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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. [ABSTRACT FROM AUTHOR]

Background: Due to trisomy of chromosome 21 and the resultant extra copy of the amyloid precursor protein gene, nearly all adults with Down syndrome develop Alzheimer's disease pathology by the age of 40 years and are at high risk for dementia given their increased life expectancy compared with adults with Down syndrome in the past. We aimed to compare CSF biomarker patterns in Down syndrome with those of carriers of autosomal dominant Alzheimer's disease mutations to enhance our understanding of disease mechanisms in these two genetic groups at high risk for Alzheimer's disease.Methods: We did a cross-sectional study using data from adults enrolled in the Alzheimer's Biomarker Consortium-Down Syndrome (ABC-DS) study, a multisite longitudinal study of Alzheimer's disease in Down syndrome, as well as a cohort of carriers of autosomal dominant Alzheimer's disease mutations and non-carrier sibling controls enrolled in the Dominantly Inherited Alzheimer Network (DIAN) study. For ABC-DS, participants with baseline CSF, available clinical diagnosis, and apolipoprotein E genotype as of Jan 31, 2019, were included in the analysis. DIAN participants with baseline CSF, available clinical diagnosis, and apolipoprotein E genotype as of June 30, 2018, were evaluated as comparator groups. CSF samples obtained from adults with Down syndrome, similarly aged carriers of autosomal dominant Alzheimer's disease mutations, and non-carrier siblings (aged 30-61 years) were analysed for markers of amyloid β (Aβ1-40, Aβ1-42); tau phosphorylated at threonine 181-related processes; neuronal, axonal, or synaptic injury (total tau, visinin-like protein 1, neurofilament light chain [NfL], synaptosomal-associated protein 25); and astrogliosis and neuroinflammation (chitinase-3-like protein 1 [YKL-40]) via immunoassay. Biomarker concentrations were compared as a function of dementia status (asymptomatic or symptomatic), and linear regression was used to evaluate and compare the relationship between biomarker concentrations and age among groups.Findings: We assessed CSF samples from 341 individuals (178 [52%] women, 163 [48%] men, aged 30-61 years). Participants were adults with Down syndrome (n=41), similarly aged carriers of autosomal dominant Alzheimer's disease mutations (n=192), and non-carrier siblings (n=108). Individuals with Down syndrome had patterns of Alzheimer's disease-related CSF biomarkers remarkably similar to carriers of autosomal dominant Alzheimer's disease mutations, including reductions (all p<0·0080) in Aβ1-42 to Aβ1-40 ratio and increases in markers of phosphorylated tau-related processes; neuronal, axonal, and synaptic injury (p<0·080); and astrogliosis and neuroinflammation, with greater degrees of abnormality in individuals with dementia. Differences included overall higher concentrations of Aβ and YKL-40 (both p<0·0008) in Down syndrome and potential elevations in CSF tau (p<0·010) and NfL (p<0·0001) in the asymptomatic stage (ie, no dementia symptoms).Funding: National Institute on Aging, Eunice Kennedy Shriver National Institute of Child Health and Human Development, German Center for Neurodegenerative Diseases, and Japan Agency for Medical Research and Development. [ABSTRACT FROM AUTHOR]

Introduction: Mutations in presenilin-1 (PSEN1) account for the majority of cases of familial autosomal dominant early-onset Alzheimer's disease (AD) as well as in sporadic forms. Atypical presentations are reported including extrapyramidal signs. In the last years, a pleiotropic effect of some PSEN1 variants has been reported in Parkinson's disease (PD).Objective: to report a new PSEN1 mutation characterized by early-onset Parkinsonism (EOPD) without dementia or classical AD biomarkers phenotype.Patient and Methods: An Argentinian 46 years old woman was diagnosed with EOPD at 35 years old with no family history of neurodegenerative disorders. Her medical history included iron deficiency and anemia since childhood. A brain MRI showed moderate frontal atrophy. 18FDG-PET and PiB-PET as well as CSF biomarkers were inconclusive for AD. Two neuropsychological examinations were compatible with a mild non amnestic cognitive impairment. Whole blood DNA was extracted and whole exome sequencing and analysis was performed.Results and Conclusion: A heterozygous novel missense PSEN1 mutation (position 14:73637540, A > T, pArg41Ser) was identified as a likely causative mutation in this patient. To the best of our knowledge, this case is the first PSEN1 mutation with a l-dopa responsive Parkinsonism lacking distinctive classical AD biomarkers. This case opens a new window to explore the pathophysiological link among PSEN1 and EOPDs and contributes to increase the phenotypes of PSEN1 variants. [ABSTRACT FROM AUTHOR]

Background: Autosomal dominant familial Alzheimer's disease (ADAD) is a rare disorder with non-amnestic neurological symptoms in some clinical presentations. We aimed to compile and compare data from symptomatic participants in the Dominantly Inherited Alzheimer Network observational study (DIAN-OBS) with those reported in the literature to estimate the prevalences of non-amnestic neurological symptoms in participants with ADAD.Methods: We prospectively collected data from the DIAN-OBS database, which recruited participants from study centres in the USA, Europe, and Australia, between Feb 29, 2008, and July 1, 2014. We also did a systematic review of publications to extract individual-level clinical data for symptomatic participants with ADAD. We used data for age of onset (from first report of cognitive decline), disease course from onset to death, and the presence of 13 neurological findings that have been reported in association with ADAD. Using multivariable linear regression, we investigated the prevalences of various non-amnestic neurological symptoms and the contributions of age of onset and specific mutation type on symptoms.Findings: The DIAN-OBS dataset included 107 individuals with detailed clinical data (forming the DIAN-OBS cohort). Our systematic review yielded 188 publications reporting on 1228 symptomatic individuals, with detailed neurological examination descriptions available for 753 individuals (forming the published data cohort). The most prevalent non-amnestic cognitive manifestations in participants in the DIAN-OBS cohort were those typical of mild to moderate Alzheimer's disease, including visual agnosia (55·1%, 95% CI 45·7-64·6), aphasia (57·9%, 48·6-67·3), and behavioural changes (61·7%, 51·5-70·0). Non-amnestic cognitive manifestations were less prevalent in the published data cohort (eg, visual agnosia [5·6%, 3·9-7·2], aphasia [23·0%, 20·0-26·0], and behavioural changes [31·7%, 28·4-35·1]). Prevalence of non-cognitive neurological manifestations in the DIAN-OBS cohort was low, including myoclonus and spasticity (9·3%, 95% CI 3·8-15·0), and seizures (2·8%, 0·5-5·9) and moderate for parkinsonism (11·2%, 5·3-17·1). By constrast, prevalence was higher in the published data cohort for myoclonus and spasticity (19·4%, 16·6-22·2 and 15·0%, 12·5-17·6, respectively), parkinsonism (12·5%, 10·1-15·0), and seizures (20·3%, 17·4-23·2). In an analysis of the published data cohort, ischaemic stroke was more prevalent at older ages of onset of symptoms of ADAD (odds ratio 1·09 per 1 year increase in age of onset, 95% CI 1·04-1·14, p=0·0003); and motor symptoms were more common at younger age of onset (myoclonus 0·93, 0·90-0·97, p=0·0007; seizures 0·95, 0·92-0·98, p=0·0018; corticobulbar deficits 0·91, 0·86-0·96, p=0·0012; and cerebellar ataxia 0·82, 0·74-0·91, p=0·0002). In the DIAN-OBS cohort, non-cognitive symptoms were more common at more severe stages of disease.Interpretation: The non-cognitive clinical manifestations of Alzheimer's disease seem to affect a small proportion of participants with mild to moderate ADAD, and are probably influenced by disease severity, environmental, and genetic factors. When evaluating patients with potential ADAD, clinicians should note that cognitive symptoms typical of sporadic Alzheimer's disease are the most consistent finding, with some patients manifesting non-cognitive neurological symptoms. Future work is needed to determine the environmental and genetic factors that cause these neurological symptoms.Funding: National Institutes of Health and German Center for Neurodegenerative Diseases. [ABSTRACT FROM AUTHOR]

The Clinical Dementia Rating Scale (CDR) is a tool designed to quantify the severity of dementia symptoms and is also useful to assess disease progression, in Alzheimer's disease (AD). A new version of the scale was developed by adding two extra domains that focused on the core aspects of frontotemporal dementia symptomatology, Language and Behavior/Comportment/Personality. Objectives In this study, we adapted and validated the modified CDR scale in our setting and language (Rioplatense-Spanish). Materials and methods 46 patients with probable AD, 27 behavioral variant of Frontotemporal Dementia (bvFTD), 18 Primary Progressive Aphasia (PPA) and 40 healthy participants were included. The adapted version of the scale was administered by a blind rater who interviewed patients together with patient's caregiver. Results Using ROC curves, the domain language and behavior were superior to the memory domain in accuracy for detecting PPA and bvFTD, respectively, but both of them had equivalent diagnostic accuracies for probable AD. Logistic regression analyses showed that either the LANG or BEHAV domains significantly improved the discrimination between probable AD, bvFTD and PPA. Conclusions The Spanish version of the modified CDR adds value for the characterization of the non-amnestic symptoms in patients with neurodegenerative dementias. [ABSTRACT FROM AUTHOR]

Different subtypes of depressive syndromes exist in late life; many of them have cognitive impairment and sometimes it is difficult to differentiate them from dementia. This research aimed to investigate subtypes of geriatric depression associated with cognitive impairment, searched for differential variables and tried to propose a study model. A hundred and eighteen depressive patients and forty normal subjects matched by age and educational level were evaluated with an extensive neuropsychological battery, scales to evaluate neuropsychiatric symptoms and daily life activities (DLA). Depressive patients were classified in groups by SCAN 2.1: Major Depression Disorder (MDD) (n: 31), Dysthymia Disorder (DD) (n: 31), Subsyndromal Depression Disorder (SSD) (n: 29), Depression due to Dementia (n: 27) (DdD). Neuropsychological significant differences (p < 0.05) were observed between depressive groups, demonstrating distinctive cognitive profiles. Moreover, significant differences (p < 0.05) were found in DLA between DdD vs all groups and MDD vs controls and vs SSD. Age of onset varied in the different subtypes of depression. Beck Depression Inventory (BDI) and Mini Mental State Examination (MMSE) were significant variables that helped to differentiate depressive groups. Significant correlations between BDI and Neuropsychological tests were found in MDD and DD groups. Depressive symptoms and its relation with neuropsychological variables, MMSE, cognitive profiles, DLA and age of onset of depression should be taken into consideration for the study of subtypes of geriatric depression. [ABSTRACT FROM AUTHOR]

Abstract: Objective: There is a paucity of evidence about insurance status and the likelihood of receiving medical services in Latin America. The objective of this analysis was to examine the association between insurance status and pharmacologic treatment for depression. Methods: Patients referred to a memory clinic of a public hospital in Buenos Aires, Argentina, and identified with any of four types of depression (subsyndromal, dysthymia, major, and due to dementia) were included. Age, years of education, insurance status, Beck Depression Inventory score, and number of comorbidities were considered. Associations between these factors and not receiving pharmacologic treatment for depression were examined with logistic regression. Use of prescription neuroleptics, hypnotics, and anticholinesterase inhibitors was also explored. Results: Out of 100 patients, 92 with insurance status data were used. Sixty-one patients (66%) had formal insurance and 31 patients (34%) lacked insurance. Twenty-seven (44%) insured patients and 23 (74%) uninsured patients did not receive antidepressants (P = 0.001). Controlling for other factors, uninsured patients had 7.12 higher odds of not receiving treatment compared to insured patients (95% confidence interval 1.88–28.86). Older patients and those with more comorbidities had higher odds of not receiving treatment. More educated patients, those with higher Beck Depression Inventory score, and those without subsyndromal depression had lower odds of not receiving treatment. None of those associations were statistically significant. Conclusions: These results suggest a potential negative effect of the lack of formal insurance regarding pharmacologic treatment for depression. These findings should be confirmed with larger samples, and for other diseases. [Copyright &y& Elsevier]

Abstract: Negative symptoms have been associated with frontal lobe dysfunction in schizophrenia. However, neuropsychological studies that evaluated the correlation between performance in tests sensitive to the dorsolateral prefrontal cortex (DLPFC) and negative symptoms have shown inconsistent results. Growing evidence has appeared that not only the DLPFC but other prefrontal regions could be involved in schizophrenia. We evaluated schizophrenic patients and healthy controls using three “frontal tests”: the Wisconsin Card Sorting Test (WCST), the Iowa Gambling Task (GT) and a Theory of Mind test (Faux Pas), and studied the relationship between performance in these tests and negative symptomatology. Schizophrenic patients had worse performance than normal controls on the WCST, GT and Faux Pas test. The severity of the negative symptoms showed a moderate to high correlation with performance in the Faux Pas test. Our findings support the idea that different prefrontal regions could be affected in people with schizophrenia and that the damage to each of these regions could be, at least in part, independent of the damage to the others. Some negative symptoms could be associated with frontal medial cortex dysfunction. [Copyright &y& Elsevier]