Synaptic alterations in CA1 in mild Alzheimer disease and mild cognitive impairment

Objective: To evaluate the total number of synapses in the stratum radiatum (str rad) of the human hippocampal CA1 subfield in individuals with mild Alzheimer disease (mAD), mild cognitive impairment (MCI), or no cognitive impairment (NCI) and determine if synapse loss is an early event in the progression of the disease. Methods: Short postmortem autopsy tissue was obtained, and an unbiased stereologic sampling scheme coupled with transmission electron microscopy was used to directly visualize synaptic contacts. Results: Individuals with mAD had fewer synapses (55%) than the other two diagnostic groups. Individuals with MCI had a mean synaptic value that was 18% lower than the NCI group mean. The total number of synapses showed a correlation with several cognitive tests including those involving both immediate and delayed recall. Total synaptic numbers showed no relationship to the subject's Braak stage or to APOE genotype. The volume of the str rad was reduced in mAD vs the other two diagnostic groups that were not different from each other. Conclusion: These results strongly support the concept that synapse loss is a structural correlate involved very early in cognitive decline in mild Alzheimer disease (mAD) and supports mild cognitive impairment as a transitional stage between mAD and no cognitive impairment.

[1]  D. Jones,et al.  Determination of the numerical density of perforated synapses in rat neocortex , 1987, Cell and Tissue Research.

[2]  S. DeKosky,et al.  Synapse loss in frontal cortex biopsies in Alzheimer's disease: Correlation with cognitive severity , 1990, Annals of neurology.

[3]  G. Šimić,et al.  Volume and number of neurons of the human hippocampal formation in normal aging and Alzheimer's disease , 1997, The Journal of comparative neurology.

[4]  L. Wahlund,et al.  Structural correlates of mild cognitive impairment , 2004, Neurobiology of Aging.

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

[6]  H. Gundersen,et al.  Unbiased stereological estimation of the total number of neurons in the subdivisions of the rat hippocampus using the optical fractionator , 1991, The Anatomical record.

[7]  L. R. Hill,et al.  Hippocampal connectivity and Alzheimer's dementia , 1994, Neurology.

[8]  J. Morrison,et al.  Stereologic Evidence for Persistence of Viable Neurons in Layer II of the Entorhinal Cortex and the CA1 Field in Alzheimer Disease , 2003, Journal of neuropathology and experimental neurology.

[9]  D. Bennett,et al.  Mild cognitive impairment in different functional domains and incident Alzheimer’s disease , 2005, Journal of Neurology, Neurosurgery & Psychiatry.

[10]  M. Smith,et al.  Oxidative stress in Alzheimer's disease. , 2000, Biochimica et biophysica acta.

[11]  J. Price,et al.  Cerebral amyloid deposition and diffuse plaques in ``normal'' aging , 1996, Neurology.

[12]  J. M. Anderson,et al.  A quantitative histological study of early clinical and preclinical Alzheimer's disease , 1990, Neuropathology and applied neurobiology.

[13]  D. Amaral,et al.  Topographical organization of the entorhinal projection to the dentate gyrus of the monkey , 1989, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[14]  S. Wisniewski,et al.  Upregulation of choline acetyltransferase activity in hippocampus and frontal cortex of elderly subjects with mild cognitive impairment , 2002, Annals of neurology.

[15]  J. Troncoso,et al.  Differences in the pattern of hippocampal neuronal loss in normal ageing and Alzheimer's disease , 1994, The Lancet.

[16]  L. Beckett,et al.  Entorhinal Cortex β-Amyloid Load in Individuals with Mild Cognitive Impairment , 1999, Experimental Neurology.

[17]  A. Drzezga,et al.  Cerebral metabolic changes accompanying conversion of mild cognitive impairment into Alzheimer's disease: a PET follow-up study , 2003, European Journal of Nuclear Medicine and Molecular Imaging.

[18]  D. Amaral,et al.  The three-dimensional organization of the hippocampal formation: A review of anatomical data , 1989, Neuroscience.

[19]  J. Price,et al.  Mild cognitive impairment represents early-stage Alzheimer disease. , 2001, Archives of neurology.

[20]  M. Mesulam,et al.  Cholinergic nucleus basalis tauopathy emerges early in the aging‐MCI‐AD continuum , 2004, Annals of neurology.

[21]  J. Kril,et al.  Neuron loss from the hippocampus of Alzheimer's disease exceeds extracellular neurofibrillary tangle formation , 2002, Acta Neuropathologica.

[22]  E. Cochran,et al.  Loss of nucleus basalis neurons containing trkA immunoreactivity in individuals with mild cognitive impairment and early Alzheimer's disease , 2000, The Journal of comparative neurology.

[23]  A. Nunomura,et al.  Oxidative Damage Is the Earliest Event in Alzheimer Disease , 2001, Journal of neuropathology and experimental neurology.

[24]  J. Price,et al.  The distribution of tangles, plaques and related immunohistochemical markers in healthy aging and Alzheimer's disease , 1991, Neurobiology of Aging.

[25]  E. Bigio,et al.  Contribution of asymmetric synapse loss to lateralizing clinical deficits in frontotemporal dementias. , 2001, Archives of neurology.

[26]  J. Schneider,et al.  Parahippocampal tau pathology in healthy aging, mild cognitive impairment, and early Alzheimer's disease , 2002, Annals of neurology.

[27]  M. J. Wade,et al.  Neuron number in the entorhinal cortex and CA1 in preclinical Alzheimer disease. , 2001, Archives of neurology.

[28]  Mark J West,et al.  Hippocampal neurons in pre-clinical Alzheimer’s disease , 2004, Neurobiology of Aging.

[29]  Bradley T. Hyman,et al.  Distribution of Alzheimer‐type pathologic changes in nondemented elderly individuals matches the pattern in Alzheimer's disease , 1992, Neurology.

[30]  M. Mesulam,et al.  Neurofibrillary tangles, amyloid, and memory in aging and mild cognitive impairment. , 2003, Archives of neurology.

[31]  F. Schmitt,et al.  Hippocampal synaptic loss in early Alzheimer's disease and mild cognitive impairment , 2006, Neurobiology of Aging.

[32]  D. A. Bennett,et al.  Natural history of mild cognitive impairment in older persons , 2002, Neurology.

[33]  C. J. Rivara,et al.  Cognitive impact of neuronal pathology in the entorhinal cortex and CA1 field in Alzheimer's disease , 2006, Neurobiology of Aging.

[34]  J. Morris,et al.  Tangles and plaques in nondemented aging and “preclinical” Alzheimer's disease , 1999, Annals of neurology.

[35]  F. Schmitt,et al.  Evidence of increased oxidative damage in subjects with mild cognitive impairment , 2005, Neurology.

[36]  H. Gundersen.  Stereology of arbitrary particles * , 1986, Journal of microscopy.

[37]  P. R. Hof,et al.  Design-based stereology in neuroscience , 2005, Neuroscience.

[38]  J. Price,et al.  Absence of cognitive impairment or decline in preclinical Alzheimer’s disease , 2001, Neurology.

[39]  E. Tangalos,et al.  Mild Cognitive Impairment Clinical Characterization and Outcome , 1999 .

[40]  D. Sparks,et al.  Quantitative assessment of synaptic density in the outer molecular layer of the hippocampal dentate gyrus in Alzheimer's disease. , 1996, Dementia.

[41]  J. Schneider,et al.  Neuropathology of older persons without cognitive impairment from two community-based studies , 2006, Neurology.

[42]  D. Bennett,et al.  Loss and atrophy of layer II entorhinal cortex neurons in elderly people with mild cognitive impairment , 2001, Annals of neurology.

[43]  D. Bennett,et al.  Entorhinal cortex beta-amyloid load in individuals with mild cognitive impairment. , 1999, Experimental neurology.

[44]  F. Schmitt,et al.  Alzheimer neuropathologic alterations in aged cognitively normal subjects. , 1999, Journal of neuropathology and experimental neurology.

[45]  D. Salmon,et al.  Physical basis of cognitive alterations in alzheimer's disease: Synapse loss is the major correlate of cognitive impairment , 1991, Annals of neurology.

[46]  S. Folstein,et al.  "Mini-mental state". A practical method for grading the cognitive state of patients for the clinician. , 1975, Journal of psychiatric research.

[47]  J. Land,et al.  β‐Amyloid inhibits integrated mitochondrial respiration 
and key enzyme activities , 2001, Journal of neurochemistry.

[48]  R. Coggeshall,et al.  Methods for determining numbers of cells and synapses: A case for more uniform standards of review , 1996, The Journal of comparative neurology.

[49]  Bruce G. Link,et al.  Diagnosis of dementia in a heterogeneous population. A comparison of paradigm-based diagnosis and physician's diagnosis. , 1992, Archives of neurology.

[50]  K. Davis,et al.  Regional distribution of neuritic plaques in the nondemented elderly and subjects with very mild Alzheimer disease. , 1998, Archives of neurology.

[51]  A. Lawrence,et al.  A dissociation in the relation between memory tasks and frontal lobe tests in the normal elderly , 1994, Neuropsychologia.

[52]  S. Scheff,et al.  Synaptic pathology in Alzheimer’s disease: a review of ultrastructural studies , 2003, Neurobiology of Aging.

[53]  R. Petersen.  Mild cognitive impairment as a diagnostic entity , 2004, Journal of internal medicine.

[54]  J. Schneider,et al.  Mild cognitive impairment is related to Alzheimer disease pathology and cerebral infarctions , 2005, Neurology.

[55]  B. Reisberg,et al.  Mild cognitive impairment in the elderly , 1991, Neurology.

[56]  Charles D. Smith,et al.  Neuropathologic substrate of mild cognitive impairment. , 2006, Archives of neurology.

[57]  N. Foster,et al.  Metabolic reduction in the posterior cingulate cortex in very early Alzheimer's disease , 1997, Annals of neurology.

[58]  G. Alexander,et al.  Regional glucose metabolic abnormalities are not the result of atrophy in Alzheimer's disease , 1998, Neurology.

[59]  C. Caltagirone,et al.  Word-List Forgetting in Young and Elderly Subjects: Evidence for Age-Related Decline in Transferring Information from Transitory to Permanent Memory Condition , 1997, Cortex.

[60]  W M Cowan,et al.  The commissural connections of the monkey hippocampal formation , 1984, The Journal of comparative neurology.