[Mental competence and neuropsychologic impairments in demented patients]. / Einwilligungsfähigkeit und neuropsychologische Einschränkungen bei dementen Patienten.

The study aim was to examine if neuropsychological tests and clinical dementia scales identify incompetent patients with dementia. Eighteen demented outpatients (ICD-10: F00-F03) underwent psychiatric examination, neuropsychological testing, and formal (MacArthur Competence Assessment Tool Treatment, Hopkins Competency Assessment Test) and clinical assessment of competence. Clinical dementia scales but not neuropsychological testing correlate with formal and clinical assessment of competence in patients with dementia. Our results do not support a neuropsychological model of competence assessment. However, in cases with poor results in clinical dementia scales, clinicians should assess the patients' competence in more detail. It remains open which is the best and ethically grounded methodology for competence assessment.

The time course of nerve growth factor content in different neuropsychiatric diseases--a unifying hypothesis.

Nerve growth factor (NGF) is the prototype of related neurotrophic proteins, the so-called neurotrophins. NGF is essential for proper development of sympathetic and neural crest-derived sensory neurons of the peripheral nervous system (PNS) as well as of the neurons in the cholinergic basal forebrain (CBF). In the mature peripheral and central nervous system (CNS) NGF is also biologically active; NGF facilitates neuronal plasticity and regulates synaptic transmission and connectivity. Besides this well established neurotrophic function, recent findings suggest a role of NGF in neuroimmune and stress-associated processes, which NGF imparts not only as the classical "target-derived messenger", that is retrogradely transported within NGF-sensitive neurons, but also as para- and autocrine cytokine modulating the function of non-neuronal cells. Since neurotrophins are produced in very small amounts in vivo, NGF-sensitive cells have to compete for the limited NGF even under physiological conditions, so that normally only less than 10% of NGF receptors (NGFR) are saturated with their endogenous ligand. Consequently, it is feasable that minute changes in NGF concentrations can influence neuronal function in an extensive way. Hence, one plausible pathomechanism of disease(s) may be that a deficiency in NGF leads to malfunction of NGF-sensitive neurons. The change in NGF concentrations in the course of several diseases, namely during alcoholic and diabetic neuropathy as well as in Alzheimer's disease (AD) and several lesion-models of the CBF, indicates that fluctuations of endogenous NGF concentrations in PNS and CNS follow a distinctive pattern. An initial deficit of NGF at the onset of pathological processes is typically followed by its temporary elevation, during which some neuronal deficits may be partially ameliorated. However, if the disease progresses a decrease of NGF is typically observed, which appears to be a "normalization" of formerly elevated NGF concentrations. In our hypothesis we postulate that after acute or chronic injuries NGF is up-regulated as an intrinsic attempt to regenerate NGF-sensitive neurons. After long-term exposure to noxious processes, however, this compensatory increase of NGF cannot be maintained and eventually breaks down. The extent of such a compensatory up-regulation may depend on age and condition of NGF-sensitive neurons as well as on the type of lesion (acute or chronic). Furthermore, we also postulate that an exceeding level of NGF or its chronic elevation could even be detrimental to neuronal functioning under certain conditions. Thus, endogenous NGF has the capacity to modulate and even to compensate different kinds of harmful processes and in this way it may reinstate the homeostatic equilibrium. In our view, it seems to be a more appropriate approach to regard NGF changes as independent of classical constructs of neuropsychiatric diseases. Perhaps our understanding of NGF may even model for a new approach to the aetiology of multifactorial neuropsychiatric disorders.

NGF content in the cerebral cortex of non-demented patients with amyloid-plaques and in symptomatic Alzheimer's disease.

There is increasing evidence that in Alzheimer's disease nerve growth factor (NGF) protein and NGF mRNA content in postmortem cortex is not decreased, but may even be elevated although the NGF-sensitive cholinergic basal forebrain neurons are preferentially affected. However, only little is known about the early pathophysiological events leading to Alzheimer's disease. We therefore measured the post-mortem NGF concentrations in temporal and frontal cortex of Alzheimer's disease patients, non-demented controls without Alzheimer's disease-related pathology, as well as non-demented patients with beta A4 plaques who might be classified as 'preclinical' cases. In the Alzheimer's disease group we found up to 43% increase in NGF concentrations in the frontal and temporal cortex as compared to the two other groups. In a subgroup analysis of the non-demented patients with plaques, NGF concentrations were lower in the frontal cortex when beta A4 plaques were present (46% of the control temporal area) than in patients without evidence of frontal plaques (81% of the control temporal area). This NGF decrease was paralleled to a similar decrease of choline acetyltransferase activity, which is regulated by NGF in the cholinergic basal forebrain. These findings support the hypothesis of lower cortical NGF content at the onset of plaque formation and of elevated NGF levels in the clinically manifest and neuropathologically advanced stage of the disease.

NGF level in the rat sciatic nerve is decreased after long-term consumption of ethanol.

Long-term effects of ethanol consumption on endogenous nerve growth factor (NGF) level were investigated in NGF-producing target organs and tissues of the peripheral nervous system. Rats were treated with ethanol (20% v/v) for 9 months, detoxified for an additional 2 weeks and kept without ethanol for an additional month prior to sacrifice. NGF level in the NGF-producing target tissues such as iris and submandibular gland and in the trigeminal ganglion and superior cervical ganglion, where NGF-responsive perikarya are located, did not differ significantly from corresponding controls. In contrast, NGF level in the sciatic nerve was significantly reduced by 54%. This indicates that long-term ethanol consumption affects retrograde axonal transport of the neurotrophic factor NGF, suggesting that NGF deficiency may be part of the pathophysiology of peripheral neuropathy due to chronic alcoholism.

Axonal transport of endogenous nerve growth factor (NGF) and NGF receptor in experimental diabetic neuropathy.

There is increasing evidence that deprivation of the retrogradely transported neurotrophic protein nerve growth factor (NGF) accounts for some functional deficits known to occur in experimental diabetic neuropathy. Here we have studied changes in the axonal transport of endogenous NGF, NGF receptor (NGFR), and NGFR saturation (NGF/NGFR ratio) in the rat sciatic nerve after 2 months of streptozotocin (STZ)-induced diabetes mellitus. Compared with vehicle-treated control rats (blood glucose: 6-12 mM), there was a very clear reduction in the retrograde transport of NGF by 50% (P < 0.001) in STZ-treated, diabetic animals (blood glucose: 33-62 mM). No significant reduction in NGF axonal transport was observed in a subpopulation of STZ-treated rats (poor responders) with nearly normal glucose levels (range: 9-12 mM). No change was observed in any group in the retrograde transport of NGFR. Compared with control rats, however, the apparent NGFR saturation was reduced by 45% (P < 0.002) in STZ diabetics, whereas no change in NGFR saturation was observed in the STZ-poor responders. Moreover, the NGFR saturation and amount of retrogradely transported NGF were negatively correlated to the individual glucose concentration in diabetics (r2 = 0.47 and 0.55, respectively; P < 0.0001). These findings indicate that, while NGFR expression is normal in the STZ-diabetic neuropathy model, the marked decrease in receptor saturation observed in diabetics may reflect low peripheral NGF levels, which in consequence leads to the apparent deprivation of neuronal NGF in diabetic rats.

Diabetes mellitus-associated decrease in nerve growth factor levels is reversed by allogeneic pancreatic islet transplantation.

After an untreated 5-month duration of streptozotocin (STZ)-induced diabetes mellitus (DM), nerve growth factor (NGF) levels in BDE rats were decreased to 45-65% of control in the sympathetically innervated target organs iris and submandibular gland, in the superior cervical ganglion (containing NGF-dependent sympathetic perikarya projecting to the cranial targets), and in the NGF-transporting sciatic nerve. Successful allogeneic pancreatic islet transplantation (providing a physiological glucose homeostasis without immunosuppression) after 3-4 weeks of DM reversed the DM-related decrease in NGF levels 4 months after transplantation as compared with untreated diabetic rats. By contrast, NGF levels in the treated vas deferens (innervated by short postganglionic sympathetic neurons) remained increased as in the untreated diabetic rats (175% of control). Thus, DM-associated changes in endogenous NGF levels seem to be reversible by institution of metabolic control, at least at an early stage of DM when NGF-responsive neurons have not been deprived of NGF for a long time.

Endogenous levels of nerve growth factor (NGF) are altered in experimental diabetes mellitus: a possible role for NGF in the pathogenesis of diabetic neuropathy.

Sympathetic and neural-crest derived sensory neurons consisting of unmyelinated and small myelinated fibers are known to be affected at an early stage in diabetes mellitus (DM). Since these peripheral neurons need nerve growth factor (NGF) for their development and maintenance of function in adulthood, changes in endogenous NGF levels could be of relevance for the pathogenesis of diabetic neuropathy (DNP). Using an improved two-site enzyme immunoassay for NGF, we have investigated whether endogenous NGF levels are altered in Sprague-Dawley rats with DM induced by a single injection of streptozotocin (STZ). STZ-treated rats are known to develop in many respects equivalents to neuropathic complications observed in human DM. We found in some sympathetically innervated target organs decreased NGF contents by maximally 56%: transiently in the iris 2 weeks and in the ventricle 12-24 weeks after DM induction and permanently in the submandibular gland already 3 days after DM induction. Several weeks after onset of DM, NGF content was increased by maximally 145-300% in most peripheral targets investigated, such as in iris, cardiac atrium and ventricle, spleen, prostate gland, and vas deferens. This is suggestive for an impaired NGF removal by NGF-sensitive neurons in diabetic rats. Moreover, NGF levels were decreased to minimally 42.6 +/- 4% of control in the NGF-transporting sciatic nerve. NGF levels began to decrease not before 3 weeks after DM induction and remained decreased with 54.0 +/- 5% of control even after 6 months duration of DM. About the same time (i.e., 2 weeks after induction of DM) NGF levels began to decrease in the superior cervical ganglion (where the sympathetic perikarya are located) to minimally 53.2 +/- 4% of control 12 weeks after DM induction. No altered NGF levels were observed during a 3-month duration of DM in the terminal ileum and sensory trigeminal ganglion. Since NGF exerts its neurotrophic action in the perikarya after its retrograde transport from the NGF-producing periphery, our results are consistent with the hypothesis that an alteration in NGF levels may play a role in the pathogenesis of DNP as far as sympathetic neurons are concerned. Thus, our results suggest that DM influences the production and/or transport of endogenous NGF and consequently, that a deprivation of this neurotrophic factor may account for some of the functional deficits known to occur in DNP, such as impaired catecholaminergic transmitter synthesis. This hypothesis possibly opens the way for new concepts in the therapy of DNP.