High prevalence of malignant melanoma in Israeli patients with Parkinson's disease.

The risk of melanoma is higher in patients with Parkinson's disease (PD) than in the general population. Whether the association is disease related or treatment related is unclear. The objective of this study was to assess melanoma prevalence in PD patients in Israel using active dermatologic screening. Consecutive patients with idiopathic PD were recruited by 12 Israeli centers. A movement disorder specialist assessed the severity of PD and obtained a medical, neurological, and medication history. Subsequently, a dermatologist assessed melanoma risk factors, recorded a dermatologic history, proactively performed a whole-body skin examination, and biopsied suspicious skin lesions. Of the enrolled patients (n = 1,395, mean age 69.5 ± 10.6 years, mean PD duration 7.3 ± 6.0 years), 95.3% were treated with dopaminergic agents. Biopsies revealed 8 patients with melanoma in situ and 1 with invasive malignant melanoma; 14 patients reported a melanoma prior to enrollment. The observed 5-year limited duration prevalence of melanoma in PD patients was 4.4 times greater (95% CI 2.6-7.6) than expected from melanoma prevalence in an age- and sex-matched cohort from the Israel National Cancer Registry. The increase was accounted for by an elevated prevalence of melanoma in situ [relative risk 12.5 (95% CI 6.7-23.2)]. Occurrence of melanoma did not correlate with levodopa therapy or time of onset of PD. Melanoma prevalence in PD patients was higher than expected in the general Israeli population. This was not related to levodopa treatment. PD patients should be actively screened for melanoma on a routine basis.

Effect of rasagiline as adjunct therapy to levodopa on severity of OFF in Parkinson's disease.

BACKGROUND: The LARGO study demonstrated that rasagiline 1 mg/day as adjunct to levodopa significantly reduces OFF time to the same magnitude as adjunct entacapone. This substudy of LARGO aimed to assess the effect of rasagiline and entacapone on the motor symptoms of PD during the practically defined OFF state. METHODS: LARGO was a randomized, double-blind, multicenter trial that assessed the efficacy and safety of rasagiline (1 mg/day), entacapone (200 mg with each levodopa dose), and placebo in 687 levodopa-treated PD patients with motor fluctuations. A substudy of LARGO measured UPDRS motor scores in the practically defined OFF state in 32 rasagiline, 36 entacapone, and 37 placebo patients. RESULTS: Treatment with rasagiline produced a significant improvement over placebo of 5.64 units in UPDRS motor OFF score (P = 0.013 vs. placebo). By contrast, the effect of adjunct entacapone was not significant (P = 0.14 vs. placebo). Whereas rasagiline also showed a trend in reducing the UPDRS-ADL OFF score (P = 0.058 vs. placebo), no such trend was noted for entacapone (P = 0.26 vs. placebo). Retrospective analysis, using the Bonferroni correction, of UPDRS motor subdomains further revealed that rasagiline, but not entacapone, significantly improved bradykinesia (P < 0.001) and showed trends for improvements in facial expression, speech, and axial impairment during OFF time. CONCLUSIONS: This study provides the first objectively measured evidence that adjunct rasagiline 1 mg/day is effective in reducing the severity of motor symptoms in the OFF state. This suggests a continuous effect of rasagiline 1 mg/day throughout the day and night and is consistent with its extended duration of therapeutic action.

Long-term follow-up of patients with asymptomatic occlusion of the internal carotid artery with good and impaired cerebral vasomotor reactivity.

BACKGROUND: Cerebral hemodynamic status might be prognostic for either the symptomatic or asymptomatic course of carotid occlusive disease. It is determined by evaluating cerebral vasomotor reactivity (VMR). We assessed VMR in asymptomatic patients with total occlusion of the internal carotid artery (ICA) and followed them to evaluate the role of impaired VMR in predicting ischaemic stroke (IS). METHODS: Thirty-five patients (21 men, mean age ± SD 68 ± 7.5 years) with unilateral asymptomatic ICA occlusion were studied by transcranial Doppler and the Diamox test (intravenous 1.0 g acetazolamide) and followed for 48 months or until reaching the end-points of IS, transient ischaemic attack, or vascular death. VMR% was evaluated by recording the percent differences in peak systolic blood flow velocities in each middle cerebral artery at baseline and after Diamox administration. RESULTS: Based on VMR% calculations, 14 (40%) patients had good VMRs and 21 (60%) had impaired VMRs. The global annual risk of ipsilateral ischaemic events was 5.7%. The annual ipsilateral ischaemic event risk was 1.8% in patients with good VMRs, whilst it was 7.1% in patients with impaired VMRs. An impaired VMR was significantly correlated with ipsilateral IS (Kaplan-Meier log rank statistic, P = 0.04). CONCLUSIONS: Our results support the value of VMR assessment for identifying asymptomatic patients with carotid occlusion who belong to a high-risk subgroup for IS. New trials using extracranial-to-intracranial bypass surgery in patients with asymptomatic ICA occlusion and impaired VMRs are warranted.

Evolving pattern of Guillain-Barre syndrome in a community hospital in Israel.

OBJECTIVES: To investigate the frequency of axonal Guillain-Barre syndrome (GBS) in our ward over 6 years (1999-2005). MATERIALS AND METHODS: Clinical and electrophysiological findings of 40 patients admitted to neurology with abnormalities compatible with acute motor axonal neuropathy (AMAN), acute motor sensory axonal neuropathy (AMSAN) and acute inflammatory demyelinating polyneuropathy (AIDP) were reviewed. RESULTS: Electrophysiological findings showed that 25 (63%) patients had AIDP, nine (22%) AMAN and six (15%) AMSAN. There were significant differences in disease severity. Most axonal patients (87%) were hospitalized with moderate or severe symptoms (3-4 Hughes grade score) and progressed to severe grade (4-6) in comparison with AIDP patients (64% admitted with mild forms) (1-2 Hughes grade score) and progressed to severe in 44% of cases. Cranial nerve involvement was more frequent in AIDP (56%) in comparison with the axonal type (13%). Raised cerebrospinal fluid protein at the time of hospitalization was observed in 76% of demyelinating and 33% of axonal patients. CONCLUSIONS: Axonal GBS occurred more frequently in Israel compared with other Western countries.

Low dose methylphenidate improves freezing in advanced Parkinson's disease during off-state.

Five men with advanced idiopathic Parkinson's disease (PD) were examined to assess the effect of low dose methylphenidate (MPD) on gait. The patients were tested during "off" state before and two hours after the intake of 10 mg MPD while walking an "8 trajectory". The total walking time, total freezing time, number of freezing episodes and the non-freezing walking time were assessed. The obtained data were compared by the Wilcoxon Signed Rank test with a type I error rate of 0.05. The results showed a statistically significant improvement in all gait parameters after MPD intake. Moreover, a good correlation in the grade of improvement for each individual gait characteristic was found. The study demonstrates that low dose of MPD may improve gait, and especially freezing, in patients with severe PD, without the need for exogenous L-dopa. The mechanism of MPD action in patients with advanced PD is further discussed.

The effect of quetiapine in psychotic Parkinsonian patients with and without dementia. An open-labeled study utilizing a structured interview.

OBJECTIVES: We studied the effect of quetiapine in drug induced psychosis (DIP) in Parkinson's disease (PD) patients with dementia (PDDEM) and without dementia (PDNODEM) in a 6-month open study. METHODS: Thirty five consecutive PD patients with DIP (19 of them demented [DSMIV criteria]) were examined. Assessment included Mini-Mental State Examination (MMSE), UPDRS (motor part), Brief Psychiatric Rating Scale (BPRS), Clinical Global Improvement Scale (CGIS) and Hamilton test (for depression). Quetiapine was administered in a flexible dose 25-600 mg daily. Out of the 35 patients included in the study, 24 completed treatment with quetiapine (14 demented and 10 without dementia). Treatment was stopped in 11 patients (5 demented). RESULTS: Intention to treat patient (ITT) analysis did not show a significant quetiapine effect (BPRS), although in about 30% a good outcome was reported by the family (CGIS). Among the patients who completed the study (n = 24), in the PDNODEM group (n = 10) BPRS improved almost significantly (p = 0.06) while in the PDDEM group the BPRS did not change. According to the CGIS, a good improvement was observed in 50% of the PDDEM group (7/14) and 40% of the PDNODEM group (4/10). Motor features of PD patients worsened mildly (p = 0.05) in the PDDEM group. CONCLUSION: In this open trial, quetiapine was not beneficial in the ITT group using the BPRS, although families reported improvement in about 30% of patients (CGIS). Among patients who completed the study, quetiapine was more effective in the PDNODEM group. A double blind study with quetiapine is required.

Electroencephalography findings in adult patients with West Nile virus-associated meningitis and meningoencephalitis.

Eighteen adult patients with serologically confirmed West Nile virus (WNV)-associated meningitis or meningoencephalitis were admitted to our hospital during the 2000 West Nile fever outbreak in Israel. Thirteen of the patients had a more severe and prolonged clinical course, and an electroencephalogram (EEG) was, therefore, requested. A specific EEG pattern was seen in 8 patients, consisting of generalized slowing, which was more prominent over the anterior regions. Generalized slowing that was prominent over the temporal area was seen in 2 patients, and intermittent slowing over the temporal region was seen in 1 patient. Two patients had normal EEG findings. We suggest that WNV meningoencephalitis should be considered in the differential diagnosis of meningitis or meningoencephalitis with a prolonged clinical course and anteriorly predominant slowing on an EEG.

Cortisol, ACTH, and beta-endorphin after dexamethasone administration in Parkinson's dementia.

The dexamethasone suppression test (DST) has been suggested as an effective tool for differentiating between depression and dementia. After administering 1 mg dexamethasone, we measured cortisol, ACTH, and beta-endorphin levels in 32 nondepressed patients with idiopathic Parkinson's disease (PD) (14 also with dementia) and 20 healthy, age-matched controls. Four of the 20 controls, 9 of the 18 with PD alone, and 8 of the 14 with PD and dementia were dexamethasone nonsuppressors (cortisol value greater than or equal to 5 micrograms/100 ml). PD patients without dementia (nonsuppressors) showed higher basal plasma values of cortisol (22.06 +/- 5.30 micrograms/100 ml) compared with the suppressors (13.38 +/- 3.30 micrograms/100 ml). Plasma ACTH and beta-endorphin responded in a coupled way to dexamethasone challenge. Higher basal levels of both peptides were found among PD patients (demented and nondemented), nonresponders to DST. Thus, the DST does not appear to be effective in differentiating between depression and dementia in PD. In addition, PD nonsuppressors showed higher basal values of plasma ACTH, beta-endorphin, and cortisol (similar to patients with major depression). This suggests that although the depression is clinically undetectable, both disorders may share some pathophysiological features at the hypothalamic hypophyseal adrenal level.

Decreased (3H) quinuclidinyl benzilate binding to lymphocytes in Gilles de la Tourette syndrome.

In spite of an unknown pathophysiology, it has been suggested that central dopaminergic hyperactivity exists in Gilles de la Tourette syndrome (TS). Cholinergic influences have also been postulated as a dopaminergic-cholinergic balance seems to be important in other movement disorders. If TS is due to alterations of cholinergic activity, this may also be expressed at postsynaptic levels. Recently, we showed that circulating lymphocytes may serve as useful peripheral markers reflecting induced alterations or inherent changes in muscarinic receptors in the central nervous system (CNS). In the present study, we compared the muscarinic binding characteristics in peripheral lymphocytes as measured by (3H) quinuclidinyl benzilate [(3H)-QNB] in 27 unmedicated TS patients, against 22 healthy (age and gender-matched) controls. B(max) and Kd values were determined using Lineweaver-Burke plots. The mean B(max) values in nontreated TS patients was markedly and significantly lower than in controls (10.59 +/- 8.4 versus 40.16 +/- 9.2 fmole/10(6) cells, p less than 10(-6), while Kd values were similar in both groups. Our findings suggest that changes in cholinergic receptors may play a role in the pathophysiology of Tourette syndrome.

Decreased dopamine uptake into platelet storage granules in Gilles de la Tourette disease.

The movement disorder of Gilles de la Tourette (GdlT) disease may reflect hyperactivity of the basal ganglionic dopamine system. Since platelets have been suggested as peripheral models for the study of catecholamine neurons, we developed a method to measure the uptake of [3H]-DA into platelet storage granules (PSG). In the present report, PSG were incubated with [3H] DA, and Vmax and Km values were calculated by linear regression analysis (Lineweaver Burke plot). The uptake of DA (0.5-5 microM) by PSG from 18 GdlT patients was significantly lower (p < .0001) compared to 15 controls (Vmax mean +/- SD, 107.5 +/- 42.5 and 265.3 +/- 66.5 fmole/mg protein resp.). The decrease of DA uptake in GdlT may reflect compensatory presynaptic changes that reduce DA activity.

Dopamine uptake by platelet storage granules in first-degree relatives of Tourette's syndrome patients.

BACKGROUND: Considering that platelets have been established to be good peripheral markers for the study of catecholaminergic neurons, we have applied an assay to measure the uptake of (3H)-dopamine (DA) into platelet storage granules (PSG). Recently, we reported that Tourette's syndrome (TS) patients (pts) show decreased DA uptake into PSG. METHODS: In the present study, 28 first-degree relatives (3 with chronic motor tics, 3 with transient tics, 6 with obsessive-compulsive behavior, and 16 without symptomatology) belonging to the families of 13 patients, and 14 unrelated healthy controls were studied. RESULTS: Double reciprocal plots were constructed for each subject, and the apparent maximum velocity (Vmax) and Michaelis constant (K(m)) were determined by linear regression analysis (Lineaweaver-Burke plots). The uptake of DA (0.5-5 mumol/L) (mean +/- SEM) by PSG from relatives with symptomatology was similar to the TS patients (symptomatic relatives Vmax 181 +/- 22.2 fmol/mg protein, K(m) (mumol/L) 6.42 +/- 0.29; TS pts Vmax 108 +/- 6.9, K(m) 7.79 +/- 0.64). Relatives without symptomatology on the contrary showed DA affinity characteristics similar to the controls (t test, paired t test, multivariate analysis of variance, and log transformation). CONCLUSIONS: The data presented suggest that TS is hereditary, but they do not distinguish between an autosomal dominant inheritance and a mixed or polygenic model.

Selective influence of rat genotype on age-related regional changes in forebrain muscarinic binding.

Muscarinic binding was analyzed in the hippocampus and frontal cerebral cortex of 3 (young) and 24-month-old (aged) inbred Wistar-Kyoto (WKY), Brown-Norway (BN) and Lewis rats, by the specific binding of the antagonist quinuclidinylbenzilate (QNB). While no age-related changes were detected in the hippocampus of all strains, complex changes were found in the cortex. Maximal binding capacity (Bmax) of [3H]QNB was decreased in the cortex of aged WKY rats, remained unchanged in the BN strain and was elevated in Lewis rats. We conclude that regional differences exist in age-related changes in forebrain muscarinic binding which are probably due to differences in the types and connections of cholinoceptive neurons in these regions. The results suggest that it is the rate of these changes which is affected by the rat genotype.

Low-dose clozapine in the treatment of levodopa-induced mental disturbances in Parkinson's disease.

Delusions and other manifestations of psychotic behavior are common side effects in Parkinson's disease (PD) patients chronically treated with dopaminergic drugs. Clozapine, a dibenzodiazepine derivative, is an antipsychotic drug largely devoid of extrapyramidal side effects. We evaluated the effects of low doses of clozapine on the mental and motor functions in PD patients requiring antipsychotic treatment. Twenty-seven PD patients taking dopaminergic drugs and who had psychotic behavior received clozapine at 12.5 to 75 mg/d. Fifteen patients received clozapine for 1 to 11 months (mean, 6.8 months) and seven received it for 12 to 24 months (mean, 18 months). No patient exhibited motor deterioration, and the psychotic features disappeared immediately, allowing discontinuation of clozapine after several months in 10 patients. Fifteen patients are still receiving clozapine and are free of psychiatric symptoms. The clozapine treatment was discontinued after 5 days (25 mg/d) in two patients because of somnolence. No patient developed neutropenia. Clozapine in low doses is effective in the treatment of drug-induced delusions and hallucinations in PD.

Double-blind comparison of cabergoline and bromocriptine in Parkinson's disease patients with motor fluctuations.

In the present study we compared the efficacy and safety of the new dopamine agonist cabergoline (CBG) with bromocriptine (BCR) in Parkinson's disease (PD). CBG has a very long half-life and can be administered as a single daily dose. Forty-four PD patients with uncontrolled motor fluctuations participated in the study. Patients were randomly and blindly assigned to equivalent doses of either CBG or BCR in addition to preexisting levodopa. Dosage was titrated to optimal, using up to 6 mg of CBG or 40 mg of BCR daily. CBG was given as a single morning dose whereas BCR was administered tid. Sixteen patients were followed for 1 year and 16 additional patients for 6 months. The mean follow-up duration was 9 +/- 5 months. The main effect of both drugs was observed on motor UPDRS scores, rigidity, bradykinesia items, and the percentage of awake hours spent during "on" and "off". In general, the effect of CBG was similar to that of BCR. The percentage of awake hours spent during "on" was higher with CBG as compared with BCR. Adverse events included dyskinesias, orthostatism, confusion, edema, and paresthesias in limbs. These effects were seen at similar frequencies with both drugs. The study shows that CBG given as a single morning dose is at least as efficacious as BCR given tid. CBG is a promising dopamine agonist for the treatment of motor fluctuations in PD.

The polyamine stress response: tissue-, endocrine-, and developmental-dependent regulation.

Transient alterations in polyamine (PA) metabolism, termed the polyamine stress response (PSR), constitute a common cellular response to stressful stimuli. In contrast to the adult brain and liver, the PSR in the adrenal gland and thymus is characterized by a reduction in PA metabolism. The brain PSR undergoes an early postnatal period of non-responsiveness. The aim of the present study was twofold: i) to determine whether the PSR in the liver, thymus, and adrenal gland is developmentally regulated as that in the brain and ii) to establish whether neuronal and hormonal signals can activate the PSR independently. Ornithine decarboxylase (ODC) activity and tissue PA concentrations served as markers of the PSR. Changes were measured in male Wistar rats during postnatal development and at 2 weeks after adrenalectomy in adults. Unlike the brain, the direction of the PSR in peripheral organs did not undergo developmental changes. After adrenalectomy, the PSR was not activated in the thymus and liver by acute (2-hr) restraint stress, but a characteristic PSR was induced in the hippocampus. However, dexamethasone injection (3 mg/kg) did induce a characteristic PSR in all organs of adrenalectomized rats. The results justify the following conclusions: i) Unlike peripheral organs, the PSR in the brain is developmentally regulated; ii) The developmental switch to a mature PSR in the brain corresponds in time to the cessation of the "stress hypo-responsive period" in the hypothalamic-pituitary-adrenocortical (HPA) axis; iii) In the periphery, the PSR appears to be dependent principally on stress-induced activation of the HPA axis and on increased circulating glucocorticoid concentrations rather than on neuronal activation; iv) In the brain, however, the PSR can be induced independently by glucocorticoids or by direct activation of the neuronal circuitry; and v) up-regulation of the PSR, as in the brain and liver, is constructive and may be implicated in cell survival, while its down-regulation, as in the adrenal and thymus, may be implicated in cell death.

Metabolism of agmatine into urea but not into nitric oxide in rat brain.

Agmatine is a guanidino compound abundant in bacteria and plants where it serves as a precursor for polyamine synthesis. It can interfere with several neurotransmission-related functions and can exert neuroprotective effects after brain injury. Agmatine was recently identified in mammalian brain and its synthesis by arginine decarboxylation was characterized. Its metabolism by the brain is, however, unknown. Here we report evidence indicating that agmatine can be selectively metabolized in the rat brain (cerebellum) into urea and thus, may lead to formation of putrescine, the precursor of polyamine synthesis. In addition, while agmatine can inhibit brain nitric oxide synthase, it did not serve as a substrate for nitric oxide formation.

Cholinergic muscarinic binding by rat lymphocytes: effects of antagonist treatment, strain and aging.

Cholinergic muscarinic binding by viable peripheral lymphocytes was assessed by measuring specific binding of the muscarinic antagonist [3H]quinuclidinyl benzylate. After atropine treatment maximal lymphocyte muscarinic binding was increased by about 30%, as it did in the hippocampus of the same rats. Strain-dependent differences in muscarinic binding by peripheral lymphocytes were correlated with similar differences in selective brain regions. Higher muscarinic binding was observed in lymphocytes derived from aged (24 months old) rats. We conclude: atropine treatment causes an increase in lymphocyte muscarinic binding as it does in the brain; strain differences in brain muscarinic binding are paralleled by similar differences in lymphocytes; and in aged rats muscarinic binding capacity by lymphocytes is elevated. The results indicate that circulating lymphocytes may serve as a useful peripheral marker reflecting induced alterations or inherent differences in muscarinic binding.

Strain-dependent and stress-induced changes in rat hippocampal cholinergic system.

The study demonstrates that in the hippocampus of inbred Wistar-Kyoto (WKY) rats [3H]choline uptake is 38% higher than in Brown-Norway (BN) rats. In contrast, the maximum binding capacity of [3H]quinuclidinylbenzilate (QNB) is 28% lower in WKY than in BN rats. After immobilization stress there is a reduction in [3H]choline accumulation which is more pronounced in WKY rats. Furthermore, maximal QNB binding after stress is increased only in WKY rats. Choline acetyltransferase activity, which was 83.5% higher in WKY rats, was not altered after stress in both strains. We conclude that: (1) choline accumulation is directly related to choline acetyltransferase activity in hippocampal synaptosomes; (2) maximum cholinergic muscarinic binding capacity is inversely related to the above two presynaptic activities and (3) immobilization stress results in a decreased choline accumulation and may lead to an increased QNB binding. The results imply that reduction in choline accumulation may be a compensatory mechanism of cholinergic synapses during adaptation to lengthly periods of neuronal activity.

Dynamics of cholinergic synaptic mechanisms in rat hippocampus after stress.

Changes in high affinity [3H]choline uptake, newly synthesized [3H]acetylcholine release and [3H]quinuclidinylbenzilate (QNB) binding were characterized in crude synaptosomal preparations from rat hippocampus immediately after different intervals of immobilization stress and at different times following chronic intermittent stress (2h once daily for 5 days). Choline uptake was increased to 125% of unhandled controls after 10 min of stress, after 2 h it returned to control levels and after chronic stress uptake was reduced to 75% of control. Acetylcholine release was enhanced after all stress intervals. Maximal muscarinic (QNB) binding capacity (Bmax) was increased to 135% of control only after chronic stress, with no change in Kd values. Following chronic stress the changes observed in cholinergic synaptic mechanisms all persist for up to 2 days. Recovery occurred only by the 7th post-stress day. We conclude: presynaptic hippocampal cholinergic terminals are rapidly activated by stressful stimuli and this is expressed by an increase in choline uptake and newly synthesized acetylcholine release; after prolonged periods of stress adaptive changes in the cholinergic terminals are expressed by a reduction in choline uptake and an elevation in the number of muscarinic binding sites; and the chronic stress-induced changes are slow to recover. The results demonstrate that the septo-hippocampal cholinergic system is an integral part of the adaptive response to stress.

Age-dependent loss and compensatory changes of septohippocampal cholinergic neurons in two rat strains differing in longevity and response to stress.

Inbred Wistar-Kyoto rats which are behaviorally more reactive to stress have a shorter life span than Brown-Norway rats. This is paralleled by higher basal activity and more pronounced changes in the septohippocampal cholinergic system of Wistar-Kyotos after stress. Age- and strain-dependent differences were therefore characterized in the septohippocampal system of 3- and 24-month-old (aged) Wistar-Kyotos and Brown-Norways, and in 30-month-old Brown-Norways. High affinity [3H]choline uptake and newly synthesized [3H]acetylcholine release served as markers for cholinergic terminals in the hippocampus. [3H]Quinuclidinylbenzilate binding served as a marker of muscarinic receptors in the hippocampus. Choline acetyltransferase activity served as a marker for cholinergic neurons and their terminals in the septum and hippocampus respectively. Acetylcholinesterase histochemical staining served to localize cholinergic neurons and their terminals in the septum and hippocampus respectively. In the hippocampus of aged Wistar-Kyotos choline uptake and acetylcholine release were reduced by approximately 50% compared to their young counterparts, but remained unchanged in aged Brown-Norways. Hippocampal choline acetyltransferase activity, acetylcholinesterase staining and muscarinic binding were unchanged in aged rats of both strains. Pyramidal cell loss (observed in Cresyl violet stained sections) was detected in hippocampus of 24-month-old Wistar-Kyotos and 30-month-old, but not younger Brown-Norways. Numbers of acetylcholinesterase-stained cells in the septum were reduced by 45 and 25% in 24-month-old Wistar-Kyotos and Brown-Norways respectively, and by 50% in 30-month-old Brown-Norways. Mean diameter of these cells was increased only in aged Wistar-Kyotos (approximately 46%) and in 30-month-old Brown-Norways (40%). The results indicate: (1) there is an ongoing age-dependent degeneration of septohippocampal cholinergic neurons which is associated with two principal compensatory changes in remaining cholinergic neurons: (a) hypertrophy of perikarya and (b) relative increase in activity of presynaptic markers in terminals with unchanged regional distribution, suggesting possible collateral sprouting; (2) age-dependent loss of septal cholinergic neurons precedes loss of hippocampal pyramidal neurons and (3) loss of pyramidal neurons in the hippocampus is associated with a compensatory increased muscarinic binding by remaining target hippocampal neurons. The results imply that higher basal and stress-induced activity of septohippocampal cholinergic neurons may be correlated with an accelerated and more pronounced age-dependent degeneration of this cholinergic system.(ABSTRACT TRUNCATED AT 400 WORDS)