be associated with sex differences seen in adulthood on episodic memory measures.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.21697DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8408665PMC
August 2021

A Spanish Neuropsychological Battery Discriminates Between the Behavioral Variant of Frontotemporal Dementia and Primary Progressive Aphasia in a Colombian Sample.

Front Neurol 2021 5;12:656478. Epub 2021 Jul 5.

Neuroscience Group of Antioquia, The University of Antioquia, Medellín, Colombia.

The differential diagnosis among the behavioral variant of frontotemporal dementia FTD (bvFTD) and the linguist one primary progressive aphasia (PPA) is challenging. Presentations of dementia type or variants dominated by personality change or aphasia are frequently misinterpreted as psychiatric illness, stroke, or other conditions. Therefore, it is important to identify cognitive tests that can distinguish the distinct FTD variants to reduce misdiagnosis and best tailor interventions. We aim to examine the discriminative capacity of the most frequently used cognitive tests in their Spanish version for the context of dementia evaluation as well as the qualitative aspects of the neuropsychological performance such as the frequency and type of errors, perseverations, and false positives that can best discriminate between bvFTD and PPA. We also described mood and behavioral profiles of participants with mild to moderate probable bvFTD and PPA. A total of 55 subjects were included in this cross-sectional study: 20 with PPA and 35 with bvFTD. All participants underwent standard dementia screening that included a medical history and physical examination, brain MRI, a semistructured caregiver interview, and neuropsychological testing. We found that bvFTD patients had worse performance in executive function tests, and the PPA presented with the lower performance in language tests and the global score of Mini-Mental State Examination (MMSE). After running the linear discriminant model, we found three functions of cognitive test and subtests combination and three functions made by the Montreal Cognitive Assessment (MoCA) language subtest and performance errors that predicted group belonging. Those functions were more capable to classify bvFTD cases rather than PPA. In conclusion, our study supports that the combination of an individual test of executive function and language, MoCA's subtest, and performance errors as well have good accuracy to discriminate between bvFTD and PPA.
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http://dx.doi.org/10.3389/fneur.2021.656478DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8287023PMC
July 2021

PET evidence of preclinical cerebellar amyloid plaque deposition in autosomal dominant Alzheimer's disease-causing Presenilin-1 E280A mutation carriers.

Neuroimage Clin 2021 4;31:102749. Epub 2021 Jul 4.

Banner Alzheimer's Institute, Phoenix, AZ, USA; Arizona Alzheimer's Consortium, Phoenix, AZ, USA; Arizona State University, Tempe, AZ, USA; University of Arizona, Tucson, AZ, USA; Translational Genomics Research Institute, Phoenix, AZ, USA. Electronic address:

Background: In contrast to sporadic Alzheimer's disease, autosomal dominant Alzheimer's disease (ADAD) is associated with greater neuropathological evidence of cerebellar amyloid plaque (Aβ) deposition. In this study, we used positron emission tomography (PET) measurements of fibrillar Aβ burden to characterize the presence and age at onset of cerebellar Aβ deposition in cognitively unimpaired (CU) Presenilin-1 (PSEN1) E280A mutation carriers from the world's largest extended family with ADAD.

Methods: F florbetapir and C Pittsburgh compound B (PiB) PET data from two independent studies - API ADAD Colombia Trial (NCT01998841) and Colombia-Boston (COLBOS) longitudinal biomarker study were included. The tracers were selected independently by the respective sponsors prior to the start of each study and used exclusively throughout. Template-based cerebellar Aβ-SUVR (standard-uptake value ratios) using a known-to-be-spared pons reference region (cerebellar SUVR_pons), to a) compare 28-56-year-old CU carriers and non-carriers; b) estimate the age at which cerebellar SUVR_pons began to differ significantly in carrier and non-carrier groups; and c) characterize in carriers associations with age, cortical SUVR_pons, delayed recall memory, and API ADAD composite score.

Results: Florbetapir and PiB cerebellar SUVR_pons were significantly higher in carriers than non-carriers (p < 0.0001). Cerebellar SUVR_pons began to distinguish carriers from non-carriers at age 34, 10 years before the carriers' estimated age at mild cognitive impairment onset. Florbetapir and PiB cerebellar SUVR_pons in carriers were positively correlated with age (r = 0.44 & 0.69, p < 0.001), cortical SUVR_pons (r = 0.55 & 0.69, p < 0.001), and negatively correlated with delayed recall memory (r = -0.21 & -0.50, p < 0.05, unadjusted for cortical SUVR_pons) and API ADAD composite (r = -0.25, p < 0.01, unadjusted for cortical SUVR_pons in florbetapir API ADAD cohort).

Conclusion: This PET study provides evidence of cerebellar Aβ plaque deposition in CU carriers starting about a decade before the clinical onset of ADAD. Additional studies are needed to clarify the impact of using a cerebellar versus pons reference region on the power to detect and track ADAD changes, even in preclinical stages of this disorder.
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http://dx.doi.org/10.1016/j.nicl.2021.102749DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8278433PMC
September 2021

Characterizing the Genetic Architecture of Parkinson's Disease in Latinos.

Ann Neurol 2021 Sep 22;90(3):353-365. Epub 2021 Jul 22.

Neuroscience and Cell Death Research Groups, Medical School and Genetic Institute, Universidad Nacional de Colombia, Bogotá, Colombia.

Objective: This work was undertaken in order to identify Parkinson's disease (PD) risk variants in a Latino cohort, to describe the overlap in the genetic architecture of PD in Latinos compared to European-ancestry subjects, and to increase the diversity in PD genome-wide association (GWAS) data.

Methods: We genotyped and imputed 1,497 PD cases and controls recruited from nine clinical sites across South America. We performed a GWAS using logistic mixed models; variants with a p-value <1 × 10 were tested in a replication cohort of 1,234 self-reported Latino PD cases and 439,522 Latino controls from 23andMe, Inc. We also performed an admixture mapping analysis where local ancestry blocks were tested for association with PD status.

Results: One locus, SNCA, achieved genome-wide significance (p-value <5 × 10 ); rs356182 achieved genome-wide significance in both the discovery and the replication cohorts (discovery, G allele: 1.58 OR, 95% CI 1.35-1.86, p-value 2.48 × 10 ; 23andMe, G allele: 1.26 OR, 95% CI 1.16-1.37, p-value 4.55 × 10 ). In our admixture mapping analysis, a locus on chromosome 14, containing the gene STXBP6, achieved significance in a joint test of ancestries and in the Native American single-ancestry test (p-value <5 × 10 ). A second locus on chromosome 6, containing the gene RPS6KA2, achieved significance in the African single-ancestry test (p-value <5 × 10 ).

Interpretation: This study demonstrated the importance of the SNCA locus for the etiology of PD in Latinos. By leveraging the demographic history of our cohort via admixture mapping, we identified two potential PD risk loci that merit further study. ANN NEUROL 2021;90:353-365.
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http://dx.doi.org/10.1002/ana.26153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8457043PMC
September 2021

Neuroticism Is Associated with Tau Pathology in Cognitively Unimpaired Individuals with Autosomal Dominant Alzheimer's Disease.

J Alzheimers Dis 2021 ;82(4):1809-1822

Grupo de Neurociencias de Antioquia, Universidad de Antioquia, Medellín, Colombia.

Background: Greater neuroticism has been associated with higher risk for Alzheimer's disease (AD) dementia. However, the directionality of this association is unclear. We examined whether personality traits differ between cognitively-unimpaired carriers of autosomal-dominant AD (ADAD) and non-carriers, and are associated with in vivo AD pathology.

Objective: To determine whether personality traits differ between cognitively unimpaired ADAD mutation carriers and non-carriers, and whether the traits are related to age and AD biomarkers.

Methods: A total of 33 cognitively-unimpaired Presenilin-1 E280A mutation carriers and 41 non-carriers (ages 27-46) completed neuropsychological testing and the NEO Five-Factor Personality Inventory. A subsample (n = 46; 20 carriers) also underwent tau and amyloid PET imaging.

Results: Carriers reported higher neuroticism relative to non-carriers, although this difference was not significant after controlling for sex. Neuroticism was positively correlated with entorhinal tau levels only in carriers, but not with amyloid levels.

Conclusion: The finding of higher neuroticism in carriers and the association of this trait with tau pathology in preclinical stages of AD highlights the importance of including personality measures in the evaluation of individuals at increased risk for cognitive impairment and dementia. Further research is needed to characterize the mechanisms of these relationships.
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http://dx.doi.org/10.3233/JAD-210185DOI Listing
January 2021

Subjective Cognitive Decline and its Relation to Verbal Memory and Sex in Cognitively Unimpaired Individuals from a Colombian Cohort with Autosomal-Dominant Alzheimer's Disease.

J Int Neuropsychol Soc 2021 Jun 30:1-9. Epub 2021 Jun 30.

Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA02129, USA.

Objective: Subjective Cognitive Decline (SCD) may be an early indicator of risk for Alzheimer's disease (AD). Findings regarding sex differences in SCD are inconsistent. Studying sex differences in SCD within cognitively unimpaired individuals with autosomal-dominant AD (ADAD), who will develop dementia, may inform sex-related SCD variations in preclinical AD. We examined sex differences in SCD within cognitively unimpaired mutation carriers from the world's largest ADAD kindred and sex differences in the relationship between SCD and memory performance.

Methods: We included 310 cognitively unimpaired Presenilin-1 (PSEN-1) E280A mutation carriers (51% females) and 1998 noncarrier family members (56% females) in the study. Subjects and their study partners completed SCD questionnaires and the CERAD word list delayed recall test. ANCOVAs were conducted to examine group differences in SCD, sex, and memory performance. In carriers, partial correlations were used to examine associations between SCD and memory performance covarying for education.

Results: Females in both groups had greater self-reported and study partner-reported SCD than males (all p < 0.001). In female mutation carriers, greater self-reported (p = 0.02) and study partner-reported SCD (p < 0.001) were associated with worse verbal memory. In male mutation carriers, greater self-reported (p = 0.03), but not study partner-reported SCD (p = 0.11) was associated with worse verbal memory.

Conclusions: Study partner-reported SCD may be a stronger indicator of memory decline in females versus males in individuals at risk for developing dementia. Future studies with independent samples and preclinical trials should consider sex differences when recruiting based on SCD criteria.
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http://dx.doi.org/10.1017/S1355617721000801DOI Listing
June 2021

Associations between subregional thalamic volume and brain pathology in autosomal dominant Alzheimer's disease.

Brain Commun 2021 10;3(2):fcab101. Epub 2021 May 10.

Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.

Histopathological reports suggest that subregions of the thalamus, which regulates multiple physiological and cognitive processes, are not uniformly affected by Alzheimer's disease. Despite this, structural neuroimaging studies often consider the thalamus as a single region. Identification of Alzheimer's-dependent volumetric changes in thalamic subregions may aid the characterization of early nuclei-specific neurodegeneration in Alzheimer's disease. Here, we leveraged access to the largest single-mutation cohort of autosomal-dominant Alzheimer's disease to test whether cross-sectional abnormalities in subregional thalamic volumes are evident in non-demented mutation carriers ( = 31), compared to non-carriers ( = 36), and whether subregional thalamic volume is associated with age, markers of brain pathology and cognitive performance. Using automatic parcellation we examined the thalamus in six subregions (anterior, lateral, ventral, intralaminar, medial, and posterior) and their relation to age and brain pathology (amyloid and tau), as measured by PET imaging. No between-group differences were observed in the volume of the thalamic subregions. In carriers, lower volume in the medial subregion was related to increased cortical amyloid and entorhinal tau burden. These findings suggest that thalamic Alzheimer's-related volumetric reductions are not uniform even in preclinical and prodromal stages of autosomal-dominant Alzheimer's disease and therefore, this structure should not be considered as a single, unitary structure in Alzheimer's disease research.
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http://dx.doi.org/10.1093/braincomms/fcab101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8172494PMC
May 2021

Global Cardiovascular Risk Profile and Cerebrovascular Abnormalities in Presymptomatic Individuals with CADASIL or Autosomal Dominant Alzheimer's Disease.

J Alzheimers Dis 2021 ;82(2):841-853

Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

Background: Cardiovascular risk factors increase the risk of developing dementia, including Alzheimer's disease and vascular dementia.

Objective: Studying individuals with autosomal dominant mutations leading to the early onset of dementia, this study examines the effect of the global cardiovascular risk profile on early cognitive and neuroimaging features of Alzheimer's disease and vascular dementia.

Methods: We studied 85 non-demented and stroke-free individuals, including 20 subjects with Presenilin1 (PSEN1) E280A mutation leading to the early onset of autosomal dominant Alzheimer's disease (ADAD), 20 subjects with NOTCH3 mutations leading to cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and to the early onset of vascular dementia, and 45 non-affected family members (non-carriers). All subjects underwent clinical and neuropsychological evaluations and an MRI. The global cardiovascular risk profile was estimated using the office-based Framingham Cardiovascular Risk Profile (FCRP) score.

Results: In individuals with CADASIL, a higher FCRP score was associated with a reduced hippocampal volume (B = -0.06, p < 0.05) and an increased severity of cerebral microbleeds (B = 0.13, p < 0.001), lacunes (B = 0.30, p < 0.001), and perivascular space enlargement in the basal ganglia (B = 0.50, p < 0.05). There was no significant association between the FCRP score and neuroimaging measures in ADAD or non-carrier subjects. While the FCRP score was related to performance in executive function in non-carrier subjects (B = 0.06, p < 0.05), it was not significantly associated with cognitive performance in individuals with CADASIL or ADAD.

Conclusion: Our results suggest that individuals with CADASIL and other forms of vascular cognitive impairment might particularly benefit from early interventions aimed at controlling cardiovascular risks.
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http://dx.doi.org/10.3233/JAD-210313DOI Listing
September 2021

A Comprehensive Machine Learning Framework for the Exact Prediction of the Age of Onset in Familial and Sporadic Alzheimer's Disease.

Diagnostics (Basel) 2021 May 17;11(5). Epub 2021 May 17.

Grupo de Investigación en Psiquiatría (GIPSI), Departamento de Psiquiatría, Instituto de Investigaciones Médicas, Facultad de Medicina, Universidad de Antioquia, Medellín 050010, Colombia.

Machine learning (ML) algorithms are widely used to develop predictive frameworks. Accurate prediction of Alzheimer's disease (AD) age of onset (ADAOO) is crucial to investigate potential treatments, follow-up, and therapeutic interventions. Although genetic and non-genetic factors affecting ADAOO were elucidated by other research groups and ours, the comprehensive and sequential application of ML to provide an exact estimation of the actual ADAOO, instead of a high-confidence-interval ADAOO that may fall, remains to be explored. Here, we assessed the performance of ML algorithms for predicting ADAOO using two AD cohorts with early-onset familial AD and with late-onset sporadic AD, combining genetic and demographic variables. Performance of ML algorithms was assessed using the root mean squared error (RMSE), the R-squared (), and the mean absolute error (MAE) with a 10-fold cross-validation procedure. For predicting ADAOO in familial AD, boosting-based ML algorithms performed the best. In the sporadic cohort, boosting-based ML algorithms performed best in the training data set, while regularization methods best performed for unseen data. ML algorithms represent a feasible alternative to accurately predict ADAOO with little human intervention. Future studies may include predicting the speed of cognitive decline in our cohorts using ML.
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http://dx.doi.org/10.3390/diagnostics11050887DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8156402PMC
May 2021

Specific Abnormalities in White Matter Pathways as Interface to Small Vessels Disease and Cognition in Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy Individuals.

Brain Connect 2021 Jun 29. Epub 2021 Jun 29.

Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is characterized by leukoencephalopathy leading to cognitive impairment. Subtle cognitive deficits can be observed early in the course of the disease, before the occurrence of the first stroke. Therefore, markers that can predict disease progression at this early stage, when interventions are likely to alter disease course, are needed. We aimed to examine the biological cascade of microstructural and macrostructural white matter (WM) abnormalities underlying cognitive deficits in CADASIL. We examined 20 nondemented CADASIL mutation carriers and 23 noncarriers who underwent neuropsychological evaluation and magnetic resonance imaging. Using probabilistic tractography of key WM tracts, we examined group differences in diffusivity measures and WM hyperintensity volume. Successive mediation models examined whether tract-specific WM abnormalities mediated subtle cognitive differences between CADASIL mutation carriers and noncarriers. The largest effect size differentiating the two groups was observed for left superior longitudinal fasciculus-temporal (SLFt) diffusivity (Cohen's  = 0.49). No group differences were observed with a global diffusion measure. These specific microstructural differences in the SLFt were associated with higher WM hyperintensities burden, and subtle executive deficits in CADASIL mutation carriers. Worse diffusivity in the left SLFt is related to greater severity of small vessel disease and worse executive functioning in the asymptomatic stage of the disease. Worse diffusivity of the left SLFt may potentially hold promise as an indicator of disease progression.
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http://dx.doi.org/10.1089/brain.2020.0980DOI Listing
June 2021

The Multi-Partner Consortium to Expand Dementia Research in Latin America (ReDLat): Driving Multicentric Research and Implementation Science.

Front Neurol 2021 11;12:631722. Epub 2021 Mar 11.

Cognitive Neuroscience Center, Universidad de San Andrés, Buenos Aires, Argentina.

Dementia is becoming increasingly prevalent in Latin America, contrasting with stable or declining rates in North America and Europe. This scenario places unprecedented clinical, social, and economic burden upon patients, families, and health systems. The challenges prove particularly pressing for conditions with highly specific diagnostic and management demands, such as frontotemporal dementia. Here we introduce a research and networking initiative designed to tackle these ensuing hurdles, the Multi-partner consortium to expand dementia research in Latin America (ReDLat). First, we present ReDLat's regional research framework, aimed at identifying the unique genetic, social, and economic factors driving the presentation of frontotemporal dementia and Alzheimer's disease in Latin America relative to the US. We describe ongoing ReDLat studies in various fields and ongoing research extensions. Then, we introduce actions coordinated by ReDLat and the Latin America and Caribbean Consortium on Dementia (LAC-CD) to develop culturally appropriate diagnostic tools, regional visibility and capacity building, diplomatic coordination in local priority areas, and a knowledge-to-action framework toward a regional action plan. Together, these research and networking initiatives will help to establish strong cross-national bonds, support the implementation of regional dementia plans, enhance health systems' infrastructure, and increase translational research collaborations across the continent.
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http://dx.doi.org/10.3389/fneur.2021.631722DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7992978PMC
March 2021

Extracellular Vesicles From 3xTg-AD Mouse and Alzheimer's Disease Patient Astrocytes Impair Neuroglial and Vascular Components.

Front Aging Neurosci 2021 19;13:593927. Epub 2021 Feb 19.

Área de Neurobiología Celular y Molecular, Grupo de Neurociencias de Antioquia, Universidad de Antioquia, Medellin, Colombia.

Astrocytes are specialized glial cells that are essential components of the neurovascular unit (NVU) and are involved in neurodevelopment, brain maintenance and repair, and neurodegeneration. Astrocytes mediate these processes by releasing cellular mediators such as extracellular vesicles (EVs). EVs are vehicles of cell-cell communication and have been proposed as mediators of damage in AD. However, the transcellular mechanism by which Alzheimer disease (AD) astrocytes impair the function of NVU components is poorly understood. Therefore, we evaluated the effects of adult PS1-KI and 3xTg-AD astrocyte conditioned media (CM) and EVs on NVU components (neuroglia and endothelium) . Additionally, SAD and FAD astrocyte-derived EVs (A-EVs) were characterized, and we evaluated their effects on NVU in cocultured cells and on intrahippocampal CA1 cells . Surprisingly, cultured 3xTg-AD astrocytes showed increased glial fibrillary acidic protein (GFAP) reactivity compared to PS1-KI astrocytes, which denotes astrocytic hyperreactivity. CM from adult mice 3xTg-AD astrocytes increased cell-cell gaps between endothelial cells, filopodia-like dendritic protrusions in neurons and neuronal and endothelial cell death. 3xTg-AD A-EVs induced neurotoxicity and increased astrocyte GFAP reactivity. Cultured human astrocytes from AD patients also increased GFAP reactivity and EVs release. No differences in the size or number of A-EVs were detected between AD and control samples; however, both SAD and FAD A-EVs showed increased expression of the surface marker aquaporin 4. A-EVs induced cytotoxicity and astrocyte hyperactivation: specifically, FAD A-EVs induced neuroglial cytotoxicity and increased gaps between the endothelium, while SAD A-EVs mainly altered the endothelium. Similarly, both AD A-EVs increased astrocyte GS reactivity and vascular deterioration . We associated this finding with perivascular reactive astrocytes and vascular deterioration in the human AD brain. In summary, these results suggest that AD A-EVs impair neuroglial and vascular components.
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http://dx.doi.org/10.3389/fnagi.2021.593927DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7933224PMC
February 2021

Quality of life in early-onset Alzheimer's disease due to a PSEN1-E280A mutation.

Neurol Sci 2021 Nov 5;42(11):4637-4645. Epub 2021 Mar 5.

Grupo de Neurociencias de Antioquia, Facultad de Medicina, Universidad de Antioquia, Medellín, Colombia.

Purpose: The present study aims to explore the association between the quality of life (QoL) score and the clinical and sociodemographic variables in patients with the PSEN1-E280A mutation. We also seek to evaluate the differences between the QoL reported by the patients (P-QoL) and the scores reported by the caregivers (C-QoL).

Methods: An analysis of 75 patients with the PSEN1-E280A mutation with mild cognitive impairment and dementia was performed. We used the Quality of Life in Alzheimer Disease (QoL-AD) survey to evaluate QoL as an outcome and evaluated its association with sociodemographic, lifestyle, clinical, and past medical history variables.

Results: The largest difference in the median of the QoL-AD score was in those who needed help to eat, those with moderate or severe dementia, those classified as frail or pre-frail, those with moderate social risk, and those with depression. Also, C-QoL was lower than the P-QoL, and the QoL-AD of individuals with severe dementia was lower than for milder forms of the disease. Not needing help to eat, not having a stressful situation in the past 3 months, and the years of education were positively correlated with QoL-AD in the linear model.

Conclusion: As studies in similar populations with AD, factors with more impact on QoL are those related to loss of functionality and independence. These factors are also associated with variables related to the current literature with the burden of the disease for the caregivers.
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http://dx.doi.org/10.1007/s10072-021-05136-yDOI Listing
November 2021

Dementia in Latin America: Paving the way toward a regional action plan.

Alzheimers Dement 2021 02 20;17(2):295-313. Epub 2020 Nov 20.

Hospital Geral de Fortaleza, University of Fortaleza, Brazil.

Across Latin American and Caribbean countries (LACs), the fight against dementia faces pressing challenges, such as heterogeneity, diversity, political instability, and socioeconomic disparities. These can be addressed more effectively in a collaborative setting that fosters open exchange of knowledge. In this work, the Latin American and Caribbean Consortium on Dementia (LAC-CD) proposes an agenda for integration to deliver a Knowledge to Action Framework (KtAF). First, we summarize evidence-based strategies (epidemiology, genetics, biomarkers, clinical trials, nonpharmacological interventions, networking, and translational research) and align them to current global strategies to translate regional knowledge into transformative actions. Then we characterize key sources of complexity (genetic isolates, admixture in populations, environmental factors, and barriers to effective interventions), map them to the above challenges, and provide the basic mosaics of knowledge toward a KtAF. Finally, we describe strategies supporting the knowledge creation stage that underpins the translational impact of KtAF.
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http://dx.doi.org/10.1002/alz.12202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7984223PMC
February 2021

Resting-state EEG alpha/theta ratio related to neuropsychological test performance in Parkinson's Disease.

Clin Neurophysiol 2021 03 13;132(3):756-764. Epub 2021 Jan 13.

Centre for Age-Related Medicine (SESAM), Stavanger University Hospital. Stavanger, Norway; KCL-PARCOG Group, Institute of Psychiatry, Psychology, and Neuroscience, King's College London. London, UK.

Objective: To determine possible associations of hemispheric-regional alpha/theta ratio (α/θ) with neuropsychological test performance in Parkinson's Disease (PD) non-demented patients.

Methods: 36 PD were matched to 36 Healthy Controls (HC). The α/θ in eight hemispheric regions was computed from the relative power spectral density of the resting-state quantitative electroencephalogram (qEEG). Correlations between α/θ and performance in several neuropsychological tests were conducted, significant findings were included in a moderation analysis.

Results: The α/θ in all regions was lower in PD than in HC, with larger effect sizes in the posterior regions. Right parietal, and right and left occipital α/θ had significant positive correlations with performance in Judgement of Line Orientation Test (JLOT) in PD. Adjusted moderation analysis indicated that right, but not left, occipital α/θ influenced the JLOT performance related to PD.

Conclusions: Reduction of the occipital α/θ, in particular on the right side, was associated with visuospatial performance impairment in PD.

Significance: Visuospatial impairment in PD, which is highly correlated with the subsequent development of dementia, is reflected in α/θ in the right posterior regions. The right occipital α/θ may represent a useful qEEG marker for evaluating the presence of early signs of cognitive decline in PD and the subsequent risk of dementia.
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http://dx.doi.org/10.1016/j.clinph.2021.01.001DOI Listing
March 2021

Associations between plasma neurofilament light, in vivo brain pathology, and cognition in non-demented individuals with autosomal-dominant Alzheimer's disease.

Alzheimers Dement 2021 05 1;17(5):813-821. Epub 2021 Feb 1.

Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.

Background: Neurofilament light (NfL) is a promising biomarker of early neurodegeneration in Alzheimer's disease (AD). We examined whether plasma NfL was associated with in vivo amyloid beta and tau, and cognitive performance in non-demented presenilin-1 (PSEN1) E280A mutation carriers.

Methods: Twenty-five mutation carriers and 19 non-carriers (age range: 28 to 49 years) were included in this study. Participants underwent 11C Pittsburgh compound B (PiB)-PET (positron emission tomography), flortaucipir-PET, blood sampling, and cognitive testing.

Results: Mutation carriers exhibited higher plasma NfL levels than non-carriers. In carriers, higher NfL levels were related to greater regional tau burden and worse cognition, but not amyloid beta load. When we adjusted for age, a proxy of disease progression, elevated plasma NfL levels were only correlated with worse memory recall.

Conclusions: Findings support an association between plasma NfL, cognition, and tau pathology in non-demented individuals at genetic risk for developing AD dementia. Plasma NfL may be useful for selecting individuals at increased risk and tracking disease progression in AD.
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http://dx.doi.org/10.1002/alz.12248DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8158654PMC
May 2021

Longitudinal amyloid and tau accumulation in autosomal dominant Alzheimer's disease: findings from the Colombia-Boston (COLBOS) biomarker study.

Alzheimers Res Ther 2021 01 15;13(1):27. Epub 2021 Jan 15.

Massachusetts General Hoospital, Harvard Medical School, Boston, MA, USA.

Background: Neuroimaging studies of autosomal dominant Alzheimer's disease (ADAD) enable characterization of the trajectories of cerebral amyloid-β (Aβ) and tau accumulation in the decades prior to clinical symptom onset. Longitudinal rates of regional tau accumulation measured with positron emission tomography (PET) and their relationship with other biomarker and cognitive changes remain to be fully characterized in ADAD.

Methods: Fourteen ADAD mutation carriers (Presenilin-1 E280A) and 15 age-matched non-carriers from the Colombian kindred underwent 2-3 sessions of Aβ (11C-Pittsburgh compound B) and tau (18F-flortaucipir) PET, structural magnetic resonance imaging, and neuropsychological evaluation over a 2-4-year follow-up period. Annualized rates of change for imaging and cognitive variables were compared between carriers and non-carriers, and relationships among baseline measurements and rates of change were assessed within carriers.

Results: Longitudinal measurements were consistent with a sequence of ADAD-related changes beginning with Aβ accumulation (16 years prior to expected symptom onset, EYO), followed by entorhinal cortex (EC) tau (9 EYO), neocortical tau (6 EYO), hippocampal atrophy (6 EYO), and cognitive decline (4 EYO). Rates of tau accumulation among carriers were most rapid in parietal neocortex (~ 9%/year). EC tau PET signal at baseline was a significant predictor of subsequent neocortical tau accumulation and cognitive decline within carriers.

Conclusions: Our results are consistent with the sequence of biological changes in ADAD implied by cross-sectional studies and highlight the importance of EC tau as an early biomarker and a potential link between Aβ burden and neocortical tau accumulation in ADAD.
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http://dx.doi.org/10.1186/s13195-020-00765-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7811244PMC
January 2021

A multifactorial model of pathology for age of onset heterogeneity in familial Alzheimer's disease.

Acta Neuropathol 2021 02 14;141(2):217-233. Epub 2020 Dec 14.

Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Presenilin-1 (PSEN1) mutations cause familial Alzheimer's disease (FAD) characterized by early age of onset (AoO). Examination of a large kindred harboring the PSEN1-E280A mutation reveals a range of AoO spanning 30 years. The pathophysiological drivers and clinical impact of AoO variation in this population are unknown. We examined brains of 23 patients focusing on generation and deposition of beta-amyloid (Aβ) and Tau pathology profile. In 14 patients distributed at the extremes of AoO, we performed whole-exome capture to identify genotype-phenotype correlations. We also studied kinome activity, proteasome activity, and protein polyubiquitination in brain tissue, associating it with Tau phosphorylation profiles. PSEN1-E280A patients showed a bimodal distribution for AoO. Besides AoO, there were no clinical differences between analyzed groups. Despite the effect of mutant PSEN1 on production of Aβ, there were no relevant differences between groups in generation and deposition of Aβ. However, differences were found in hyperphosphorylated Tau (pTau) pathology, where early onset patients showed severe pathology with diffuse aggregation pattern associated with increased activation of stress kinases. In contrast, late-onset patients showed lesser pTau pathology and a distinctive kinase activity. Furthermore, we identified new protective genetic variants affecting ubiquitin-proteasome function in early onset patients, resulting in higher ubiquitin-dependent degradation of differentially phosphorylated Tau. In PSEN1-E280A carriers, altered γ-secretase activity and resulting Aβ accumulation are prerequisites for early AoO. However, Tau hyperphosphorylation pattern, and its degradation by the proteasome, drastically influences disease onset in individuals with otherwise similar Aβ pathology, hinting toward a multifactorial model of disease for FAD. In sporadic AD (SAD), a wide range of heterogeneity, also influenced by Tau pathology, has been identified. Thus, Tau-induced heterogeneity is a common feature in both AD variants, suggesting that a multi-target therapeutic approach should be used to treat AD.
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http://dx.doi.org/10.1007/s00401-020-02249-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7847436PMC
February 2021

Trajectory of Unawareness of Memory Decline in Individuals With Autosomal Dominant Alzheimer Disease.

JAMA Netw Open 2020 12 1;3(12):e2027472. Epub 2020 Dec 1.

Department of Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Charlestown, Massachusetts.

Importance: Recent studies have suggested that unawareness, or anosognosia, of memory decline is present in predementia stages of Alzheimer disease (AD) and may serve as an early symptomatic indicator of AD.

Objective: To investigate the evolution of anosognosia of memory decline in individuals who carry the PSEN1 E280A variant for autosomal dominant AD compared with family members who do not carry the variant.

Design, Setting, And Participants: This cohort study investigated a total of 2379 members of a Colombian kindred with autosomal dominant AD who were part of the Alzheimer's Prevention Initiative Registry. Assessments were completed at the University of Antioquia, Colombia, with data collected between January 1, 2000, and July 31, 2019.

Main Outcomes And Measures: Awareness of memory function was operationalized using the discrepancy between self-report and study partner report on a memory complaint scale. Linear mixed effects models were used to assess memory self-awareness over age separately in variant carriers and noncarriers.

Results: This study included 396 variant carriers (mean [SD] age, 32.7 [11.9] years; 200 [50.5%] female), of whom 59 (14.9%) were cognitively impaired, and 1983 cognitively unimpaired noncarriers (mean [SD] age, 33.5 [12.5] years; 1129 [56.9%] female). The variant carriers demonstrated increased awareness until the mean (SD) age of 35.0 (2.0) years and had anosognosia at approximately 43 years of age, approximately 6 years before their estimated median age of dementia onset (49 years; 95% CI, 49-51 years). Cognitively unimpaired noncarriers reported more complaints than their study partners aged 20 and 60 years (10.1 points, P < .001). On the awareness index, a decrease with age (mean [SE] estimate, -0.04 [0.02] discrepant-points per years; t = -2.2; P = .03) in the noncarriers and in the variant carriers (mean [SE] estimate, -0.21 [0.04] discrepant-points per years; t = -5.1; P < .001) was observed.

Conclusions And Relevance: In this cohort study, increased participant complaints were observed in both groups, suggesting that increased awareness of memory function was common and nonspecific to AD in this cohort. In variant carriers, awareness of memory function decreased in the predementia stages, reaching anosognosia close to the age of mild cognitive impairment onset, providing support for the usefulness of awareness of memory decline.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.27472DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7711319PMC
December 2020

Dominantly inherited Alzheimer's disease in Latin America: Genetic heterogeneity and clinical phenotypes.

Alzheimers Dement 2021 04 23;17(4):653-664. Epub 2020 Nov 23.

Department of Neurology, Washington University in St. Louis, St. Louis, Missouri, USA.

Introduction: A growing number of dominantly inherited Alzheimer's disease (DIAD) cases have become known in Latin American (LatAm) in recent years. However, questions regarding mutation distribution and frequency by country remain open.

Methods: A literature review was completed aimed to provide estimates for DIAD pathogenic variants in the LatAm population. The search strategies were established using a combination of standardized terms for DIAD and LatAm.

Results: Twenty-four DIAD pathogenic variants have been reported in LatAm countries. Our combined dataset included 3583 individuals at risk; countries with highest DIAD frequencies were Colombia (n = 1905), Puerto Rico (n = 672), and Mexico (n = 463), usually attributable to founder effects. We found relatively few reports with extensive documentation on biomarker profiles and disease progression.

Discussion: Future DIAD studies will be required in LatAm, albeit with a more systematic approach to include fluid biomarker and imaging studies. Regional efforts are under way to extend the DIAD observational studies and clinical trials to Latin America.
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http://dx.doi.org/10.1002/alz.12227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8140610PMC
April 2021

The Role of Gait Speed in Dementia: A Secondary Analysis from the SABE Colombia Study.

Dement Geriatr Cogn Disord 2020 18;49(6):565-572. Epub 2020 Nov 18.

Semillero de Neurociencias y Envejecimiento, Facultad de Medicina, Instituto de Envejecimiento, Pontificia Universidad Javeriana, Bogotá, Colombia.

Introduction: Gait speed (GS) is a predictor of negative outcomes in older adults and in those in risk to develop cognitive impairment; as such, it has been associated with dementia. Studies in Latin-American older adults showing this association are scarce. This study aimed to evaluate the relationship between GS and dementia in a representative sample of Colombian older adults.

Methods: This study is a secondary analysis from the Survey on Health, Well-Being, and Aging, SABE (from initials in Spanish: Salud, Bienestar & Envejecimiento) Colombia's survey conducted in 2015 with a sample of 23,694 elderly adults aged 60 years or older.

Results: A total of 19,470 participants from the SABE Colombia survey were available for analysis. The multivariate analysis shows that dementia was associated with slow GS (PR 2.39; CI 1.91-3.01) independently to the other variables (p < 0.001). Similarly, GS as a continuous variable shows a statistically significant association with dementia in the adjusted analysis (OR 0.06; CI 0.04-0.09; p < 0.001).

Conclusion: Dementia was associated with slow GS. This finding provides evidence to include GS as a complementary parameter in the assessment of Colombian elderly adults.
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http://dx.doi.org/10.1159/000510494DOI Listing
October 2021

Retinal Imaging Findings in Carriers With PSEN1-Associated Early-Onset Familial Alzheimer Disease Before Onset of Cognitive Symptoms.

JAMA Ophthalmol 2021 01;139(1):49-56

Retina Service, Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston.

Importance: Individuals with autosomal dominant mutations for Alzheimer disease are valuable in determining biomarkers present prior to the onset of cognitive decline, improving the ability to diagnose Alzheimer disease as early as possible. Optical coherence tomography (OCT) has surfaced as a potential noninvasive technique capable of analyzing central nervous system tissues for biomarkers of Alzheimer disease.

Objective: To evaluate whether OCT can detect early retinal alterations in carriers of the presenilin 1 (PSEN1 [OMIM 104311]) E280A mutation who are cognitively unimpaired.

Design, Setting, And Participants: A cross-sectional imaging study conducted from July 13, 2015, to September 16, 2020, included 10 carriers of the PSEN1 E280A mutation who were cognitively unimpaired and 10 healthy noncarrier family members, all leveraged from a homogenous Colombian kindred. Statistical analysis was conducted from September 9, 2017, to September 16, 2020.

Main Outcomes And Measures: Mixed-effects multiple linear regression was performed to compare the thickness values of the whole retina and individual retinal layers on OCT scans between mutation carriers and noncarriers. Simple linear-effects and mixed-effects multiple linear regression models were used to assess whether age was an effect modifier for PSEN1 mutation of amyloid β levels and retinal thickness, respectively. Fundus photographs were used to compare the number of arterial and venous branch points, arterial and venous tortuosity, and fractal dimension.

Results: This study included 10 carriers of the PSEN1 E280A mutation who were cognitively unimpaired (7 women [70%]; mean [SD] age, 36.3 [8.1] years) and 10 healthy noncarrier family members (7 women [70%]; mean [SD] age, 36.4 [8.2] years). Compared with noncarrier controls, PSEN1 mutation carriers who were cognitively unimpaired had a generalized decrease in thickness of the whole retina as well as individual layers detected on OCT scans, with the inner nuclear layer (outer superior quadrant, β = -3.06; P = .007; outer inferior quadrant, β = -2.60; P = .02), outer plexiform layer (outer superior quadrant, β = -3.44; P = .03), and outer nuclear layer (central quadrant, β = -8.61; P = .03; inner nasal quadrant, β = -8.39; P = .04; inner temporal quadrant, β = -9.39; P = .02) showing the greatest amount of statistically significant thinning. Age was a significant effect modifier for the association between PSEN1 mutation and amyloid β levels in cortical regions (β = 0.03; P = .001) but not for the association between PSEN1 mutation and retinal thickness. No statistical difference was detected in any of the vascular parameters studied.

Conclusions And Relevance: These findings suggest that OCT can detect functional and morphologic changes in the retina of carriers of familial Alzheimer disease who are cognitively unimpaired several years before clinical onset, suggesting that OCT findings and retinal vascular parameters may be biomarkers prior to the onset of cognitive decline.
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http://dx.doi.org/10.1001/jamaophthalmol.2020.4909DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7662482PMC
January 2021

Genome-Wide Analysis of Copy Number Variation in Latin American Parkinson's Disease Patients.

Mov Disord 2021 02 5;36(2):434-441. Epub 2020 Nov 5.

Neuroscience and Cell Death Research Groups, Medical School and Genetic Institute, Universidad Nacional de Colombia, Bogotá, Colombia.

Background: Parkinson's disease is the second most common neurodegenerative disorder and affects people from all ethnic backgrounds, yet little is known about the genetics of Parkinson's disease in non-European populations. In addition, the overall identification of copy number variants at a genome-wide level has been understudied in Parkinson's patients. The objective of this study was to understand the genome-wide burden of copy number variants in Latinos and its association with Parkinson's disease.

Methods: We used genome-wide genotyping data from 747 Parkinson's disease patients and 632 controls from the Latin American Research Consortium on the Genetics of Parkinson's disease.

Results: Genome-wide copy number burden analysis showed that patients were significantly enriched for copy number variants overlapping known Parkinson's disease genes compared with controls (odds ratio, 3.97; 95%CI, 1.69-10.5; P = 0.018). PRKN showed the strongest copy number burden, with 20 copy number variant carriers. These patients presented an earlier age of disease onset compared with patients with other copy number variants (median age at onset, 31 vs 57 years, respectively; P = 7.46 × 10 ).

Conclusions: We found that although overall genome-wide copy number variant burden was not significantly different, Parkinson's disease patients were significantly enriched with copy number variants affecting known Parkinson's disease genes. We also identified that of 250 patients with early-onset disease, 5.6% carried a copy number variant on PRKN in our cohort. Our study is the first to analyze genome-wide copy number variant association in Latino Parkinson's disease patients and provides insights about this complex disease in this understudied population. © 2020 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28353DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8059262PMC
February 2021

Genetic and nongenetic factors associated with CADASIL: A retrospective cohort study.

J Neurol Sci 2020 Dec 13;419:117178. Epub 2020 Oct 13.

Neuroscience Group of Antioquia, University of Antioquia, Medellín, Colombia.

Objective: To explore the role of cardiovascular risk factors and the different NOTCH-3 mutations to explain the variability observed in the clinical presentation of CADASIL.

Methods: This was a retrospective cohort study of 331 individuals, 90 were carriers of four mutations in the NOTCH3 gene. These four mutations are the ones identified in our region from the genetic evaluation of probands. Cox proportional hazards models were fitted to estimate the effect of genetic and cardiovascular factors on the onset of migraine, first stroke, and dementia. Competing risk regression models considered death as risk.

Results: Noncarriers (healthy controls from the same families without NOTCH3 mutations) and NOTCH3 mutation carriers had similar frequencies for all cardiovascular risk factors. Diabetes (SHR 2.74, 95% CI 1.52-4.94) was associated with a younger age at onset of strokes among carriers. Additionally, a genotype-phenotype relationship was observed among C455R mutation carriers, with higher frequency of migraines (100%), younger age at onset of migraine (median age 7 years, IQR 8) and strokes (median age 30.5 years, IQR 26). Moreover, fewer carriers of the R141C mutation exhibited migraines (20%), and it was even lower than the frequency observed in the noncarrier group (44.8%).

Conclusions: This study characterizes extended family groups, allowing us a comparison in the genotype-phenotype. The results suggest a complex interplay of genetic and cardiovascular risk factors that may help explain the variability in the clinical presentation and severity of CADASIL.
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http://dx.doi.org/10.1016/j.jns.2020.117178DOI Listing
December 2020

Genetics of dementia: insights from Latin America.

Dement Neuropsychol 2020 Jul-Sep;14(3):223-236

Neurosciences Group of Antioquia, School of Medicine, Universidad de Antioquia - Medellín, Colombia.

Alzheimer's disease (AD) and frontotemporal dementia (FTD) are neurodegenerative disorders that result in a significant burden to both patients and caregivers. By 2050, the number of people with dementia in Latin America will increase 4-fold. A deep understanding of the relevant genetic factors of AD and FTD is fundamental to tackle this reality through prevention. A review of different genetic variants that cause AD or FTD in Latin America was conducted. We searched Medline and PubMed databases using the keywords "Alzheimer's disease," "frontotemporal dementia," "mutation," "America," and "Latin America," besides specific Latin American countries. Forty-five items were chosen and analyzed. mutations are the commonest cause of genetic early-onset Alzheimer's disease (EOAD), followed by and mutations. Genetic FTD can be mainly explained by and mutations, as well as repeat expansion. ε4 can modify the prevalence and incidence of late-onset Alzheimer's disease (LOAD), in addition to the cognitive performance in affected carriers.
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http://dx.doi.org/10.1590/1980-57642020dn14-030004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7500810PMC
September 2020

Examining Sex Differences in Markers of Cognition and Neurodegeneration in Autosomal Dominant Alzheimer's Disease: Preliminary Findings from the Colombian Alzheimer's Prevention Initiative Biomarker Study.

J Alzheimers Dis 2020 ;77(4):1743-1753

Department of Psychiatry, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA.

Background: Growing evidence suggests that there may be a sex-specific biological risk for Alzheimer's disease (AD). Individuals with autosomal dominant AD due to a mutation (E280A) in Presenilin-1 (PSEN1) are genetically determined to develop early-onset dementia and thus, have few age-related risk factors for AD that are known to vary by sex (i.e., cardiovascular disease, menopause, life expectancy).

Objective: Investigate sex differences in markers of cognition and neurodegeneration in autosomal dominant AD.

Methods: We conducted a retrospective study in 19 cognitively-unimpaired PSEN1 mutation carriers (age range 20-44; 11 females), 11 symptomatic carriers (age range 42-56; 8 females), and 23 matched non-carriers family members (age range 20-50; 13 females). We examined hippocampal volume ratio, CERAD Total Score, and CERAD Word List (i.e., Learning, Delayed Recall, and Recognition). Mann-Whitney U tests, Spearman correlations and regression models were conducted.

Results: There were no differential associations between age, CERAD Total Score, CERAD Word List-Learning, Delayed Recall, Recognition, and hippocampal volume ratio in male and female carriers and non-carriers. Cognitively-unimpaired female carriers showed better CERAD Total scores and CERAD Word List-Learning than cognitively-unimpaired male carriers, despite having similar hippocampal volume ratios. The interaction of sex and hippocampal volume ratio did not predict cognitive performance across groups.

Conclusion: Our preliminary findings suggest that cognitively-unimpaired female carriers showed a verbal memory reserve, and as disease progresses, female carriers did not exhibit a cognitive susceptibility to AD-related neurodegeneration. Future studies with larger samples of autosomal dominant AD are warranted to further understand sex differences in AD-related clinical and pathological markers.
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http://dx.doi.org/10.3233/JAD-200723DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8075106PMC
September 2021

The Latin American Spanish version of the Face-Name Associative Memory Exam is sensitive to cognitive and pathological changes in preclinical autosomal dominant Alzheimer's disease.

Alzheimers Res Ther 2020 09 10;12(1):104. Epub 2020 Sep 10.

Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

Background: To determine whether performance on the Latin American Spanish version of the Face-Name Associative Memory Exam (LAS-FNAME) can differentiate between cognitively intact carriers of an autosomal dominant Alzheimer's disease mutation (E280A) in Presenilin-1, who are genetically determined to develop early-onset dementia, from matched non-carriers. We also sought to examine whether LAS-FNAME performance is associated with amyloid-β and regional tau burden in mutation carriers.

Methods: A total of 35 cognitively intact mutation carriers (age range 26-41), 19 symptomatic carriers, and 48 matched non-carriers (age range 27-44) completed a neuropsychological assessment including the LAS-FNAME. A subset of participants (31 carriers [12 symptomatic] and 35 non-carriers) traveled from Colombia to Boston to undergo positron emission tomography (PET) using Pittsburgh compound B to measure mean cortical amyloid-β and flortaucipir for regional tau. ANOVA analyses and Spearman correlations were used to examine group differences and relationships among LAS-FNAME performance and amyloid-β and tau accumulation.

Results: Compared to non-carriers, cognitively intact mutation carriers had lower scores on the LAS-FNAME Total Scores (p = .040). Across all carriers (including symptomatic carriers), higher levels of amyloid-β (r = - .436, p = .018) and regional tau in the entorhinal (r = - .394, p = .031) and inferior temporal cortex (r = - .563, p = .001) were associated with lower LAS-FNAME Total Scores.

Conclusions: Performance on the LAS-FNAME differentiated between cognitively intact mutation carriers from non-carriers and was associated with greater amyloid and tau burden when examining all carriers. Findings suggest that the LAS-FNAME is sensitive to early clinical and pathological changes and can potentially help track disease progression in Spanish-speaking individuals.
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http://dx.doi.org/10.1186/s13195-020-00671-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7488408PMC
September 2020
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