The Hypothalamus in Alzheimer’s Disease

Alzheimer’s disease is a progressive, irreversible neurodegenerative disorder, characterized by gradual decline of mental faculties, including learning capacity, emotional and behavioral alterations, serious decline of motor skills, and dysfunction of the autonomic nervous system with disruption of circadian rhythms. Among the potential modifiable risk factors, diabetes and obesity may play a considerable role in the pathogenetic background of the disease. We describe some of the morphological alterations of the hypothalamic nuclei in early cases of Alzheimer’s disease, using silver impregnation techniques and electron microscopy. The morphological and morphometric study revealed substantial decrease of the neuronal population, which was particularly marked in the suprachiasmatic, the supraoptic, and the paraventricular nuclei of the hypothalamus. The silver staining demonstrated an obvious shortage of the dendritic arborization of neurons, associated with marked spinal pathology and axonal dystrophy. It must be underlined that Alzheimer’s pathology, such as neuritic plaques and neurofibrillary degeneration, was minimal in the hypothalamus in comparison with other cortical and subcortical areas of the brain. Mitochondrial alterations and fragmentation of Golgi complex were observed by electron microscopy in a substantial number of neurons and astrocytes in the hypothalamic nuclei. The hypothalamic pathology may be related to instability of autonomic regulation which occurs gradually in Alzheimer’s disease

The Hypothalamus in Alzheimer’s Disease: A Golgi and Electron and Microscope Study

Alzheimer’s disease is a progressive irreversible neurodegenerative disorder, characterized by gradual decline of mental faculties including learning capacity, emotional and behavioral alterations, serious decline of motor skills, and dysfunction of the autonomic nervous system with disruption of circadian rhythms. Among the potential modifiable risk factors diabetes and obesity may play a considerable role in the pathogenetic background of the disease. We describe some of the morphological alterations of the hypothalamic nuclei in early cases of Alzheimer’s disease, using silver impregnation techniques and electron microscopy. The morphological and morphometric study revealed substantial decrease of the neuronal population, which was particularly marked in the suprachiasmatic, the supraoptic and the paraventricular nuclei of the hypothalamus. The silver staining demonstrated an obvious shortage of the dendritic arborization of neurons, associated with marked spinal pathology and axonal dystrophy. It must be underlined that Alzheimer’s pathology, such as neuritic plaques and neurofibrillary degeneration was minimal in hypothalamus in comparison with other areas of the brain. Mitochondrial alterations and fragmentation of Golgi complex were observed by electron microscopy in a substantial number of neurons and astrocytes in the hypothalamic nuclei. The hypothalamic pathology may be related to instability of autonomic regulation which occurs gradually in Alzheimer’s disease

World psychiatric association section of old age psychiatry consensus statement on ethics and capacity in older people with mental disorders

The World Psychiatric Association (WPA) Section of Old Age Psychiatry, since 1997, has developed Consensus Statements relevant to the practice of Old Age Psychiatry. Since 2006 the Section has worked to develop a Consensus Statement on Ethics and Capacity in older people with mental disorders, which was completed in Prague, September 2008, prior to the World Congress in Psychiatry. This Consensus meets one of the goals of the WPA Action Plan 2008–2011, ”to promote the highest ethical standards in psychiatric practice and advocate the rights of persons with mental disorders in all regions of the world“. This Consensus Statement offers to mental health clinicians caring for older people with mental disorders, caregivers, other health professionals and the general public the setting out of and discourse in ethical principles which can often be complex and challenging, supported by practical guidance in meeting such ethical needs and standards, and to encouraged good clinical practice. Copyright © 2009 John Wiley & Sons, Ltd.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/64443/1/2279_ftp.pd

Hearing and dementia

Hearing deficits associated with cognitive impairment have attracted much recent interest, motivated by emerging evidence that impaired hearing is a risk factor for cognitive decline. However, dementia and hearing impairment present immense challenges in their own right, and their intersection in the auditory brain remains poorly understood and difficult to assess. Here, we outline a clinically oriented, symptom-based approach to the assessment of hearing in dementias, informed by recent progress in the clinical auditory neuroscience of these diseases. We consider the significance and interpretation of hearing loss and symptoms that point to a disorder of auditory cognition in patients with dementia. We identify key auditory characteristics of some important dementias and conclude with a bedside approach to assessing and managing auditory dysfunction in dementia

Three-dimensional reconstruction of synapses and dendritic spines in the rat and ground squirrel hippocampus: New structural-functional paradigms for synaptic function

Published data are reviewed along with our own data on synaptic plasticity and rearrangements of synaptic organelles in the central nervous system. Contemporary laser scanning and confocal microscopy techniques are discussed, along with the use of serial ultrathin sections for in vivo and in vitro studies of dendritic spines, including those addressing relationships between morphological changes and the efficiency of synaptic transmission, especially in conditions of the long-term potentiation model. Different categories of dendritic spines and postsynaptic densities are analyzed, as are the roles of filopodia in originating spines. The role of serial ultrathin sections for unbiased quantitative stereological analysis and three-dimensional reconstruction is assessed. The authors data on the formation of more than two synapses on single mushroom spines on neurons in hippocampal field CA1 are discussed. Analysis of these data provides evidence for new paradigms in both the organization and functioning of synapses

Redox regulation of mitochondrial fission, protein misfolding, synaptic damage, and neuronal cell death: potential implications for Alzheimer’s and Parkinson’s diseases

Normal mitochondrial dynamics consist of fission and fusion events giving rise to new mitochondria, a process termed mitochondrial biogenesis. However, several neurodegenerative disorders manifest aberrant mitochondrial dynamics, resulting in morphological abnormalities often associated with deficits in mitochondrial mobility and cell bioenergetics. Rarely, dysfunctional mitochondrial occur in a familial pattern due to genetic mutations, but much more commonly patients manifest sporadic forms of mitochondrial disability presumably related to a complex set of interactions of multiple genes (or their products) with environmental factors (G × E). Recent studies have shown that generation of excessive nitric oxide (NO), in part due to generation of oligomers of amyloid-β (Aβ) protein or overactivity of the NMDA-subtype of glutamate receptor, can augment mitochondrial fission, leading to frank fragmentation of the mitochondria. S-Nitrosylation, a covalent redox reaction of NO with specific protein thiol groups, represents one mechanism contributing to NO-induced mitochondrial fragmentation, bioenergetic failure, synaptic damage, and eventually neuronal apoptosis. Here, we summarize our evidence in Alzheimer’s disease (AD) patients and animal models showing that NO contributes to mitochondrial fragmentation via S-nitrosylation of dynamin-related protein 1 (Drp1), a protein involved in mitochondrial fission. These findings may provide a new target for drug development in AD. Additionally, we review emerging evidence that redox reactions triggered by excessive levels of NO can contribute to protein misfolding, the hallmark of a number of neurodegenerative disorders, including AD and Parkinson’s disease. For example, S-nitrosylation of parkin disrupts its E3 ubiquitin ligase activity, and thereby affects Lewy body formation and neuronal cell death

Defects in Mitochondrial Dynamics and Metabolomic Signatures of Evolving Energetic Stress in Mouse Models of Familial Alzheimer's Disease

The identification of early mechanisms underlying Alzheimer's Disease (AD) and associated biomarkers could advance development of new therapies and improve monitoring and predicting of AD progression. Mitochondrial dysfunction has been suggested to underlie AD pathophysiology, however, no comprehensive study exists that evaluates the effect of different familial AD (FAD) mutations on mitochondrial function, dynamics, and brain energetics.We characterized early mitochondrial dysfunction and metabolomic signatures of energetic stress in three commonly used transgenic mouse models of FAD. Assessment of mitochondrial motility, distribution, dynamics, morphology, and metabolomic profiling revealed the specific effect of each FAD mutation on the development of mitochondrial stress and dysfunction. Inhibition of mitochondrial trafficking was characteristic for embryonic neurons from mice expressing mutant human presenilin 1, PS1(M146L) and the double mutation of human amyloid precursor protein APP(Tg2576) and PS1(M146L) contributing to the increased susceptibility of neurons to excitotoxic cell death. Significant changes in mitochondrial morphology were detected in APP and APP/PS1 mice. All three FAD models demonstrated a loss of the integrity of synaptic mitochondria and energy production. Metabolomic profiling revealed mutation-specific changes in the levels of metabolites reflecting altered energy metabolism and mitochondrial dysfunction in brains of FAD mice. Metabolic biomarkers adequately reflected gender differences similar to that reported for AD patients and correlated well with the biomarkers currently used for diagnosis in humans.Mutation-specific alterations in mitochondrial dynamics, morphology and function in FAD mice occurred prior to the onset of memory and neurological phenotype and before the formation of amyloid deposits. Metabolomic signatures of mitochondrial stress and altered energy metabolism indicated alterations in nucleotide, Krebs cycle, energy transfer, carbohydrate, neurotransmitter, and amino acid metabolic pathways. Mitochondrial dysfunction, therefore, is an underlying event in AD progression, and FAD mouse models provide valuable tools to study early molecular mechanisms implicated in AD