The Emerging Role of the Gut-Brain-Microbiota Axis in Neurodevelopmental Disorders.

Autism spectrum disorder (ASD; autism) is a prevalent neurodevelopmental disorder associated with changes in gut-brain axis communication. Gastrointestinal (GI) symptoms are experienced by a large proportion of individuals diagnosed with autism. Several mutations associated with autism modify cellular communication via neuronal synapses. It has been suggested that modifications to the enteric nervous system, an intrinsic nervous system of the GI tract, could contribute to GI dysfunction. Changes in gut motility, permeability, and the mucosal barrier as well as shifts in the large population of microbes inhabiting the GI tract could contribute to GI symptoms. Preclinical research has demonstrated that mice expressing the well-studied R451C missense mutation in Nlgn3 gene, which encodes cell adhesion protein neuroligin-3 at neuronal synapses, exhibit GI dysfunction. Specifically, NL3R451C mice show altered colonic motility and faster small intestinal transit. As well as dysmotility, macrophages located within the gut-associated lymphoid tissue of the NL3R451C mouse caecum show altered morphology, suggesting that neuro-inflammation pathways are modified in this model. Interestingly, NL3R451C mice maintained in a shared environment demonstrate fecal microbial dysbiosis indicating a role for the nervous system in regulating gut microbial populations. To better understand host-microbe interactions, further clarification and comparison of clinical and animal model profiles of dysbiosis should be obtained, which in turn will provide better insights into the efforts taken to design personalized microbial therapies. In addition to changes in neurophysiological measures, the mucosal component of the GI barrier may contribute to GI dysfunction more broadly in individuals diagnosed with a wide range of neurological disorders. As the study of GI dysfunction advances to encompass multiple components of the gut-brain-microbiota axis, findings will help understand future directions such as microbiome engineering and optimisation of the mucosal barrier for health.

Towards Identifying Genetic Biomarkers for Gastrointestinal Dysfunction in Autism.

This study investigated genetic biomarkers for gastrointestinal dysfunction symptoms in order to provide further information on the genetic risk for GI dysfunction associated with autism. The single nucleotide polymorphisms of sixty participants with autism and/or gastrointestinal dysfunction were analyzed. The autism group had a moderate statistical significance for the Prolactin (PRL) (OR 6.35, p value 0.069) and Interleukin 10 (IL-10) (OR 0.25, p value 0.087) SNPs. The GI dysfunction group had a strong statistical significance for the Cluster of Differentiation 38 (CD38) (OR 6.88, p value 0.005) and oxytocin receptor (OXTR) (OR 0.27, p value 0.036) SNPs. The potential use of PRL, IL-10, CD38, and OXTR SNP expression as biomarkers for GI dysfunction in autism warrants further research.

Language disintegration in dementia: effects of etiology and severity.

The speech characteristics on a standardized picture description task of 26 subjects with presumed senile dementia of the Alzheimer type (SDAT) and 13 subjects with stroke-related dementia (SRD) were compared to 15 normal subjects over age 59 years. Compared to the normal subjects, the dementia subjects used fewer total words, fewer unique words, fewer prepositional phrases, fewer subordinate clauses, and more incomplete sentence fragments. Lexical deficits tended to be more severe than syntactic ones, confirming prior suggestions that lexicon is more vulnerable to disruption in dementia than syntax. Greater dementia severity among the SDAT subjects was associated with marked difficulties in accessing the mental lexicon (increased use of empty words, indefinite anaphora, and pronouns). Greater dementia severity in the SRD subjects was associated with laconic speech that was syntactially less complex. Diffuse brain injury (as typified by SDAT) appears to disproportionately affect lexicon whereas multifocal injury (as typified by SRD) has a disproportionate effect on syntax (assuming that focal lesions of the posterior language zone have been excluded). The speech characteristics of the mild SDAT subjects showed similarities to those of anomic or semantic aphasia whereas the speech of the more advanced SDAT subjects showed similarities to Wernicke aphasia or transcortical sensory aphasia. The speech of the subjects with more severe SRD showed some similarities to Broca aphasia. The most important nonlinguistic deficit in both the SRD and the SDAT groups was a failure to make relevant observations during the picture description task. Perseverations were present in the speech of both the SRD and SDAT subjects, whereas aposiopesis, logorrhea, and palilalia were more typical of the SDAT subjects. Laconic speech was more characteristic of the SRD subjects.

Altered patterns of word associations in dementia and aphasia.

The word associations of 38 demented, 17 aphasic, and 22 normal subjects were studied. Both normal and brain-injured subjects appear to make judgments about the grammatical class of the word stimulus. Certain stimulus words (especially nouns and adjectives) elicit paradigmatic responses whereas other words (especially verbs and adverbs) elicit syntagmatic responses. The mechanism producing syntagmatic responses seems relatively resistant to deterioration in dementia or aphasia. However, in dementia the mechanism that generates paradigmatic responses becomes progressively less efficient (possibly due to a loss of semantic markers) and consequently more random (idiosyncratic) responses emerge. Perseverative responses, inhibited in normal subjects, are more prevalent in dementia. Anomic aphasics show a pattern of word associations similar to that of subjects with mild dementia. Broca's aphasics, while making fewer paradigmatic associations than normals, retain enough self-monitoring mechanisms so that few idiosyncratic and perseverative responses are made while more null responses occur. Wernicke's aphasics show a marked shift away from a paradigmatic word association strategy, possibly due to an inability to access semantic markers or a true loss of these markers. Metalinguistic deficits (i.e., a failure to adopt an appropriate strategy) may also contribute to this shift away from paradigmatic associations. Furthermore, a disruption of self-monitoring mechanisms in Wernicke's aphasia leads to an increase in perseverative and idiosyncratic responses.

Intrusions and perseverations.

Twenty-two subjects with presumed senile dementia of the Alzheimer's type (SDAT), twenty-two with dementia other than SDAT, twenty with aphasia, and seventeen healthy controls over 50 years of age were examined for intrusions and perseverations. Perseverations were defined as the immediate inappropriate repetition of a prior response whereas intrusions were defined as the inappropriate repetition of prior responses after intervening stimuli. Intrusions and perseverations occurred in demented and aphasic subjects, but were rare in controls. Intrusions occurred most often in SDAT or Wernicke aphasia, but also in dementia other than SDAT. Intrusions were not correlated with dementia severity. Intrusions are a useful sign of dementia, but they cannot be considered pathognomonic of SDAT. They appear to arise when subjects are unable to access correct responses from long-term memory and instead substitute erroneous responses selected from short-term memory. Perseverations were most common in the Wernicke aphasics and subjects with dementia due to communicating hydrocephalus. Although frontal lobe dysfunction is prominent in communicating hydrocephalus, it is absent in cases of Wernicke aphasia. Thus, we have confirmed prior suggestions that perseveration can occur in the absence of frontal lobe injury. Failure to self-monitor speech as well as an inability to change mental set probably plays an important role in the genesis of perseverations. There was no statistically significant correlation between dementia severity and number of perseverations. Low correlations were found between intrusions and perseverations suggesting that these seemingly similar behaviors are distinct and are probably produced by separate neuropsychological mechanisms.

A case of subcortical dementia due to sarcoidosis of the hypothalamus and fornices.

A patient with sarcoidosis involving predominantly the hypothalamus and fornices was evaluated for dementia. He showed a relative sparing of fund of knowledge and orientation. Memory skills, particularly short-term memory, were severely impaired. Behavioral changes included apathy and a lack of spontaneity. Insight was relatively preserved. The pattern of his deficits showed some similarities to the pattern reported in patients with Huntington's disease and was different from that described in Alzheimer's disease. The dementia caused by subcortical pathology may differ in important respects from that caused by diffuse cortical dysfunction.