- Email: [email protected]
From care to cure
Brain Research Bulletin 80 (2009) 171–172
Contents lists available at ScienceDirect
Brain Research Bulletin journal homepage: www.elsevier.com/locate/brainresbull
Editorial
From care to cure
Our topic for this special issue is timely in view of the progression of neurodegenerative diseases among the aging population – together with suffering and distress of the whole family and social environment. It is also strongly influenced by the need to identify basic mechanisms of the underlying pathological cascades in order to be able to slow their progression or even stop it. In this issue, we included all aspects of neurodegenerative diseases, but with an accent on Alzheimer’s disease (AD). As an alternate title one could imagine “between bed and bench side” to provide a link between care and cure and possibly close the gap. Indeed, it becomes more and more obvious that a communication between different types of professionals and between different research trends is essential to open novel ground for exchange of information, keeping in view the final improvement of patients. In the first part, some clinical aspects and promises will show that an early diagnosis can contribute – through cognitive evaluation and appropriate medication – to a mental improvement and an improved care. Büla and Wietlisbach assess cognition in long term care residents, using the Cognitive Performance Scale to detect cognitive impairment in acute care settings and demonstrate its validity for predicting institutionalization and death in elderly medical inpatients aged 75 years and over. von Gunten and colleagues review the impact of personality characteristics on the clinical expression of neurodegenerative disorders. Clinical experience suggests that longstanding personality most likely plays a role in how a patient with dementia copes with increasing deficiencies. Huntington’s disease (HD) is characterized by a complex set of motor, neuropsychological and psychiatric symptoms, starting slowly and progressing over many years to a state of complete dependency. Veenhuizen and Tibben report on coordinated multidisciplinary care offered by a team of neurologists, psychologists, occupational therapists, speech and language therapists, social workers and nursing home physicians, to patients diagnosed with Huntington’s disease in the Northern part of the Netherlands. Research on neurodegenerative diseases uses either autopsy tissue of well-characterized patients or animal models, mostly transgenic mice, that mimic specific phenotypes of the disease. Therefore, the second part of this issue focuses on a variety of basic neuropathological aspects. In order to understand relationships between executive and structural deficits in the frontal cortex of patients within normal aging or Alzheimer’s disease, Leuba and colleagues describe changes of -amyloid and neurofibrillary tangle distribution in young and old controls and cases with sporadic (SAD) or familial Alzheimer’s disease (FAD) in several Brodmann areas, indicating differences in vulnerability of frontal cortex areas
0361-9230/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.brainresbull.2009.08.005
and a higher pathological burden in FAD. Kövari and colleagues review the neuropathological aspects of Lewy body disorders. The spectrum of Lewy body disorders includes not only Parkinson’s disease and its associated dementia, and dementia with Lewy bodies, but also Lewy body dysphagia and autonomic failure with Lewy bodies. Dementia with Lewy bodies is thought to be the second most frequent degenerative cause of cognitive decline in the elderly after Alzheimer’s disease. Zurich and Monnet-Tschudi review the importance of in vitro neurotoxicological studies in the elucidation of neurodegenerative processes. As the etiologies of frequent SAD and Parkinson’s disease seem to involve both genetic and environmental factors, environmental compounds are now extensively studied for their possible contribution to neurodegeneration. The combined use of in vitro models and new analytical approaches using “omics” technologies should help to map toxicity pathways and advance understanding of the possible role of xenobiotics in the etiology of neurodegenerative diseases. Vickers and colleagues focus on the axon as the initial site for pathological changes in three major neurodegenerative diseases (amyotrophic lateral sclerosis (ALS), multiple sclerosis and AD), with emphasis on key cellular changes that may underlie axonal dysfunction and pathology. Potentially, the degeneration of neurons can be seen as the result of an initial perturbation of the axon and cytoskeleton, ultimately followed by slow neuronal degeneration and loss of connectivity. Several mechanisms and animal models are discussed in the third part, providing tools to treat disturbed mechanisms. In addition, one paper emphasizes the role of neural networks in the progressive dysfunction of AD. Rossi and Volterra focus on astrocytic dysfunction and provide insights on their role in neurodegeneration. Astrocytes possess functional neurotransmitter receptors and can release gliotransmitters, which result in intracellular calcium elevation. This lead to a new concept of neuron-glia intercommunication, where astrocytes play an unsuspected dynamic role by integrating neuronal inputs and modulating synaptic activity. Neuroinflammation was characterized by astrocytic and microglial activation and has been reported in several neurodegenerative disorders, including AIDS dementia complex, AD and ALS. Protein oxidation and ubiquitination of brain proteins are part of mechanisms that modulate protein function or that inactivate proteins and target misfolded proteins to degradation. Riederer and colleagues focus on brain aging and on mechanisms involved in neurodegeneration in AD. The glial fibrillary acidic and tau proteins are shown to be more ubiquitinated in brain tissues of AD patients, indicating that not only neurons but also glial cells are dysfunctioning. Quintanilla and Johnson review the role of mitochondrial dysfunction in the pathogenesis of HD, an
172
Editorial / Brain Research Bulletin 80 (2009) 171–172
autosomal dominant neurodegenerative disorder that is caused by a pathological expansion of CAG repeats within the gene encoding for a 350 kDa protein called huntingtin. This polyglutamine expansion within huntingtin is responsible for the pathogenesis of HD. Furthermore, alterations in mitochondrial function may play key roles in the pathogenic processes leading to compromised energy metabolism and increased oxidative damage, which eventually contribute to neuronal dysfunction and the death of striatal cells. A variety of proteins and enzymes seem to be involved in the evolution of neurodegenerative diseases. In a mini-review Hernández and colleagues discuss the role of glycogen synthase kinase 3 in Alzheimer’s disease. Although changes in amyloid precursor protein (APP), and presenilin 1 and 2 may contribute to an increase in the amount of -amyloid peptide, a clear correlation to onset and severity of AD is still lacking. Therefore, other factors may explain how gene mutations or posttranslational modifications lead to neurodegeneration. Glycogen synthase kinase 3 was proposed to be one of those factors, both in familial and sporadic AD. Bulat and Widmann review caspase substrates in neurodegenerative diseases. Apoptosis is induced by the cleavage of a subset of cellular proteins by proteases of the caspase family. The main focus was directed towards the caspase substrates, seen as the actual “workers” doing the job of mediating and regulating the apoptotic process and neurodegeneration. MicroRNAs (miRNAs) are short noncoding regulatory RNA molecules that modulate protein expression by inhibiting mRNA translation or promoting RNA degradation. Wang and colleagues report a deregulation of miRNA function involved in the pathogenesis of neurodegenerative disease in an AD mouse model, indicating bcl2 as a target for miRNAs. Beeler and colleagues address the role of the JNK-interacting protein 1/islet brain 1 (IB1/JIP-1) as a key for the control of cell degeneration in AD and diabetes. Several epidemiological studies point to a close connection between AD and type 2 diabetes. The use of diabetes drugs to slow cognitive decline, and the finding that both JNK and IB1/JIP-1 co-localize with amyloid and hyperphosphorylated tau in NFT and islets of AD and diabetes patients, therefore open up a vast area for future research and discussion. Perrot and Eyer review the relation of neuronal intermediate filaments and neurodegenerative disorders. Intermediate filaments represent the most abundant cytoskeletal elements in mature neurons. Mutations and/or accumulations of neuronal intermediate
filament proteins are frequently observed in several human neurodegenerative disorders and are discussed in detail. Animal models are essential to study a variety of aspects, and allow specific studies to investigate neural networks. Eder-Colli and colleagues report on a specific early-onset familial Alzheimer type mutation of presenilin-1 and on a decreased differentiation of embryonic murine neural progenitor cells. In adult transgenic mice this mutation leads to decreased neurogenesis in the dentate gyrus, suggesting that alterations in embryonic development may contribute to an increased severity of AD phenotype in adulthood. Morris maze behavioral studies of Giuliani and colleagues on transgenic APP mice with anti-TNF treatment or TNF-alpha receptor gene deletion indicate a dissociation between cognitive and behavioral impairment. The differential vulnerability of brain networks in the associative cortical areas, entorhinal cortex and hippocampus are addressed by Savioz and colleagues with respect to the differential distribution of pathological AD hallmarks. Overall, converging results from studies of biological as well as artificial neural networks lead to the conclusion that changes in neural networks contribute strongly to AD progression. Last but not least, a review by Mohajeri and Leuba on prevention and cure underlines the possibilities of treating early AD with interventions against -amyloid depositions and preventing cognitive decline by lifestyle adjustment. Indeed, an early integrative strategy, combining pharmacological, immunological and life style factors such as nutritional habits and physical activity may help to slow the progression of age-associated dementia. Beat M. Riederer ∗ Geneviève Leuba Center for Psychiatric Neuroscience, Department of Psychiatry, CHUV, 1008 Prilly-Lausanne, Switzerland ∗ Corresponding author. Center for Psychiatric Neuroscience, Department of Psychiatry, CHUV, 1008 Prilly-Lausanne, Switzerland. Tel.: +41 21 643 6335; fax: +41 21 643 6950. E-mail address: [email protected] (B.M. Riederer)
Available online 13 August 2009
Contents lists available at ScienceDirect
Brain Research Bulletin journal homepage: www.elsevier.com/locate/brainresbull
Editorial
From care to cure
Our topic for this special issue is timely in view of the progression of neurodegenerative diseases among the aging population – together with suffering and distress of the whole family and social environment. It is also strongly influenced by the need to identify basic mechanisms of the underlying pathological cascades in order to be able to slow their progression or even stop it. In this issue, we included all aspects of neurodegenerative diseases, but with an accent on Alzheimer’s disease (AD). As an alternate title one could imagine “between bed and bench side” to provide a link between care and cure and possibly close the gap. Indeed, it becomes more and more obvious that a communication between different types of professionals and between different research trends is essential to open novel ground for exchange of information, keeping in view the final improvement of patients. In the first part, some clinical aspects and promises will show that an early diagnosis can contribute – through cognitive evaluation and appropriate medication – to a mental improvement and an improved care. Büla and Wietlisbach assess cognition in long term care residents, using the Cognitive Performance Scale to detect cognitive impairment in acute care settings and demonstrate its validity for predicting institutionalization and death in elderly medical inpatients aged 75 years and over. von Gunten and colleagues review the impact of personality characteristics on the clinical expression of neurodegenerative disorders. Clinical experience suggests that longstanding personality most likely plays a role in how a patient with dementia copes with increasing deficiencies. Huntington’s disease (HD) is characterized by a complex set of motor, neuropsychological and psychiatric symptoms, starting slowly and progressing over many years to a state of complete dependency. Veenhuizen and Tibben report on coordinated multidisciplinary care offered by a team of neurologists, psychologists, occupational therapists, speech and language therapists, social workers and nursing home physicians, to patients diagnosed with Huntington’s disease in the Northern part of the Netherlands. Research on neurodegenerative diseases uses either autopsy tissue of well-characterized patients or animal models, mostly transgenic mice, that mimic specific phenotypes of the disease. Therefore, the second part of this issue focuses on a variety of basic neuropathological aspects. In order to understand relationships between executive and structural deficits in the frontal cortex of patients within normal aging or Alzheimer’s disease, Leuba and colleagues describe changes of -amyloid and neurofibrillary tangle distribution in young and old controls and cases with sporadic (SAD) or familial Alzheimer’s disease (FAD) in several Brodmann areas, indicating differences in vulnerability of frontal cortex areas
0361-9230/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.brainresbull.2009.08.005
and a higher pathological burden in FAD. Kövari and colleagues review the neuropathological aspects of Lewy body disorders. The spectrum of Lewy body disorders includes not only Parkinson’s disease and its associated dementia, and dementia with Lewy bodies, but also Lewy body dysphagia and autonomic failure with Lewy bodies. Dementia with Lewy bodies is thought to be the second most frequent degenerative cause of cognitive decline in the elderly after Alzheimer’s disease. Zurich and Monnet-Tschudi review the importance of in vitro neurotoxicological studies in the elucidation of neurodegenerative processes. As the etiologies of frequent SAD and Parkinson’s disease seem to involve both genetic and environmental factors, environmental compounds are now extensively studied for their possible contribution to neurodegeneration. The combined use of in vitro models and new analytical approaches using “omics” technologies should help to map toxicity pathways and advance understanding of the possible role of xenobiotics in the etiology of neurodegenerative diseases. Vickers and colleagues focus on the axon as the initial site for pathological changes in three major neurodegenerative diseases (amyotrophic lateral sclerosis (ALS), multiple sclerosis and AD), with emphasis on key cellular changes that may underlie axonal dysfunction and pathology. Potentially, the degeneration of neurons can be seen as the result of an initial perturbation of the axon and cytoskeleton, ultimately followed by slow neuronal degeneration and loss of connectivity. Several mechanisms and animal models are discussed in the third part, providing tools to treat disturbed mechanisms. In addition, one paper emphasizes the role of neural networks in the progressive dysfunction of AD. Rossi and Volterra focus on astrocytic dysfunction and provide insights on their role in neurodegeneration. Astrocytes possess functional neurotransmitter receptors and can release gliotransmitters, which result in intracellular calcium elevation. This lead to a new concept of neuron-glia intercommunication, where astrocytes play an unsuspected dynamic role by integrating neuronal inputs and modulating synaptic activity. Neuroinflammation was characterized by astrocytic and microglial activation and has been reported in several neurodegenerative disorders, including AIDS dementia complex, AD and ALS. Protein oxidation and ubiquitination of brain proteins are part of mechanisms that modulate protein function or that inactivate proteins and target misfolded proteins to degradation. Riederer and colleagues focus on brain aging and on mechanisms involved in neurodegeneration in AD. The glial fibrillary acidic and tau proteins are shown to be more ubiquitinated in brain tissues of AD patients, indicating that not only neurons but also glial cells are dysfunctioning. Quintanilla and Johnson review the role of mitochondrial dysfunction in the pathogenesis of HD, an
172
Editorial / Brain Research Bulletin 80 (2009) 171–172
autosomal dominant neurodegenerative disorder that is caused by a pathological expansion of CAG repeats within the gene encoding for a 350 kDa protein called huntingtin. This polyglutamine expansion within huntingtin is responsible for the pathogenesis of HD. Furthermore, alterations in mitochondrial function may play key roles in the pathogenic processes leading to compromised energy metabolism and increased oxidative damage, which eventually contribute to neuronal dysfunction and the death of striatal cells. A variety of proteins and enzymes seem to be involved in the evolution of neurodegenerative diseases. In a mini-review Hernández and colleagues discuss the role of glycogen synthase kinase 3 in Alzheimer’s disease. Although changes in amyloid precursor protein (APP), and presenilin 1 and 2 may contribute to an increase in the amount of -amyloid peptide, a clear correlation to onset and severity of AD is still lacking. Therefore, other factors may explain how gene mutations or posttranslational modifications lead to neurodegeneration. Glycogen synthase kinase 3 was proposed to be one of those factors, both in familial and sporadic AD. Bulat and Widmann review caspase substrates in neurodegenerative diseases. Apoptosis is induced by the cleavage of a subset of cellular proteins by proteases of the caspase family. The main focus was directed towards the caspase substrates, seen as the actual “workers” doing the job of mediating and regulating the apoptotic process and neurodegeneration. MicroRNAs (miRNAs) are short noncoding regulatory RNA molecules that modulate protein expression by inhibiting mRNA translation or promoting RNA degradation. Wang and colleagues report a deregulation of miRNA function involved in the pathogenesis of neurodegenerative disease in an AD mouse model, indicating bcl2 as a target for miRNAs. Beeler and colleagues address the role of the JNK-interacting protein 1/islet brain 1 (IB1/JIP-1) as a key for the control of cell degeneration in AD and diabetes. Several epidemiological studies point to a close connection between AD and type 2 diabetes. The use of diabetes drugs to slow cognitive decline, and the finding that both JNK and IB1/JIP-1 co-localize with amyloid and hyperphosphorylated tau in NFT and islets of AD and diabetes patients, therefore open up a vast area for future research and discussion. Perrot and Eyer review the relation of neuronal intermediate filaments and neurodegenerative disorders. Intermediate filaments represent the most abundant cytoskeletal elements in mature neurons. Mutations and/or accumulations of neuronal intermediate
filament proteins are frequently observed in several human neurodegenerative disorders and are discussed in detail. Animal models are essential to study a variety of aspects, and allow specific studies to investigate neural networks. Eder-Colli and colleagues report on a specific early-onset familial Alzheimer type mutation of presenilin-1 and on a decreased differentiation of embryonic murine neural progenitor cells. In adult transgenic mice this mutation leads to decreased neurogenesis in the dentate gyrus, suggesting that alterations in embryonic development may contribute to an increased severity of AD phenotype in adulthood. Morris maze behavioral studies of Giuliani and colleagues on transgenic APP mice with anti-TNF treatment or TNF-alpha receptor gene deletion indicate a dissociation between cognitive and behavioral impairment. The differential vulnerability of brain networks in the associative cortical areas, entorhinal cortex and hippocampus are addressed by Savioz and colleagues with respect to the differential distribution of pathological AD hallmarks. Overall, converging results from studies of biological as well as artificial neural networks lead to the conclusion that changes in neural networks contribute strongly to AD progression. Last but not least, a review by Mohajeri and Leuba on prevention and cure underlines the possibilities of treating early AD with interventions against -amyloid depositions and preventing cognitive decline by lifestyle adjustment. Indeed, an early integrative strategy, combining pharmacological, immunological and life style factors such as nutritional habits and physical activity may help to slow the progression of age-associated dementia. Beat M. Riederer ∗ Geneviève Leuba Center for Psychiatric Neuroscience, Department of Psychiatry, CHUV, 1008 Prilly-Lausanne, Switzerland ∗ Corresponding author. Center for Psychiatric Neuroscience, Department of Psychiatry, CHUV, 1008 Prilly-Lausanne, Switzerland. Tel.: +41 21 643 6335; fax: +41 21 643 6950. E-mail address: [email protected] (B.M. Riederer)
Available online 13 August 2009