Could ecosystem management provide a new framework for Alzheimer's disease?

Alzheimer's disease (AD) is a progressive neurodegenerative brain disorder that involves a plethora of molecular pathways. In the context of therapeutic treatment and biomarker profiling, the amyloid-beta (Aß) peptide constitutes an interesting research avenue that involves interactions within a complex mixture of Aß alloforms and other disease-modifying factors. Here, we explore the potential of an ecosystem paradigm as a novel way to consider AD and Aß dynamics in particular. We discuss the example that the complexity of the Aß network not only exhibits interesting parallels with the functioning of complex systems such as ecosystems but that this analogy can also provide novel insights into the neurobiological phenomena in AD and serve as a communication tool. We propose that combining network medicine with general ecosystem management principles could be a new and holistic approach to understand AD pathology and design novel therapies.

Homoarginine levels are regulated by L-arginine:glycine amidinotransferase and affect stroke outcome: results from human and murine studies.

BACKGROUND: Endogenous arginine homologues, including homoarginine, have been identified as novel biomarkers for cardiovascular disease and outcomes. Our studies of human cohorts and a confirmatory murine model associated the arginine homologue homoarginine and its metabolism with stroke pathology and outcome. METHODS AND RESULTS: Increasing homoarginine levels were independently associated with a reduction in all-cause mortality in patients with ischemic stroke (7.4 years of follow-up; hazard ratio for 1-SD homoarginine, 0.79 [95% confidence interval, 0.64-0.96]; P=0.019; n=389). Homoarginine was also independently associated with the National Institutes of Health Stroke Scale+age score and 30-day mortality after ischemic stroke (P<0.05; n=137). A genome-wide association study revealed that plasma homoarginine was strongly associated with single nucleotide polymorphisms in the L-arginine:glycine amidinotransferase (AGAT) gene (P<2.1 × 10(-8); n=2806), and increased AGAT expression in a cell model was associated with increased homoarginine. Next, we used 2 genetic murine models to investigate the link between plasma homoarginine and outcome after experimental ischemic stroke: (1) an AGAT deletion (AGAT(-/-)) and (2) a guanidinoacetate N-methyltransferase deletion (GAMT(-/-)) causing AGAT upregulation. As suggested by the genome-wide association study, homoarginine was absent in AGAT(-/-) mice and increased in GAMT(-/-) mice. Cerebral damage and neurological deficits in experimental stroke were increased in AGAT(-/-) mice and attenuated by homoarginine supplementation, whereas infarct size in GAMT(-/-) mice was decreased compared with controls. CONCLUSIONS: Low homoarginine appears to be related to poor outcome after ischemic stroke. Further validation in future trials may lead to therapeutic adjustments of homoarginine metabolism that alleviate stroke and other vascular disorders.

Cognitive, affective and behavioural disturbances following vascular thalamic lesions: a review.

During the last decades, many studies have shown that the thalamus is crucially involved in language and cognition. We critically reviewed a study corpus of 465 patients with vascular thalamic lesions published in the literature since 1980. 42 out of 465 (9%) cases with isolated thalamic lesions allowed further neurocognitive analysis. On the neurolinguistic level, fluent output (=31/33; 93.9%), normal to mild impairment of repetition (=33/35; 94.3%), mild dysarthria (=8/9; 88.9%) and normal to mild impairment of auditory comprehension (=27/34; 79.4%) were most commonly found in the group of patients with left and bilateral thalamic lesions. The taxonomic label of thalamic aphasia applied to the majority of the patients with left thalamic damage (=7/11; 63.6%) and to one patient with bithalamic lesions (=1/1). On the neuropsychological level, almost 90% of the left thalamic and bithalamic patient group presented with amnestic problems, executive dysfunctions and behaviour and/or mood alterations. In addition, two thirds (2/3) of the patients with bilateral thalamic damage presented with a typical cluster of neurocognitive disturbances consisting of constructional apraxia, anosognosia, desorientation, global intellectual dysfunctioning, amnesia, and executive dysfunctions associated with behaviour and/or mood alterations. Our study supports the long-standing view of a 'lateralised linguistic thalamus' but restates the issue of a 'lateralised cognitive thalamus'. In addition, critical analysis of the available literature supports the view that aphasia following left or bithalamic damage constitutes a prototypical linguistic syndrome.

Crossed aphasia and visuo-spatial neglect following a right thalamic stroke: a case study and review of the literature.

Crossed aphasia in dextrals (CAD) following pure subcortical lesions is rare. This study describes a right-handed patient with an ischemic lesion in the right thalamus. In the post-acute phase of the stroke, a unique combination of 'crossed thalamic aphasia' was found with left visuo-spatial neglect and constructional apraxia. On the basis of the criteria used in Mariën et al. [67], this case-report is the first reliable representative of vascular CAD following an isolated lesion in the right thalamus. Furthermore, this paper presents a detailed analysis of linguistic and cognitive impairments of 'possible' and 'reliable' subcortical CAD-cases published since 1975. Out of 25 patients with a pure subcortical lesion, nine cases were considered as 'possibly reliable or reliable'. A review of these cases reveals that: 1) demographic data are consistent with the general findings for the entire group of vascular CAD, 2) the neurolinguistic findings do not support the data in the general CAD-population with regard to a) the high prevalence of transcortical aphasia and b) the tendency towards a copresence of an oral versus written language dissociation and a 'mirror-image' lesion-aphasia profile, 3) subcortical CAD is not a transient phenomenon, 4) the lesion-aphasia correlations are not congruent with the high incidence of anomalous cases in the general CAD-population, 5) neuropsychological impairments may accompany subcortical CAD.

Effect of genetic background on acoustic startle response in fragile X knockout mice.

To study the effect of genetic background on the Fmr1 knockout mutation in mice, we compared the acoustic startle response (ASR) of male fragile X knockout mice bred in three different genetic backgrounds, including C57BL/6J (C57BL/6J x 129P2/OlaHsd) F1 and F2 intercross. ASR is used as a behavioural tool to assess the neuronal basis of behavioural plasticity. For each background studied, fragile X knockouts clearly differed in ASR from their control littermates. C57BL/6J knockouts showed an increase in ASR in response to the lowest stimulus of 90 dB and a decrease in ASR in response to the highest stimulus of 110 dB when compared with control mice, whereas knockouts of the F1 generation showed significantly lower ASRs for all the three stimulus intensities used when compared with control littermates. These data demonstrate that the expression of the fragile X phenotype in ASR of fragile X knockout mice may be influenced by the presence of 129 genes in the genetic background and that modifier genes may influence the fragile X phenotype. Surprisingly, and in contrast with knockouts of the F1 generation that showed a decreased ASR, knockouts of the F2 generation showed a significantly increased ASR compared with their control littermates. This is especially remarkable as both F1 and F2 mice consist of 50% of the genetic material from each of the parental strains C57BL/6J and 129P2/OlaHsd strain. Thus, the different distribution of the genetic background seems to be responsible for the difference in ASR between F1 and F2. This opposite ASR in the F1 and F2 generations is unique in behavioural studies and has, to our knowledge, not been previously reported.

Disrupted auto-activation, dysexecutive and confabulating syndrome following bilateral thalamic and right putaminal stroke.

OBJECTIVE: Clinical, neuropsychological, structural and functional neuroimaging results are reported in a patient who developed a unique combination of symptoms after a bi-thalamic and right putaminal stroke. The symptoms consisted of dysexecutive disturbances associated with confabulating behavior and auto-activation deficits. BACKGROUND: Basal ganglia and thalamic lesions may result in a variety of motor, sensory, neuropsychological and behavioral syndromes. However, the combination of a dysexecutive syndrome complicated at the behavioral level with an auto-activation and confabulatory syndrome has never been reported. METHODS: Besides clinical and neuroradiological investigations, an extensive set of standardized neuropsychological tests was carried out. RESULTS: In the post-acute phase of the stroke, a dysexecutive syndrome was found in association with confabulating behavior and auto-activation deficits. MRI showed focal destruction of both thalami and the right putamen. Quantified ECD SPECT revealed bilateral hypoperfusions in the basal ganglia and thalamus but no perfusion deficits were found at the cortical level. CONCLUSION: The combination of disrupted auto-activation, dysexecutive and confabulating syndrome in a single patient following isolated subcortical damage renders this case exceptional. Although these findings do not reveal a functional disruption of the striato-ventral pallidal-thalamic-frontomesial limbic circuitry, they add to the understanding of the functional role of the basal ganglia in cognitive and behavioral syndromes.

Guanidino compounds after creatine supplementation in renal failure patients and their relation to inflammatory status.

BACKGROUND: Specific guanidino compounds have been described as uraemic toxins and their concentrations are increased in renal failure due to dimished glomerular filtration, whereas the guanidino compound creatine is used as a performance-enhancing substance in athletes. The present study investigates the effects of creatine supplementation on plasma guanidino compounds in a chronic haemodialysis population. METHODS: Twenty male haemodialysis patients were included in a placebo-controlled cross-over trial. Patients were treated with creatine (2 g/day) or placebo during two treatment periods of 4 weeks, separated by a washout of 4 weeks. Plasma guanidino compounds and routine biochemical parameters were determined, as well as the prognostic inflammatory and nutritional index (PINI). RESULTS: Upon creatine supplementation, guanidinoacetate concentrations decreased by 15%, due to inhibition of creatine synthesis. Concentrations of alpha-keto-delta-guanidinovaleric acid increased three-fold and argininic acid concentrations doubled. Guanidinosuccinate concentrations did not change, but correlated inversely with CRP (r = -0.736; P = 0.001), PINI-score (r = -0.716; P = 0.002) and correlated positively with plasma urea concentration (r = 0.54; P = 0.02). CONCLUSIONS: Creatine supplementation in haemodialysis patients significantly altered the concentration of specific guanidino compounds. Guanidinosuccinate correlated positively with plasma urea and negatively with inflammation markers.

Epileptic fits and epilepsy in the elderly: general reflections, specific issues and therapeutic implications.

Seizures and epilepsy are commonly encountered in the elderly. Diagnosis is not always straightforward as reliable history is often difficult to obtain and EEG findings can be non-specific. When to treat and how may be difficult choices as adequate studies in elderly are rather scarce. Treatment should be based on careful assessment and comparison of risk/benefit profiles of various anti-epileptic drugs (AEDs) in this specific elderly population. Since most AEDs are effective in terms of seizure control in the elderly, the choice of treatment is often determined by tolerability, pharmacokinetic profile and drug interactions of AEDs. As recently introduced AEDs have a better safety profile compared to older agents it seems logical to initiate treatment in the frail elderly patient with those more modern AEDs. In this review some distinctive clinical features of epilepsy in the elderly are discussed in three sections (general issues, special issues and selected treatment options with special reference to medicinal treatment).

Impairment of syntax and lexical semantics in a patient with bilateral paramedian thalamic infarction.

Bilateral vascular thalamic lesions are rare. Although a variety of neurobehavioral manifestations have been described, the literature is less documented with regard to accompanying linguistic disturbances. This article presents an in-depth neurolinguistic analysis of the language symptoms of a patient who incurred bilateral paramedian ischemic damage of the thalamus. In the post-acute phase of the stroke, a unique combination of transcortical sensory aphasia with syntactic impairment was found. Because of this atypical semiological association, additional analyses of spontaneous speech were performed. In spite of the typological affinity with the grammatic characteristic of marked simplification of syntax observed in Broca's aphasia, only a wordclass specific, lexical-semantic deficit for verbs was objectified. The hypothesis that lexical-semantic disturbances in our patient might result from a functional deafferentiation of both thalami with the frontal lobe is supported by: (1) associated neuropsychological deficits of frontal origin and (2) frontal-like behavioral disturbances.

Pathophysiology of language switching and mixing in an early bilingual child with subcortical aphasia.

Acquired aphasia after circumscribed vascular subcortical lesions has not been reported in bilingual children. We report clinical and neuroimaging findings in an early bilingual boy who incurred equally severe transcortical sensory aphasia in his first language (L1) and second language (L2) after a posterior left thalamic hemorrhage. Following recurrent bleeding of the lesion the aphasic symptoms substantially aggravated. Spontaneous pathological language switching and mixing were found in both languages. Remission of these phenomena was reflected on brain perfusion SPECT revealing improved perfusion in the left frontal lobe and left caudate nucleus. The parallelism between the evolution of language symptoms and the SPECT findings may demonstrate that a subcortical left frontal lobe circuity is crucially involved in language switching and mixing.

Plasma guanidino compounds are altered by oral creatine supplementation in healthy humans.

Although creatine is one of the most widely used nutritional supplements for athletes as well as for patients with neuromuscular disorders, the effects of oral creatine supplementation on endogenous creatine synthesis in humans remains largely unexplored. The aim of the present study was to investigate the metabolic consequences of a frequently used, long-term creatine ingestion protocol on the circulating creatine synthesis precursor molecules, guanidinoacetate and arginine, and their related guanidino compounds. For this purpose, 16 healthy young volunteers were randomly divided to ingest in a double-blind fashion either creatine monohydrate or placebo (maltodextrine) at a dosage of 20 g/day for the first week (loading phase) and 5 g/day for 19 subsequent wk (maintenance phase). Fasting plasma samples were taken at baseline and at 1, 10, and 20 wk of supplementation, and guanidino compounds were determined. Plasma guanidinoacetate levels were reduced by 50% after creatine loading and remained approximately 30% reduced throughout the maintenance phase. Several circulating guanidino compound levels were significantly altered after creatine loading but not during the maintenance phase: homoarginine (+35%), alpha-keto-delta-guanidinovaleric acid (+45%), and argininic acid (+75%) were increased, whereas guanidinosuccinate was reduced (-25%). The decrease in circulating guanidinoacetate levels suggests that exogenous supply of creatine chronically inhibits endogenous synthesis at the transamidinase step in humans, supporting earlier animal studies showing a powerful repressive effect of creatine on l-arginine:glycine amidinotransferase. Furthermore, these data suggest that this leads to enhanced utilization of arginine as a substrate for secondary pathways.