'Too withdrawn' or 'too friendly': considering social vulnerability in two neuro-developmental disorders.

In some neuro-developmental disorders, the combined effect of intellectual disability and atypicalities of social cognition may put individuals at increased vulnerability in their social environment. The neuro-developmental disorders Williams syndrome, characterised by 'hypersociability', and autism spectrum disorders, characterised by 'social withdrawal', are at two extremes of atypical social functioning in humans. In this article, we use Williams syndrome and autism spectrum disorders as exemplars to demonstrate how atypicalities of social cognition may contribute to social vulnerability in these populations. The lives of individuals with both these disorders are marred by an increased risk of social isolation, bullying, unsteady relationships, employment difficulties and abuse. While different behavioural interventions have been tried to improve social functioning in these populations, there has been great variability in their success. Finally, we discuss different issues regarding social independence of these individuals; including employment, safety and decision making.

Does apolipoprotein E genotype modify the clinical expression of ALS?

BACKGROUND: The presence of the apolipoprotein E (ApoE) 4 genotype is associated with an earlier age of onset for Alzheimer's disease (AD) and several other neurodegenerative disorders. The objective of this study was to investigate the effect of ApoE genotypes on the clinical course of amyotrophic lateral sclerosis (ALS). METHODS: Eight hundred and fifty-two consecutive patients with sporadic ALS evaluated at a tertiary care center were investigated for the effect of ApoE genotype on age of onset, rate of motor disease progression, cognitive functioning, and survival in ALS. RESULTS: The frequencies of individual ApoE genotypes did not differ between patients with ALS and ALS-free Caucasian populations. Patients with different ApoE genotypes did not differ in the age of onset for ALS (years) (ApoE2 = 57.8 ± 13.7, ApoE3 = 57.3 ± 13.7, ApoE4 = 57.7 ± 13.2; P = 0.97), the rate of disease progression (Appel ALS score/month) (ApoE2 = 2.91 ± 2.66, ApoE3 = 2.67 ± 2.66, ApoE4 = 2.61 ± 2.47; P = 0.89), cognitive status (% cognitively impaired) (ApoE2 = 31.7, ApoE3 = 26.8, ApoE4 = 34.3, P = 0.28), or survival in years (ApoE2 = 3.79 ± 3.70, ApoE3 = 3.17 ± 2.27, ApoE4 = 3.05 ± 1.75; P = 0.85). CONCLUSIONS: Our results suggest that ApoE genotype does not modify clinical course of sporadic ALS, in stark contrast to the influence of ApoE genotype on the disease course of AD and other neurodegenerative disorders.

Frontal-lobe mediated behavioral dysfunction in amyotrophic lateral sclerosis.

BACKGROUND: Cognitive impairment secondary to frontal lobe atrophy exists in 40-60% of Amyotrophic Lateral Sclerosis (ALS) cases. We aimed to determine the prevalence of frontal-lobe mediated behavioral impairment in (ALS) and to ascertain its relationship to cognitive impairment. METHODS: Two-hundred and twenty five patients diagnosed with sporadic ALS were evaluated for behavioral dysfunction using the Frontal Systems Behavior Scale (FrSBe), a validated measure used to examine frontal-lobe mediated behaviors, specifically apathy, executive dysfunction and disinhibition; a total behavior score is also provided. Additionally, a subset of patients also underwent a comprehensive neuropsychological evaluation. RESULTS: Changes in the total FrSBe scores were observed in 24.4% of the patients and 39.6% of the patients had impairment in at least one behavioral domain with symptoms of Apathy being the most common (31.1%). Cognitively impaired ALS patients had worse total (P = 0.05) and apathy scores (P < 0.01); however, behavioral dysfunction was also present in 16% of the cognitively intact patients. Half of the behaviorally intact patients exhibited cognitive impairment. Significant correlations were observed for performance on certain neuropsychological tests (Animal fluency, Block Design, Logical Memory I and Verbal Series Attention Test) and severity of behavioral dysfunction on certain FrSBe sub scores. CONCLUSIONS: Frontal-lobe mediated behavioral dysfunction appears to be common in ALS. Cognitively impaired ALS patients had greater behavioral dysfunction. Recognition of behavioral and cognitive dysfunction may assist health-care providers and care-givers recognize changes in decision-making capacity and treatment compliance of patients with ALS.

ALS disease onset may occur later in patients with pre-morbid diabetes mellitus.

BACKGROUND: Several metabolic derangements associated with diabetes mellitus type 2 (DM) have been associated with a better outcome in amyotrophic lateral sclerosis (ALS), including hyperlipidemia and obesity. Here, we tested the hypothesis that DM would have a positive effect on the motor and cognitive findings of ALS. METHODS: We compared data from ALS patients with pre-morbid DM (ALS-DM; n = 175) versus without DM (ALS; n = 2196) with regard to the age of onset, rate of motor progression, survival, and neuropsychological test performance. RESULTS: The age of onset was later for women, Caucasians and patients with bulbar-onset ALS. However, we also found that after adjusting for gender, ethnicity and site of onset, DM was associated with a 4-year later onset of ALS (ALS = 56.3, ALS-DM = 60.3, P < 0.05). CONCLUSION: Diabetes mellitus type 2 may delay the onset of motor symptoms in ALS. These findings support other studies suggesting a relationship between the pathophysiology of ALS and metabolic derangements. Further investigations are needed to ascertain whether manipulating metabolic parameters would improve outcomes in ALS.

Basal ganglia calcifications in a case of biotinidase deficiency.

Biotinidase deficiency leads to a biotin-deficient state, with cardinal symptoms of ataxia, alopecia, and skin rash presenting in infancy. Previous reports of head CTs in patients with biotinidase deficiency did not note basal ganglia calcifications. We report the first case of biotinidase deficiency with basal ganglia calcifications. There were no symptoms referable to basal ganglia dysfunction.

Brain metabolism of progesterone, coping behaviour and emotional reactivity in male rats from two psychogenetically selected lines.

Brain metabolites of progesterone such as tetrahydroprogesterone (THP) act on GABAA receptors and have anxiolytic properties. The formation of THP and its 5 alpha-reduced precursor, dihydroprogesterone (DHP) was measured in vitro in various microdissected brain areas obtained from males of two psychogenetically selected rat lines, i.e. the Roman High-(RHA/Verh) and low-(RLA/Verh) Avoidance rats, which are known to differ in emotional reactivity and/or anxiety. The behavioural and neuroendocrine responses of these rats were also measured following exposure to a novel environment in two different test situations. The formation of DHP and THP was found to be significantly higher in the frontal cortex (FCX), and DHP in the bed nucleus of the stria terminalis (BST), of the hypoemotional RHA/Verh rats. In addition, enzymatic activity in the FCX was found to be inversely correlated with behavioural measures of anxiety. These results suggest that individual, possibly genetically-determined differences in brain production of endogenous anxiolytics derived from progesterone may account at least in part for the behavioural differences characterizing these two lines, and provide further evidence that neurosteroids acting on the GABAergic system may play an important role in modulating physiological and/or behavioural responses to environmental stressors.

Using paired-pulse facilitation to probe the mechanisms for long-term potentiation (LTP).

Paired-pulse facilitation (PPF) of excitatory synaptic transmission at Schaffer collateral synapses in the hippocampus was examined in relationship to long-term potentiation (LTP). PPF is a relatively simple-to-measure presynaptic form of synaptic plasticity. It is hypothesized that if the expression of LTP includes a presynaptic component, then PPF and LTP may interfere with one another. When averaged over more than 100 experiments, we observed no change in average PPF with LTP, as reported previously by a number of investigators. When individual experiments were analyzed, however, PPF significantly increased or decreased with LTP in direct relation to the initial value of PPF. There was also a linear relationship between the change in PPF and the magnitude of LTP. The PPF changes were specific to LTP and presynaptic in origin as they were input-specific and persisted with low concentrations of CNQX, GABAA and GABAB antagonists, different interstimulus intervals, and different Ca2+ concentrations. To understand the interaction between LTP and PPF, we constructed a simple model of LTP in which potential contributions by increases in three synaptic parameters were examined: the number of neurotransmitter release sites (n), the probability of release (p), and the postsynaptic unit potential (q). The data were fit by a model in which there were increases in n that changed the average p of the population, but not by a model that increased p or q alone. This is the first experimental evidence for an increase in the number of release sites with LTP, which could be due to pre- or postsynaptic mechanisms.

Pineal nitric oxide synthase: characteristics, adrenergic regulation and function.

Available studies indicate that the adrenergic stimulation of pineal cyclic GMP production involves stimulation of guanylyl cyclase activity by nitric oxide (NO) derived from arginine. This line of investigation was extended in the present study. Using a highly sensitive microassay, it was found that pineal NO synthase activity is present at levels approximately 30% of those in the cerebellum, that approximately 95% of enzyme activity is cytoplasmic, that the enzyme is Ca2+/calmodulin-dependent and that enzyme activity is inhibited by the arginine analog NG-nitro-L-arginine methyl ester (L-NAME). Norepinephrine treatment of intact glands in culture increased [3H]citrulline formation from [3H]arginine. This treatment also increased the formation of an NO-like compound, indicating that NO synthase activity in the intact gland is elevated by adrenergic stimulation. Studies on the effects of inhibition of NO synthase activity indicated that treatments known to inhibit NO synthase activity and the adrenergic stimulation of cyclic GMP accumulation did not inhibit adrenergic stimulation of pineal cyclic AMP, N-acetyltransferase activity or melatonin production. These observations support the hypothesis that NE stimulation of pineal cyclic GMP accumulation involves stimulation of a Ca2+/calmodulin-sensitive form of NO synthase, resulting in enhanced accumulation of NO; and, that although NO appears to play a role in the adrenergic stimulation of pineal cyclic GMP accumulation, it does not appear to play a critical role in the adrenergic stimulation of cyclic AMP, N-acetyltransferase activity or melatonin production.

Cognitive impairment in familial ALS.

BACKGROUND: ALS is a progressive neurodegenerative disorder that affects upper and lower motor neurons. Recent reports demonstrate cognitive impairment in patients with sporadic ALS (sALS). OBJECTIVE: To test whether patients with familial ALS (fALS) have cognitive impairment and whether it is of the same type and degree as observed in sporadic ALS. METHODS: Thirty-seven consecutive patients with fALS underwent comprehensive neuropsychological testing. Cognitive impairment was categorized by 1) cluster analysis of non-timed, non-motor dependent neuropsychological tests, 2) cutoff scores, and 3) clinical impression. RESULTS: By cluster analysis, 23 of 37 (62%) patients with fALS and 190 of 392 (48.5%) patients with sALS had cognitive impairment (difference not significant). Similar rates of impairment were found using clinical diagnostic criteria and cutoff score analysis. Neither motor scores nor the site of symptom onset correlated with cognitive impairment. Only age differed between the affected and unaffected fALS groups. CONCLUSIONS: The prevalence and pattern of cognitive impairment in familial ALS (fALS) is similar to that of sporadic ALS. For patients with fALS, the site of symptom onset did not correlate with cognitive impairment, but age did. Future studies will determine whether cognitive impairment in fALS correlates with specific genetic mutations or polymorphisms.

Prevalence and patterns of cognitive impairment in sporadic ALS.

OBJECTIVE: To investigate the prevalence and nature of cognitive changes associated with sporadic amyotrophic lateral sclerosis (ALS) using a large scale study. METHODS: Consecutive patients with sporadic ALS (n = 279) underwent comprehensive neurologic evaluation and neuropsychological testing. Testing data from normal controls (n = 129) were used for classification and comparison purposes. RESULTS: On non-motor, non-speed-dependent tasks, 51% of patients with ALS had evidence of cognitive impairment compared to 5% of controls. Cluster analysis suggested four patient subgroups: 49% intact, 32% with mild impairment, 13% with moderate impairment, and 6% with severe impairment. Forty-one patients (15%) met criteria for frontotemporal dementia (FTD). ALS patient subgroups, excluding the intact group, performed significantly lower on tests of executive function and memory than normal controls. Patients with more severe disease also had deficits in confrontation naming. Although memory function declined with increasing severity of overall cognitive impairment, only two patients had the severe memory loss typical of Alzheimer disease. Cognitive impairment was correlated with clinical measures of word-finding, phrase length, and motor programming. Cognitive impairment was not correlated with depression scores or severity or duration of motor or bulbar symptoms. Patients with bulbar vs limb-onset ALS were not different in either level of impairment or pattern of performance. CONCLUSIONS: These data confirm the presence of cognitive impairment in 50% of patients with ALS and particularly implicate executive dysfunction and mild memory decline in the disease process. More severe impairment occurs in a subset of patients with ALS and has features consistent with FTD.

Long-term potentiation involves increases in the probability of neurotransmitter release.

There is great interest in understanding the mechanisms of expression underlying long-term potentiation (LTP). They are agreed to involve an increase in synaptic efficacy, which is described by three multiplicative parameters: p, the probability of neurotransmitter release; n, the number of active release sites; and q, the postsynaptic unit response to transmitter release. We report three new lines of evidence suggesting that increases in p contribute to LTP expression. (i) When the contributions to LTP by p, n, and q are maximized, and p alone is decreased, another high-frequency stimulation elicits additional LTP. The additional potentiation is only associated with decreases in paired-pulse facilitation (PPF) suggesting an increase in p. (ii) There is an inverse relationship between baseline p [corrected] and the magnitude of LTP elicited, consistent with p [corrected] having more or less room to increase when p is smaller or greater. (iii) It has been shown that there is an inverse relationship between the magnitude of LTP induced and the associated changes in PPF. Now I find that decreasing p before inducing LTP moves the set-point for measuring those changes in PPF from before to after p is decreased, which would only occur if p contributes to LTP. Three lines of evidence, then, suggest that increases in p contribute to LTP expression, which is consistent with a presynaptic contribution to LTP. These experiments do not address potential postsynaptic contributions.

Differing mechanisms of expression for short- and long-term potentiation.

Long-term potentiation (LTP) is a use-dependent form of synaptic plasticity that is of great interest as a cellular mechanism that may contribute to memory storage. It is the sustained phase of population excitatory postsynaptic potential induced by high-frequency stimulation (HFS). HFS can also induce short-term potentiation (STP), a decremental potentiation lasting approximately 15 min. It has been unclear whether STP is simply a reversible form of LTP elicited by subthreshold stimuli or whether it is an independently expressed form of synaptic plasticity. We have attempted to clarify the relationship between LTP and STP in the extracellular recording technique in area CA1 of the adult rat hippocampal slice preparation to test four predictions of the hypothesis that LTP and STP are expressed via the same mechanism. First, occluding LTP expression should block STP expression. Saturating LTP under six different conditions, however, did not occlude STP expression. Second, occluding STP expression should occlude LTP expression. The partial or full occlusion of STP by two maneuvers (increasing the stimulus intensity used for HFS or applying 3-isobutyl-1-methylxanthine), however, did not occlude LTP expression. Third, LTP increases and decreases paired-pulse facilitation (PPF), and STP should have the same effect. STP did not change PFF, however. The first three results, then, suggest that STP and LTP are expressed via different mechanisms. Fourth, STP should be maximal near the LTP induction threshold, and then decrease above it. Surprisingly, STP was maximal at or very close to the LTP induction threshold, but it did not decrease above this threshold. This relationship suggests the possibility that STP and LTP share an induction step(s). What is the function of the independently expressed STP? We find that LTP can be induced by two HFSs, each of which is subthreshold for LTP, if the second is given during STP from the first. This suggests that STP can temporarily lower the LTP induction threshold. Three lines of evidence, then, suggest that STP and LTP may be expressed via different mechanisms; however, the proximity of STP saturation to LTP induction suggests that they may share an induction step(s). STP may also have the very important function of temporarily lowering the LTP induction threshold. Finally, these data suggestion caution in interpreting LTP data obtained <20-30 min after HFS, because they may be contaminated by STP, which appears to have different underlying mechanisms.

Inadequacy of information about drugs.

A questionary was sent back by 52 interns in three internal medicine services. It showed that approximately 60% of doctors lack "often" or "very often" pharmacological facts. Information about comparative efficacy is the most difficult to obtain.

Photoneural regulation of rat pineal nitric oxide synthase.

We report here a photoneural regulation of nitric oxide synthase (NOS) activity in the rat pineal gland. In the absence of the adrenergic stimulation following constant light exposure (LL) or denervation, pineal NOS activity is markedly reduced. A maximal drop is measured after 8 days in LL. When rats are housed back in normal light:dark (LD) conditions (12:12), pineal NOS activity returns to normal after 4 days. A partial decrease in pineal NOS activity is also observed when rats are placed for 8 days in LD 18:6 or shorter dark phases, indicating that pineal NOS activity reflects the length of the dark phase. Because it is known that norepinephrine (NE) is released at night from the nerve endings in the pineal gland and this release is blocked by exposure to light, our data suggest that NOS is controlled by adrenergic mechanisms. Our observation may also explain the lack of cyclic GMP response to NE observed in animals housed in constant light.

Changes in paired-pulse facilitation suggest presynaptic involvement in long-term potentiation.

Long-term potentiation (LTP) is a use-dependent form of synaptic plasticity that is of great interest as a potential cellular substrate underlying memory. It is important to determine the pre- and/or postsynaptic locus of LTP expression in order to study its underlying mechanisms. Despite intensive investigation, however, its locus of expression remains uncertain. It has been hypothesized that if LTP expression includes a presynaptic locus then it may alter the expression of another presynaptically mediated form of potentiation like paired-pulse facilitation (PPF), which is an increase in a second population excitatory postsynaptic potential when it is elicited shortly after a first. Previous authors have found no change in PPF in association with LTP. We re-examined the hypothesis, however, to reconcile the negative PPF data with other data that have suggested presynaptic involvement in LTP. Extracellular recordings were made in area CA1 of the rat hippocampal slice preparation. Surprisingly, PPF both increased and decreased significantly in association with LTP. The changes in PPF occurred in a predictable way, however. They correlated inversely with initial PPF magnitude so that a larger initial PPF was associated with a decrease in PPF with LTP while a smaller initial PPF was associated with an increase. Because PPF increased or decreased in individual slices in association with LTP, the average PPF of all slices did not change, in agreement with previous studies. The changes in PPF were also specific to LTP; that is, they were input specific, were not due to changes in inhibition or nonspecific effects of high-frequency stimulation, were not due to active postsynaptic currents or their nonlinear summation, and PPF changed with the same time course as LTP. We conclude that the mechanism of early LTP expression includes at least the presynaptic locus. Two hypotheses regarding the presynaptic mechanism underlying LTP expression, which are consistent with finding both increases and decreases in PPF with LTP, are (1) that there is an increase in the number of release sites with LTP or (2) that there is an increase in both the number of release sites and the probability of neurotransmitter release. Increases in the probability of neurotransmitter release alone would not appear to account for our findings since such increases have been associated only with decreases in PPF. Our findings do not exclude additional postsynaptic involvement.(ABSTRACT TRUNCATED AT 400 WORDS)