Paolo Liberini

Olfaction in Parkinson's disease: methods of assessment and clinical relevance.

Abstract Several neurological conditions have been reported to be associated with peripheral or central deficits of olfactory system. In recent years particular emphasis has been placed on the early and severe olfactory impairment in Parkinson’s disease (PD), in which limited neuropathological studies have revealed a marked dopaminergic deficit in the olfactory tubercles. Moreover, indirect evidence suggests that dysfunction of the dopaminergic pathways from mesencephalon to the piriform cortex may play a role in olfactory impairment in PD. A large number of clinical studies have reported that olfactory loss in idiopathic PD is bilateral, present in hemiparkinsonism, unrelated to the stage or clinical subtype of the disease, and independent of antiparkinsonian medication. In addition, major olfactory alterations have been reported in familial PD and dementia with Lewy bodies but not in progressive supranuclear palsy and essential tremor. These findings might stimulate further research targeted to determine the biological substrate of dissimilar olfactory performances in these movement disorders. The present review summarizes standardized procedures for the assessment of olfactory acuity (detection threshold), identification (multiple choice odor naming), discrimination (differentiation between similar/dissimilar odorants), and memory (recognition of a substance previously smelled). Specific suggestions concerning the psychometric and neuropsychological evaluation of PD patients are provided.

Long-term protective effects of human recombinant nerve growth factor and monosialoganglioside GM1 treatment on primate nucleus basalis cholinergic neurons after neocortical infarction

Neocortical infarction induces biochemical and morphological retrograde degenerative changes in cholinergic neurons of the rat nucleus basalis magnocellularis [Sofroniew et al. (1983) Brain Res. 289, 370-374]. In the present study, this lesion model has been reproduced in the non-human primate (Cercopithecus aethiops) to investigate whether degenerative changes affecting the cortex surrounding the lesioned area and the ipsilateral basal forebrain are prevented by the early administration of recombinant human nerve growth factor alone or in combination with the monosialoganglioside GM1. Six months after surgery and treatment, the monkeys were processed either for biochemistry (choline acetyltransferase assay) or immunocytochemistry. In lesioned vehicle-treated animals, choline acetyltransferase activity significantly decreased by 28% in the cortex surrounding the injured area and by 31% in the ipsilateral nucleus basalis of Meynert when compared with values of sham-operated monkeys. These biochemical changes were fully prevented with the administration of nerve growth factor alone or in combination with the monosialoganglioside GM1. The morphometrical analysis revealed a significant shrinkage of cholinergic neurons (61 +/- 1.4% of sham-operated cell size) and loss of neuritic processes (59 +/- 10% of sham-operated values) within the intermediate nucleus basalis region of lesioned vehicle-treated animals. Although a protection of the cholinergic cell bodies within the nucleus basalis was found with both treatments, a significant recovery of the neuritic processes (84 +/- 7.2% of sham-operated values) was assessed only in the double-treated monkeys. These results indicate that the early administration of nerve growth factor alone or in combination with the monosialoganglioside GM1 induces a long-term protective effect on the nucleus basalis cholinergic neurons in cortical injured non-human primates.

NGF-mediated synaptic sprouting in the cerebral cortex of lesioned primate brain.

In the present study, coronal brain sections of cortically devascularized non-human primates (Cercopithecus aethiops) were used to assess the lesion-associated synaptic loss, and the effect of exogenous nerve growth factor (NGF) in preventing or reversing this neurodegeneration. The sections were immunolabeled with antibodies against the synaptic marker protein synaptophysin (SYN), as well as choline acetyltransferase (ChAT) and parvalbumin (PV) markers that identify cholinergic neurons and interneurons, respectively. We found that, compared to sham-operated animals, in the lesioned vehicle treated animals SYN immunoreactivity near the lesioned site in the frontoparietal cortex was decreased by 31%. Similarly, corrected optical density values of immunostained sections specific for ChAT in the nucleus basalis of Meynert (ipsilateral to the lesion) decreased by 20% and PV-immunoreactive neurons near the lesion decreased by 47%. In contrast, NGF-treated lesioned animals showed levels of SYN, ChAT, and PV immunoreactivity similar to sham controls. These results are consistent with previous studies and support the view that NGF may not only prevent neurodegenerative changes after neocortical infarction by protecting vulnerable neurons, but also is capable of inducing sprouting and synaptogenesis.

Neocortical infarction in subhuman primates leads to restricted morphological damage of the cholinergic neurons in the nucleus basalis of Meynert

The aim of the present study was to investigate the long-term effect of cortical infarction on the subhuman primate (Cercopithecus aethiops) basal forebrain. The lesion, carried out by cauterizing the pial blood vessels supplying the left fronto-parieto-temporal neocortex, induced retrograde degenerative processes within the ipsilateral nucleus basalis of Meynert. The morphometrical analysis revealed that significant shrinkage of cholinergic neurons and loss of neuritic processes were localized within the intermediate regions of the nucleus basalis. The average cross-sectional areas of choline acetyltransferase-immunoreactive neurons in the intermedio-ventral (Ch4iv) and intermedio-dorsal (Ch4id) nucleus basalis were decreased to 62.5 +/- 9.5 and 58.0 +/- 8.6%, respectively, of the sham-operated values. Although an apparent loss of Nissl-stained magnocellular neurons in Ch4iv and Ch4id was found by applying a quantitative analysis based on a perikaryal-size criterion, data obtained by the quantification of immunostained material failed to reveal any significant decrease of cholinergic cell density. Results are discussed in view of future application of this ischemic model to study processes of retrograde degeneration following cortical target removal and to assess potential neurotrophic and neuroprotective properties of pharmacologic agents.

Chapter 26 Cooperative effects of gangliosides on trophic factor-induced neuronal cell recovery and synaptogenesis: studies in rodents and subhuman primates

Publisher Summary To better estimate the potential therapeutic value of gangliosides or neurotrophins in central nervous system (CNS) trauma or degenerative processes, this chapter presents the rodent experimental model, involving loss of a portion of the cortical cholinergic network of nucleus basalis magnocellularis (nbm) projections in subhuman primates. A similar cholinergic atrophic reaction was elicited in primates ( Cercopithecus aethiops ) and the neurotrophic therapy was equally effective in such animals. The details of these investigations are also discussed in this chapter. The studies applying putative neurotrophic agents (NGF) in the cholinergic basolo-cortical lesion model suggested that these substances might induce an important re-arrangement of the cholinergic innervations. The chapter also investigates the incidence of CUT-IR varicosities in animals as these are sites for storage of acetylcholine as well as the enzyme involved in its synthesis, and are where physiological release of the neurotransmitter occurs. This study was accomplished by using a image analysis system combined with immunohistochemistry, except that 24 fields per animal were scanned at higher magnification. The program employed was designed to recognize immunoreactive elements, falling within the size range of nerve varicosities, along fibers.

Alz-50 immunoreactivity in the central nervous system of adult rat and primate

The purpose of this work was to investigate the distribution and density of Alz-50 immunoreactivity in the central nervous system of normal adult and cortically injured rats and primates (Cercopithecus aethiops). In control animals of both species a consistent pattern of fiber immunoreactivity was detected within the hypothalamus (arcuate nucleus and median eminence) and the spinal cord (posterior horn and dorsal root nerve). Immunoreactive perikarya were predominantly observed throughout the anterior region of the third ventricle. An identical localization and density of Alz-50 staining was observed in lesioned animals. These experiments reveal that the pattern of Alz-50 immunoreactivity is not affected by the neurodegenerative processes that follow the cortical devascularizing lesion. These observations suggest that the monoclonal antibody Alz-50, besides recognizing cytoskeletal components in degenerating neurons, reacts with specific epitopes located in the hypothalamus and spinal cord of normal mammalian central nervous system.

Increase of aldosterone secretion following acute haloperidol administration : possible clinical implications

The present study was designed to investigate the effect of haloperidol on plasma corticosteroid levels in a small sample of unmediated psychiatric patients requiring acute care. Seven young male normotensive subjects in metabolic balance received a single dose of haloperidol (2 mg i.v.). Blood samples were collected for the radioimmunoassay of plasma renin activity, cortisol and aldosterone concentration at baseline and 3, 6, 12 and 24 h after injection. In five out of seven patients a significant, transient elevation of plasma aldosterone level was observed within 12 h from administration. In contrast, plasma renin activity and cortisol concentration were unchanged. Possible clinical implications of the neuroleptic-associated aldosterone elevations are discussed.

Effect of Cortical Ischemic Damage on Primate Nucleus Basalis

The retrograde damage which occurs in rodent nucleus basalis magnocellularis (nbm) after a cortical devascularizing lesion is a useful experimental model to investigate the processes of retrograde degeneration (Cuello et al., 1986, 1989). This model has attracted remarkable attention because a marked loss of cholinergic neurons and a reduction of choline acetyltransferase activity (ChAT) in the cerebral cortex and nucleus basalis of Meynert (nbM) was detected in Alzheimer’s disease (AD) (Whitehouse et al., 1982; Arendt et al., 1983). The severity of these neuropathological changes affecting the cholinergic neurons within the basal forebrain follows a regional distribution which correlates with the degenerative changes observed in the neocortex receiving the corresponding projections (Mufson et al., 1989a). Several investigations indicate that the involvement of the nbM in this disease is most likely a result of primary cortical pathology resulting in a reduction of nerve growth factor (NGF) retrogradely transported (Appel 1981; Hefti and Weiner, 1986; Vogels et al, 1990). It has been extensively reported that the degeneration of these neurons and the accompanying loss of cholinergic projections to various cortical regions is related to the emerging cognitive impairment (Bartus et al., 1982; Damasio et al. 1989; Morris et al., 1992).