Ciccarelli, Mariateresa (2024) A pilot 18(F)-Flutemetamol PET and neurocognitive assessment study in severe cognitive impaired schizophrenia patients. [Tesi di dottorato]

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Abstract

State of the art: Multiple lines of evidence suggest that schizophrenia (SZ) has neurodevelopmental origins (Rund, 2018). However, this theory alone cannot explain the numerous progressive neurodegenerative processes described in SZ that partially justify its heterogeneity, including the more severe difficult-to-treat condition known as treatment-resistant schizophrenia (TRS) (O. D. Howes et al., 2017). According to this view of a complex neurodevelopmental neurodegenerative progressive disorder, multiple pieces of evidence showed a prominent cognitive impairment in TRS patients compared to those who respond to treatment with antipsychotics (de Bartolomeis et al., 2013), reinforcing the theory that TRS may represent a categorically different illness to treatment-responsive schizophrenia (Gillespie, Samanaite, Mill, Egerton, & MacCabe, 2017). This project aims to investigate the cerebral β-amyloid (Aβ) accumulation as putative measures of neurodegeneration in patients affected by SZ with cognitive impairment, using 18(F)-Flutemetamol Positron Emission Tomography (PET) to define molecular biomarkers leading to neuropathological progression (Rice & Bisdas, 2017). Methods: TRS patients (n=12) underwent amyloid PET acquisition. All patients were recruited from the Department of Neuroscience, Unit of Treatment Resistant Psychosis, University of Naples "Federico II". The diagnosis was made according to Structured Interview for Diagnosis (SCID-I). Treatment resistance was assessed according to TRRIP (Treatment Response and Resistance in Psychosis) Working Group consensus guidelines (O. D. Howes et al., 2017). Inclusion criteria were age between 18 and 55 years; disease duration >2 years; no substantial medication switch or dose changes (6 months); no evidence of recent (3 months) worsening of psychotic symptoms. Exclusion criteria were macroscopic brain structural anomalies or other major systemic, psychiatric, or neurological disorders, and substance use (6 months). Antipsychotic doses were transformed into chlorpromazine equivalents (Gardner, Murphy, O'Donnell, Centorrino, & Baldessarini, 2010). The clinical features were evaluated using the Positive and Negative Syndrome Scale (PANSS), the PANSS 5-factor model (van der Gaag et al., 2006), the Scale for the Assessment of Positive Symptoms (SAPS), the Scale for the Assessment of Negative Symptoms (SANS), and the Thought and Language Disorder (TALD) scale (Kircher et al., 2014). The cognitive symptoms were assessed using the Brief Assessment of Cognition in Schizophrenia (BACS) (Keefe et al., 2004), the Mini-Mental State Examination (MMSE), the Brief Intelligence Test (TIB), the Facial Emotion Identification Test (FEIT), and The Awareness of Social Inference Test (TASIT). Statistical procedures for clinical and demographic data were performed with the Statistical Package for the Social Sciences (SPSS) using a t-test (p≤0.01). TRS patients were assessed with the BACS and classified according to the severity of cognitive deficits into patients with Mild Cognitive Impairment (n=5) and Severe Cognitive Impairment (n=7). Patients performed amyloid PET acquisition at the Department of Advanced Biomedical Sciences, Nuclear Medicine, University of Naples “Federico II” to detect Aβ plaques after receiving an intravenous injection of 185 MBq of 18(F)-Flutemetamol. Early images were acquired immediately after the injection (early-phase), and late images approximately 90 minutes post-injection (late-phase). PET images were reconstructed using iterative reconstruction Ordered Subset Expectation Maximization (OSEM) and corrected for attenuation with Computed Tomography (CT) images. Mild or Severe Cognitive Impairment was assessed with raw data adjusted according to the normative values of the Italian population (Anselmetti et al., 2008), (Galderisi et al., 2014). Corrected scores were fitted into a 4-point scale to collect equivalent scores, based on which patients were classified as having Severe Cognitive Impairment (SCI, more than two cognitive domains with scores from 0 to 1) or Mild Cognitive Impairment (MCI, at least two cognitive domains with scores from 0 to 1 and the other domains with score ≥2) (Anselmetti et al., 2008). For TRS patients, the standardized uptake value region (SUVr) was calculated. SUVr expresses the ratio between the brain uptake of the amyloid tracer in the cerebral cortex and the uptake in the Cerebellum (i.e. a reference region not or less affected by disease). The visual analysis between the TRS patients with MCI and SCI in the early- and late-phase scanning was performed with SPM12 (Statistical Parametric Mapping) software, and the images were spatially normalized in the anatomical brain space MNI (Montreal Neurological Institute). The Pearson's correlation analysis between SUVr and the clinical scores was performed (p≤0.01) with Bonferroni's post hoc correction (p≤0.003). This study was approved and registered through the Ethical Committee for Clinical Studies of the University of “Naples Federico II” (Prot. CE n. 195/19, Substantive Amendment I). Results: 1) Demographic, clinical, and cognitive features: TRS patients (males 8, females 4; mean age 36.25±8.82; disease duration 17.33±7.81; chlorpromazine equivalents 552.67±238.81; education years 13.25±1.36; age at onset 18.83±4) performed amyloid PET. Patients did not differ in all the demographic and clinical characteristics. Cognitive scores at BACS domains such as verbal fluency, processing speed, problem solving, the BACS composite t-score, and TIB scores were significantly lower in SCI patients compared to MCI patients (p≤0.01). 2) Pet amyloid SUVr descriptive analysis in TRS patients with Mild and Severe Cognitive Impairment: TRS patients with MCI (n=5) and SCI (n=7) performed amyloid PET scans. Amyloid levels did not reach a deposition threshold that would be significant in TRS patients at the individual level. The average amyloid SUVr did not statistically differ between groups of TRS patients with MCI and SCI. 3) Visual analysis of the 18F-Flutemetamol PET distribution in the TRS patient with Mild and Severe Cognitive Impairment: The early-phase images in both groups exhibit a similar pattern of reduced uptake in the frontal cortex. In the SCI group, visual analysis reveals a moderate reduction in radiotracer uptake in the posterior cortical regions (i.e., the parietal and temporal cortices). The late-phase images do not show increased uptake in the cerebral cortex in either group. 4) Pet amyloid SUVr correlation analysis with clinical scores in TRS patients: The correlation analysis between amyloid SUVr and clinical scores in TRS patients revealed significant negative correlations between the Left Parietal Cortex and PANSS POS scores (p<0.003, r=0.597) and 5-factor DIS scores (p<0.002, r=0.645). Moreover, amyloid SUVr in the Right Sensorimotor Cortex was negatively correlated with PANSS POS scores (p<0.003, r=0.602) and 5-factor EXC scores (p<0.002, r=0.619), indicating an inverse significant relationship between the degree of prodromal amyloid pathology and the severity of clinical symptoms in TRS patients. There was no significant correlation between cognitive deficits and cortical amyloid SUV region. Conclusions: In conclusion, the results of this proof-of-concept amyloid PET imaging study did not reveal significant differences in regional cerebral cortical amyloid deposition between TRS patients with Mild and Severe Cognitive Impairment. Interestingly, however, the amyloid load was negatively correlated with clinical scores but not cognitive dysfunctions, suggesting a link between prodromal amyloid pathology and psychotic symptoms. These findings suggest that understanding the potential role of β-amyloid accumulation in TRS could be of interest for possible targeted therapeutic strategies and improved clinical outcomes in this challenging patient population. Future studies investigating longitudinal amyloid changes in TRS patients could provide further insights into this issue.

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