Single-nucleus RNA sequencing demonstrates an autosomal dominant Alzheimer's disease profile and possible mechanisms of disease protection.

Highly penetrant autosomal dominant Alzheimer's disease (ADAD) comprises a distinct disease entity as compared to the far more prevalent form of AD in which common variants collectively contribute to risk. The downstream pathways that distinguish these AD forms in specific cell types have not been deeply explored. We compared single-nucleus transcriptomes among a set of 27 cases divided among PSEN1-E280A ADAD carriers, sporadic AD, and controls. Autophagy genes and chaperones clearly defined the PSEN1-E280A cases compared to sporadic AD. Spatial transcriptomics validated the activation of chaperone-mediated autophagy genes in PSEN1-E280A. The PSEN1-E280A case in which much of the brain was spared neurofibrillary pathology and harbored a homozygous APOE3-Christchurch variant revealed possible explanations for protection from AD pathology including overexpression of LRP1 in astrocytes, increased expression of FKBP1B, and decreased PSEN1 expression in neurons. The unique cellular responses in ADAD and sporadic AD require consideration when designing clinical trials.

Effect of apolipoprotein genotype and educational attainment on cognitive function in autosomal dominant Alzheimer's disease.

Autosomal dominant Alzheimer's disease (ADAD) is genetically determined, but variability in age of symptom onset suggests additional factors may influence cognitive trajectories. Although apolipoprotein E (APOE) genotype and educational attainment both influence dementia onset in sporadic AD, evidence for these effects in ADAD is limited. To investigate the effects of APOE and educational attainment on age-related cognitive trajectories in ADAD, we analyzed data from 675 Presenilin-1 E280A mutation carriers and 594 non-carriers. Here we show that age-related cognitive decline is accelerated in ADAD mutation carriers who also have an APOE e4 allele compared to those who do not and delayed in mutation carriers who also have an APOE e2 allele compared to those who do not. Educational attainment is protective and moderates the effect of APOE on cognition. Despite ADAD mutation carriers being genetically determined to develop dementia, age-related cognitive decline may be influenced by other genetic and environmental factors.

Comorbidities in Early-Onset Sporadic versus Presenilin-1 Mutation-Associated Alzheimer's Disease Dementia: Evidence for Dependency on Alzheimer's Disease Neuropathological Changes.

Autopsy studies have demonstrated that comorbid neurodegenerative and cerebrovascular disease occur in the great majority of subjects with Alzheimer disease dementia (ADD), and are likely to additively alter the rate of decline or severity of cognitive impairment. The most important of these are Lewy body disease (LBD), TDP-43 proteinopathy and cerebrovascular disease, including white matter rarefaction (WMR) and cerebral infarcts. Comorbidities may interfere with ADD therapeutic trials evaluation of ADD clinical trials as they may not respond to AD-specific molecular therapeutics. It is possible, however, that at least some comorbidities may be, to some degree, secondary consequences of AD pathology, and if this were true then effective AD-specific therapeutics might also reduce the extent or severity of comorbid pathology. Comorbidities in ADD caused by autosomal dominant mutations such as those in the presenilin-1 (PSEN1) gene may provide an advantageous perspective on their pathogenesis, and deserve attention because these subjects are increasingly being entered into clinical trials. As ADD associated with PSEN1 mutations has a presumed single-cause etiology, and the average age at death is under 60, any comorbidities in this setting may be considered as at least partially secondary to the causative AD mechanisms rather than aging, and thus indicate whether effective ADD therapeutics may also be effective for comorbidities. In this study, we sought to compare the rates and types of ADD comorbidities between subjects with early-onset sporadic ADD (EOSADD; subjects dying under age 60) versus ADD associated with different types of PSEN1 mutations, the most common cause of early-onset autosomal dominant ADD. In particular, we were able to ascertain, for the first time, the prevalences of a fairly complete set of ADD comorbidities in United States (US) PSEN1 cases as well as the Colombian E280A PSEN1 kindred. Data for EOSADD and US PSEN1 subjects (with multiple different mutation types) was obtained from the National Alzheimer Coordinating Center (NACC). Colombian cases all had the E280A mutation and had a set of neuropathological observations classified, like the US cases according to the NACC NP10 definitions. Confirmatory of earlier reports, NACC-defined Alzheimer Disease Neuropathological Changes (ADNC) were consistently very severe in early-onset cases, whether sporadic or in PSEN1 cases, but were slightly less severe in EOSADD. Amyloid angiopathy was the only AD-associated pathology type with widely-differing severity scores between the 3 groups, with median scores of 3, 2 and 1 in the PSEN1 Colombia, PSEN1 US and EOSADD cases, respectively. Apoliprotein E genotype did not show significant proportional group differences for the possession of an E-4 or E-2 allele. Of ADD comorbidities, LBD was most common, being present in more than half of all cases in all 3 groups. For TDP-43 co-pathology, the Colombian PSEN1 group was the most affected, at about 27%, vs 16% and 11% for the US PSEN1 and sporadic US cases, respectively. Notably, hippocampal sclerosis and non-AD tau pathological conditions were not present in any of the US or Colombian PSEN1 cases, and was seen in only 3% of the EOSADD cases. Significant large-vessel atherosclerosis was present in a much larger percentage of Colombian PSEN1 cases, at almost 20% as compared to 0% and 3% of the US PSEN1 and EOSADD cases, respectively. Small-vessel disease, or arteriolosclerosis, was much more common than large vessel disease, being present in all groups between 18% and 37%. Gross and microscopic infarcts, however, as well as gross or microscopic hemorrhages, were generally absent or present at very low percentages in all groups. White matter rarefaction (WMR) was remarkably common, at almost 60%, in the US PSEN1 group, as compared to about 18% in the EOSADD cases, a significant difference. White matter rarefaction was not assessed in the Colombian PSEN1 cases. The results presented here, as well as other evidence, indicates that LBD, TDP-43 pathology and WMR, as common comorbidities with autosomal dominant and early-onset sporadic ADD, should be considered when planning clinical trials with such subjects as they may increase variability in response rates. However, they may be at least partially dependent on ADNC and thus potentially addressable by anti-amyloid or and/anti-tau therapies.

Multi-ancestry meta-analysis and fine-mapping in Alzheimer's disease.

Genome-wide association studies (GWAS) of Alzheimer's disease are predominantly carried out in European ancestry individuals despite the known variation in genetic architecture and disease prevalence across global populations. We leveraged published GWAS summary statistics from European, East Asian, and African American populations, and an additional GWAS from a Caribbean Hispanic population using previously reported genotype data to perform the largest multi-ancestry GWAS meta-analysis of Alzheimer's disease and related dementias to date. This method allowed us to identify two independent novel disease-associated loci on chromosome 3. We also leveraged diverse haplotype structures to fine-map nine loci with a posterior probability >0.8 and globally assessed the heterogeneity of known risk factors across populations. Additionally, we compared the generalizability of multi-ancestry- and single-ancestry-derived polygenic risk scores in a three-way admixed Colombian population. Our findings highlight the importance of multi-ancestry representation in uncovering and understanding putative factors that contribute to risk of Alzheimer's disease and related dementias.

Novel computational protocol to support transfemoral prosthetic alignment procedure using machine learning techniques.

BACKGROUND: The prosthetic alignment procedure considers biomechanical, anatomical and comfort characteristics of the amputee to achieve an acceptable gait. Prosthetic malalignment induces long-term disease. The assessment of alignment is highly variable and subjective to the experience of the prosthetist, so the use of machine learning could assist the prosthetist during the judgment of optimal alignment. RESEARCH OBJECTIVE: To assist the prosthetist during the assessment of prosthetic alignment using a new computational protocol based on machine learning. METHODS: Sixteen transfemoral amputees were recruited for training and validation of the alignment protocol. Four misalignments and one nominal alignment were performed. Eleven prosthetic limb ground reaction force parameters were recorded. A support vector machine with a Gaussian kernel radial basis function and a Bayesian regularization neural network were trained to predict the alignment condition, as well as the magnitude and angle of required to align the prosthesis correctly. The alignment protocol was validated by one junior and one senior prosthetist during the prosthetic alignment of two transfemoral amputees. RESULTS: The support vector machine-based model detected the nominal alignment 92.6 % of the time. The neural network recovered 94.11 % of the angles needed to correct the prosthetic misalignment with a fitting error of 0.51°. During the validation of the alignment protocol, the computational models and the prosthetists agreed on the alignment assessment. The gait quality evaluated by the prosthetists reached a satisfaction level of 8/10 for the first amputee and 9.6/10 for the second amputee. IMPORTANCE: The new computational prosthetic alignment protocol is a tool that helps the prosthetist during the prosthetic alignment procedure thereby decreasing the likelihood of gait deviations and musculoskeletal diseases associated with misalignments and consequently improving the amputees-prosthesis adherence.

Genetic associations with age at dementia onset in the PSEN1 E280A Colombian kindred.

INTRODUCTION: Genetic associations with Alzheimer's disease (AD) age at onset (AAO) could reveal genetic variants with therapeutic applications. We present a large Colombian kindred with autosomal dominant AD (ADAD) as a unique opportunity to discover AAO genetic associations. METHODS: A genetic association study was conducted to examine ADAD AAO in 340 individuals with the PSEN1 E280A mutation via TOPMed array imputation. Replication was assessed in two ADAD cohorts, one sporadic early-onset AD study and four late-onset AD studies. RESULTS: 13 variants had p<1×10-7 or p<1×10-5 with replication including three independent loci with candidate associations with clusterin including near CLU. Other suggestive associations were identified in or near HS3ST1, HSPG2, ACE, LRP1B, TSPAN10, and TSPAN14. DISCUSSION: Variants with suggestive associations with AAO were associated with biological processes including clusterin, heparin sulfate, and amyloid processing. The detection of these effects in the presence of a strong mutation for ADAD reinforces their potentially impactful role.

Distinct tau neuropathology and cellular profiles of an APOE3 Christchurch homozygote protected against autosomal dominant Alzheimer's dementia.

We describe in vivo follow-up PET imaging and postmortem findings from an autosomal dominant Alzheimer's disease (ADAD) PSEN1 E280A carrier who was also homozygous for the APOE3 Christchurch (APOE3ch) variant and was protected against Alzheimer's symptoms for almost three decades beyond the expected age of onset. We identified a distinct anatomical pattern of tau pathology with atypical accumulation in vivo and unusual postmortem regional distribution characterized by sparing in the frontal cortex and severe pathology in the occipital cortex. The frontal cortex and the hippocampus, less affected than the occipital cortex by tau pathology, contained Related Orphan Receptor B (RORB) positive neurons, homeostatic astrocytes and higher APOE expression. The occipital cortex, the only cortical region showing cerebral amyloid angiopathy (CAA), exhibited a distinctive chronic inflammatory microglial profile and lower APOE expression. Thus, the Christchurch variant may impact the distribution of tau pathology, modulate age at onset, severity, progression, and clinical presentation of ADAD, suggesting possible therapeutic strategies.

The effect of prosthetic alignment on the stump temperature and ground reaction forces during gait in transfemoral amputees.

BACKGROUND: Lower limb prosthetic alignment is a procedure mostly subjective. A prosthetic misaligned induces gait deviations and long-term joint diseases. The alignment effects for each lower limb and the stump stays uncertain. RESEARCH OBJECTIVE: To identify the effect of the transfemoral alignment prosthesis on ground reaction forces and thermal images of the residual limb. METHODS: The effect of misalignment and nominal alignment was evaluated in sixteen transfemoral amputees. The nominal alignment was considered as the optimal alignment for each subject. Misalignment included random variations in the anterior-posterior and medial-lateral translation of the prosthetic foot and the angle of flexion-extension, abduction-adduction, and internal-external rotation of the socket and prosthetic foot. The control group consisted of fifteen non-amputee individuals. The ground reaction force parameters and stump temperature were analyzed for each alignment condition. The statistical analysis included the one-way ANOVA, Kruskal-Wallis, and multiple comparison tests. RESULTS: The prosthesis did not produce statistically significant changes in the average temperature of residual limbs. However, the temperature distribution on the stump skin was different (P < 0.05). The transfemoral prosthesis misalignment produced an irregular heat diffusion on the anterior, posterior, and lateral sides of the stump contour compared to the nominal alignment (P < 0.05). The sound limb did not show differences between nominal alignments and misalignments for most ground reaction force parameters. For almost all GRF parameters, significant differences were observed for the prosthetic limb between misalignment and nominal alignment (P < 0.001). The symmetry indices of ground reaction force parameters of transfemoral amputees did not show any kind of significant improvements after aligning the prosthesis nominally. SIGNIFICANCE: The stump's temperature distribution and the ground reaction force findings for the prosthetic limb provide a better understanding of the alignment procedure of the transfemoral prosthesis and improve the amputees' compliance to the prosthesis.

A neurodegenerative disease landscape of rare mutations in Colombia due to founder effects.

BACKGROUND: The Colombian population, as well as those in other Latin American regions, arose from a recent tri-continental admixture among Native Americans, Spanish invaders, and enslaved Africans, all of whom passed through a population bottleneck due to widespread infectious diseases that left small isolated local settlements. As a result, the current population reflects multiple founder effects derived from diverse ancestries. METHODS: We characterized the role of admixture and founder effects on the origination of the mutational landscape that led to neurodegenerative disorders under these historical circumstances. Genomes from 900 Colombian individuals with Alzheimer's disease (AD) [n = 376], frontotemporal lobar degeneration-motor neuron disease continuum (FTLD-MND) [n = 197], early-onset dementia not otherwise specified (EOD) [n = 73], and healthy participants [n = 254] were analyzed. We examined their global and local ancestry proportions and screened this cohort for deleterious variants in disease-causing and risk-conferring genes. RESULTS: We identified 21 pathogenic variants in AD-FTLD related genes, and PSEN1 harbored the majority (11 pathogenic variants). Variants were identified from all three continental ancestries. TREM2 heterozygous and homozygous variants were the most common among AD risk genes (102 carriers), a point of interest because the disease risk conferred by these variants differed according to ancestry. Several gene variants that have a known association with MND in European populations had FTLD phenotypes on a Native American haplotype. Consistent with founder effects, identity by descent among carriers of the same variant was frequent. CONCLUSIONS: Colombian demography with multiple mini-bottlenecks probably enhanced the detection of founder events and left a proportionally higher frequency of rare variants derived from the ancestral populations. These findings demonstrate the role of genomically defined ancestry in phenotypic disease expression, a phenotypic range of different rare mutations in the same gene, and further emphasize the importance of inclusiveness in genetic studies.

Resistance to autosomal dominant Alzheimer's disease in an APOE3 Christchurch homozygote: a case report.

We identified a PSEN1 (presenilin 1) mutation carrier from the world's largest autosomal dominant Alzheimer's disease kindred, who did not develop mild cognitive impairment until her seventies, three decades after the expected age of clinical onset. The individual had two copies of the APOE3 Christchurch (R136S) mutation, unusually high brain amyloid levels and limited tau and neurodegenerative measurements. Our findings have implications for the role of APOE in the pathogenesis, treatment and prevention of Alzheimer's disease.

Genetic origin of a large family with a novel PSEN1 mutation (Ile416Thr).

INTRODUCTION: A small percentage of Alzheimer's disease (AD) cases are caused by genetic mutations with autosomal dominant inheritance. We report a family with a novel variant in PSEN1. METHODS: We performed clinical and genetic evaluation of 93 related individuals from a Colombian admixed population. 31 individuals had whole-genome sequencing. RESULTS: Genetic analysis revealed a missense variant in PSEN1 (NM_000021.3: c.1247T>C p.Ile416Thr), which originated on an African haplotype and segregated with AD logarithm of the odds score of 6. Their clinical phenotype is similar to sporadic AD except for earlier age at onset: the mean age at onset for mild cognitive impairment was 47.6 years (standard deviation 5.83) and for dementia 51.6 years (standard deviation 5.03). DISCUSSION: Ile416Thr is a novel pathogenic variant that causes AD in the sixth decade of life. The history of the region that included slave importation and admixtures within a confined geographic locale represents a "mini-population bottleneck" and subsequent emergence of a rare dominant mutation.

Caracterización clínica y epidemiológica del síndrome de dificultad respiratoria aguda en pacientes adultos con fractura diafisaria de fémur / Clinical and epidemiological characterization of acute respiratory distress syndrome in adult patients with femoral shaft fractures

Objetivo general: Describir la epidemiología del Síndrome de Dificultad Respiratoria Aguda (SDRA) postraumático. Metodología: Estudio observacional descriptivo de pacientes con fractura traumática de la diáfisis femoral que requirieron manejo quirúrgico. Se analizaron variables demográficas, gravedad del trauma, métodos de tratamiento y desenlaces intrahospitalarios. Se realizó un análisis descriptivo y multivariado para explorar factores asociados al desarrollo de SDRA. Resultados: Doscientos sesenta y siete pacientes con fractura femoral, el 86% fueron hombres con edad media de 28,7 años e Índice de Severidad del Trauma (ISS) de 12,7. Se observó una prevalencia de SDRA del 8,6% en toda la población y del 20% en politraumatizados. La mortalidad fue del 7,5%. Las variables asociadas al SDRA en el análisis bivariado fueron: tiempo entre el trauma y el ingreso, ISS, contusión pulmonar, fractura asociada de tibia, requerimiento de cirugía urgente y necesidad de transfusión de glóbulos rojos. En el análisis multivariado, las variables asociadas fueron: trauma contuso de tórax, tiempo transcurrido hasta la fijación definitiva y la transfusión de glóbulos rojos en cirugía. En la cohorte hubo un incremento en la prevalencia de SDRA anual, siendo del 4,3% en 2006 comparado con el 26,1% en 2011, al igual que el politrauma que pasó del 14,5% en 2006 al 23,6% en 2011. Se evidenció también un cambio en el tratamiento, aumentando el control temprano total y el control de daño ortopédico. Conclusiones: En nuestra población, la prevalencia de SDRA en pacientes con fracturas de fémur aumenta cuando hay trauma contuso de tórax, cuando se prolonga el tiempo de fijación y la transfusión sanguínea.

Objective: To describe the epidemiology of post-traumatic acute respiratory distress syndrome. Methodology: Descriptive observational study of patients with traumatic femoral shaft fracture requiring surgical management. The variables included in the analysis were demographics, injury severity, treatment methods, and in-hospital outcomes. A descriptive multivariate analysis was performed in order to explore the factors associated with the development of Acute Respiratory Distress Syndrome (ARDS). Results: Of the 267 patients with femoral fractures, 86% were male patients with a mean age of 28.7 years and Injury Severity Score (ISS) of 12.7. The overall prevalence of ARDS was 8.6% while the prevalence among multiple trauma patients was 20%. Mortality was 7.5%. In the bivariate analysis, the variables associated with ARDS were the following: time between the trauma and hospital admission, ISS, contused lung, associated tibial fracture, urgent surgery requirement, and need for red blood cell transfusion. In the multivariate analysis, the associated variables were: blunt chest trauma, time elapsed until definitive fixation, and red blood celltrans fusion during surgery. In the cohort, there was an increase in the annual prevalence of ARDS, from 4.3% in 2006 to 26.1% in 2011, as was also the case with multiple trauma, which increased from 14.5% in 2006 to 23.6% in 2011. A change in treatment was also evidenced, with increase in early total care (ETC) and damage control orthopaedics (DCO). Conclusions: In our population, the prevalence of ARDS in patients with femoral fractures increases when associated with blunt chest trauma, delayed stabilization time, and the need for blood transfusion.