Advanced structural brain aging in preclinical autosomal dominant Alzheimer disease.

BACKGROUND: "Brain-predicted age" estimates biological age from complex, nonlinear features in neuroimaging scans. The brain age gap (BAG) between predicted and chronological age is elevated in sporadic Alzheimer disease (AD), but is underexplored in autosomal dominant AD (ADAD), in which AD progression is highly predictable with minimal confounding age-related co-pathology. METHODS: We modeled BAG in 257 deeply-phenotyped ADAD mutation-carriers and 179 non-carriers from the Dominantly Inherited Alzheimer Network using minimally-processed structural MRI scans. We then tested whether BAG differed as a function of mutation and cognitive status, or estimated years until symptom onset, and whether it was associated with established markers of amyloid (PiB PET, CSF amyloid-ß-42/40), phosphorylated tau (CSF and plasma pTau-181), neurodegeneration (CSF and plasma neurofilament-light-chain [NfL]), and cognition (global neuropsychological composite and CDR-sum of boxes). We compared BAG to other MRI measures, and examined heterogeneity in BAG as a function of ADAD mutation variants, APOE Îµ4 carrier status, sex, and education. RESULTS: Advanced brain aging was observed in mutation-carriers approximately 7 years before expected symptom onset, in line with other established structural indicators of atrophy. BAG was moderately associated with amyloid PET and strongly associated with pTau-181, NfL, and cognition in mutation-carriers. Mutation variants, sex, and years of education contributed to variability in BAG. CONCLUSIONS: We extend prior work using BAG from sporadic AD to ADAD, noting consistent results. BAG associates well with markers of pTau, neurodegeneration, and cognition, but to a lesser extent, amyloid, in ADAD. BAG may capture similar signal to established MRI measures. However, BAG offers unique benefits in simplicity of data processing and interpretation. Thus, results in this unique ADAD cohort with few age-related confounds suggest that brain aging attributable to AD neuropathology can be accurately quantified from minimally-processed MRI.

Neuropsychological profile of Alzheimer's disease based on amyloid biomarker findings results from a South American cohort.

OBJECTIVE: Increased life expectancy and exponential growth of adults suffering from Alzheimer's disease (AD) worldwide, has led to biomarkers incorporation for diagnosis in early stages. Use of neuropsychological testing remains limited. This study aimed to identify which neuropsychological tests best indicated underlying AD pathophysiology. METHODS: One hundred and forty-one patients with MCI (Mild Cognitive Impairment) were studied. A neuropsychological test battery based on the Uniform Data Set (UDS) from the Alzheimer's Disease Centers program of the National Institute on Aging (NIA) was performed and amyloid markers recorded; according to presence or absence of amyloid identified by positive PIB-PET findings, or low CSF Aß42 levels, patients were separated into MCI amyloid-(n:58) and MCI amyloid + (n = 83) cases. RESULTS: Statistical differences were found in all memory tests between groups. Delayed recall score at thirty minutes on the Rey Auditory Verbal Learning Test (AVLT) was the best predictor of amyloid pathology presence (AUC 0.68), followed by AVLT total learning (AUC 0.66) and AVLT Recognition (AUC 0.59) scores, providing useful cut off values in the clinical setting. CONCLUSIONS: Use of neuropsychological testing, specifically AVLT scores with cutoff values, contributed to the correct diagnosis of MCI due to AD in this SouthAmerican cohort.

Generation of a human induced pluripotent stem cell line from a familial Alzheimer's disease PSEN1 T119I patient.

Human induced pluripotent stem cells (hiPSC) line FLENIi001-A was reprogrammed from dermal fibroblasts using the lentiviral-hSTEMCCA-loxP vector. Fibroblasts were obtained from a skin biopsy of a 72-year-old Caucasian male familial Alzheimer's disease patient carrying the T119I mutation in the PSEN1 gene. PSEN1 genotype was maintained and stemness and pluripotency confirmed in the FLENIi001-A hiPSC line.

Prognostic value of ATN Alzheimer biomarkers: 60-month follow-up results from the Argentine Alzheimer's Disease Neuroimaging Initiative.

PURPOSE: To describe results of the Amyloid, Tau, Neurodegeneration (ATN) research framework classification in the Argentine-Alzheimer's Disease Neuroimaging Initiative (arg-ADNI) cohort. METHODS: Twenty-three patients with mild cognitive impairment (MCI), 12 dementia of Alzheimer's type (DAT), and 14 normal controls were studied following the ADNI2 protocol. Patients were categorized according to presence or absence of the biomarkers for amyloid beta (Aß; A: amyloid positron emission tomography [PET] scan or cerebrospinal fluid [CSF] Aß42), tau (T: CSF phosphorylated-tau), and neurodegeneration (N: CSF total-tau, fluorodeoxyglucose [FDG]-PET scan, or structural magnetic resonance imaging [MRI] scan). RESULTS: A+T+N+ biomarker profile was identified at baseline in 91% of mild dementia patients, 20% of early MCI patients, 46% of late MCI patients, and 14% of control subjects. Suspected non-AD pathophysiology (SNAP, A-T-N+) was found in 8% of mild dementia, 20% of early MCI, 15% of late MCI, and 7% of control subjects. Conversion rates to dementia after 5-year follow-up were 85% in A+T+N+ MCI patients and 50% in A-T-N+ patients. CONCLUSIONS: We present initial 5-year follow-up results of a regional ADNI based on AD biomarkers and the ATN classification.

A novel mutation in PSEN1 (p.T119I) in an Argentine family with early- and late-onset Alzheimer's disease.

Mutations in PSEN1 are the most common cause of early-onset Alzheimer's disease (AD). In this article, we present an Argentine family with autosomal dominant early- and late-onset AD. The proband and 6 family members were available for genetic testing and clinical and neuropsychological assessments. Cerebrospinal fluid biomarkers were analyzed in the proband and a cousin (mutation carrier), who also underwent positron emission tomography using F-18-2-fluoro-2-deoxy-D-glucose and Pittsburgh compound B. Exon sequencing of PSEN1, PSEN2, and APP revealed a novel heterozygous variant in PSEN1 (c.356C>T; p.T119I). Median age of onset in the family was 56 years. However, the proband's uncle showed initial symptoms at age 71. Although no DNA was available, he was an obligate carrier because his daughter (proband's cousin) carried the mutation. Both the proband and his cousin exhibited biomarker evidence (cerebrospinal fluid or imaging) of underlying Alzheimer's pathology. Overall, our results support that the PSEN1 p.T119I variant is likely pathogenic.

Biomarkers for Alzheimer's disease. Where we stand and where we are headed.

Alzheimer disease (AD) is one of the major unresolved health burdens accompanying the increase in life expectancy. The great paradigm shift for this disease has resulted from finding amyloid deposition and neurobrillary degeneration 20 years and 10 years, respectively, prior to onset of the typical clinical memory loss symptoms. The advent of AD biomarkers has enabled a molecular definition of AD, making the clinical definition almost dispensable. Various types of AD biomarkers are available in our country. Each biomarker reflects a particular process and stage of the disease. Although costs restrict their use, the biomarker analysis may be justified in certain clinical scenarios, such as an early onset or an atypical presentation of the disease. Today, the usefulness of biomarkers in AD clinical research is beyond question. Furthermore, the introduction of biomarkers into medical practice has led to significant changes in therapeutic interventions, even in the absence of disease-modifying drugs.

La enfermedad de Alzheimer (EA) es uno de los mayores flagelos aún no resueltos que acompañan al aumento de la expectativa de vida. El gran cambio de paradigma en los últimos años fue consecuencia de descubrir que el depósito amiloideo se presenta hasta 20 años antes, y la degeneración neurofibrilar hasta 10 años antes, de que aparezca la sintomatología clínica típica de pérdida de memoria. La aparición de los biomarcadores permitió reestructurar el concepto de la EA, intentándose llegar a una definición molecular de la misma casi prescindiendo de la emblemática clínica. Existen distintos tipos de biomarcadores de EA disponibles en nuestro país. Cada uno nos habla de un proceso y un momento distinto de la enfermedad. Aunque su uso clínico aún se encuentra restringido por cuestiones de costos, existen escenarios particulares en donde sí se justifica, casi siempre en relación a presentaciones clínicas atípicas o de comienzo muy temprano. Sin embargo, hoy en día ya nadie discute que son imprescindibles en investigaciones clínicas sobre EA. La incorporación de biomarcadores en la práctica médica ha generado cambios significativos en la intervención terapéutica de los pacientes, incluso en un contexto en el que todavía no hay medicamentos modificadores de la enfermedad.

Evaluation of Cerebrospinal Fluid Neurofilament Light Chain as a Routine Biomarker in a Memory Clinic.

Systematic evaluation of biomarkers in representative populations is needed to validate their clinical utility. In this work, we assessed the diagnostic performance of cerebrospinal fluid (CSF) neurofilament light chain (NfL) in a neurocognitive clinical setting. A total of 51 patients with different cognitive clinical syndromes and 11 cognitively normal individuals were evaluated in a memory clinic in Argentina. Clinical conditions included mild cognitive impairment (MCI, n = 12), dementia of Alzheimer's type (DAT, n = 14), behavioral variant frontotemporal dementia (bvFTD, n = 13), and primary progressive aphasia (logopenic [n = 6], semantic [n = 2], and nonfluent [n = 4]). We quantified CSF NfL and core Alzheimer's disease biomarkers using commercially available ELISA kits. Cortical thickness was analyzed on brain magnetic resonance imaging scans from 10 controls and 10 patients. CSF NfL was significantly increased in MCI, FTD, and DAT patients compared with controls (Kruskal-Wallis, p < .0001). Interestingly, receiver operating characteristic curve analysis showed the highest area under the curve (AUC) value when analyzing control versus bvFTD patients (AUC = 0.9441). Also, we observed a marginally significant correlation between NfL levels and left orbitofrontal cortex thickness in a small group of patients with FTD. Overall, our results further support CSF NfL as a promising biomarker in the diagnostic workup of bvFTD.

Prevalence of amyloid-ß pathology in distinct variants of primary progressive aphasia.

OBJECTIVE: To estimate the prevalence of amyloid positivity, defined by positron emission tomography (PET)/cerebrospinal fluid (CSF) biomarkers and/or neuropathological examination, in primary progressive aphasia (PPA) variants. METHODS: We conducted a meta-analysis with individual participant data from 1,251 patients diagnosed with PPA (including logopenic [lvPPA, n = 443], nonfluent [nfvPPA, n = 333], semantic [svPPA, n = 401], and mixed/unclassifiable [n = 74] variants of PPA) from 36 centers, with a measure of amyloid-ß pathology (CSF [n = 600], PET [n = 366], and/or autopsy [n = 378]) available. The estimated prevalence of amyloid positivity according to PPA variant, age, and apolipoprotein E (ApoE) ε4 status was determined using generalized estimating equation models. RESULTS: Amyloid-ß positivity was more prevalent in lvPPA (86%) than in nfvPPA (20%) or svPPA (16%; p < 0.001). Prevalence of amyloid-ß positivity increased with age in nfvPPA (from 10% at age 50 years to 27% at age 80 years, p < 0.01) and svPPA (from 6% at age 50 years to 32% at age 80 years, p < 0.001), but not in lvPPA (p = 0.94). Across PPA variants, ApoE ε4 carriers were more often amyloid-ß positive (58.0%) than noncarriers (35.0%, p < 0.001). Autopsy data revealed Alzheimer disease pathology as the most common pathologic diagnosis in lvPPA (76%), frontotemporal lobar degeneration-TDP-43 in svPPA (80%), and frontotemporal lobar degeneration-TDP-43/tau in nfvPPA (64%). INTERPRETATION: This study shows that the current PPA classification system helps to predict underlying pathology across different cohorts and clinical settings, and suggests that age and ApoE genotype should be considered when interpreting amyloid-ß biomarkers in PPA patients. Ann Neurol 2018;84:737-748.

Intrafamilial variable phenotype including corticobasal syndrome in a family with p.P301L mutation in the MAPT gene: first report in South America.

Frontotemporal lobar degeneration is a neuropathological disorder that causes a variety of clinical syndromes including frontotemporal dementia (FTD), progressive supranuclear palsy, and corticobasal syndrome (CBS). FTD associated with parkinsonism occurs frequently as a result of mutations in the C9orf72 gene and also in the genes coding for the protein associated with microtubule tau (MAPT) and progranulin (GRN) on chromosome 17 (FTDP-17). Herein, we report an Argentinean family, of Basque ancestry, with an extensive family history of behavioral variant of FTD. Twenty-one members over 6 generations composed the pedigree. An extensive neurologic and neurocognitive examination was performed on 2 symptomatic individuals and 3 nonsymptomatic individuals. Two different phenotypes were identified among affected members, CBS in the proband and FTD in his brother. DNA was extracted from blood for these 5 individuals and whole-exome sequencing was performed on 3 of them followed by Sanger sequencing of candidate genes on the other 2. In both affected individuals, a missense mutation (p.P301L; rs63751273) in exon 10 of the MAPT gene (chr17q21.3) was identified. Among MAPT mutations, p.P301L is the most frequently associated to different phenotypes: (1) aggressive, symmetrical, and early-onset Parkinsonism; (2) late parkinsonism associated with FTD; and (3) progressive supranuclear palsy but only exceptionally it is reported associated to CBS. This is the first report of the occurrence of the p.P301L-MAPT mutation in South America and supports the marked phenotypic heterogeneity among members of the same family as previously reported.

Predicting episodic memory performance using different biomarkers: results from Argentina-Alzheimer's Disease Neuroimaging Initiative.

PURPOSE: Argentina-Alzheimer's Disease Neuroimaging Initiative (Arg-ADNI) is the first ADNI study to be performed in Latin America at a medical center with the appropriate infrastructure. Our objective was to describe baseline characteristics and to examine whether biomarkers related to Alzheimer's disease (AD) physiopathology were associated with worse memory performance. PATIENTS AND METHODS: Fifteen controls and 28 mild cognitive impairment and 13 AD dementia subjects were included. For Arg-ADNI, all biomarker parameters and neuropsychological tests of ADNI-II were adopted. Results of positron emission tomography (PET) with fluorodeoxyglucose and 11C-Pittsburgh compound-B (PIB-PET) were available from all participants. Cerebrospinal fluid biomarker results were available from 39 subjects. RESULTS: A total of 56 participants were included and underwent baseline evaluation. The three groups were similar with respect to years of education and sex, and they differed in age (F=5.10, P=0.01). Mean scores for the baseline measurements of the neuropsychological evaluation differed significantly among the three groups at P<0.001, showing a continuum in their neuropsychological performance. No significant correlations were found between the principal measures (long-delay recall, C-Pittsburgh compound-B scan, left hippocampal volume, and APOEε4) and either age, sex, or education (P>0.1). Baseline amyloid deposition and left hippocampal volume separated the three diagnostic groups and correlated with the memory performance (P<0.001). CONCLUSION: Cross-sectional analysis of baseline data revealed links between cognition, structural changes, and biomarkers. Follow-up of a larger and more representative cohort, particularly analyzing cerebrospinal fluid and brain biomarkers, will allow better characterization of AD in our country.

Analysis of C9orf72 in patients with frontotemporal dementia and amyotrophic lateral sclerosis from Argentina.

Pathologic expansion of the G4C2 repeat in C9orf72 is the main genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). To evaluate the frequency of the G4C2 expansion in a Latin American cohort of FTD and ALS patients, we used a 2-step genotyping strategy. For FTD, we observed an overall expansion frequency of 18.2% (6 of 33 unrelated cases). Moreover, the C9orf72 expansion accounted for 37.5% of all familial FTD cases (6 of 16 families). The expansion frequency in sporadic ALS cases was 2% (1 of 47 unrelated patients), whereas we observed the expansion in 1 of 3 families with a positive history for ALS. Overall, the expansion frequency in our FTD group was similar to that reported for patients in Europe and North America, whereas the frequency in our sporadic ALS group was significantly lower. To our knowledge, this is the first report on the frequency of the C9orf72 expansion in a Latin American population.

Cognitive reserve and Aß1-42 in mild cognitive impairment (Argentina-Alzheimer's Disease Neuroimaging Initiative).

BACKGROUND: The purpose of this study was to investigate the relationship between cognitive reserve and concentration of Aß1-42 in the cerebrospinal fluid (CSF) of patients with mild cognitive impairment, those with Alzheimer's disease, and in control subjects. METHODS: Thirty-three participants from the Argentina-Alzheimer's Disease Neuroimaging Initiative database completed a cognitive battery, the Cognitive Reserve Questionnaire (CRQ), and an Argentinian accentuation reading test (TAP-BA) as a measure of premorbid intelligence, and underwent lumbar puncture for CSF biomarker quantification. RESULTS: The CRQ significantly correlated with TAP-BA, education, and Aß1-42. When considering Aß1-42 levels, significant differences were found in CRQ scores; higher levels of CSF Aß1-42 were associated with higher CRQ scores. CONCLUSION: Reduced Aß1-42 in CSF is considered as evidence of amyloid deposition in the brain. Previous results suggest that individuals with higher education, higher occupational attainment, and participation in leisure activities (cognitive reserve) have a reduced risk of developing Alzheimer's disease. Our results support the notion that enhanced neural activity has a protective role in mild cognitive impairment, as evidenced by higher CSF Aß1-42 levels in individuals with more cognitive reserve.