The Hypothalamus in Alzheimer’s Disease

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder, characterized by irreversible decline of mental faculties, emotional and behavioral changes, loss of motor skills, and dysfunction of autonomic nervous system and disruption of circadian rhythms (CRs). We attempted to describe the morphological findings of the hypothalamus in early cases of AD, focusing our study mostly on the suprachiasmatic nucleus (SCN), the supraoptic nucleus (SON), and the paraventricular nucleus (PVN). Samples were processed for electron microscopy and silver impregnation techniques. The hypothalamic nuclei demonstrated a substantial decrease in the neuronal population, which was particularly prominent in the SCN. Marked abbreviation of dendritic arborization, in association with spinal pathology, was also seen. The SON and PVN demonstrated a substantial number of dystrophic axons and abnormal spines. Alzheimer’s pathology, such as deposits of amyloid-β peptide and neurofibrillary degeneration, was minimal. Electron microscopy revealed mitochondrial alterations in the cell body and the dendritic branches. The morphological alterations of the hypothalamic nuclei in early cases of AD may be related to the gradual alteration of CRs and the instability of autonomic regulation.

[1]  S. Bengtsson,et al.  Stress steroids as accelerators of Alzheimer's disease. : Effects of chronically elevated levels of allopregnanolone in transgenic AD models. , 2013 .

[2]  C. Behl,et al.  Protein Homeostasis, Aging and Alzheimer’s Disease , 2012, Molecular Neurobiology.

[3]  Hyoung-Gon Lee,et al.  Impaired mitochondrial biogenesis contributes to mitochondrial dysfunction in Alzheimer’s disease , 2012, Journal of neurochemistry.

[4]  C. Jack,et al.  Tracking pathophysiological processes in Alzheimer's disease: an updated hypothetical model of dynamic biomarkers , 2013, The Lancet Neurology.

[5]  F. LaFerla,et al.  Synaptic Impairment in Alzheimer’s Disease: A Dysregulated Symphony , 2017, Trends in Neurosciences.

[6]  Eric J. Nestler,et al.  New approaches to antidepressant drug discovery: beyond monoamines , 2006, Nature Reviews Neuroscience.

[7]  G. Román,et al.  Autonomic dysfunction in neurodegenerative dementias , 2011, Journal of the Neurological Sciences.

[8]  Richard J Martin,et al.  Assessment of Behavioral and Affective Symptoms in Alzheimer's Disease , 1990, Journal of geriatric psychiatry and neurology.

[9]  D. Cai,et al.  Hypothalamic microinflammation: a common basis of metabolic syndrome and aging , 2015, Trends in Neurosciences.

[10]  J. Auwerx,et al.  Enhancing mitochondrial proteostasis reduces amyloid-β proteotoxicity , 2017, Nature.

[11]  A Hofman,et al.  Diabetes mellitus and the risk of dementia , 1999, Neurology.

[12]  Stavros J. Baloyannis Mitochondria Are Related to Synaptic Pathology in Alzheimer's Disease , 2011, International journal of Alzheimer's disease.

[13]  D. Katare,et al.  Shared links between type 2 diabetes mellitus and Alzheimer's disease: A review. , 2016, Diabetes & metabolic syndrome.

[14]  C. Hetz,et al.  Disturbance of endoplasmic reticulum proteostasis in neurodegenerative diseases , 2014, Nature Reviews Neuroscience.

[15]  J. Waterhouse Circadian rhythms and cognition. , 2010, Progress in brain research.

[16]  Jennifer L. Ciuchta,et al.  Dendritic spine density, morphology, and fibrillar actin content surrounding amyloid-β plaques in a mouse model of amyloid-β deposition. , 2013, Journal of neuropathology and experimental neurology.

[17]  G. Casadesus,et al.  Hypothalamic–Pituitary–Gonadal Axis Involvement in Learning and Memory and Alzheimer’s Disease: More than “Just” Estrogen , 2015, Front. Endocrinol..

[18]  G. Schellenberg,et al.  The genetics and neuropathology of Alzheimer’s disease , 2012, Acta Neuropathologica.

[19]  George Perry,et al.  Slower Dynamics and Aged Mitochondria in Sporadic Alzheimer's Disease , 2017, Oxidative medicine and cellular longevity.

[20]  M. West The precision of estimates in stereological analyses. , 2012, Cold Spring Harbor protocols.

[21]  Stavros J. Baloyannis Alterations of Mitochondria and Golgi Apparatus Are Related to Synaptic Pathology in Alzheimer's Disease , 2013 .

[22]  J. Herbert,et al.  The Suprachiasmatic Nucleus. The Mind's Clock. , 1994 .

[23]  Thomas C. Thannickal Hypocretin (orexin) pathology in Alzheimer’s disease , 2015 .

[24]  D. Maysinger,et al.  Letrozole Potentiates Mitochondrial and Dendritic Spine Impairments Induced by β Amyloid , 2013, Journal of aging research.

[25]  A. Hernández-Pinto,et al.  Somatostatin and Alzheimer's disease , 2008, Molecular and Cellular Endocrinology.

[26]  R. Tanzi,et al.  Role of free radicals and metal ions in the pathogenesis of Alzheimer's disease. , 1999, Metal ions in biological systems.

[27]  A. Coyne,et al.  Negative symptoms in Alzheimer's disease. , 1996, The American journal of psychiatry.

[28]  Stavros J. Baloyannis,et al.  Mitochondrial alterations in Alzheimer's disease. , 2006, Journal of Alzheimer's disease : JAD.

[29]  M. West Counting and measuring ultrastructural features of biological samples. , 2013, Cold Spring Harbor protocols.

[30]  M. Solas,et al.  Interactions Between Age, Stress and Insulin on Cognition: Implications for Alzheimer's Disease , 2010, Neuropsychopharmacology.

[31]  Dan Mungas,et al.  Progression of mild cognitive impairment to dementia in clinic- vs community-based cohorts. , 2009, Archives of neurology.

[32]  Stavros J. Baloyannis The golgi apparatus in Alzheimer?s disease , 2014 .

[33]  B. C. Manning,et al.  Sundowning and circadian rhythms in Alzheimer's disease. , 2001, The American journal of psychiatry.

[34]  S. Ancoli-Israel,et al.  Circadian activity rhythms and risk of incident dementia and mild cognitive impairment in older women , 2011, Alzheimer's & Dementia.

[35]  Yuxiang Sun,et al.  Increased food intake leads to obesity and insulin resistance in the tg2576 Alzheimer's disease mouse model. , 2010, Endocrinology.

[36]  P. Deyn,et al.  Sleep and Alzheimer's disease : A pivotal role for the suprachiasmatic nucleus , 2017 .

[37]  H. Braak,et al.  Staging of alzheimer's disease-related neurofibrillary changes , 1995, Neurobiology of Aging.

[38]  B. Hyman,et al.  Do defecs in mitochondrial energy metabolism underlie the pathology of neurodegenerative diseases? , 1993, Trends in Neurosciences.

[39]  L. Hasche Specificity of symptoms of depression in Alzheimer disease: a longitudinal analysis. , 2006, The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry.

[40]  Stavros J. Baloyannis,et al.  The vascular factor in Alzheimer's disease: A study in Golgi technique and electron microscopy , 2012, Journal of the Neurological Sciences.

[41]  T. Maurice,et al.  Deregulation of hypothalamic-pituitary-adrenal axis functions in an Alzheimer's disease rat model , 2013, Neurobiology of Aging.

[42]  W. Rosenblum The pathogenesis of Alzheimer disease: an alternative to the amyloid hypothesis. , 1997, Journal of neuropathology and experimental neurology.

[43]  Richard G Stefanacci,et al.  The costs of Alzheimer's disease and the value of effective therapies. , 2011, The American journal of managed care.

[44]  A. Alzheimer Uber eine eigenartige Erkrankung der Hirnrinde , 1907 .

[45]  M. Roth,et al.  The Association Between Quantitative Measures of Dementia and of Senile Change in the Cerebral Grey Matter of Elderly Subjects , 1968, British Journal of Psychiatry.

[46]  W. Balch,et al.  Membrane Dynamics at the Endoplasmic Reticulum–Golgi Interface , 1997, The Journal of cell biology.

[47]  Ashok Balasubramanyam,et al.  The Role of the Immune System in Obesity and Insulin Resistance , 2013, Journal of obesity.

[48]  W. Thies,et al.  2013 Alzheimer's disease facts and figures , 2013, Alzheimer's & Dementia.

[49]  H. Braak,et al.  Neurofibrillary pathology in the human paraventricular and supraoptic nuclei , 1997, Acta Neuropathologica.

[50]  Sholl Da Dendritic organization in the neurons of the visual and motor cortices of the cat. , 1953 .

[51]  D. German,et al.  Hypothalamic pathology in Alzheimer's disease , 1987, Neuroscience Letters.

[52]  Wei Jia,et al.  Hyperinsulinemia, insulin resistance and cognitive decline in older cohort. , 2012, Biomedical and environmental sciences : BES.

[53]  Stavros J. Baloyannis Golgi apparatus and protein trafficking in Alzheimer's disease. , 2014, Journal of Alzheimer's disease : JAD.

[54]  H. Gundersen,et al.  Direct and efficient stereological estimation of total cell quantities using electron microscopy , 2006, Journal of microscopy.

[55]  D. Swaab,et al.  The human pineal gland and melatonin in aging and Alzheimer's disease , 2005, Journal of pineal research.

[56]  Q. Tian,et al.  Melatonin in Alzheimer’s Disease , 2013, International journal of molecular sciences.

[57]  E. Peskind,et al.  Hypothalamic pituitary adrenocortical and sympathetic nervous system responses to the cold pressor test in Alzheimer’s disease , 2000, Biological Psychiatry.

[58]  E. Sibille,et al.  Reduced brain somatostatin in mood disorders: a common pathophysiological substrate and drug target? , 2013, Front. Pharmacol..

[59]  D. Marks,et al.  Hypothalamic mechanisms in cachexia , 2010, Physiology & Behavior.

[60]  Stavros J. Baloyannis The Hypothalamus in Alzheimer’s Disease , 2015 .

[61]  W. M. van der Flier,et al.  Injury markers but not amyloid markers are associated with rapid progression from mild cognitive impairment to dementia in Alzheimer's disease. , 2012, Journal of Alzheimer's disease : JAD.

[62]  Olivier Piguet,et al.  Eating and hypothalamus changes in behavioral-variant frontotemporal dementia , 2011, Annals of neurology.

[63]  Philip Scheltens,et al.  Circadian rest—activity rhythm disturbances in alzheimer's disease , 1996, Biological Psychiatry.

[64]  Eric D Vidoni,et al.  Is Alzheimer's disease a systemic disease? , 2014, Biochimica et biophysica acta.

[65]  J. Quinn,et al.  Mitochondria are a direct site of A beta accumulation in Alzheimer's disease neurons: implications for free radical generation and oxidative damage in disease progression. , 2006, Human molecular genetics.

[66]  D. Praticò,et al.  Stress and HPA Axis Dysfunction in Alzheimer’s Disease , 2013 .

[67]  Stavros J. Baloyannis,et al.  Dendritic and spinal pathology in the acoustic cortex in Alzheimer's disease: morphological and morphometric estimation by Golgi technique and electron microscopy , 2007, Acta oto-laryngologica.

[68]  M. West Estimating volume in biological structures. , 2012, Cold Spring Harbor protocols.

[69]  P. Reddy,et al.  Common neurodegenerative pathways in obesity, diabetes, and Alzheimer's disease. , 2017, Biochimica et biophysica acta. Molecular basis of disease.

[70]  David Loewenstein,et al.  Depression and risk for Alzheimer disease: systematic review, meta-analysis, and metaregression analysis. , 2006, Archives of general psychiatry.

[71]  C. Saper,et al.  From Lesions to Leptin Hypothalamic Control of Food Intake and Body Weight , 1999, Neuron.

[72]  Seung-Chul Hong,et al.  Sleep and Alzheimer’s Disease , 2015 .

[73]  S. Budd,et al.  Mitochondria in the life and death of neurons. , 1998, Essays in biochemistry.

[74]  C. You,et al.  The circadian rhythm of arterial blood pressure in Alzheimer disease (AD) patients without hypertension , 2013, Blood pressure.

[75]  G. Knudsen,et al.  Depression and Alzheimer's disease: is stress the initiating factor in a common neuropathological cascade? , 2011, Journal of Alzheimer's disease : JAD.

[76]  J R Hodges,et al.  Changes in appetite, food preference, and eating habits in frontotemporal dementia and Alzheimer’s disease , 2002, Journal of neurology, neurosurgery, and psychiatry.

[77]  Estimating surface area in biological structures. , 2013, Cold Spring Harbor protocols.

[78]  N. Mercuri,et al.  Hypothalamic dysfunction is related to sleep impairment and CSF biomarkers in Alzheimer’s disease , 2017, Journal of Neurology.

[79]  E. Stopa,et al.  Circadian locomotor activity and core-body temperature rhythms in Alzheimer's disease , 1995, Neurobiology of Aging.

[80]  Stavros J. Baloyannis Dendritic pathology in Alzheimer's disease , 2009, Journal of the Neurological Sciences.

[81]  M. Folstein,et al.  Clinical diagnosis of Alzheimer's disease , 1984, Neurology.

[82]  R. Mayeux,et al.  Review - Part of the Special Issue: Alzheimer's Disease - Amyloid, Tau and Beyond Alzheimer disease: Epidemiology, diagnostic criteria, risk factors and biomarkers , 2014 .

[83]  Stavros J. Baloyannis Recent progress of the Golgi technique and electron microscopy to examine dendritic pathology in Alzheimer’s disease , 2013 .

[84]  U. Schibler,et al.  The mammalian circadian timing system: organization and coordination of central and peripheral clocks. , 2010, Annual review of physiology.

[85]  M. Beal,et al.  Amyloid beta, mitochondrial dysfunction and synaptic damage: implications for cognitive decline in aging and Alzheimer's disease. , 2008, Trends in molecular medicine.

[86]  M. Beal,et al.  Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases , 2006, Nature.

[87]  S. Lacalle,et al.  Cell loss in supraoptic and paraventricular nucleus in Alzheimer's disease , 1993, Brain Research.

[88]  J. Xia,et al.  Alzheimer's Disease Risk Genes and Lipid Regulators. , 2016, Journal of Alzheimer's disease : JAD.

[89]  M. Abercrombie Estimation of nuclear population from microtome sections , 1946, The Anatomical record.

[90]  M. Haan Therapy Insight: type 2 diabetes mellitus and the risk of late-onset Alzheimer's disease , 2006, Nature Clinical Practice Neurology.

[91]  Stavros J. Baloyannis Oxidative stress and mitochondria alterations in Alzheimer's disease , 2000, Neurobiology of Aging.

[92]  B. Jacobs,et al.  Life‐span dendritic and spine changes in areas 10 and 18 of human cortex: A quantitative golgi study , 1997, The Journal of comparative neurology.

[93]  Berislav V. Zlokovic,et al.  Neurovascular mechanisms and blood–brain barrier disorder in Alzheimer’s disease , 2009, Acta Neuropathologica.

[94]  S. M. Sumi,et al.  Subcortical degeneration in Alzheimer's disease , 1985, Neurology.

[95]  D. C. Sterio The unbiased estimation of number and sizes of arbitrary particles using the disector , 1984, Journal of microscopy.

[96]  J. Fiala,et al.  Cylindrical diameters method for calibrating section thickness in serial electron microscopy , 2001, Journal of microscopy.

[97]  H. J. G. Gundersen,et al.  Unbiased stereological estimation of the total number of synapses in a brain region , 1996, Journal of neurocytology.

[98]  Virginia M. Y. Lee,et al.  Molecular features of hypothalamic plaques in Alzheimer's disease. , 1991, The American journal of pathology.

[99]  H J Gundersen,et al.  The efficiency of systematic sampling in stereology and its prediction * , 1987, Journal of microscopy.

[100]  R. Hales,et al.  J Neuropsychiatry Clin Neurosci , 1992 .

[101]  D. Butterfield,et al.  Oxidatively modified, mitochondria-relevant brain proteins in subjects with Alzheimer disease and mild cognitive impairment , 2009, Journal of bioenergetics and biomembranes.

[102]  A. Feuerverger,et al.  Statistical methods for assessing the dimensions of synaptic vesicles in nerve terminals , 2000, Journal of Neuroscience Methods.

[103]  Stavros J. Baloyannis Staining neurons with Golgi techniques in degenerative diseases of the brain , 2015, Neural regeneration research.

[104]  W. Brooks,et al.  Reduced limbic and hypothalamic volumes correlate with bone density in early Alzheimer's disease. , 2010, Journal of Alzheimer's disease : JAD.

[105]  M. Beal,et al.  Mitochondrial Dysfunction in Neurodegenerative Diseases , 2012, Journal of Pharmacology and Experimental Therapeutics.

[106]  Josep Garre-Olmo,et al.  Severity of dementia, anosognosia, and depression in relation to the quality of life of patients with Alzheimer disease: discrepancies between patients and caregivers. , 2014, The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry.

[107]  S. Gauthier,et al.  Depression in Alzheimer's Disease: Receiver Operating Characteristic Analysis of the Cornell Scale for Depression in Dementia and the Hamilton Depression Scale , 1994, Journal of geriatric psychiatry and neurology.

[108]  Stuart Maudsley,et al.  Metabolic dysfunction in Alzheimer's disease and related neurodegenerative disorders. , 2012, Current Alzheimer research.

[109]  The cardinal features of cognitive and noncognitive dysfunction and the differential efficacy of tacrine in Alzheimer's disease patients. , 1996, Journal of biopharmaceutical statistics.

[110]  D. Bennett,et al.  Proneness to psychological distress and risk of Alzheimer disease in a biracial community , 2005, Neurology.

[111]  K. Jellinger,et al.  Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature , 2012, Journal of neuropathology and experimental neurology.

[112]  Stavros J. Baloyannis Staining of dead neurons by the Golgi method in autopsy material. , 2015, Methods in molecular biology.

[113]  R. Kalaria,et al.  Plasma and platelet clusterin ratio is altered in Alzheimer's disease patients with distinct neuropsychiatric symptoms: findings from a pilot study , 2015, International journal of geriatric psychiatry.

[114]  Bernhard T. Baune,et al.  The Circadian System in Alzheimer’s Disease: Disturbances, Mechanisms, and Opportunities , 2013, Biological Psychiatry.

[115]  Filippo Caraci,et al.  Depression and Alzheimer's disease: neurobiological links and common pharmacological targets. , 2010, European journal of pharmacology.

[116]  T. Hökfelt,et al.  Critical role of somatostatin receptor 2 in the vulnerability of the central noradrenergic system: new aspects on Alzheimer’s disease , 2015, Acta Neuropathologica.

[117]  Alzheimer’s Association 2010 Alzheimer's disease facts and figures , 2010, Alzheimer's & Dementia.

[118]  P. Reddy,et al.  Abnormal interaction between the mitochondrial fission protein Drp1 and hyperphosphorylated tau in Alzheimer's disease neurons: implications for mitochondrial dysfunction and neuronal damage. , 2012, Human molecular genetics.

[119]  S. Ortolano,et al.  New Insights in the Amyloid-Beta Interaction with Mitochondria , 2012, Journal of aging research.

[120]  Stavros J. Baloyannis,et al.  Dendritic and spinal pathology in the acoustic cortex in Alzheimer's disease: Morphological estimation in Golgi technique and electron microscopy , 2011, Acta oto-laryngologica.

[121]  D F Swaab,et al.  Decreased melatonin levels in postmortem cerebrospinal fluid in relation to aging, Alzheimer's disease, and apolipoprotein E-epsilon4/4 genotype. , 1999, The Journal of clinical endocrinology and metabolism.

[122]  J. Geddes,et al.  Synaptic Mitochondria Are More Susceptible to Ca2+Overload than Nonsynaptic Mitochondria* , 2006, Journal of Biological Chemistry.

[123]  R. Mrak,et al.  Microglia and neuroinflammation: a pathological perspective , 2004 .

[124]  K. Blennow,et al.  Cerebrospinal fluid substance P concentrations are elevated in patients with Alzheimer's disease , 2015, Neuroscience Letters.

[125]  E. Fliers,et al.  The supraoptic and paraventricular nuclei of the human hypothalamus in relation to sex, age and Alzheimer's disease , 1990, Neurobiology of Aging.

[126]  B. Ott,et al.  Apathy and loss of insight in Alzheimer's disease: a SPECT imaging study. , 1996, The Journal of neuropsychiatry and clinical neurosciences.

[127]  Claire S. Adjiman,et al.  Efficient Screening and Selection of Post-combustion CO2 Capture Solvents , 2014 .

[128]  M. Storandt,et al.  Temporal memory for remote events in healthy aging and dementia. , 1998, Psychology and aging.

[129]  M. Wikström,et al.  Age-related changes in electrophysiological properties of the mouse suprachiasmatic nucleus in vitro , 2005, Brain Research Bulletin.

[130]  B. Kolb,et al.  The Cerebral cortex of the rat , 1990 .

[131]  John E. Johnson Current trends in morphological techniques , 1981 .