Alterations in catecholamine neurons of the locus coeruleus in senile dementia of the Alzheimer type and in Parkinson's disease with and without dementia and depression

Abstract

The present study provides qualitative and quantitative investigations of the norepinephrine (NE) neurons in the locus coeruleus (LC) in two neurodegenerative disorders, the senile dementia of the Alzheimer type (SDAT) and Parkinson's disease (PD). The group of PD subjects was subdivided into cases without dementia (P - D), cases with dementia, L-dopa responsive (P + D), and cases with fulminant dementia whose motor disorder symptoms were L-dopa nonresponsive (P + D/L-dopa non-responsive). NE neurons were demonstrated by immunocytochemistry against tyrosine hydroxylase (TH). Quantitations of neuronal parameters and cell numbers and three-dimensional reconstructions of the LC were carried out with a computer-assisted system. In SDAT cases, the rostrocaudal LC length (13 +/- 2.2 mm) is shorter than in controls (14.9 +/- 1.4 mm). The four basic LC neuron classes found in the normal human brain (large multipolar, large "bipolar," small multipolar, and small "bipolar" neurons; Chan-Palay and Asan: J. Comp. Neurol. this issue) are recognizable, but many cell somata are swollen and misshapen with fore-shortened, thick, and less branched dendrites. LC neuron numbers are reduced (between -3.5% and -87.5%). Neuron loss is greatest in the rostral part, less in the middle, and least in the caudal part. In PD cases, the rostrocaudal length (12.4 +/- 1.5 mm) is shorter than in SDAT and controls. The neuronal morphology is more severely altered than in SDAT. The basic neuron classes are hardly distinguishable. Most cell bodies are swollen; they frequently contain Lewy bodies; and the dendrites are short and thin with absent or reduced arborizations. Neuron numbers are more reduced than in SDAT (between -26.4% and -94.4%). Alterations are as severe caudally as rostrally in P - D, and P + D/L-dopa nonresponsive cases. P + D cases are more severely affected rostrally. The presence of depression in SDAT and Parkinson's patients is accompanied by the greatest loss of LC neurons. On the basis of morphological alterations of the TH-immunoreactive neurons, and the degree and topographical distribution of neuron loss, a differentiation is possible between the LC in normal brain and that in SDAT and PD for diagnostic purposes.

The neuropathological basis for depression in Parkinson's disease

“…We observed a higher prevalence of cell loss and gliosis in the LC of depressed compared to non-depressed PD patients. Whereas previous research has independently observed NE/LC pathology [18,19] and the absence of serotonin dysfunction [9][10][11] in depressed PD patients, our study's findings are the first to directly emphasize that NE (and to a lesser extent DA) may play a more critical role than 5-HT in modulating affective disturbances in PD. Indeed, pathological abnormalities within the DRN, a serotonergic center, were absent in both our depressed and nondepressed PD patients.…”

“…Furthermore, dopamine (DA) agonists (e.g., pramipexole and pergolide) have recently proven useful in treating depression in PD patients [17]. An older postmortem study observed that the presence of depression in PD was accompanied by a significant loss of locus coeruleus (LC) neurons [18]. Finally, a recent PET study has observed reduced NE and DA outflow from brain stem regions (e.g., LC) to the limbic system (e.g., amygdala) in depressed patients in comparison to non-depressed PD subjects [19].…”

The role of iron and copper molecules in the neuronal vulnerability of locus coeruleus and substantia nigra during aging

“…Neuronal loss in LC occurs in conditions such as Parkinson's disease (PD) and Alzheimer's disease and Down's syndrome (5,6) with different cellular loss in rostral and caudal parts of LC. In Alzheimer's disease and Down's syndrome, it is not clear whether neuronal loss in LC is a primary event or a consequence of retrograde degeneration of cortically projecting cells due to the loss of cortical synapses.…”

“…In Alzheimer's disease and Down's syndrome, it is not clear whether neuronal loss in LC is a primary event or a consequence of retrograde degeneration of cortically projecting cells due to the loss of cortical synapses. In idiopathic PD, most studies have documented a higher degree of neuronal loss in substantia nigra (SN) compared to LC (5)(6)(7)(8). However, a recent study reported extensive impairment of LC neurons in PD (9).…”

Astrocytic Adrenoceptors: A Major Drug Target in Neurological and Psychiatric Disorders?

“…This nucleus plays a major role in attention, behavioral flexibility, and cognitive processes [67][68][69]. In the normal human brain the right and left nuclei combined contain at most 50,000 noradrenergic neurons [70][71], and the number is decreased in Alzheimer's disease [72][73]. Ascending fibers from locus coeruleus constitute the dorsal noradrenergic bundle, which contains noradrenergic fibers but no adrenergic fibers and supplies the cerebral cortex with virtually its entire source of noradrenaline [74][75].…”