Selective targeting of 3 repeat Tau with brain penetrating single chain antibodies for the treatment of neurodegenerative disorders.

Alzheimer's disease (AD) is the most common form of dementia in the elderly affecting more than 5 million people in the U.S. AD is characterized by the accumulation of ß-amyloid (Aß) and Tau in the brain, and is manifested by severe impairments in memory and cognition. Therefore, removing tau pathology has become one of the main therapeutic goals for the treatment of AD. Tau (tubulin-associated unit) is a major neuronal cytoskeletal protein found in the CNS encoded by the gene MAPT. Alternative splicing generates two major isoforms of tau containing either 3 or 4 repeat (R) segments. These 3R or 4RTau species are differentially expressed in neurodegenerative diseases. Previous studies have been focused on reducing Tau accumulation with antibodies against total Tau, 4RTau or phosphorylated isoforms. Here, we developed a brain penetrating, single chain antibody that specifically recognizes a pathogenic 3RTau. This single chain antibody was modified by the addition of a fragment of the apoB protein to facilitate trafficking into the brain, once in the CNS these antibody fragments reduced the accumulation of 3RTau and related deficits in a transgenic mouse model of tauopathy. NMR studies showed that the single chain antibody recognized an epitope at aa 40-62 of 3RTau. This single chain antibody reduced 3RTau transmission and facilitated the clearance of Tau via the endosomal-lysosomal pathway. Together, these results suggest that targeting 3RTau with highly specific, brain penetrating, single chain antibodies might be of potential value for the treatment of tauopathies such as Pick's Disease.

[Pick's disease].

Pick's disease is a type of frontotemporal lobar degeneration(FTLD) with circumscribed atrophy in the frontotemporal lobe. The terminology for Pick's disease has evolved over time. Pick's disease was a term formerly used to define a disorder with symptoms caused by frontal and temporal lobe dysfunction. Therefore, the diagnosis was previously based on clinical features and the distribution of brain atrophy. Pick's disease is currently defined by the presence of tau-positive Pick bodies, and thus can be diagnosed only pathologically. The clinical phenotypes of Pick's disease include behavioral variant FTD (bvFTD), progressive nonfluent aphasia (PNFA) and semantic dementia (SD).

Neuroprotective effects of Cerebrolysin in triple repeat Tau transgenic model of Pick's disease and fronto-temporal tauopathies.

BACKGROUND: Tauopathies are a group of neurodegenerative disorders with accumulation of three-repeat (3R) or four-repeat (4R) Tau. While 3R tau is found in Pick's disease and Alzheimer's disease (AD), 4R tau is more abundant in corticobasal degeneration, progressive supranuclear palsy, and AD. We have previously shown that Cerebrolysin™ (CBL), a neuropeptide mixture with neurotrophic effects, ameliorates the pathology in amyloid precursor protein transgenic (tg) mouse model of AD and 4R tau, however it is unclear if CBL ameliorates the deficits and neuropathology in the mouse model of Pick's disease over expressing 3R tau. RESULTS: Mice expressing 3R tau (L266V and G272V mutations) under the mThy-1 promoter were treated with CBL in two separate groups, the first was 3 months old (treated for 3 months, IP) and the second was 6 months old (treated for 3 months, IP) at the start of the treatment. We found that although the levels of total 3R tau were unchanged, CBL reduced the levels of hyper-phosphorylated tau in both groups of mice. This was accompanied by reduced neurodegenerative pathology in the neocortex and hippocampus in both groups and by improvements in the behavioral deficits in the nest-building test and water maze in the 3-6 month group. CONCLUSION: Taken together these results support the notion that CBL may be beneficial in other taupathy models by reducing the levels of aberrantly phosphorylated tau.

Pharmacological treatment of frontotemporal lobar degeneration: systematic review.

OBJECTIVE: To identify the therapeutic options available for treatment of cognitive and behavioral symptoms in frontotemporal lobar degeneration. METHOD: Systematic review using the descriptors "frontotemporal lobar degeneration" OR "frontotemporal dementia" OR "fronto-temporal dementia" OR "fronto-temporal degeneration" OR "Pick's disease" OR "Pick's atrophy" OR "semantic dementia" OR "progressive aphasia" AND "pharmacotherapy" OR "treatment" OR "efficacy" OR "effects" OR "management" was performed in the Medline and Lilacs databases. SELECTION CRITERIA: Quality A - randomized clinical trials. Quality B - open studies or reports of six or more cases. Quality C - reports of five or fewer cases. Two reviewers independently assessed the clinical studies. Information collected included diagnostic criteria used, sample size, duration, efficacy and tolerability measures used and results obtained. RESULTS: From the 532 studies found, 29 complied with the inclusion criteria. All studies worked with a small sample, had short duration of treatment and used non-uniform measures in evaluating efficacy and tolerability. Studies showed disparate results with respect to behavior and cognition. CONCLUSION: There is still little, and poor, evidence available for treatment of frontotemporal lobar degeneration and studies with better methodological background are needed.

Pharmacological treatment of frontotemporal lobar degeneration: systematic review / Tratamento farmacológico da degeneração lobar frontotemporal: revisão sistemática

OBJECTIVE: To identify the therapeutic options available for treatment of cognitive and behavioral symptoms in frontotemporal lobar degeneration. METHOD: Systematic review using the descriptors "frontotemporal lobar degeneration" OR "frontotemporal dementia" OR "fronto-temporal dementia" OR "fronto-temporal degeneration" OR "Pick's disease" OR "Pick's atrophy" OR "semantic dementia" OR "progressive aphasia" AND "pharmacotherapy" OR "treatment" OR "efficacy" OR "effects" OR "management" was performed in the Medline and Lilacs databases. Selection criteria: Quality A - randomized clinical trials. Quality B - open studies or reports of six or more cases. Quality C - reports of five or fewer cases. Two reviewers independently assessed the clinical studies. Information collected included diagnostic criteria used, sample size, duration, efficacy and tolerability measures used and results obtained. RESULTS: From the 532 studies found, 29 complied with the inclusion criteria. All studies worked with a small sample, had short duration of treatment and used non-uniform measures in evaluating efficacy and tolerability. Studies showed disparate results with respect to behavior and cognition. CONCLUSION: There is still little, and poor, evidence available for treatment of frontotemporal lobar degeneration and studies with better methodological background are needed.

OBJETIVO: Identificar as opções terapêuticas disponíveis para tratamento dos sintomas cognitivos e comportamentais da degeneração lobar frontotemporal. MÉTODO: Revisão sistemática utilizando os descritores "frontotemporal lobar degeneration OR frontotemporal dementia OR fronto-temporal dementia OR fronto-temporal degeneration OR Pick's disease OR Pick's atrophy OR semantic dementia OR progressive aphasia AND pharmacotherapy OR treatment OR efficacy OR effects OR management" nas bases Medline e Lilacs. Critérios de seleção: Qualidade A - Estudos clínicos randomizados. Qualidade B - Estudos abertos ou relatos de seis ou mais casos. Qualidade C - Relatos de cinco ou menos casos. Dois revisores avaliaram independentemente os estudos clínicos. As informações coletadas incluíram critérios de diagnóstico utilizados, número da amostra, duração, medidas de eficácia e tolerabilidade utilizadas e os resultados obtidos. RESULTADOS: Encontraram-se 532 estudos e 29 preenchiam os critérios. Todos os estudos incluíam uma amostra pequena, com curta duração de tratamento, com utilização de medidas não uniformes na avaliação da eficácia e da tolerabilidade. O comportamento e a cognição apresentaram resultados díspares entre os estudos. CONCLUSÃO: São poucas as evidências disponíveis para tratamento da degeneração lobar frontotemporal e de qualidade insatisfatória, sendo necessários estudos com maior rigor metodológico.

[Rivastigmine in a case of autopsy proved frontotemporal dementia (Pick's disease)]. / Rivastigmina en un caso de demencia frontotemporal, enfermedad de Pick verificada por autopsia.

INTRODUCTION: Cholinesterase inhibitors are useful in the treatment of behavioural and psychological symptoms in Alzheimer's disease. Their effectiveness in frontotemporal dementia has not been proved, since such a claim has only been backed by the publication of one open-label trial in which the behavioural and psychological symptoms of the patients treated with rivastigmine over a 12-month period improved significantly with respect to those belonging to a group that were given a placebo. We report a case of frontotemporal dementia, Pick's disease, which improved with rivastigmine treatment. CASE REPORT: A 61-year-old male who presented a progressive clinical picture of behavioural disorders and executive-cognitive impairment that had begun two years earlier. Magnetic resonance imaging of the head revealed severe frontotemporal atrophy. Neuropsychological Inventory (NPI). Overall score 36/144 (6/12: anxiety, disinhibition and aberrant motor behaviour, 4/12: agitation, irritability and apathy; 3/12: sleep and eating disorders. After three months' treatment with rivastigmine, the overall score on the NPI was 10/144. This improvement remained stable over the months that followed. The patient died eight months later after developing liver cancer with metastasis. The microscopic study of the brain showed tau-positive neuronal inclusions, gliosis and neuronal loss. The inclusions were well-circumscribed Pick bodies, which were present in the frontal and temporal cortices and in the dentate gyrus of the hippocampus. CONCLUSIONS: This case confirms the idea that treatment with cholinesterase inhibitors can be effective in the behavioural and psychological symptoms of frontotemporal dementia.

Rivastigmina en un caso de demencia frontotemporal, enfermedad de Pick verificada por autopsia / Rivastigmine in a case of autopsy proved frontotemporal dementia (pick´s disease)

Introducción. Los inhibidores de la colinesterasa son útiles en el tratamiento de los síntomas conductuales y psicológicos en la enfermedad de Alzheimer. Su eficacia en la demencia frontotemporal no está demostrada, pues sólo la avala la publicación de un estudio abierto en el que los síntomas conductuales y psicológicos de los pacientes tratados con rivastigmina durante 12 meses mejoraron significativamente respecto de los del grupo placebo. Describimos un caso de demencia frontotemporal, enfermedad de Pick, que mejoró con el tratamiento con rivastigmina. Caso clínico. Varón de 61 años de edad que presentaba un cuadro clínico progresivo de alteraciones de conducta y afectación ejecutivocognitiva de dos años de evolución. En la resonancia magnética craneal se observó una atrofia frontotemporal grave. En el inventario neuropsicológico (NPI) alcanzó una puntuación global de 36/144 (6/12: ansiedad, desinhibición y conducta motora aberrante, 4/12: agitación, irritabilidad y apatía; 3/12: alteraciones del sueño y de la conducta alimentaria). Tras tres meses de tratamiento con rivastigmina, la puntuación global en el NPI fue de 10/144. Esta mejoría se mantuvo estable en los siguientes meses. Falleció ocho meses después tras desarrollar un hepatocarcinoma con metástasis. En el estudio microscópico del cerebro se observaron inclusiones neuronales tau positivas, pérdida neuronal y gliosis. Las inclusiones eran cuerpos de Pick, bien circunscritos, presentes en la corteza frontal, temporal y en el giro dentado del hipocampo. Conclusión. Este caso confirma que el tratamiento con inhibidores de la colinesterasa puede ser eficaz en los síntomas conductuales y psicológicos de demencia frontotemporal (AU)

Introduction. Cholinesterase inhibitors are useful in the treatment of behavioural and psychological symptoms in Alzheimer's disease. Their effectiveness in frontotemporal dementia has not been proved, since such a claim has only been backed by the publication of one open-label trial in which the behavioural and psychological symptoms of the patients treated with rivastigmine over a 12-month period improved significantly with respect to those belonging to a group that were given a placebo. We report a case of frontotemporal dementia, Pick’s disease, which improved with rivastigmine treatment. Case report. A 61-year-old male who presented a progressive clinical picture of behavioural disorders and executive-cognitive impairment that had begun two years earlier. Magnetic resonance imaging of the head revealed severe frontotemporal atrophy. Neuropsychological Inventory (NPI). Overall score 36/144 (6/12: anxiety, disinhibition and aberrant motor behaviour, 4/12: agitation, irritability and apathy; 3/12: sleep and eating disorders. After three months’ treatment with rivastigmine, the overall score on the NPI was 10/144. This improvement remained stable over the months that followed. The patient died eight months later after developing liver cancer with metastasis. The microscopic study of the brain showed tau-positive neuronal inclusions, gliosis and neuronal loss. The inclusions were well-circumscribed Pick bodies, which were present in the frontal and temporal cortices and in the dentate gyrus of the hippocampus. Conclusions. This case confirms the idea that treatment with cholinesterase inhibitors can be effective in the behavioural and psychological symptoms of frontotemporal dementia (AU)

Un caso de enfermedad de Pick con síntomas catatónicos / A Pick´s disease case with catatonic symptoms

Introducción: En 1998 se estableció el último consenso para la definición de la demencia frontotemporal, prevaleciendo los síntomas neuropsiquiátricos. El caso que presentamos tuvo un inicio muy precoz, con síntomas catatoniformes. Caso clínico: Presentamos el caso de un paciente varón, de 42 años. A la edad de 30 años y progresivamente, fue desapareciendo el lenguaje dirigido, predominando el mutismo y la vociferación, con oposicionismo y estereotipias motoras. Con el tiempo se ha instaurado un déficit cognitivo generalizado, compatible con una demencia, con implicación de áreas corticales frontales. Conclusiones: La evolución del cuadro ha permitido establecer el diagnóstico codificado según la CIE-10 de demencia en la enfermedad de Pick (F.02.0). Dos aspectos del caso otorgan su interés: por una parte, el inicio temprano y por otra, su confusión diagnóstica en las fases iniciales con otras entidades psiquiátricas, en este caso una esquizofrenia catatónica

Introduction: The poor clarification of the etiology has promote a recent agreed sorting for the frontotemporal dementia diagnostic. At 1998 last consensus for TFD was created. Clinical case: We present the case of a 42 year old male patient. There were no problems during pregnancy or childbirth. Just some psychomotor slowdown during his childhood, no other alterations. With 30 years old he gave up in some usual activities he used to be envolved in; irritable, dream alterations, anxiety against neutral stimulations, self aggressions strollness. Later on, directed language disappeared, predominating mutism and screaming in different psychomotor agitation episodes. Conclusion: The schedule evolution, has allowed to stablish, the encoded diagnosis according to CIE-10. Dementia in the Pick’s disease (F.02.0). Two aspects of the case award their interest, first, the early beginning, after, its diagnosis confusion during first stages with other psychiatric organizations

Propentofylline for dementia.

BACKGROUND: Propentofylline is a novel therapeutic agent for dementia that readily crosses the blood-brain barrier and acts by blocking the uptake of adenosine and inhibiting the enzyme phosphodiesterase. In vitro and in vivo its mechanism of action appears to be twofold; it inhibits the production of free radicals and reduces the activation of microglial cells. It therefore interacts with the inflammatory processes that are thought to contribute to dementia, and given its mechanism of action is a possible disease modifying agent rather than a purely symptomatic treatment. OBJECTIVES: To determine the clinical efficacy and safety of propentofylline for people with dementia. SEARCH STRATEGY: The trials were identified from a search of the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group on 5 February 2003. Aventis, the manufacturing pharmaceutical company, was asked for data from unpublished studies but declined to enter into correspondence. SELECTION CRITERIA: Unconfounded double-blind randomized controlled trials of propentofylline compared with a placebo or another treatment group. DATA COLLECTION AND ANALYSIS: There were detailed reports of only four of the nine included studies. The efficacy of propentofylline was reviewed for undifferentiated dementia as there were not enough data to attempt a subgroup analysis for the types of dementia. MAIN RESULTS: The following statistically significant treatment effects in favour of propentofylline are reported. Cognition at 3, 6 and 12 months including MMSE at 12 months. [MD 1.2, 95%CI 0.12 to 2.28, P=0.03] Severity of dementia at 3, 6 and 12 months including CGI at 12 months [MD -0.21, 95%CI -0.39 to -0.03, P=0.03]. Activities of Daily Living (NAB) at 6 and 12 months [MD -1.20, 95%CI -2.22 to -0.18, P=0.02]. Global Assessment (CGI) at 3 months [MD -0.48, 95% CI -0.75 to -0.21, P=0.0006], but not at later times. Tolerability There were minimal data on adverse effects and drop-outs. There were a statistically significant treatment effects in favour of placebo at 12 months, for the number of dropouts, [OR=1.43, 95%CI 1.04 to 1.90, P=0.03]. REVIEWER'S CONCLUSIONS: There is limited evidence that propentofylline might benefit cognition, global function and activities of daily living of people with Alzheimer's disease and/or vascular dementia. The meta-analyses reported here are far from satisfactory as a summary of the efficacy of propentofylline, considering the unpublished information on another 1200 patients in randomized trials that exists. Unfortunately Aventis has been unwilling to correspond with the authors, significantly limiting the scope of this review.