Disfunción inmunológica en enfermedad de Alzheimer; proinflamatoria en etapas iniciales y regulatoria, y exhausta en etapas avanzadas / Immune dysfunction in disease Alzheimer's; proinflammatory in stages initial and regulatory, and exhaustive in advanced stages

Alzheimer disease (AD) is the main cause of dementia worldwide and a source of important population morbidity and mortality. It is estimate that its prevalence will increase dramatically in the upcoming years. The classical clinical presentation of AD is an amnesic hippocampal syndrome, and Mild Cognitive impairment (MCI) is considered the initial stage between normal cognition and dementia. The most accepted pathogenesis establishes amyloid beta (Ab) deposition in brain parenchyma as the initial mechanism, followed by the intracellular accumulation of hyperphosphorylated tau finally leading to the loss of synapses and neurons. Recently, the study of AD pathogenesis is focusing on immune mechanisms as main actors of disease development. Microglia is the macrophagic resident cell in the central nervous system (CNS), and initiates the inflammatory response and Ab phagocytosis, interacting with other glia and recruiting diverse immune cells to the CNS. The role of the adaptive immune system, and, especially T lymphocytes' role, is still controversial. We hypothesize that the pathogenesis of AD is dynamic; with a preponderant proinflammatory activity initially, but later on, the persistent presence of Ab due to the lack of its proper elimination leads to a phenomena of lymphocyte dysfunction and immunological tolerance that have a deleterious role at advanced stages of the disease. (AU)

[Frontotemporal dementia: Review of 63 cases]. / Demencia frontotemporal: Experiencia clínica.

BACKGROUND: Front temporal dementias (FTD) are neurodegenerative disorders characterized by alterations in behavior, affection and language, with relative sparing of episodic memory. There are three major forms of FTD: the frontal or behavioral form, progressive non-fluent aphasia and semantic dementia (that may begin as a fluent progressive aphasia). AIM: To report a retrospective clinical experience of patients with frontotemporal dementia. MATERIAL AND METHODS: Review of 3,700 records of neuropsychological assessments of patients with behavioral disturbances, studied between 1981 and 2008. Of these, 63 patients (59% females) complied with the criteria for frontotemporal dementia. RESULTS: There were 47 cases with the frontal variant, four with non-fluent progressive aphasia and six with fluent progressive aphasias (2 evolved to semantic dementia). The mean age of onset was 60+/-11 years. There were no familiar cases of FTD. CONCLUSIONS: It is clinically difficult to diagnose FTD, since evaluation of attitude or language is required. In addition to structural images, functional images were helpful in some cases, but the definitive diagnosis is anatomical.

Demencia frontotemporal: experiencia clínica / Frontotemporal dementia: review of 63 cases

Background: Front temporal dementias (FTD) are neurodegenerative disorders characterized by alterations in behavior, affection and language, with relative sparing of episodic memory. There are three major forms of FTD: the frontal or behavioral form, progressive non-fluent aphasia and semantic dementia (that may begin as a fluent progressive aphasia). Aim: To report a retrospective clinical experience of patients with frontotemporal dementia. Material and methods: Review of 3,700 records of neuropsychological assessments of patients with behavioral disturbances, studied between 1981 and 2008. Of these, 63 patients (59 percent females) complied with the criteria for frontotemporal dementia. Results: There were 47 cases with the frontal variant, four with non-fluent progressive aphasia and six with fluent progressive aphasias (2 evolved to semantic dementia). The mean age of onset was 60±11 years. There were no familiar cases of FTD. Conclusions: It is clinically difficult to diagnose FTD, since evaluation of attitude or language is required. In addition to structural images, functional images were helpful in some cases, but the definitive diagnosis is anatomical.

Asociación inversa entre enfermedad de Alzheimer y cáncer / Inverse relationship between Alzheimer's disease and cancer

The increase in life expectancy is accompanied by a concomitant increase in the prevalence of age related disorders, including neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, and various types of cancers. We here report epidemiologic findings suggesting thatthe development of the Alzheimer and a history of cancer are inversely related. The inverse relationship was found when all cancer types were analyzed and also when skin cancers (bothmelanomas and those with good prognosis, that constitute 50% of all cancers) were analyzed separately. In addition, in a population study we found that this inverse relationship was found with dementia of the Alzheimer type and mixed dementia, but not with vascular dementia, suggesting that the association is only with degenerative diseases. We discuss possible explanations for this inverse relationship, among them, the possibility that a common biological mechanism might be regulated in opposite directions in neurodegenerative diseases and cancer.

[One hundred years of Alzheimer's disease: immunotherapy a hope?]. / Cien años de la enfermedad de Alzheimer: La inmunoterapia ¿una esperanza?

In 1906 Alois Alzheimer, described the cerebral lesions characteristic of the disorder that received his name: senile plaques and neurofibrillary tangles. Alzheimer's disease (AD) is now, 100 years after, the most prevalent form of dementia in the world. The longer life expectancy and aging of the population renders it as a serious public health problem of the future. Urgent methods of diagnosis and treatment are required, since the definitive diagnosis of AD continues to be neuropathologic. In the last 30 years several drugs have been approved to retard the progression of the disease; however, there are still no curative or preventive treatments. Although still in experimentation, the visualization of amyloid deposition by positron emission tomography or magnetic resonance imaging will allow in vivo diagnosis of AD. In addition, experiments with the amyloid vaccine are still ongoing, and very recent data suggest that intravenous gammaglobulins may be beneficial and safe for the treatment of AD.

Afasia progresiva fluente: ¿una forma de presentación inicial de demencia semántica? / Fluent progressive aphasia: a form of inicial presentation of semantic dementia?

Se presenta el caso de un hombre de 57 años que presenta un cuadro degenerativo con afasia fluente y moderadas alteraciones de conducta, sin defecto semántico significativo, agnosia visual ni agrafia lexical y su estudio imagenológico cerebral. Se discuten los conceptos de afasia progresiva fluente y demencia semántica, concluyendo que la primera puede evolucionar hacia esta última. Nuestro caso se encontraría en esta situación. Se señala que la patología de las afasias progresivas es variable, siendo lo más frecuente una degeneración frontotemporal (con o sin inclusiones de proteína tau); con menor frecuencia corresponde a una enfermedad de Alzheimer o una degeneración corticobasal.

We report a 57-year-old man presenting with progressive fluent aphasia and behaviour disorder, with no visual semantic loss, visual agnosia, lexical agraphia, nor alexia. We include in this report the brain images, and we discuss the borders between fluent progressive aphasia and semantic dementia. We conclude that fluent progressive aphasia may be the first stage of semantic dementia, noting that the neuropathology of progressive fluent aphasia usually corresponds to frontotemporal lobar degeneration, with or without Tau protein inclusions, as in Alzheimer's Disease or corticobasal degeneration.

Cien años de la enfermedad de Alzheimer: La inmunoterapia ¿una esperanza? / One hundred years of Alzheimer's disease: Immunotherapy a hope?

In 1906 Alois Alzheimer, described the cerebral lesions characteristic of the disorder that received his name: senile plaques and neurofibrillary tangles. Alzheimer's disease (AD) is now, 100 years after, the most prevalent form of dementia in the world. The longer life expectancy and aging of the population renders it as a serious public health problem of the future. Urgent methods of diagnosis and treatment are required, since the definitive diagnosis of AD continues to be neuropathologic. In the last 30 years several drugs have been approved to retard the progression of the disease; however, there are still no curative or preventive treatments. Although still in experimentation, the visualization of amyloid deposition by positron emission tomography or magnetic resonance imaging will allow in vivo diagnosis of AD. In addition, experiments with the amyloid vaccine are still ongoing, and very recent data suggest that intravenous gammaglobulins may be beneficial and safe for the treatment of AD.

Migraña con aura: Una mirada molecular a un problema hereditario / Migraine with aura: A molecular view to a hereditary disorder

Migraine with aura (MA) is a common neurological disorder characterized by severe episodes of headache, generally unilateral, which are preceded by a focal reversible neurological deficit. The studies on MA reveal the existence of familiar aggregation compatible with a high degree of heritability and a complex multifactorial mode of transmission. The genetic factors of MA are unknown. An association to a locus in the long arm of chromosome 4 at the level of 4q22-q25 was recently reported in families with MA in Finland. Objetive: To analyze the genomic DNA of 5 Chilean families with MA to determine if there is linkage to the locus described in Finish families. Metodology: Families with MA were selected applying the diagnostic criteria of the International Headache Society (ICD-10), in which the index case or a member of the family should have MA. The genomic DNA was extracted from peripheral lymphocytes of members of each family (n = 25). Highly polymorphic genomic markers were used for the systematic analysis of the locus on 4q22-q25. Results and Discussion: The LOD score analysis of the 5 Chilean families investigated showed absence of linkage to the marker D4S1578 (maximum 0,35; p = 0.24). Due to the complexity of MA heritability it is possible that one or more loci different from the studied region are involved in the pathophysiology of MA. The study will continue with the inclusion of more family members and isolated MA cases, with the purpose of comparing Chilean and German families in an independent sample.

La migraña con aura (MA) es una patología común, caracterizada por ataques severos de cefalea generalmente unilateral, precedidos por un déficit neurológico focal reversible. Los estudios en MA revelan la existencia de agregación familiar compatible con un alto grado de herencia y un modo de transmisión multifactorial complejo. Los factores genéticos de la MA con herencia compleja son desconocidos. En familias finlandesas con MA se encontró recientemente ligamiento a un locus en el brazo largo del cromosoma 4 a nivel de 4q22-q25. Objetivo: Analizar el DNA genómico de 5 familias chilenas con MA para determinar si hay ligamiento al locus descrito en familias finlandesas. Metodología: Se seleccionaron familias con MA aplicando los criterios diagnósticos de la Sociedad Internacional de Cefalea (ICD-10), donde el caso índice o algún miembro de la familia debían tener MA. El DNA genómico se extrajo de leucocitos en sangre periférica de miembros seleccionados de cada familia (n = 25). Se usaron marcadores genómicos altamente polimórficos (microsatélites) para el análisis sistemático del locus 4q22-q25. Resultados y Discusión: El cálculo del LOD score mostró ausencia de ligamiento en las 5 familias analizadas (máximo de 0,35; p = 0,24) con el marcador D4S1578. Dado el carácter complejo de herencia en la MA es posible que existan uno o varios loci involucrados en su etiopatogenia, distintos al de la región estudiada. El estudio se continuará a través de la ampliación de las familias estudiadas y de la recolección de casos aislados de MA, con el objetivo de realizar futuros estudios de asociación para comparar los hallazgos en familias chilenas con los de familias alemanas en una muestra independiente.

[Clinical variants of Alzheimer disease]. / Variabilidad y variantesde la enfermedad de Alzheimer.

The heterogeneity and variants of Alzheimer disease (AD) are reviewed. There are cases with a slow or fast evolution and with early or late onset. Most cases are sporadic but there are also hereditary forms. About 50% of patients show neuropsychiatric disorders (depression and psychoses). Some cases have a greater deficit of right or left hemispheric functions. Among the variants, there are forms that start as pure aphasias, predominantly prefrontal cases and posterior cortical forms. Occasionally AD may simulate other disorders such as supranuclear palsy, corticobasal ganglionar degeneration and Jacob-Creutzfeldt disease. Finally, there are mixed forms, in which AD is associated with cerebrovascular disease (very commonly) and with other diseases such as dementia with Lewy bodies. We conclude that AD is a heterogeneous disorder and, therefore, clinical diagnosis may be insufficient. Biological markers and specific imaging studies are needed for a correct clinical diagnosis.

Síndrome de Capgras en enfermedad de Alzheimer: presentación de 2 casos / Capgras syndrome in Alzheimer's disease: two cases

Se presentan dos casos de síndrome de Capgras (SC) en mujeres con enfermedad de Alzheimer. Ambas tenían la convicción delirante de que su esposo no era tal sino que un impostor; la primera en forma consistente y duradera, la segunda en forma fluctuante. La revisión de la literatura permite comparar el SC con la paramnesia reduplicativa y el “jamais vu” y contrastarlo con la prosopagnosia. La fisiopatología del SC dependería de que al percibir un rostro se procesan en forma paralela a) los detalles visuales que permiten reconocerlo como un rostro característico (capacidad que se pierde en la prosopagnosia), y b) la respuesta emocional que se pierde en el SC. La pérdida de familiaridad de una persona conocida induce la sensación de que se trata de un impostor. Los estudios de imágenes funcionales permiten suponer que en el procesamiento de los rostros y voces familiares participa en forma destacada la parte posterior del girus cingulado.

Two cases Capgras syndrome (CS) are presented in women with Alzheimer’s disease. Both patients had the conviction that their husbands had been supplanted by an impostor; in the first one consistently and permanently, and the second one in a fluctuating form. Revision of the literature allows to compare CS with reduplicative paramnesia and “jamais vu”; and contrast these with prosopagnosia. The physiopathology of CS can be explained by assuming that during face recognition two processes are participating in parallel: a) the recognition of visual details, that allow identification of a face (which is lost in prosopagnosia), and b) the emotional response, which is lost in CS. The loss of familiarity of a known person induces the sensation of an impostor. Functional imaging studies suggest that the posterior cingulate gyrus has a predominant role in the processing of familiar faces and voices.

Variabilidad y variantes de la enfermedad de Alzheimer / Clinical variants of Alzheimer disease

The heterogeneity and variants of Alzheimer disease (AD) are reviewed. There are cases with a slow or fast evolution and with early or late onset. Most cases are sporadic but there are also hereditary forms. About 50 percent of patients show neuropsychiatric disorders (depression and psychoses). Some cases have a greater deficit of right or left hemispheric functions. Among the variants, there are forms that start as pure aphasias, predominantly prefrontal cases and posterior cortical forms. Occasionally AD may simulate other disorders such as supranuclear palsy, corticobasal ganglionar degeneration and Jacob-Creutzfeldt disease. Finally, there are mixed forms, in which AD is associated with cerebrovascular disease (very commonly) and with other diseases such as dementia with Lewy bodies. We conclude that AD is a heterogeneous disorder and, therefore, clinical diagnosis may be insufficient. Biological markers and specific imaging studies are needed for a correct clinical diagnosis.