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Background: The largest identified kindred worldwide with a single mutation causing autosomal-dominant Alzheimer's disease (ADAD) is a family from Antioquia, Colombia, carrying the Presenilin-1 (PSEN1) E280A (Paisa) mutation. The majority of mutation carriers develop dementia, typically commencing in their late 30 s, with a median onset age of 49 years. Cognitive decline is a hallmark feature., Objective: This review synthesizes the existing literature on neuropsychological assessments in PSEN1 E280A mutation carriers throughout their lifespan. We provide a comprehensive overview of cognitive outcomes in this unique population., Methods: We reviewed and integrated the published research, analyzing studies on neuropsychological assessments in PSEN1 E280A carriers. Our focus was on measures of verbal, semantic, episodic, and spatial memory, and encompassed other cognitive domains such as language, attention, visuospatial memory, and executive functioning., Results: Verbal, semantic, episodic, and spatial memory emerged as the most sensitive indicators of preclinical changes in PSEN1 E280A carriers. Inconsistencies were noted in findings from tests assessing language, attention, visuospatial memory, and executive functioning, suggesting potential limitations in detecting early cognitive changes in PSEN1 mutation carriers. Specific cognitive tasks developed for this population proved effective but underutilized., Conclusions: The review underscores the importance of continued test development tailored to detect early cognitive changes in PSEN1 E280A carriers, potentially enhancing ADAD screening. Furthermore, investigating ADAD mutations in children may identify early changes in AD and enhance our understanding of neuropsychological functioning across the lifespan. This synthesis provides valuable insights for researchers, clinicians, and policymakers engaged in the study and management of ADAD.

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., (© 2021 the Alzheimer's Association.)

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.

Introduction: The API AutosomalDominant AD (ADAD) Colombia Trial is a placebo-controlled clinical trial of crenezumab in 252 cognitively unimpaired 30 to 60-year-old Presenilin 1 (PSEN1) E280A kindred members, including mutation carriers randomized to active treatment or placebo and non-carriers who receive placebo., Methods: Of the 252 enrolled, we present data on a total of 242 mutation carriers and non-carriers matched by age range, excluding data on 10 participants to protect participant confidentiality, genetic status, and trial integrity., Results: We summarize demographic, clinical, cognitive, and behavioral data from 167 mutation carriers and 75 non-carriers, 30 to 53 years of age. Carriers were significantly younger than non-carriers ((mean age ± SD) 37 ± 5 vs 42 ± 6), had significantly lower Mini Mental Status Exam (MMSE) scores (28.8 ± 1.4 vs 29.2 ± 1.0), and had consistently lower memory scores., Discussion: Although PSEN1 E280A mutation carriers in the Trial are cognitively unimpaired, they have slightly lower MMSE and memory scores than non-carriers. Their demographic characteristics are representative of the local population., (© 2020 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

The mutation E280A in PSEN1 (presenilin-1) is the most common cause of early-onset familial Alzheimer's Disease (fAD). It presents autosomal dominant inheritance and frequently leads to the manifestation of the disease in relatively young individuals. Here we report the generation of one PSEN1 E280A iPSC line derived from an early-onset patient. OriP/EBNA1-based episomal plasmids containing OCT3/4, SOX2, KLF4, L-MYC, LIN28, BCL-xL and shp53 were used to reprogram oral mucosa fibroblasts. The iPSC line generated has normal karyotype, carry the E280A mutation, is free of plasmid integration, express high levels of pluripotency markers and can differentiate into all three germ layers., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Importance: It is critically important to improve our ability to diagnose and track Alzheimer disease (AD) as early as possible. Individuals with autosomal dominant forms of AD can provide clues as to which and when biological changes are reliably present prior to the onset of clinical symptoms., Objective: To characterize the associations between amyloid and tau deposits in the brains of cognitively unimpaired and impaired carriers of presenilin 1 (PSEN1) E280A mutation., Design, Setting, and Participants: In this cross-sectional imaging study, we leveraged data from a homogeneous autosomal dominant AD kindred, which allowed us to examine measurable tau deposition as a function of individuals' proximity to the expected onset of dementia. Cross-sectional measures of carbon 11-labeled Pittsburgh Compound B positron emission tomography (PET) and flortaucipir F 18 (previously known as AV 1451, T807) PET imaging were assessed in 24 PSEN1 E280A kindred members (age range, 28-55 years), including 12 carriers, 9 of whom were cognitively unimpaired and 3 of whom had mild cognitive impairment, and 12 cognitively unimpaired noncarriers., Main Outcomes and Measures: We compared carbon 11-labeled Pittsburgh Compound B PET cerebral with cerebellar distribution volume ratios as well as flortaucipir F 18 PET cerebral with cerebellar standardized uptake value ratios in mutation carriers and noncarriers. Spearman correlations characterized the associations between age and mean cortical Pittsburgh Compound B distribution volume ratio levels or regional flortaucipir standardized uptake value ratio levels in both groups., Results: Of the 24 individuals, the mean (SD) age was 38.0 (7.4) years, or approximately 6 years younger than the expected onset of clinical symptoms in carriers. Compared with noncarriers, cognitively unimpaired mutation carriers had elevated mean cortical Pittsburgh Compound B distribution volume ratio levels in their late 20s, and 7 of 9 carriers older than 30 years reached the threshold for amyloidosis (distribution volume ratio level > 1.2). Elevated levels of tau deposition were seen within medial temporal lobe regions in amyloid-positive mutation carriers 6 years before clinical onset of AD in this kindred. Substantial tau deposition in the neocortex was only observed in 1 unimpaired carrier and in those with mild cognitive impairment. β-Amyloid uptake levels were diffusely elevated in unimpaired carriers approximately 15 years prior to expected onset of mild cognitive impairment. In carriers, higher levels of tau deposition were associated with worse performance on the Mini-Mental State Examination (entorhinal cortex: r = -0.60; P = .04; inferior temporal lobe: r = -0.54; P = .06) and the Consortium to Establish a Registry for Alzheimer Disease Word List Delayed Recall (entorhinal cortex: r = -0.86; P < .001; inferior temporal lobe: r = -0.70; P = .01)., Conclusions and Relevance: The present findings add to the growing evidence that molecular markers can characterize biological changes associated with AD in individuals who are still cognitively unimpaired. The findings also suggest that tau PET imaging may be useful as a biomarker to distinguish individuals at high risk to develop the clinical symptoms of AD and to track disease progression.

Lipids are considered important factors in the pathogenesis of Alzheimer's disease (AD). In this study, we realized a comparative analysis of the phospholipid profile and phospholipid composition of the temporal cortex from E280A-familiar AD (FAD), sporadic AD (SAD), and healthy human brains. Findings showed a significant decrease of lysophosphatidylcholine and phosphatidylethanolamine formed by low levels of polyunsaturated fatty acids (20 : 4, 22 : 6) in AD brains. However, phosphatidylethanolamine-ceramide and phosphoglycerol were significantly increased in SAD, conformed by high levels of (18 : 0/18 : 1) and (30/32/36 : 0/1/2), respectively. Together, the findings suggest a deficiency in lysophosphacholine and phosphatidylethanolamine, and alteration in the balance between poly- and unsaturated fatty acids in both types of AD, and a differential pattern of phospholipid profile and fatty acid composition between E280A FAD and SAD human brains.

Background: There is a need to find cognitive markers that can help identify individuals at risk for Alzheimer's disease (AD), and that can be used to reliably measure cognitive decline., Objective: We tested whether a theoretically driven three-factor structure would characterize cognitive functioning in individuals who are genetically-determined to develop AD due to a mutation in Presenilin-1 (PSEN1) gene. We also examined whether these factors could distinguish cognitively unimpaired PSEN1 mutation carriers from age-matched non-carrier family members., Methods: 1,395 cognitively unimpaired members of a Colombian kindred with the PSEN1 E280A mutation were included in the study. A confirmatory factor analysis examined the fit of the three-factor model comprising episodic memory (MMSE memory recall, CERAD-COL Word list recall, and Constructional praxis recall), executive function (Phonemic fluency and WCST perseverative errors), and psychomotor processing speed (TMT-A and WAIS-III Digit Symbol)., Results: The three-factor model provided an excellent fit for all participants (p = 0.24; RMSEA = 0.01). Further, the episodic memory (p = 0.0004, d = 0.25) and executive functioning (p = 0.001, d = 0.18) factors distinguished cognitively unimpaired carriers from non-carriers. The episodic memory factor provided the earliest indication of preclinical cognitive decline at 35 years of age, nine years before individuals' estimated age of clinical onset., Conclusions: The three theoretically derived cognitive factors provide a reliable measure of cognition and may be useful for the early detection of AD, as well as for measuring disease progression. However, longitudinal studies are needed to confirm that these factors can be used to track the progression of cognitive decline in preclinical AD.

Background: This study aimed to determine Consortium to Establish a Registry for Alzheimer's Disease (CERAD) Neuropsychological Assessment Battery total score diagnostic accuracy in the diagnosis of mild cognitive impairment (MCI) and dementia in familial Alzheimer's disease (FAD) with E280A mutation on presenilin-1 gene (PSEN1)., Methods: A cross-sectional study was conducted in a cohort of PSEN1 E280A carriers and non-carriers assessed between January 1995 and February 2013. During the first neuropsychological assessment, 76 were having dementia, 46 had MCI, and 1,576 were asymptomatic. CERAD cut-off points were established for MCI and dementia using a Receiver Operating Characteristics (ROC) analysis, and were further analyzed according to education level in two groups: low education level (eight years or less), and high education level (over eight years)., Results: The area under curve-ROC CERAD total score for dementia was 0.994 (95% CI = 0.989-0.999), and that for MCI was 0.862 (95% CI = 0.816-0.908). The dementia diagnosis cut-off point for the low education group was 54, (98.4% sensitivity, 92.6% specificity), and that for the high education group was 67 (100% sensitivity, 94.1% specificity). The MCI diagnosis cut-off point for the low education group was 66 (91.2% sensitivity, 56.4% specificity), and that for the high education group was 72 (91.7% sensitivity, 76.3% specificity)., Conclusions: The CERAD total score is a useful screening tool for dementia and MCI in a population at risk of FAD.

Background: A mutation in presenilin 1 (E280A) causes early-onset Alzheimer's disease. Understanding the origin of this mutation will inform medical genetics., Methods: We sequenced the genomes of 102 individuals from Antioquia, Colombia. We applied identity-by-descent analysis to identify regions of common ancestry. We estimated the age of the E280A mutation and the local ancestry of the haplotype harboring this mutation., Results: All affected individuals share a minimal haplotype of 1.8 Mb containing E280A. We estimate a time to most recent common ancestor of E280A of 10 (95% credible interval, 7.2-12.6) generations. We date the de novo mutation event to 15 (95% credible interval, 11-25) generations ago. We infer a western European geographic origin of the shared haplotype., Conclusions: The age and geographic origin of E280A are consistent with a single founder dating from the time of the Spanish Conquistadors who began colonizing Colombia during the early 16th century., (Copyright © 2014 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

Background: Alzheimer's disease (AD) is the most common cause of dementia; the main risk factors are age and several recently identified genes. A major challenge for AD research is the early detection of subjects at risk. The aim of this study is to develop a predictive model using proton magnetic resonance spectroscopy (1H-MRS), a noninvasive technique that evaluates brain chemistry in vivo, for monitoring the clinical outcome of carriers of a fully penetrant mutation that causes AD., Methods: We studied 75 subjects from the largest multigenerational pedigree in the world (∼5000 people) that segregates a unique form of early-onset Alzheimer's disease (EOAD) caused by a fully penetrant mutation in the Presenilin-1 gene (PSEN1 p.Glu280Ala [E280 A]). Forty-four subjects were carriers of the mutation, and 31 were noncarriers. Seventeen carriers had either mild cognitive impairment (MCI) or early-stage AD (collectively MCI-AD). In right and left parietal white mater and parasagittal parietal gray matter (RPPGM and LPPGM) of the posterior cingulate gyrus and precuneus, we measured levels of the brain metabolites N-acetylaspartate (NAA), inositol (Ins), choline (Cho), and glutamate-glutamine complex (Glx) relative to creatine (Cr) levels (NAA/Cr, Ins/Cr, Cho/Cr, and Glx/Cr, respectively) with two-dimensional 1H-MRS. Using advanced recursive partition analysis and random forest analysis, we built classificatory decision trees for both mutation carrier status and the presence of MCI-AD symptoms, fitting them to 1H-MRS data while controlling for age, educational level, and sex., Results: We found that (1) the combination of LPPGM Cho/Cr<0.165 and RPPGM Glx/Cr>1.54 fully excluded carriers; (2) LPPGM Cho/Cr>0.165, RPPGM Glx/Cr<1.54, and left parietal white mater NAA/Cr>1.16 identified asymptomatic carriers with sensitivity of 97.7% and specificity of 77.4%; and (3) RPPGM NAA/Cr>1.05 defined asymptomatic subjects (independent of carrier status) with sensitivity of 100% and a specificity of 96.6%., Conclusions: Brain metabolites measured by 1H-MRS in the posterior cingulate gyrus and precuneus are optimally sensitive and specific potential noninvasive biomarkers of subclinical emergence of AD caused by the PSEN1 p.Glu280Ala (E280 A) mutation., (Copyright © 2014 The Alzheimer's Association. All rights reserved.)

Recent evidence suggests that rare genetic variants within the TREM2 gene are associated with increased risk of Alzheimer's disease. TREM2 mutations are the genetic basis for a condition characterized by polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL) and an early-onset dementia syndrome. TREM2 is important in the phagocytosis of apoptotic neuronal cells by microglia in the brain. Loss of function might lead to an impaired clearance and to accumulation of necrotic debris and subsequent neurodegeneration. In this study, we investigated a consanguineous family segregating autosomal recessive behavioral variant FTLD from Antioquia, Colombia. Exome sequencing identified a nonsense mutation in TREM2 (p.Trp198X) segregating with disease. Next, using a cohort of clinically characterized and neuropathologically verified sporadic AD cases and controls, we report replication of the AD risk association at rs75932628 within TREM2 and demonstrate that TREM2 is significantly overexpressed in the brain tissue from AD cases. These data suggest that a mutational burden in TREM2 may serve as a risk factor for neurodegenerative disease in general, and that potentially this class of TREM2 variant carriers with dementia should be considered as having a molecularly distinct form of neurodegenerative disease., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: Sporadic late-onset Alzheimer's disease (AD) dementia has been associated with a 'signature' of cortical atrophy in paralimbic and heteromodal association regions measured with MRI., Objective: To investigate whether a similar pattern of cortical atrophy is present in presymptomatic presenilin 1 E280A mutation carriers an average of 6 years before clinical symptom onset., Methods: 40 cognitively normal volunteers from a Colombian population with familial AD were included; 18 were positive for the AD-associated presenilin 1 mutation (carriers, mean age=38) whereas 22 were non-carriers. T1-weighted volumetric MRI images were acquired and cortical thickness was measured. A priori regions of interest from our previous work were used to obtain thickness from AD-signature regions., Results: Compared to non-carriers, presymptomatic presenilin 1 mutation carriers exhibited thinner cortex within the AD-signature summary measure (p<0.008). Analyses of individual regions demonstrated thinner angular gyrus, precuneus and superior parietal lobule in carriers compared to non-carriers, with trend-level effects in the medial temporal lobe., Conclusion: Results demonstrate that cognitively normal individuals genetically determined to develop AD have a thinner cerebral cortex than non-carriers in regions known to be affected by typical late-onset sporadic AD. These findings provide further support for the hypothesis that cortical atrophy is present in preclinical AD more than 5 years prior to symptom onset. Further research is needed to determine whether this method could be used to characterise the age-dependent trajectory of cortical atrophy in presymptomatic stages of AD.

Previous dual task studies have demonstrated that patients with sporadic Alzheimer's disease (AD) are impaired in their ability to perform two tasks simultaneously compared with healthy controls, despite being able to successfully perform the tasks alone relatively well. Yet, it remains unclear what the earliest clinical manifestation of this dual task coordination deficit is. This study examined dual task abilities in individuals who are at risk of early-onset familial AD due to an E280A presenilin-1 mutation. Thirty-nine carriers of the gene mutation who did not meet the criteria for AD and 29 non-carrier healthy controls were asked to perform digit recall accompanied by a secondary tracking task. Individuals who were carriers of the genetic mutation demonstrated significantly higher dual task costs than healthy non-carriers. Dual task performance was found to be more sensitive to this very early stage of FAD than episodic memory measures. The findings support the notion that a deficit in the coordination mechanism of the central executive may be a pre-clinical marker for the early detection of AD due to the E280A presenilin-1 gene mutation.

Presenilin 1 (PS1) mutations are the most common cause of early-onset familial Alzheimer's disease (EOFAD). They show a common phenotypic profile characterized by early age of onset, severe dementia and distinct neurodegeneration. The largest population of EOFAD carries the E280A mutation in PS1 and resides in Antioquia, Colombia, currently comprising around 5,000 individuals. Carriers start showing memory impairment in the third decade of life, followed by progressive impairment of language and other cognitive processes. They reach mild cognitive impairment around 45 and dementia around 50 years of age. There is some phenotypic variability among the carriers of this single PS1 mutation. Some patients present with epilepsy, verbal impairment, and cerebellar ataxia. Neuropathologically, PS1 E280A cases show pronounced brain atrophy, severe amyloid-β pathology, distinct hyperphosphorylated tau-related pathology, and cerebellar damage. The earliest event identified by functional magnetic imaging resonance is hyperactivation within the right anterior hippocampus around 33 years of age. This well-studied population with a clear pre-clinical profile and wide phenotypic variability in age of onset and clinical presentation is ideally suited for clinical trials and to study molecular mechanisms of Alzheimer's disease.

Background: Mild cognitive impairment (MCI) and pre-MCI have been proposed as stages preceding Alzheimer's disease (AD) dementia. We assessed descendants of individuals with a mutation in presenilin 1 (PSEN1) that causes familial AD, with the aim of identifying distinct stages of clinical progression to AD dementia., Methods: We retrospectively studied a cohort of descendants of carriers of the PSEN1 E280A mutation. Pre-dementia cognitive impairment was defined by a score 2 SD away from normal values in objective cognitive tests, and was subdivided as follows: asymptomatic pre-MCI was defined by an absence of memory complaints and no effect on activities of daily living; symptomatic pre-MCI was defined by a score on the subjective memory complaints checklist higher than the mean and no effect on activities of daily living; and MCI was defined by a score on the subjective memory complaints checklist higher than the mean, with no effect on basic activities of daily living and little or no effect on complex daily activities. Dementia was defined according to the diagnostic and statistical manual of mental disorders, fourth edition. Reference mean scores were those of participants who did not carry the PSEN1 E280A mutation. We used the Turnbull survival analysis method to identify ages at onset of each stage of the disease. We measured the time from birth until onset of the three pre-dementia stages, dementia, and death, and assessed decline in cognitive domains for each stage., Findings: Follow-up was from Jan 1, 1995, to Jan 27, 2010. 1784 patients were initially identified, 449 of whom were PSEN1 E280A carriers who had complete clinical follow-up. Median age at onset was 35 years (95% CI 30-36) for asymptomatic pre-MCI, 38 years (37-40) for symptomatic pre-MCI, 44 years (43-45) for MCI, and 49 years (49-50) for dementia. The median age at death was 59 years (95% CI 58-61). The median time of progression from asymptomatic to symptomatic pre-MCI was 4 years (95% CI 2-8), from symptomatic pre-MCI to MCI was 6 years (4-7), from MCI to dementia was 5 years (4-6), and from dementia to death was 10 years (9-12). The cognitive profile was predominantly amnestic and was associated with multiple domains. Affected domains showed variability in initial stages, with some transient recovery in symptomatic pre-MCI followed by continuous decline., Interpretation: Clinical deterioration can be detected as measurable cognitive impairment around two decades before dementia onset in PSEN1 E280A carriers. Onset and progression of pre-dementia stages should be considered in the investigation and use of therapeutic interventions for familial AD., Funding: Departamento Administrativo de Ciencia, Tecnología e Innovación, COLCIENCIAS, Republic of Colombia., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Introduction: Intrusive errors in verbal memory tests could be considered as a preclinical marker of familial Alzheimer disease (AD). AIMS. To analyze and to compare the number and types of intrusive errors in the CERAD verbal memory test, administered to a genealogy of affected by familial AD, with E280A presenilin-1 mutation., Patients and Methods: Sample was constituted by 30 asymptomatic non-carriers (ANC), 39 non-demented carriers (NDC) and 21 demented carriers (DC). CERAD verbal memory test was administered to the sample. Comparisons, with non parametric Kruskal-Wallis' analysis, were done., Results: NDC participants presented more intrusive errors than ANC group in the first and second trials and in the delay recall of the memory task; also they had more intrusive errors than the DC patients in intrusive errors of the first trial and delay recall of the same task. The ANC and DC groups had significantly more intrusions only in third trial., Conclusion: Intrusive errors could be considered as a cognitive preclinical marker for familial AD.

Wilson's disease is an autosomal recessive disorder of hepatic copper metabolism caused by mutations in a gene encoding a copper-transporting P-type ATPase. We report the clinical and molecular characterization of six members from three unrelated Colombian kindred. Completed sequence DNA analysis linked to the gene ATP-7B from patient wd-1 revealed a novel A to C transversion in exon 17 at position 3856 (A3856C) of the ATP-7B mRNA resulting in a threonine for proline substitution at position 1232 of the ATP-7B protein (T1232P). Additionally, two novel polymorphisms were detected (2785G:Gly875 in exon 11; and intron at +38 a > c:tgcgcccga in exon 19). All affected individuals were homozygous for the T1232P mutation and displayed neurologic and neuropsychiatric dominant onset. This work expands the knowledge about the number, type, and implication of mutations in WD.

Introduction: Early preclinical diagnosis is the greatest challenge faced by researchers into dementia. Cognitive, neuroanatomical, neurophysiological and genetic markers have been reported. One of the preclinical cognitive markers is anomia and it is often assessed using visual naming tests., Aims: The aim of this study was to analyse the type of mistakes made in a visual naming test in a group of carriers and non-carriers of the E280A PS1 mutation., Patients and Methods: The sample was made up of 91 participants who were genotyped for the E280A PS1 mutation and divided into three groups: non-carriers (n = 30), asymptomatic carriers (n = 39) and sick carriers (n = 22). Selection was performed using the Minimental and the Fast and EDG scales and mistakes in the CERAD naming test were classified. The types of mistakes taken into account were: no answer, visual, semantic, phonological, the whole for the part, and not related., Results: There is a significant difference in the number of semantic errors between non-carriers and asymptomatic carriers; on comparing the three groups, no statistically significant differences were found in visual mistakes., Conclusions: Visual mistakes are a general characteristic, even in healthy subjects and, therefore, these errors did not provide any information that could be used to classify patients with or without dementia. Semantic mistakes can be considered as being a preclinical sign in familial Alzheimer's disease (FAD). Both visual and auditory naming tests must be applied when evaluating patients with FAD.

Purpose: Alzheimer disease (AD) and epilepsy are brain disorders frequently associated with neuronal cell loss in mesial temporal lobe structures, but presenting different patterns of damage. Recently it was proposed that a causal relation may exist between AD pathology and the appearance of epilepsy in some cases with AD. This study aimed to determine the neuronal loss in CA1 hippocampal region from patients bearing the presenilin-1 [E280A] mutation (PS1[E280A]) associated with seizures., Methods: Coronal sections from the hippocampal formation (anterior one third) from controls (n = 5) and familial AD (FAD; n = 8) patients were stained by using thionin and thioflavine-S staining to evaluate the number of neurons in the CA1 field, beta-plaques, and neurofibrillary tangles, respectively., Results: Two distinct patterns of neuronal loss in the CA1 field of FAD patients were found: (a) diffuse-patchy neuronal loss (three FAD nonepilepsy patients) characterized by both a general decrease of neurons and the presence of multiple, small regions devoid of neurons; and (b) sclerotic-like neuronal loss (five FAD epilepsy patients) similar to that found typically in the CA1 field of epilepsy patients with hippocampal sclerosis., Conclusions: This investigation shows for the first time CA1 neuronal depopulation in a subpopulation of patients (five of eight) bearing the PS1[E280A] mutation with epileptic seizures, indicating a relation between hippocampal neuronal loss and epileptic seizures in FAD patients., (Copyright 2004 International League Against Epilepsy)

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is caused by mutations in the notch3 epidermal growth factor-like repeats. A Colombian kindred carries a novel C455R mutation located in the predicted ligand-binding domain. Stroke occurred in the patients at an unusually early age (median age: 31 years) in comparison to the more frequent onset in the fourth decade of life in other CADASIL populations, including a second Colombian kindred with an R1031C mutation.

Few longitudinal studies have been carried out to investigate the cognitive decline in early onset of familial Alzheimer's disease (FAD). In this study 12 patients with FAD (M age = 49.61 years, SD = 4.99), 10 patients with sporadic Alzheimer's disease (SAD) (M age = 71.40, SD =10.00), and 15 matched normal controls (M age = 45.01, SD = 7.24) were selected. A comprehensive neuropsychological battery was administered three times over a period of 18 months. Individuals designated as FAD met the criteria for dementia and were positive for the E280A presenilin 1 mutation. Participants with SAD met the criteria for dementia and were negative for the E280A presenilin 1 mutation. Normal control participants were the FAD patients' relatives, who were negative for the mutation. Two groups of neuropsychological instruments were administered: (1) The Consortium to Establish a Registry for Alzheimer's Disease (CERAD) neuropsychological test battery, and (2) additional neuropsychological tests of abstraction and constructional abilities. Patients with FAD were significantly impaired on all measures at the first examination except for reading of words. While the performance of the normal controls remained unchanged over the 18 months for most neuropsychological tests, the patients with FAD displayed a decline in verbal memory, language, constructional and abstraction tests. The greatest decline was observed on the Mini-Mental State Exam scores. Patients with SAD demonstrated a similar pattern of cognitive decline, but the decline was faster in FAD than in SAD participants.