Cary S. Kogan

Integrative cortical dysfunction and pervasive motion perception deficit in fragile X syndrome

Background: Fragile X syndrome (FXS) is associated with neurologic deficits recently attributed to the magnocellular pathway of the lateral geniculate nucleus. Objective: To test the hypotheses that FXS individuals 1) have a pervasive visual motion perception impairment affecting neocortical circuits in the parietal lobe and 2) have deficits in integrative neocortical mechanisms necessary for perception of complex stimuli. Methods: Psychophysical tests of visual motion and form perception defined by either first-order (luminance) or second-order (texture) attributes were used to probe early and later occipito-temporal and occipito-parietal functioning. Results: When compared to developmental- and age-matched controls, FXS individuals displayed severe impairments in first- and second-order motion perception. This deficit was accompanied by near normal perception for first-order form stimuli but not second-order form stimuli. Conclusions: Impaired visual motion processing for first- and second-order stimuli suggests that both early- and later-level neurologic function of the parietal lobe are affected in Fragile X syndrome (FXS). Furthermore, this deficit likely stems from abnormal input from the magnocellular compartment of the lateral geniculate nucleus. Impaired visual form and motion processing for complex visual stimuli with normal processing for simple (i.e., first-order) form stimuli suggests that FXS individuals have normal early form processing accompanied by a generalized impairment in neurologic mechanisms necessary for integrating all early visual input.

Lifespan changes in working memory in fragile X premutation males

Fragile X syndrome is the worlds most common hereditary cause of developmental delay in males and is now well characterized at the biological, brain and cognitive levels. The disorder is caused by the silencing of a single gene on the X chromosome, the FMR1 gene. The premutation (carrier) status, however, is less well documented but has an emerging literature that highlights a more subtle profile of executive cognitive deficiencies that mirror those reported in fully affected males. Rarely, however, has the issue of age-related declines in cognitive performance in premutation males been addressed. In the present study, we focus specifically on the cognitive domain of working memory and its subcomponents (verbal, spatial and central executive memory) and explore performance across a broad sample of premutation males aged 18-69 years matched on age and IQ to unaffected comparison males. We further tease apart the premutation status into those males with symptoms of the newly identified neurodegenerative disorder, the fragile X-associated tremor/ataxia syndrome (FXTAS) and those males currently symptom-free. Our findings indicate a specific vulnerability in premutation males on tasks that require simultaneous manipulation and storage of new information, so-called executive control of memory. Furthermore, this vulnerability appears to exist regardless of the presence of FXTAS symptoms. Males with FXTAS symptoms demonstrated a more general impairment encompassing phonological working memory in addition to central executive working memory. Among asymptomatic premutation males, we observed the novel finding of a relationship between increased CGG repeat size and impairment to central executive working memory.

Impact of the Fragile X mental retardation 1 (FMR1) gene premutation on neuropsychiatric functioning in adult males without fragile X-associated Tremor/Ataxia syndrome: A controlled study†

Fragile X Syndrome is the most common heritable form of mental retardation caused by silencing of the FMR1 gene, which arises from intergenerational trinucleotide repeat expansion leading to full mutation. An intermediary carrier condition, known as the premutation, is characterized by expansion up to 200 repeats without concomitant gene silencing. This prevalent allelic variant was initially thought to be free of phenotypic effects. However, recent reports have identified a degenerative disease, Fragile X‐associated Tremor/Ataxia Syndrome (FXTAS) in older men as well as premature ovarian failure in women. Previously reports are inconsistent regarding the neuropsychiatric phenotype associated with premutation due to small sample sizes, ascertainment bias, lack of adequate control groups, administration of measures with poor psychometric properties, and the confounding effects of FXTAS. We addressed these problems by conducting a controlled study of male carriers (n = 40) of the premutation without manifest symptoms of FXTAS, comparing their responses on specific, reliable, and valid measures of neuropsychiatric functioning to those of individuals with shared family environment (n = 22) and non‐carrier comparison males (n = 43). Multivariate analyses revealed that the premutation confers significant risk for working memory difficulties, an associated feature of Attention‐Deficit Disorder. Furthermore, both the family controls and men with premutation exhibited higher rates of Alcohol Abuse as compared to non‐carrier control men. These findings highlight the importance of recognizing the distinct phenotypic outcomes that characterize the Fragile X premutation and the subtle risk factors that can act as precursors to more significant psychiatric impairment.

Selective executive markers of at-risk profiles associated with the fragile X premutation

Objective: This study determined whether CGG repeat length moderates the relationship between age and performance on selective measures of executive function in premutation carriers (PM) who are asymptomatic for a recently described late-onset neurodegenerative disorder, fragile X–associated tremor/ataxia syndrome (FXTAS). Methods: Forty PM men aged 18–69 years with a family history of fragile X syndrome underwent neuropsychological tests of inhibition and working memory. We examined only men who are asymptomatic for FXTAS. Multiple regression analyses were conducted to examine the moderating role of CGG repeat length on the relation between age and performance on inhibition and working memory tasks. Results: With increasing age and only in men with an FMR1 expansion in the upper premutation range (>100 CGG repeats) was there an association between age and poorer task performance on selective executive function measures involving inhibition (p < 0.05) and executive working memory (p < 0.01). Men in the lower premutation range (<100 CGG repeats) were relatively risk-free from any cognitive aging effects associated with CGG repeat expansions. Conclusions: We conclude that neural networks in the prefrontal cortex may be highly susceptible to age-related neurotoxic effects in the upper size range of the FMR1 premutation. Future longitudinal studies will be needed to determine whether specific executive markers may serve to distinguish those at greatest risk for severe cognitive decline or dementia associated with FXTAS.

The classification of Obsessive-Compulsive and Related Disorders in the ICD-11.

BACKGROUND To present the rationale for the new Obsessive-Compulsive and Related Disorders (OCRD) grouping in the Mental and Behavioural Disorders chapter of the Eleventh Revision of the World Health Organizations International Classification of Diseases and Related Health Problems (ICD-11), including the conceptualization and essential features of disorders in this grouping. METHODS Review of the recommendations of the ICD-11 Working Group on the Classification for OCRD. These sought to maximize clinical utility, global applicability, and scientific validity. RESULTS The rationale for the grouping is based on common clinical features of included disorders including repetitive unwanted thoughts and associated behaviours, and is supported by emerging evidence from imaging, neurochemical, and genetic studies. The proposed grouping includes obsessive-compulsive disorder, body dysmorphic disorder, hypochondriasis, olfactory reference disorder, and hoarding disorder. Body-focused repetitive behaviour disorders, including trichotillomania and excoriation disorder are also included. Tourette disorder, a neurological disorder in ICD-11, and personality disorder with anankastic features, a personality disorder in ICD-11, are recommended for cross-referencing. LIMITATIONS Alternative nosological conceptualizations have been described in the literature and have some merit and empirical basis. Further work is needed to determine whether the proposed ICD-11 OCRD grouping and diagnostic guidelines are mostly likely to achieve the goals of maximizing clinical utility and global applicability. CONCLUSION It is anticipated that creation of an OCRD grouping will contribute to accurate identification and appropriate treatment of affected patients as well as research efforts aimed at improving our understanding of the prevalence, assessment, and management of its constituent disorders.

A comparative neuropsychological test battery differentiates cognitive signatures of Fragile X and Down syndrome

BACKGROUND Standardised neuropsychological and cognitive measures present some limitations in their applicability and generalisability to individuals with intellectual disability (ID). Alternative approaches to defining the cognitive signatures of various forms of ID are needed to advance our understanding of the profiles of strengths and weaknesses as well as the affected brain areas. AIM To evaluate the utility and feasibility of six non-verbal comparative neuropsychological (CN) tasks administered in a modified version of the Wisconsin General Test Apparatus (WGTA) to confirm and extend our knowledge of unique cognitive signatures of Fragile X syndrome (FXS) and Down syndrome (DS). METHOD A test battery of CN tasks adapted from the animal literature was administered in a modified WGTA. Tasks were selected that have established or emerging brain-behaviour relationships in the domains of visual-perceptual, visual-spatial, working memory and inhibition. RESULTS Despite the fact that these tasks revealed cognitive signatures for the two ID groups, only some hypotheses were supported. Results suggest that whereas individuals with DS were relatively impaired on visual-perceptual and visual-spatial reversal learning tasks they showed strengths in egocentric spatial learning and object discrimination tasks. Individuals with FXS were relatively impaired on object discrimination learning and reversal tasks, which was attributable to side preferences. In contrast, these same individuals exhibited strengths in egocentric spatial learning and reversal tasks as well as on an object recognition memory task. Both ID groups demonstrated relatively poor performance for a visual-spatial working memory task. CONCLUSION Performance on the modified WGTA tasks differentiated cognitive signatures between two of the most common forms of ID. Results are discussed in the context of the literature on the cognitive and neurobiological features of FXS and DS.

Selective spatial processing deficits in an at-risk subgroup of the fragile X premutation

Until a decade ago, it was assumed that males with the fragile X premutation were unaffected by any cognitive phenotype. Here we examined the extent to which CGG repeat toxicity extends to visuospatial functioning in male fragile X premutation carriers who are asymptomatic for a late-onset neurodegenerative disorder, fragile X-associated tremor/ataxia syndrome (FXTAS). Thirty-three premutation males aged 20-68 years [divided into two groups: 16 low-repeat carriers (CGG ≥ 55 ≤ 100) and 17 high-repeat carriers (CGG>100)] with a family history of fragile X syndrome and 62 non-affected adult males with normal FMR1 alleles were recruited. Subjects underwent neuropsychological tests of visuospatial and visual working memory functioning and visuoperceptual processing. On measures of visuospatial processing, the high-repeat carriers performed significantly worse than the normal allele group when age and IQ were covaried out. With increasing age and only in carriers of a larger (>100 repeats) premutation allele was there a greater decrement in visuospatial working memory functioning. Performance on spatial and perceptual judgement tasks failed to show similar specificity in males within the upper premutation range. We conclude that identification of selective visuospatial impairments in carriers of a larger premutation allele indicates greater CGG repeat toxicity in specific neural regions. Longitudinal follow-up studies will be needed to determine whether subtle decline in visuospatial functioning is associated with the later onset of motor symptoms of FXTAS.

Capturing the fragile X premutation phenotypes: a collaborative effort across multiple cohorts

OBJECTIVE To capture the neuropsychological profile among male carriers of the FMR1 premutation allele (55-200 CGG repeats) who do not meet diagnostic criteria for the late-onset fragile X-associated tremor/ataxia syndrome, FXTAS. METHOD We have initiated a multicenter collaboration that includes 3 independent cohorts, totaling 100 carriers of the premutation and 216 noncarriers. The initial focus of this collaboration has been on executive function. Four executive function scores are shared among the 3 cohorts (Controlled Oral Word Association Test, Stroop Color-Word Test, and Wechsler backward digit span and letter-number sequencing) whereas additional executive function scores are available for specific cohorts (Behavior Dyscontrol Scale, Hayling Sentence Completion Test Part B, and Wisconsin Card Sorting Test). Raw scores were analyzed by using statistical models that adjust for cohort-specific effects as well as age and education. RESULTS Carriers scored significantly lower compared to noncarriers on the Stroop Color-Word Test (p = .01), Hayling Sentence Completion Test Part B (p < .01), and Behavioral Dyscontrol Scale (p = .03), with the Hayling displaying a significant age-related decline (p = .01), as assessed by an age and repeat length-group interaction. Follow-up analysis of the collective data did not identify any specific age groups or repeat length ranges (i.e., low premutation = 55-70 repeats, midpremutation = 71-100 repeats, high premutation = 101-199 repeats) that were associated with an increased risk of executive function deficits. CONCLUSIONS Preliminary analyses do not indicate global executive function impairment among male carriers without FXTAS compared to noncarriers. However, impairment in inhibitory capacity may be present among a subset of carriers, though the risk factors for this group do not appear to be related to age or repeat length.

Developmental profiles of SMI-32 immunoreactivity in monkey striate cortex.

A monoclonal antibody that recognizes a nonphosphorylated epitope on the medium and high molecular weight subunits of neurofilament (NF) proteins was used to investigate laminar and cell morphology changes in monkey striate cortex during post-natal development. Six cortices were obtained from monkeys of a variety of ages: five from developing animals with ages spanning the critical period and one adult. At post-natal day (PD) 0, immunohistochemistry with the SMI-32 antibody revealed immunoreactive (IR) cells in layer IVB and in infragranular layer VI. Early in the critical period (PD 7), these layers become more defined with an increase in the density of immunopositive cells. At the height of the critical period (PD 30 and 42), a drastic increase in the density of SMI-32 labelled pyramidal neurons in layers V and VI was observed. Similarly, layer IVC showed an abundance of dendritic fragments and dendrites that appeared to originate from the infragranular layers. At the end of the critical period (PD 103), a trend toward morphological maturation for individual neurons found within each layer was observed. During any developmental time point, neurons at first appearance tended to show an immature morphology with staining largely restricted to the cell bodies. As such, the characteristic arborizations common to mature pyramidal and multipolar cells was not evident. We propose that the staining pattern seen in this study is consistent with the idea that layers anatomically associated with the magnocellular (M) pathway develop earlier than their parvocellular (P) counterparts.

2-Methyl-6-(phenylethynyl) pyridine (MPEP) reverses maze learning and PSD-95 deficits in Fmr1 knock-out mice

Fragile X Syndrome (FXS) is caused by the lack of expression of the fragile X mental retardation protein (FMRP), which results in intellectual disability and other debilitating symptoms including impairment of visual-spatial functioning. FXS is the only single-gene disorder that is highly co-morbid with autism spectrum disorder and can therefore provide insight into its pathophysiology. Lack of FMRP results in altered group I metabotropic glutamate receptor (mGluR) signaling, which is a target for putative treatments. The Hebb-Williams (H-W) mazes are a set of increasingly complex spatial navigation problems that depend on intact hippocampal and thus mGluR-5 functioning. In the present investigation, we examined whether an antagonist of mGluR-5 would reverse previously described behavioral deficits in fragile X mental retardation 1 knock-out (Fmr1 KO) mice. Mice were trained on a subset of the H-W mazes and then treated with either 20 mg/kg of an mGluR-5 antagonist, 2-Methyl-6-(phenylethynyl) pyridine (MPEP; n = 11) or an equivalent dose of saline (n = 11) prior to running test mazes. Latency and errors were dependent variables recorded during the test phase. Immediately after completing each test, marble-burying behavior was assessed, which confirmed that the drug treatment was pharmacologically active during maze learning. Although latency was not statistically different between the groups, MPEP treated Fmr1 KO mice made significantly fewer errors on mazes deemed more difficult suggesting a reversal of the behavioral deficit. MPEP treated mice were also less perseverative and impulsive when navigating mazes. Furthermore, MPEP treatment reversed post-synaptic density-95 (PSD-95) protein deficits in Fmr1 KO treated mice, whereas levels of a control protein (β-tubulin) remained unchanged. These data further validate MPEP as a potentially beneficial treatment for FXS. Our findings also suggest that adapted H-W mazes may be a useful tool to document alterations in behavioral functioning following pharmacological intervention in FXS.