The neuropathology of aminergic nuclei in Alzheimer's disease

Abstract

Neuronal loss and the presence of neurofibrillary tangles (NFTs) within aminergic nuclei were examined in a series of patients with Alzheimer's disease (AD). Neuromelanin-containing neurons within the locus ceruleus and large nucleolus-containing neurons within the dorsal raphe nucleus and the central superior (raphe) nucleus were counted in 25 patients with AD and in 12 age-matched control subjects. Numbers of NFTs were quantified in the same regions. Counts were compared with clinical data, including psychiatric evaluations, available for 21 of the patients with AD. Within the locus ceruleus in the patients with AD, abnormalities were more severe at mid level than at caudal or rostral levels (p less than 0.01). Within the dorsal raphe nucleus, neuronal loss was most severe caudally (p less than 0.05). NFTs, but not neuronal loss, were demonstrated within the central superior nucleus. Neuronal and NFT counts did not correlate at individual levels; the relative severity of both pathological processes was consistent from level to level within nuclei but was less consistent between nuclei. Neuronal loss correlated inversely with age, particularly within the locus ceruleus. Duration of disease correlated inversely with counts of NFTs, particularly within the dorsal raphe nucleus, implying a correlation between NFT counts and rate of progression of disease as all but 3 patients had severe dementia. Significantly, patients with AD complicated by major depression had fewer neurons at the mid level of the locus ceruleus and at the rostral level of the central superior nucleus in comparison with nondepressed patients. There was a trend suggesting greater loss of neurons at all levels of the locus ceruleus and dorsal raphe nucleus in depressed individuals.

Amyloid Pathology Is Associated with Progressive Monoaminergic Neurodegeneration in a Transgenic Mouse Model of Alzheimer's Disease

“…MAergic neurodegeneration precedes onset of anxiety-related behaviors in APPswe/PS1⌬E9 mice Because MAergic neurons are involved in emotional behaviors (Zweig et al, 1988;Rub et al, 2000;Parvizi et al, 2001;Grudzien et al, 2007), we asked whether MAergic degeneration in APPswe/ PS1⌬E9 mice is associated with any alterations in emotional behaviors. Mice at different ages were monitored for anxietyrelated behavior on an open-field activity test.…”

“…In addition to the degeneration of cortical and hippocampal neurons, AD is associated with the early and progressive degeneration of monoaminergic (MAergic) neurons [serotonergic (5-HT) neurons in the raphe and the noradrenergic (NA) neurons in the locus ceruleus (LC)] (Marcyniuk et al, 1986;Zweig et al, 1988;German et al, 1992;Rub et al, 2000;Parvizi et al, 2001;Lyness et al, 2003;Grudzien et al, 2007). Analysis of MAergic neuropathology in AD cases indicate that neurons that project to cortex (anterior raphe/LC) are pathologically affected, whereas neurons without cortical projections (posterior raphe/LC) are free of pathological changes (Marcyniuk et al, 1986;German et al, 1992;Parvizi et al, 2001).…”

Neural reserve, neuronal density in the locus ceruleus, and cognitive decline

“…We assessed neuronal density in brainstem aminergic nuclei (i.e., locus ceruleus, dorsal raphe nucleus, substantia nigra, and ventral tegmental area) because these nuclei support multiple cognitive processes, synthesize important monoamines that function as neurotransmitters and neuromodulators, are therapeutic targets for cognitive enhancement, 10 and bear a disproportionate burden of age-related neurodegeneration. 11,12 Participants from the Rush Memory and Aging Project had annual cognitive testing for a mean of 5.8 years, died, and underwent a neuropathologic examination that yielded neuronal counts for each brainstem nucleus From the Rush Alzheimer's Disease …”

Ectopic Cell Cycle Events Link Human Alzheimer's Disease and Amyloid Precursor Protein Transgenic Mouse Models

“…In addition, certain subcortical populations of neurons undergo substantial amounts of neurodegeneration . These include the locus ceruleus (Zweig et al, 1988;Zarow et al, 2003), the dorsal raphe (Zweig et al, 1988;Chen et al, 2000), and the basal nucleus of Meynart (Whitehouse et al, 1982).…”