The first genome-wide association study in the Argentinian and Chilean populations identifies shared genetics with Europeans in Alzheimer's disease.

INTRODUCTION: Genome-wide association studies (GWAS) are fundamental for identifying loci associated with diseases. However, they require replication in other ethnicities. METHODS: We performed GWAS on sporadic Alzheimer's disease (AD) including 539 patients and 854 controls from Argentina and Chile. We combined our results with those from the European Alzheimer and Dementia Biobank (EADB) in a meta-analysis and tested their genetic risk score (GRS) performance in this admixed population. RESULTS: We detected apolipoprotein E ε4 as the single genome-wide significant signal (odds ratio  = 2.93 [2.37-3.63], P = 2.6 × 10-23 ). The meta-analysis with EADB summary statistics revealed four new loci reaching GWAS significance. Functional annotations of these loci implicated endosome/lysosomal function. Finally, the AD-GRS presented a similar performance in these populations, despite the score diminished when the Native American ancestry rose. DISCUSSION: We report the first GWAS on AD in a population from South America. It shows shared genetics modulating AD risk between the European and these admixed populations. HIGHLIGHTS: This is the first genome-wide association study on Alzheimer's disease (AD) in a population sample from Argentina and Chile. Trans-ethnic meta-analysis reveals four new loci involving lysosomal function in AD. This is the first independent replication for TREM2L, IGH-gene-cluster, and ADAM17 loci. A genetic risk score (GRS) developed in Europeans performed well in this population. The higher the Native American ancestry the lower the GRS values.

[Cognitive dysfunction in systemic lupus erythematosus in relation to disease activity and damage]. / Disfunción cognitiva en lupus eritematoso sistémico y su asociación con actividad y daño.

Systemic lupus erythematosus (SLE) is a rheumatic disease, which during its evolution may present neurocognitive dysfunction with fronto-subcortical compromise. However, there is no enough published evidence regarding the relationship between cognitive dysfunction and SLE activity and SLE induced damage. The objective of the study was to analyze this association. We designed an observational cross-sectional study including 84 patients with SLE. We used the SLEDAI index to evaluate activity and the SLICC index to evaluate cumulative damage. We used neuropsychological tests to assess the presence of cognitive symptoms, global cognitive function, verbal and visual memory, visual-construction, semantic verbal fluency, processing speed and working memory. Scores more than 1.5 standard deviations below adjusted normal values were considered as cognitive dysfunction. We observed a statistically significant association between the higher value of SLEDAI and working memory impairment and a higher value of SLICC and viso-construction and semantic verbal fluency impairment. The association observed in SLE patients between disease activity or damage and some cognitive domains may be involving different pathophysiological brain mechanisms of different areas with different degrees of severity and vulnerability.

[Treatment of Alzheimer's Disease cognitive symptoms]. / Tratamiento de los síntomas cognitivos en la enfermedad de Alzheimer.

This chapter will focus in the currently treatments for Alzheimer Disease. The meeting points in the proposed pathogenesis of the disease are the cholinergic and the cascade amyloid hypothesis based mainly in postmortem brain changes: 1- Pathological based on greater density of neuritic plaques and the characteristic presence of neurofibrillary tangles associated with neuronal loss, synaptic alterations and evidence for chronic inflammatory reactions, 2) Biochemical based on major depletion of cortical cholinergic innervation, dramatic loss in levels of biochemically determined choline acetyltransferase, accumulation of beta-amyloid peptide, oxidation, glutamatergic excitotoxicity and activation of the apoptotic cascade. The currently available therapies based on the hypothesized pathophysiology of AD are: Acetylcholinesterase inhibitors (donepezil, rivastigmine and galantamine) and the NMDA receptor inhibitor Memantine. None of the "head to head" analyses done with cholinesterase inhibitors (CI) were able to demonstrate a between group effect for efficacy. However the treatment planning is based on their differences, their titration phase to reach the therapeutic doses, interactions and side effects. The non pharmacological treatment in the early and late stages of the disease, the different cognitive stimulation techniques and available prevention trials are also addressed and discussed.

[Social cognition and theory of mind assessment in non-demented patients with isolated cerebellar degeneration]. / Evaluación de la cognición social y teoría de la mente en pacientes con enfermedad cerebelosa degenerativa aislada no dementes.

AIM: To investigate whether the cerebellum could participate in social cognition (SC). METHOD: General neuropsychological tests, executive tests (EF), social cognition tests, which assess the ability to infer other peoples mental states, and the Beck Depression Inventory were given to 10 non-demented patients with isolated cerebellar degenerative disease, and to 10 healthy controls matched for sex, age, and years of education. ANOVA and correlation coefficients were employed for the statistical analysis. RESULTS: Patients within the cerebellar group were significantly impaired (p

[Development of a sensitive neuropsychological battery to foretell the performance in elder's car driving]. / Desarrollo de una batería neuropsicológica sensible para predecir el rendimiento en la conducción de vehículos en adultos mayores de 55 años.

INTRODUCTION: The increase in life expectancy move older people to continue driving. OBJECTIVE: Development of sensitive neuropsychological battery to evaluate driving routines. METHODS: 78 men were received at the Santojanni Hospital, derived by the General Direction of Road Education and licenses of Buenos Aires city (DGEVL) when people were transacting their driving license renovation. Age 64.2 (DS14,0) years and education 7.9 (DS4,5) years. They were evaluated with MMSE, Cognitive Reaction test (TRC); Procedural memory test (TMP); Continuous Performance test (TPC); Trail Making Test (TMT); Stroop (ST); WAIS III Subtests: Digit-Symbol (DS), Search of Symbols (BS); Digits and Construction with cubes (CC); Rey visual Complex Figure (FC); Benton Visual Discrimination test (TB) and Test of transit Signals (DST). Statistical package SPSS 12.0 was used to obtain, descriptive, frequencies and correlations statistics. RESULTS: The most sensitive tests were: FC; TMT; ST; TPC; DS; TRC; TMP signifying impairment in: perceptual organization; visuospatial skills; information processing speed; reaction capacity before decision making; maintained, selective and executive attention and procedural memory, all of them of critical importance in driving and its control in the transit. Alarming ignorance of transit signals was observed. CONCLUSIONS: Of 78 subjects, 23.1% renewed their registry; 33,3% renewed but with lower category and sooner next control; 38,5% were not renewed; 3,8% did not return to DGEVL; 1,3% we do not know data.

[Comparison study of executive functions in Parkinson's disease and degenerative cerebellar disease's patients]. / Estudio comparativo de las funciones ejecutivas entre pacientes con enfermedad de Parkinson y pacientes con enfermedad degenerativa cerebelosa.

OBJECTIVE: To compare executive functions (EF) in non-demented mild to moderate Parkinson's disease (PD) (Hoehn and Yahr < or =3) and pure degenerative cerebellar disease (CD) in order to evaluate the relative contribution and differential role of basal ganglia and cerebellum in those functions. METHOD: 14 patients with PD and 14 patients with CD matched by sex, education, disease's duration and MMSE were selected. A standardized neuropsychological battery and the Wisconsin Card Sorting Test (WCST) were administered. Z scores were compared for both groups through t-test for independent samples were used. RESULTS: The cerebellar group showed significant lower performance in measures of attention and EF, with a significant increase in both perseverative and non perseverative errors during the WCST. On the other hand the PD group showed a selective increase of non perseverative errors, without reaching significant between group difference. CONCLUSION: The CD group appears to have greater deficits in EF with a pattern of prefrontal dysfunction.

[Behavioral-cognitive disorders due to chronic exposure to industrial and environmental toxic substances]. / Trastornos cognitivo conductuales debidos a la intoxicación crónica con sustancias neurotóxicas laborales y ambientales.

UNLABELLED: A review of neurotoxics is made, given the low tendency to investigate for chronic exposure to environmental and industrial potential central nervous system toxic substances (heavy metals, insecticides, organic solvents and carbon monoxide) in the history of a patient consulting for behavioral - cognitive complains, and considering the potential overturn of the disease if a correct diagnosis and early treatment is made. OBJECTIVE: to determine the onset of the cognitive - behavioral features, presentation pattern, diagnosis and treatment of such neurotoxics (NT). METHODOLOGY: systematized search in Cochrane and Medline reviews, Embase and Lilacs. RESULTS: chronic exposure to neurotoxics can produce personality changes (sleeping problems, excitation, depression, delusions and hallucinations) as well as cognitive problems (memory, learning, language and cognitive reaction problems). NT may cause changes in the neuron morphology and its sub cellular structures, affecting its normal biochemistry and physiology (proteins and neurotransmitters synthesis). The clinical history, diagnosis and treatment of each neurotoxic are discussed. CONCLUSION: The NT must be taken in consideration among the possible different etiologies when a patient with a bizarre behavioral cognitive syndrome is examined.

[Nosography of dementia]. / Nosografía de las demencias.

Dementia diagnostic criteria presently in use are referred. The authors underline the importance of an early diagnosis for prognosis and treatment. Diagnostic criteria from international groups and their harmonization to Argentine culture proposed by the CAED (Argentine Consortium for the Study of Dementias) are reviewed.

[New assessment variables in the Clock Drawing Test (CDT) allow an early and easy diagnosis of degrees of cognitive impairment]. / Nuevas variables de evaluación del test del reloj permiten un precoz y fácil diagnóstico del grado de deterioro cognitivo.

OBJECTIVE: We developed new subroutines and scoring procedures of the CDT to detect markers of early cognitive impairment. SUBJECTS AND METHODS: We compared the performance of 41 mild Alzheimer's patients (AD) (MMSE 22.7+/-3.2); and 18 mild cognitive impairment patients (MCI) (MMSE 28.3+/-1.4), with 33 age and education matched normal controls (NC) regarding their ability in drawing a clock on command, copying a printed clock, setting hands and reading the time. We search for differences in the placement of the hands using a colloquial hour code ("a quarter to ten") and a formal numeric code ("10:45"). We focused our attention on placement and clock hands size. The drawing of hands pointing at 2:50 hs and 8:40 hs were of particular interest. RESULTS: Planning strategies, placement of clock hands using a formal numeric code, clock hands size and hands drawing pointing at 2:50 hs. and 8:40 hs. were the variables that best discriminated AD, MCI and NC ( p<0.01). A stepwise regression analysis using as dependent variables (AD - NC ) and (MCI - NC) showed in both cases that the best predictor model was that formed by: planning strategies, clock hands pointing to 8:40, clock hands size, reading hours and set up clock hands following a formal numeric code (p<.001). CONCLUSIONS: Our proposed modifications in this test convert it in an appropriate tool for cognitive impairment screening because they do not only detect visuoconstructional abilities but also frontal planning, contents and processing of the hour memory code and transcodification of semantic memory processes.

Disfunción cognitiva en lupus eritematoso sistémico y su asociación con actividad y daño / Cognitive dysfunction in systemic lupus erythematosus in relation to disease activity and damage

El lupus eritematoso sistémico (LES), es una enfermedad reumatológica, que puede presentar en su evolución alteraciones neurocognitivas, con importante compromiso fronto-subcortical. Sin embargo, existe escasa evidencia publicada sobre la relación entre la disfunción cognitiva y la actividad y daño de la enfermedad sistémica. El objetivo del trabajo fue analizar dicha asociación. Se realizó un estudio observacional de corte transversal, incluyendo 84 pacientes con LES. Se evaluó la actividad con el índice de SLEDAI y el daño acumulado con el índice de SLICC. Mediante pruebas neuropsicológicas se evaluó la presencia de síntomas cognitivos, función cognitiva global, memoria verbal y visual, viso-construcción, fluencia verbal semántica, velocidad de procesamiento y memoria de trabajo. Se consideró disfunción en un área cognitiva a un rendimiento de más de 1.5 desvíos estándares por debajo de los valores normales del test neuropsicológico. Se observó asociación estadísticamente significativa entre un mayor valor de SLEDAI y la alteración en la memoria de trabajo, y un mayor valor de SLICC y el compromiso de la viso-construcción y la fluencia verbal semántica. La asociación observada en los pacientes con LES entre el grado de actividad o daño de la enfermedad con algunos dominios cognitivos podría estar involucrando diferentes mecanismos fisiopatogénicos de la disfunción cerebral de cada área con distinto grado de afectación o vulnerabilidad.

Systemic lupus erythematosus (SLE) is a rheumatic disease, which during its evolution may present neurocognitive dysfunction with fronto-subcortical compromise. However, there is no enough published evidence regarding the relationship between cognitive dysfunction and SLE activity and SLE induced damage. The objective of the study was to analyze this association. We designed an observational cross-sectional study including 84 patients with SLE. We used the SLEDAI index to evaluate activity and the SLICC index to evaluate cumulative damage. We used neuropsychological tests to assess the presence of cognitive symptoms, global cognitive function, verbal and visual memory, visual-construction, semantic verbal fluency, processing speed and working memory. Scores more than 1.5 standard deviations below adjusted normal values were considered as cognitive dysfunction. We observed a statistically significant association between the higher value of SLEDAI and working memory impairment and a higher value of SLICC and viso-construction and semantic verbal fluency impairment. The association observed in SLE patients between disease activity or damage and some cognitive domains may be involving different pathophysiological brain mechanisms of different areas with different degrees of severity and vulnerability.

Evaluación de la cognición social y teoría de la mente en pacientes con enfermedad cerebelosa degenerativa aislada no dementes / Social cognition and theory of mind assessment in non-demented patients with isolated cerebellar degeneration

OBJETIVO: Investigar la hipótesis según la cual, el cerebelo podría participar en las alteraciones de la cognición social (CS). MÉTODO: Se administraron tests neuropsicológicos generales, de función ejecutiva (FE), de CS que evaluaban la capacidad de inferir el estado mental de otras personas y la escala de Depresión de Beck a 10 pacientes adultos con enfermedad cerebelosa adquirida aislada (GEC) y a 10 controles (GCO) apareados por edad, sexo y educación. Se analizaron los datos mediante ANOVA y correlación. RESULTADOS: El GEC obtuvo puntajes significativamente menores (p?0,05) que el grupo GCO en tareas de FE (Test de Wisconsin) y preguntas de creencia (PCr) de Teoría de la Mente (ToM). El rendimiento en las preguntas de control (PCo) de ToM fue similar en ambos grupos. El menor rendimiento en las PCr correlacionó significativamente con una menor habilidad conceptual, la severidad de la apatía (NPI) y de la ataxia estática. Las PCo correlacionaron con medidas de atención y de recuerdo diferido libre. CONCLUSíON: El cerebelo contribuiría en el monitoreo de la conducta mediante el control de datos multimodales motores, cognitivos y emocionales.

AIM: To investigate whether the cerebellum could participate in social cognition (SC). METHOD: General neuropsychological tests, executive tests (EF), social cognition tests, which assess the ability to infer other peoples mental states, and the Beck Depression Inventory were given to 10 non-demented patients with isolated cerebellar degenerative disease, and to 10 healthy controls matched for sex, age, and years of education. ANOVA and correlation coefficients were employed for the statistical analysis. RESULTS: Patients within the cerebellar group were significantly impaired (p?0.05) in EF test [Wisconsin Card Sorting Test (WSCT)] and belief questions (BQ) from Theory of Mind (ToM) tests. Performance in control questions (CQ) from ToM tests was similar for both groups. Lower scores in BQ correlated with a lower conceptual ability, the severity of apathy (NPI) and static ataxia. CQ correlated with measures of attention and free recall. CONCLUSION: The cerebellum may contribute in the control of social behavior through the processing of multimodal data, motor, cognitive and emotional.

Estudio comparativo de las funciones ejecutivas entre pacientes con enfermedad de Parkinson y pacientes con enfermedad degenerativa cerebelosa / Comparison study of executive functions in Parkinson's disease and degenerative cerebellar disease's patients

OBJETIVO: Comparar el rendimiento en tareas de función ejecutiva (FE) en sujetos con enfermedad de Parkinson (EP) leve a moderada (Hoehn y Yahr <3) no dementes y en sujetos con enfermedad degenerativa cerebelosa pura (EC), a fin de evaluar el eventual rol diferencial de los ganglios basales y el cerebelo en esa función. MÉTODO: Se evaluaron 14 pacientes con EP y 14 con EC apareados por sexo, educación, duración de enfermedad y MMSE, mediante tests neuropsicológicos estándar y el test de Wisconsin [WCST]). Se compararon puntajes Z promedio de cada grupo mediante prueba de "t" para muestras independientes. RESULTADOS: El grupo EC rindió significativamente menos en pruebas de atención y FE presentando errores perseverativos y no perseverativos durante el WCST. El grupo EP mostró aumento significativo de errores no perseverativos en relación al estándar esperado, sin alcanzar diferencias significativas con el grupo EC. CONCLUSION: el grupo EC mostró defectos significativamente mayores en tareas de FE exhibiendo un patrón de disfunción prefrontal.

OBJECTIVE: To compare executive functions (EF) in non-demented mild to moderate Parkinson's disease (PD) (Hoehn and Yahr <3) and pure degenerative cerebellar disease (CD) in order to evaluate the relative contribution and differential role of basal ganglia and cerebellum in those functions. METHOD: 14 patients with PD and 14 patients with CD matched by sex, education, disease's duration and MMSE were selected. A standardized neuropsychological battery and the Wisconsin Card Sorting Test (WCST) were administered. Z scores were compared for both groups through t-test for independent samples were used. RESULTS: The cerebellar group showed significant lower performance in measures of attention and EF, with a significant increase in both perseverative and non perseverative errors during the WCST. On the other hand the PD group showed a selective increase of non perseverative errors, without reaching significant between group difference. CONCLUSION: The CD group appears to have greater deficits in EF with a pattern of prefrontal dysfunction.

Oligoelementos en la enfermedad de Alzheimer / Trace elements in Alzheimer's disease

Se investigaron cinco metales, aluminio, calcio, cromo, manganeso y zinc en suero, orina y cabello de enfermos de Alzheimer, comparados con tres testigos sanos de edad similar. La determinación se efectuó por Absorción Atómica en la llama o electrotérmica. No se hallaron diferencias significativas con los testigos. Esto indicaría que estos oligoelementos en especial el aluminio no guardan una relación causal directa con la enfermedad.

Barrera hematoencefálica y pasaje de drogas al sistema nervioso central: parte I: consideraciones generales, histológicas, bioquímicas y farmacológicas / Hematoencephalic barrier and passage of drugs into the central nervous system

El sitio anatómico de la barrera hematoencefálica es la capa de células del endotelio capilar cerebral con sus uniones estrechas ("tight junctions") intercelulares. Entonces, la capacidad de pasaje de las drogas hacia el compartimento cerebral está regida principalmente por su facilidad de atravesar la interfase lipídica de las membranas plasmáticas de dichas células, es decir su liposolubilidad. Los antibióticos, al no utilizar mecanismos especiales de transporte hematoencefálico, no escapan a esta regla. Algunos antibióticos, cuya utilización es necesaria en casos de infecciones del sistema nerviosos central -como los aminoglucósidos-, no presentan transporte adecuado a través de la barrera, y en esto se basa el desarrollo de técnicas para hacer llegar estas drogas al compartimiento cerebral, de las cuales la más difundida es la administración directa en el líquido cefalorraquídeo. De todos modos, sería interesante realizar estudios comparativos tendientes a definir la verdadera utilidad de drogas de reciente aparición, con espectro similar y mayor liposolubilidad -como las cefalosporinas modernas-, con el fin de evitar los inconvenientes derivados de la práctica de esas técnicas de soslayo de la barrera hematoencefálica (AU)

Oligoelementos en la enfermedad de Alzheimer / Trace elements in Alzheimers disease

Se investigaron cinco metales, aluminio, calcio, cromo, manganeso y zinc en suero, orina y cabello de enfermos de Alzheimer, comparados con tres testigos sanos de edad similar. La determinación se efectuó por Absorción Atómica en la llama o electrotérmica. No se hallaron diferencias significativas con los testigos. Esto indicaría que estos oligoelementos en especial el aluminio no guardan una relación causal directa con la enfermedad. (AU)

Nuevas variables de evaluación del test del reloj permiten un precoz y fácil diagnóstico del grado de deterioro cognitivo / [New assessment variables in the Clock Drawing Test (CDT) allow an early and easy diagnosis of degrees of cognitive impairment]

OBJECTIVE: We developed new subroutines and scoring procedures of the CDT to detect markers of early cognitive impairment. SUBJECTS AND METHODS: We compared the performance of 41 mild Alzheimer’s patients (AD) (MMSE 22.7+/-3.2); and 18 mild cognitive impairment patients (MCI) (MMSE 28.3+/-1.4), with 33 age and education matched normal controls (NC) regarding their ability in drawing a clock on command, copying a printed clock, setting hands and reading the time. We search for differences in the placement of the hands using a colloquial hour code ([quot ]a quarter to ten[quot ]) and a formal numeric code ([quot ]10:45[quot ]). We focused our attention on placement and clock hands size. The drawing of hands pointing at 2:50 hs and 8:40 hs were of particular interest. RESULTS: Planning strategies, placement of clock hands using a formal numeric code, clock hands size and hands drawing pointing at 2:50 hs. and 8:40 hs. were the variables that best discriminated AD, MCI and NC ( p<0.01). A stepwise regression analysis using as dependent variables (AD - NC ) and (MCI - NC) showed in both cases that the best predictor model was that formed by: planning strategies, clock hands pointing to 8:40, clock hands size, reading hours and set up clock hands following a formal numeric code (p<.001). CONCLUSIONS: Our proposed modifications in this test convert it in an appropriate tool for cognitive impairment screening because they do not only detect visuoconstructional abilities but also frontal planning, contents and processing of the hour memory code and transcodification of semantic memory processes.

Nuevas variables de evaluación del test del reloj permiten un precoz y fácil diagnóstico del grado de deterioro cognitivo. / [New assessment variables in the Clock Drawing Test (CDT) allow an early and easy diagnosis of degrees of cognitive impairment]

OBJECTIVE: We developed new subroutines and scoring procedures of the CDT to detect markers of early cognitive impairment. SUBJECTS AND METHODS: We compared the performance of 41 mild Alzheimers patients (AD) (MMSE 22.7+/-3.2); and 18 mild cognitive impairment patients (MCI) (MMSE 28.3+/-1.4), with 33 age and education matched normal controls (NC) regarding their ability in drawing a clock on command, copying a printed clock, setting hands and reading the time. We search for differences in the placement of the hands using a colloquial hour code ([quot ]a quarter to ten[quot ]) and a formal numeric code ([quot ]10:45[quot ]). We focused our attention on placement and clock hands size. The drawing of hands pointing at 2:50 hs and 8:40 hs were of particular interest. RESULTS: Planning strategies, placement of clock hands using a formal numeric code, clock hands size and hands drawing pointing at 2:50 hs. and 8:40 hs. were the variables that best discriminated AD, MCI and NC ( p<0.01). A stepwise regression analysis using as dependent variables (AD - NC ) and (MCI - NC) showed in both cases that the best predictor model was that formed by: planning strategies, clock hands pointing to 8:40, clock hands size, reading hours and set up clock hands following a formal numeric code (p<.001). CONCLUSIONS: Our proposed modifications in this test convert it in an appropriate tool for cognitive impairment screening because they do not only detect visuoconstructional abilities but also frontal planning, contents and processing of the hour memory code and transcodification of semantic memory processes.

Barrera hematoencefálica y pasaje de drogas al sistema nervioso central: parte I: consideraciones generales, histológicas, bioquímicas y farmacológicas / Hematoencephalic barrier and passage of drugs into the central nervous system

El sitio anatómico de la barrera hematoencefálica es la capa de células del endotelio capilar cerebral con sus uniones estrechas ("tight junctions") intercelulares. Entonces, la capacidad de pasaje de las drogas hacia el compartimento cerebral está regida principalmente por su facilidad de atravesar la interfase lipídica de las membranas plasmáticas de dichas células, es decir su liposolubilidad. Los antibióticos, al no utilizar mecanismos especiales de transporte hematoencefálico, no escapan a esta regla. Algunos antibióticos, cuya utilización es necesaria en casos de infecciones del sistema nerviosos central -como los aminoglucósidos-, no presentan transporte adecuado a través de la barrera, y en esto se basa el desarrollo de técnicas para hacer llegar estas drogas al compartimiento cerebral, de las cuales la más difundida es la administración directa en el líquido cefalorraquídeo. De todos modos, sería interesante realizar estudios comparativos tendientes a definir la verdadera utilidad de drogas de reciente aparición, con espectro similar y mayor liposolubilidad -como las cefalosporinas modernas-, con el fin de evitar los inconvenientes derivados de la práctica de esas técnicas de soslayo de la barrera hematoencefálica