Cognitive Decline Preceding the Onset of Psychosis in Patients With 22q11.2 Deletion Syndrome

Vorstman, Jacob; Breetvelt, Elemi J.; Duijff, Sasja N.; Eliez, Stéphan; Schneider, Maude; Jalbrzikowski, Maria; Armando, Marco; Vicari, Stefano; Shashi, Vandana; Hooper, Stephen R.; Chow, Eva W.C.; Fung, Wai Lun Alan; Butcher, Nancy J.; Young, Donald A.; McDonald‐McGinn, Donna M.; Vogels, Annick; Amelsvoort, Thérèse van; Gothelf, Doron; Weinberger, Ronnie; Weizman, Abraham; Klaassen, Petra; Koops, Sanne; Kates, Wendy R.; Antshel, Kevin M.; Simon, Tony J.; Ousley, Opal Y.; Swillen, Ann; Gur, Raquel E.; Bearden, Carrie E.; Kahn, René S.; Bassett, Anne S.

doi:10.1001/jamapsychiatry.2014.2671

Cited by 210 publications

(232 citation statements)

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“…This finding is in line with several studies that also identified lower functioning scores as a relevant predictor of the onset of psychosis in UHR 41,[47][48][49] as well as 22q11DS samples 21,50 . Yet, contrary to other findings in 22q11DS 19,20 , baseline verbal IQ and presence of an anxiety disorder did not increase the predictive value of the model. However, it should be noted that these previous studies never included UHR status as a baseline predictor.…”

Section: Additional Predictors Of Transition To Psychosiscontrasting

confidence: 99%

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Ultra High Risk Status and Transition to Psychosis in 22q11.2 Deletion Syndrome

et al. 2017

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The 22q11.2 deletion syndrome (22q11DS) is characterized by high rates of psychotic symptoms and schizophrenia, making this condition a promising human model for studying risk factors for psychosis. We explored the predictive value of ultra high risk (UHR) criteria in a sample of patients with 22q11DS. We also examined the additional contribution of socio-demographic, clinical and cognitive variables to predict transition to psychosis within a mean interval of 32.5 6 17.6 months after initial assessment. Eighty-nine participants with 22q11DS (age range: 8-30 years; mean 16.1 6 4.7) were assessed using the Structured Interview for Psychosis-Risk Syndromes. Information on Axis I diagnoses, internalizing and externalizing symptoms, level of functioning and IQ was also collected. At baseline, 22 (24.7%) participants met UHR criteria. Compared to those without a UHR condition, they had a significantly lower functioning, more frequent anxiety disorders, and more severe psychopathology. Transition rate to psychosis was 27.3% in UHR and 4.5% in non-UHR participants. Cox regression analyses revealed that UHR status significantly predicted conversion to psychosis. Baseline level of functioning was the only other additional predictor. This is the first study investigating the predictive value of UHR criteria in 22q11DS. It indicates that the clinical path leading to psychosis is broadly comparable to that observed in other clinical high-risk samples. Nevertheless, the relatively high transition rate in non-UHR individuals suggests that other risk markers should be explored in this population. The role of low functioning as a predictor of transition to psychosis should also be investigated more in depth. . This syndrome is characterized in most cases by a microdeletion of 3 million base pairs on chromosome 22 band q11, and has an estimated prevalence of 1:2.000-4.000 live births 6 . From a clinical perspective, 22q11DS is associated with high rates of psychiatric disorders, especially schizophrenia 7 . While 23 to 45% of affected adolescents report transient psychotic experiences [8][9][10][11] , up to 40% of affected adults are diagnosed with a psychotic disorder 7 . Moreover, 22q11DS was found in 0.3 to 2.0% of patients with schizophrenia [12][13][14] , with rates of up to 5.7% in patients with childhood-onset schizophrenia 15 . Taken together, these findings indicate that 22q11DS is a highly relevant genetic risk factor for schizophrenia and the most promising human model for studying risk factors and states at risk for schizophrenia 5 .Several studies have investigated prodromal symptoms in patients with 22q11DS, reporting rates between 45 and 56% for UHR symptoms and between 10 and 21% for UHR criteria (including frequency and onset/worsening requirements) 8,10,11,[16][17][18] . Armando et al 8 compared the symptom profile of UHR patients with (N530) vs. without (N581) 22q11DS and found no significant group difference in positive symptoms, while negative symptoms were more severe in patients with 22q11DS. Yet, few stud...

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Section: Additional Predictors Of Transition To Psychosiscontrasting

confidence: 99%

“…In line with these findings, Vorstman et al 20 reported that an early cognitive decline, particularly in verbal IQ, was a robust predictor of psychosis. Finally, a recent study highlighted the role of poor premorbid adjustment during childhood and adolescence in the development of UHR symptoms and full-blown psychosis 21 .…”

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Ultra High Risk Status and Transition to Psychosis in 22q11.2 Deletion Syndrome

et al. 2017

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“…Given that the memory deficit revealed by the GOL task is reminiscent of episodic memory deficits and learning impairments in 22q11.2-deletion carriers 46,47 , impaired hippocampal ensemble dynamics may be a central component of cognitive memory dysfunctions emerging from the 22q11.2DS and SCZ in general 48 . In SCZ patients with and without the 22q11.2 deletion, cognitive dysfunction is a key manifestation of SCZ, is highly correlated with functional outcome and is a robust indicator of the risk of developing a psychotic illness 49,50 . Investigations of 22q11.2DS as a genetic model could thus aid in elucidating neurobiological mechanisms underlying the development of cognitive dysfunction under the assumption that the diversity of dysfunction that occurs at the molecular, cellular and synaptic levels could be functionally convergent at the level of altered neuronal ensembles 45 .…”

Section: Discussionmentioning

confidence: 99%

Impaired hippocampal place cell dynamics in a mouse model of the 22q11.2 deletion

et al. 2017

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Hippocampal place cells represent the cellular substrate of episodic memory. Place cell ensembles reorganize to support learning but must also maintain stable representations to facilitate memory recall. Despite extensive research, the learning-related role of place cell dynamics in health and disease remains elusive. Using chronic two-photon Ca2+ imaging in hippocampal area CA1 of wild-type and Df(16)A+/− mice, an animal model of 22q11.2 deletion syndrome, one of the most common genetic risk factors for cognitive dysfunction and schizophrenia, we found that goal-oriented learning in wild-type mice was supported by stable spatial maps and robust remapping of place fields toward the goal location. Df(16)A+/− mice showed a significant learning deficit accompanied by reduced spatial map stability and the absence of goal-directed place cell reorganization. These results expand our understanding of the hippocampal ensemble dynamics supporting cognitive flexibility and demonstrate their importance in a model of 22q11.2-associated cognitive dysfunction.

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“…5,[9][10][11][12] Several factors may contribute to developing psychosis in individuals with 22q11.2DS. Among these are longitudinal decline in verbal IQ (VIQ), 17,18 lower baseline IQ, 3,8,19 the presence of comorbid anxiety disorders, 7,8,20 and lower global functioning. 21,22 However, the comorbidity of these conditions with subthreshold psychotic symptoms has not been sufficiently explored.…”

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Subthreshold Psychosis in 22q11.2 Deletion Syndrome: Multisite Naturalistic Study

Weisman

Guri

Gur

et al. 2017

Schizophrenia Bulletin

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Nearly one-third of individuals with 22q11.2 deletion syndrome (22q11.2DS) develop a psychotic disorder during life, most of them by early adulthood. Importantly, a fullblown psychotic episode is usually preceded by subthreshold symptoms. In the current study, 760 participants (aged 6-55 years) with a confirmed hemizygous 22q11.2 microdeletion have been recruited through 10 medical sites worldwide, as part of an international research consortium. Of them, 692 were nonpsychotic and with complete measurement data. Subthreshold psychotic symptoms were assessed using the Structured Interview for Prodromal Syndromes (SIPS). Nearly one-third of participants met criteria for positive subthreshold psychotic symptoms (32.8%), less than 1% qualified for acute positive subthreshold symptoms, and almost a quarter met criteria for negative/disorganized subthreshold symptoms (21.7%). Adolescents and young adults (13-25 years) showed the highest rates of subthreshold psychotic symptoms. Additionally, higher rates of anxiety disorders and attention deficit/hyperactivity disorder (ADHD) were found among the study participants with subthreshold psychotic symptoms compared to those without. Full-scale IQ, verbal IQ, and global functioning (GAF) scores were negatively associated with participants' subthreshold psychotic symptoms. This study represents the most comprehensive analysis reported to date on subthreshold psychosis in 22q11.2DS. Novel findings include age-related changes in subthreshold psychotic symptoms and evidence that cognitive deficits are associated with subthreshold psychosis in this population. Future studies should longitudinally follow these symptoms to detect whether and how early identification and treatment of these manifestations can improve long-term outcomes in those that eventually develop a psychotic disorder.

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Cognitive Decline Preceding the Onset of Psychosis in Patients With 22q11.2 Deletion Syndrome

Cited by 210 publications

References 61 publications

Ultra High Risk Status and Transition to Psychosis in 22q11.2 Deletion Syndrome

Ultra High Risk Status and Transition to Psychosis in 22q11.2 Deletion Syndrome

Impaired hippocampal place cell dynamics in a mouse model of the 22q11.2 deletion

Subthreshold Psychosis in 22q11.2 Deletion Syndrome: Multisite Naturalistic Study

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