Prodromal or mild Alzheimer's disease: Influence of neuropsychiatric symptoms and premordid personality on caregivers' burden.

OBJECTIVE: In Alzheimer's disease (AD), the burden on caregivers is influenced by various factors, including the stage of disease progression and neuropsychiatric symptoms (NPS). To date, there has been limited research examining how patient's premorbid personality could affect this burden. The objective of this study was to investigate the impact of both premorbid personality and NPS in individuals with prodromal to mild AD on their caregivers' burden. METHOD: One hundred eighty participants with prodromal or mild AD drown from the PACO (in French: Personnalité Alzheimer COmportement) cohort were included. Personality was assessed by the Revised NEO Personality Inventory (NEO-PI-R). Neuropsychiatric symptoms were measured with the short version of the Neuropsychiatric Inventory (NPI-Q), and caregiver burden was evaluated with the Zarit burden scale. Relationships between personality, Neuro-Psychiatric Inventory (NPI) scores, and caregiver burden were determined using multivariate linear regressions controlled for age, sex, educational level, and Mini Mental State Examination. RESULTS: The total NPI score was related to increased burden (beta = 0.45; p < 0.001). High level of neuroticism (beta = 0.254; p = 0.003) et low level of conscientiousness (beta = - 0.233; p = 0.005) were associated higher burden. Extraversion (beta = -0.185; p = 0.027) and conscientiousness (beta = -0.35; p = 0.006) were negatively associated with burden. In contrast, neuroticism, openness and agreeableness were not correlated with burden. When adjusted on total NPI score, the relationship between extraversion and conscientiousness didn't persist. CONCLUSION: Our results suggest that premorbid personality of patients with prodromal to mild Alzheimer influence caregivers's burden, with a protective effect of a high level of extraversion and conscientiousness.

Cannabidiol in the prelimbic cortex modulates the comorbid condition between the chronic neuropathic pain and depression-like behaviour in rats: The role of medial prefrontal cortex 5-HT1A and CB1 receptors.

The prelimbic division (PrL) of the medial prefrontal cortex (mPFC) is a cerebral division that is putatively implicated in the chronic pain and depression. We investigated the activity of PrL cortex neurons in Wistar rats that underwent chronic constriction injury (CCI) of sciatic nerve and were further subjected to the forced swimming (FS) test and mechanical allodynia (by von Frey test). The effect of blockade of synapses with cobalt chloride (CoCl2), and the treatment of the PrL cortex with cannabidiol (CBD), the CB1 receptor antagonist AM251 and the 5-HT1A receptor antagonist WAY-100635 were also investigated. Our results showed that CoCl2 decreased the time spent immobile during the FS test but did not alter mechanical allodynia. CBD (at 15, 30 and 60 nmol) in the PrL cortex also decreased the frequency and duration of immobility; however, only the dose of 30 nmol of CBD attenuated mechanical allodynia in rats with chronic NP. AM251 and WAY-100635 in the PrL cortex attenuated the antidepressive and analgesic effect caused by CBD but did not alter the immobility and the mechanical allodynia when administered alone. These data show that the PrL cortex is part of the neural substrate underlying the comorbidity between NP and depression. Also, the previous blockade of CB1 cannabinoid receptors and 5-HT1A serotonergic receptors in the PrL cortex attenuated the antidepressive and analgesics effect of the CBD. They also suggest that CBD could be a potential medicine for the treatment of depressive and pain symptoms in patients with chronic NP/depression comorbidity.

Both serotonergic and noradrenergic systems modulate the development of tolerance to chronic stress in rats with lesions of the serotonergic neurons of the median raphe nucleus.

Acute exposure to stress induces significant behavioural changes, while repeated exposure to the same stressor leads to the development of tolerance to stress. The development of tolerance appears to involve the serotonergic projections from the Median Raphe Nucleus (MnRN) to the dorsal Hippocampus (dH), since rats with lesions of this pathway does not develop tolerance to stress. Previous data from our laboratory showed that treatment with imipramine, a serotonin (5-HT) and noradrenaline (NA) reuptake inhibitor, lead to the development of tolerance. However, it remains to be elucidated whether such tolerance involves the participation of the noradrenergic system, apart from the serotonergic projections. Therefore, the aim of this work was to investigate the behavioural and neurochemical effects of chronic treatment with desipramine (NA reuptake inhibitor) or fluoxetine (5-HT reuptake inhibitor) in chronically stressed rats with lesions of the serotonergic neurons of the MnRN. Male Wistar rats with or without lesion in the MnRN were submitted or not to acute (2 h) or chronic restraint (2 h/seven days) stress and tested in the elevated pus maze (EPM). Treatment with fluoxetine, desipramine (10 mg/kg) or saline was performed twice daily (12-12 h interval), for 7 consecutive days. EPM test was conducted 24 h after the treatment. Fluoxetine attenuated the anxiogenic-induced effect of lesion in chronically restrained rats, without changing serotonin and noradrenaline levels in the hippocampus of lesioned rats. A similar profile was also observed after treatment with desipramine. These results suggest that both the serotonergic and the noradrenergic systems are involved in the development of tolerance to chronic stress. Additionally, the integrity of the serotonergic pathway of the MnRN-dH is not essential for the anxiolytic-like effects of these drugs.

Stabilization of lumbo-pelvic region and electromyography of the abdominal muscles.

It is usual to find athletes that can perform de curl up test easily, but are unable to maintain the stabilization of the low back during the double straight leg lowering (DSLL). In spite of having strong abdominal muscles, its stabilization role seems not to be effective. Thus, the purpose of this study was to verify the relation among individuals with strong abdominal muscles and: the ability in perform posterior pelvic tilt (PPT); the ability to stabilize the low back during the DSLL and the eletromyographic activity of the abdominal muscles. Eighteen male subjects (aged 19.27 +/- 3.5), without history of muscle skeletal dysfunction, performed both the PPT and DSLL tests. During these tests electromyographic signals of the rectus abdominis (RA), obliquus internus abdominis (OI) and obliquus externus abdominis (OE) were recorded, the angle of the hip and the pressure under the low back were measured. The results of analyses of variance (ANOVA) show that most volunteers accomplished the PPT test, actively flattening the low back with regular or good quality. However, none of them was able to stabilize the low back during the DSLL test. During the PPT test all abdominal muscle portions analysed were activated without significant differences. In an attempt of maintaining the lumbo-pelvic region stabilized during the DSLL, it was observed a tendency of higher bilateral activation of OE when compared to RA and OI muscle portions between 70 and 20 degrees of hip flexion.

Tolerance to repeated stress in rats with lesions of the serotoninergic neurons of the Median Raphe Nucleus and chronically treated with imipramine.

Repeated exposure to aversive events leads to the development of tolerance to stress, which involves the serotonergic pathway originated in the Median Raphe Nucleus (MnRN) to the Dorsal Hippocampus (DH). However, it is not clear whether these lesion-induced deficits can be attenuated by treatment with antidepressants. Therefore, the aim of this work was to investigate the effects of chronic treatment with Imipramine (IMI) in rats with lesions in the MnRN and exposed to restraint stress. Male Wistar rats with or without neurochemical lesions of the MnRN serotonergic neurons with the neurotoxin 5,7-DHT were submitted to acute (2h) or chronic restraint (2h/day/seven consecutive days) and treated with saline (1 ml/kg) or imipramine (15 mg/kg) via intraperitoneal twice a day during the same period. In acutely restrained rats, stress occurred on the last day of treatment. Test in the elevated plus maze (EPM) was performed 24h later. After EPM test, animals were sacrificed and had their brains removed. Dorsal hippocampus and striatum were dissected and the levels of 5-HT and 5-hydroxy-indoleacetic acid (5-HIAA) measured by HPLC analysis. Our results showed that in control rats exposure to acute restraint stress decreased exploration of the open and enclose arms of the EPM, an effect that was attenuated by imipramine. In rats with 5,7-DHT lesions, acute restraint did not change the exploration of the EPM, independently of the treatment. On the other hand, when chronically restrained, saline treated rat with 5,7-DHT lesion showed a reduced exploration of the open arms of the EPM. This effect was attenuated by simultaneous treatment with imipramine. HPLC analysis showed significantly decreases on 5-HT and 5-HIAA levels in the hippocampus, but not in the striatum. These later results confirm that 5,7-DHT lesions of the MnRN had significant impact on the serotonergic projections to the dorsal hippocampus which seems to be essential for the development of tolerance to repeated stress in the absence of any pharmacological treatment.

Cerebral involvement in graft-versus-host disease after murine bone marrow transplantation.

Neurologic manifestation of graft-versus-host disease (GvHD) after allogeneic bone marrow transplantation (BMT) has until now been limited to rare neuromuscular syndromes. Investigating cerebral findings using a murine BMT model, the authors found parenchymal lymphocytic inflammation, microglia activation, and mild cerebral angiitis-like changes in allogeneic transplanted animals but not in syngeneic controls. These findings suggest that cerebral involvement during GvHD may be a new neurologic complication after BMT.

Immunophenotyping of lymphocyte subsets in bronchoalveolar lavage fluid. Comparison of flow cytometric and immunocytochemical techniques.

In order to compare flow cytometry with the conventional peroxidase anti-peroxidase method for the immunophenotyping of bronchoalveolar lavage fluid (BALF) lymphocytes, we studied BALF samples from 27 patients with various interstitial lung diseases. The results achieved with both methods were consistent concerning CD3+ pan T cells, CD4+ T helper/inducer, CD8+ T suppressor/cytotoxic and CD57+ natural killer cells. In contrast, a statistically significant lower anti-HLA-DR positive subset was obtained with flow cytometry than with the immunoperoxidase method (p less than 0.005). Since regression analyses and reliability counts showed further agreement between the methods, we conclude that flow cytometric immunophenotyping of BALF lymphocytes leads to similar, if not better, subset analyses than the immunoperoxidase method.

Hippocampal 5-HT receptors and consolidation of stressful memories.

It has been suggested that postsynaptic 5-HT1A receptors in the hippocampus, innervated by 5-HT neurons localized in the median raphe nucleus, mediate adaptive or coping responses to aversive events and that dysfunction of this system is related to symptoms of depression. To test this hypothesis we investigated the expression of c-fos mRNA in animals submitted to immobilization stress. The results showed that c-fos mRNA expression is significantly increased in the dentate gyrus and CA1-CA3 regions of the hippocampus after 30 min of forced restraint, suggesting that this structure is activated during stress. To investigate the role of 5-HT neurotransmission in the hippocampus on adaptation to aversive events we immobilized rats for 2 h and tested them 24 h later in an elevated plus-maze. Our results showed that the previous restraint period decreases exploration of open arms in the maze. This effect was reversed by bilateral microinjection of zimelidine (20 and 100 nmol), a 5-HT re-uptake blocker, or 8-OH-DPAT (3 nmol), a 5-HT1A agonist, into the dorsal hippocampus immediately after restraint. These results are compatible with the idea that postsynaptic 5-HT1A receptors located in the hippocampus participate in the development of tolerance to aversive events.

Expression of neuronal nitric oxide synthase mRNA in stress-related brain areas after restraint in rats.

The objective of the present study was to investigate the expression of neuronal nitric oxide synthase (nNOS) mRNA in stress-related areas after restraint. Male Wistar rats (n=4-6/group) submitted to 2 h of restraint during one (acute) or seven (chronic) days were sacrificed 24 h after the last restraint period. In situ hybridisation was performed with oligonucleotide probes radiolabeled with (35)S. Acute restraint induced a significant increase in nNOS mRNA in the paraventricular hypothalamic nucleus (PVN), medial parvocellular part, dorsolateral periaqueductal grey (DLPAG) and medial amygdaloid nucleus, but not in the hippocampal formation. This effect persisted after chronic restraint in the PVN and DLPAG. These results suggest that restraint stress induces changes in gene expression of nNOS in areas related to stress reactions.

Antidepressant-like effects of NMDA-receptor antagonist injected into the dorsal hippocampus of rats.

Exposure to uncontrollable stressors causes behavioral changes that have been related to depressive states in humans. Poststress intrahippocampal administration of amino-7-phosphonoheptanoic acid (AP-7), a glutamate NMDA-receptor antagonist, attenuated the restraint-induced decreased exploration of an elevated plus maze 24 h later. The objective of the study was to test if this treatment would also attenuate the increased immobility seem in the forced swim test (FST) due to preexposition to this stressful situation. Male Wistar rats with cannulae aimed at the dorsal hippocampus were submitted to 15 min of forced swimming and tested 24 h later. They received bilateral intrahippocampal injections of AP-7 (10 nmol) either before or after the pretest swimming session or before the test. Poststress treatment increased latency to display the first episode of immobility and tended to reduce total immobility time. The drug was ineffective when given before stress or before test and in nonstressed animals. This suggests that glutamate NMDA receptors located in the dorsal hippocampus are involved in the behavioral changes observed in the FST.

Behavioral effects in the elevated plus maze of an NMDA antagonist injected into the dorsal hippocampus: influence of restraint stress.

The objective of the study was to investigate the influence of restraint stress on the effects of 2-amino-7-phosphonoheptanoic acid (AP7), an NMDA receptor antagonist, injected into the hippocampus of rats submitted to the elevated plus maze (EPM). Male Wistar rats with cannulas aimed to the dorsal hippocampus were forced immobilized for 2 h. Twenty four hours later they received bilateral injections of saline or AP7 (10 nmol/0.5 microl), and were tested in the EPM. In another experiment the animals received the treatment immediately before or after the restraint period, and were tested in the EPM 24 h later. AP7 had no effect in any anxiety measure in non-stressed rats. In stressed animals the drug increased the percentage of open arm entries when injected before the test in the EPM. When administered immediately after the restraint period, AP7 increased the percentage of time spent in the open arms and tended to do the same with the percentage of entries in these same arms. The results suggest that interference with hippocampal NMDA receptors modify the anxiogenic effect of restraint stress in an EPM.

Restraint-induced hypoactivity in an elevated plus-maze.

Rodents submitted to restraint stress show decreased activity in an elevated plus-maze (EPM) 24 h later. The objective of the present study was to determine if a certain amount of time is needed after stress for the development of these changes. We also wanted to verify if behavioral tolerance of repeated daily restraint would be detectable in this model. Male Wistar rats were restrained for 2 h and tested in the EPM 1, 2, 24 or 48 h later. Another group of animals was immobilized daily for 2 h for 7 days, being tested in the EPM 24 h after the last restraint period. Restraint induced a significant decrease in the percent of entries and time spent in the open arms, as well as a decrease in the number of enclosed arm entries. The significant effect in the number of entries and the percentage of time spent in the open arms disappeared when the data were submitted to analysis of covariance using the number of enclosed arm entries as a covariate. This suggests that the restraint-induced hypoactivity influences the measures of open arm exploration. The modifications of restraint-induced hypoactivity are evident 24 or 48 h, but not 1 or 2 h, after stress. In addition, rats stressed daily for seven days became tolerant to this effect.

Attenuation of behavioral consequences of immobilization stress by intra-hippocampal microinjection of zimelidine.

To investigate the role of hippocampal 5-HT neurotransmission on adaptation to aversive events, individually housed male Wistar rats (200-250 g) were immobilized for 2 h and tested 24 h later in an elevated plus-maze. Immediately after the restraint period they received bilateral microinjections into the dorsal hippocampus of either saline (0.5 microliters) or the nonselective 5-HT1 antagonist dl-propranolol (20 nmol/0.5 microliters). In a second experiment the first microinjection of saline or dl-propranolol was followed by a second microinjection of saline (0.5 microliters) or the 5-HT reuptake blocker zimelidine (20 nmol/0.5 microliters). Although dl-propranolol alone did not change exploration of the elevated plus-maze, it antagonized the increase in the percentage of open arm entries induced by zimelidine (26.0 +/- 4.1 vs 5.64 +/- 3.7 in controls). These results are compatible with the view that post-synaptic 5-HT1a receptors in the hippocampus mediate adaptive or coping responses to aversive events.

Pinealectomy attenuates the effect of restraint on plus maze exploration in rats.

To investigate a possible stress modulation role of the pineal gland, male Wistar albino rats (200-250 g) were submitted to pinealectomy and divided into four groups one week after surgery: i) sham-operated unrestrained animals (N = 14); ii) pinealectomized unrestrained animals (N = 22); iii) sham-operated animals submitted to 2 h of restraint (N = 52); iv) pinealectomized animals submitted to 2 h of restraint (N = 56). Twenty-four hours later the animals were tested in the elevated plus maze for 5 min. Pinealectomized rats submitted to restraint explored the open arms of the maze to a greater extent than sham-operated restrained rats (mean percent of open arm entries = 26.4 +/- 2.3 vs 18.0 +/- 2.1, mean percent of time spent in the open arms = 11.8 +/- 2.1 vs 6.8 +/- 1.2). Pinealectomized animals not submitted to restraint showed no difference in maze exploration when compared to sham-operated rats (mean percent of open arm entries = 29.3 +/- 3.8 vs 31.1 +/- 5.8, mean percent of time spent in the open arms = 8.8 +/- 1.8 vs 12.5 +/- 2.2). The results, therefore, suggest that the pineal gland may play a modulatory role in the behavioral consequences of stress.

Role of serotonin 1A receptors in the median raphe nucleus on the behavioral consequences of forced swim stress.

Despite the intense research on the neurobiology of stress, the role of serotonin (5-HT)1A receptors still remains to be elucidated. In the hippocampus, post-synaptic 5-HT1A receptors activation induces anxiolytic effects in animals previously exposed to stressful situations. However, little is known about somatodendritic 5-HT1A receptors in the median raphe nucleus (MRN). Therefore, the aim of this study was to investigate the role of 5-HT1A receptors located in the MRN in rats exposed to forced swim stress. After recovering from surgery, rats were forced to swim for 15 min in a cylinder. Intra-MRN injections of saline, 8-OH-DPAT (3 nmol/0.2 µL) and/or WAY-100635 (0.3 nmol/0.2 µL) were performed immediately before or after pre-exposure or 24 h later (immediately before test). Non-stressed rats received the same treatment 24 h or 10 min before test. Our data showed that 8-OH-DPAT increased latency to display immobility while decreasing time spent immobile in almost all experimental conditions. These effects were not prevented by previous treatment with WAY-100635. No effects of different treatments were described in non-stressed animals. Taken together, our data suggest that in addition to activation of 5-HT1A, 5-HT7 receptors may also be involved in the behavioural consequences of exposure to swim stress.

Cerebral angiitis in four patients with chronic GVHD.

There is growing evidence that GVHD affects the central nervous system (CNS). In this study, we describe the long-term follow-up of four allogeneic BM recipients who developed cerebral angiitis-like disease probably due to GVHD. The patients developed focal neurological signs, cognitive deficits and/or coma in association with GVHD, 2-18 years after transplantation, following reduction of immunosuppressive therapy. Magnetic resonance imaging was variable, showing generalized brain atrophy, ischemic lesions or leukoencephalopathy. Diagnosis of cerebral angiitis was confirmed by histopathological analysis of bioptic brain tissue and response to immunosuppressive therapy. By means of immunohistochemistry and immunofluorescence, perivascular lymphomononuclear cerebral infiltrates were shown to express the adhesion receptor, CD11a, and the chemokine receptor, CCR5. Our findings imply that GVHD should be considered in the differential diagnosis of noninfectious angiitis-like disease of the CNS in long-term survivors after allogeneic BMT. Infiltrating cells, in analogy to typical target organs of GVHD such as skin or liver, expressed CD11a and CCR5. These findings could be of etiopathological, diagnostic and therapeutic relevance.

Two cases of symptomatic cluster-like headache suggest the importance of sympathetic/parasympathetic balance.

Despite several reports on symptomatic cluster-like headache, there is no clear explanation of how different lesions thought to be causative are related to cluster-like headache. On the basis of two additional cases of symptomatic cluster headache, we discuss the possibility that an acute imbalance of the autonomic nervous system, namely a net overactivity of the parasympathetic system, may be able to trigger these headache attacks in patients who probably have an additional individual predisposition to react with a cluster-like headache. Such an imbalance can be due to an increase in parasympathetic tone (e.g. stimulation of parasympathetic fibres) or to a reduction of the sympathetic tone (e.g. a lesion of the sympathetic fibres).

[Herpes zoster: follow-up, complications and therapy]. / Herpes zoster: Verlauf, Komplikationen und Therapie.

In clinical practice herpes zoster infections are common. The cause is the reactivation of the herpes varicella virus that persists in the sensory ganglia after an earlier primary infection with shingles. There are several neurological complications such as meningitis, ventriculitis, encephalitis, myelitis, cerebral angiitis, myositis, paresis of motor nerves, acute polyneuritis, and most commonly post-zoster neuralgia. A proposed reason for these complications is the direct infiltration of the virus or a hematogenous infection. Some of the complications can be treated symptomatically such as post-zoster neuralgia and the occurrence of certain complications that can be prevented by the right choice of acute therapy.

[Neurological complications after organ transplantation]. / Neurologische Komplikationen nach Organtransplantation.

Following organ transplantation, 30-60% of patients develop neurologic complications which can be classified as pre-existing deficits due to the underlying disease, complications during surgery, metabolic encephalopathies, neurotoxicity of immunosuppressant agents, opportunistic CNS infections, and secondary malignomas as indirect side effects of immunosuppression. While encephalopathies, seizures, or CNS infection can occur in all types of transplantation, some specific neurological complications exist for different types of organ transplantation. In this review, the clinical symptoms and treatment of both the common neurological complications as well as the particular neurological syndromes after liver, heart, and bone marrow transplantation are discussed.

[Parry-Romberg syndrome and Rasmussen syndrome: only an incidental similarity?]. / Parry-Romberg-Syndrom und Rasmussen-Syndrom: nur zufällige Ahnlichkeiten?

The Parry-Romberg syndrome is a rare and poorly understood disease characterized by slowly progressive, localized atrophy of the skin, subcutaneous tissue, muscles, and bones. The atrophy is typically localized in the face and begins in youth. In some patients, imaging can show the lesions and atrophy of the ipsilateral hemisphere of the brain. We report on a patient in whom the disease has lasted 36 years and discuss the possibility that the Parry-Romberg syndrome is related to known autoimmune disorders of the soft tissue (e.g., linear scleroderma) and Rasmussen's syndrome. There are some remarkable clinical similarities between these two syndromes, including age of onset, unilateral manifestation, and occurrence of focal seizures. It is most probable that both diseases have an autoimmunological background.