Abstract

## BACKGROUND

Monoamine oxidase-A (MAO-A) is a treatment target in neurodegenerative illness and mood disorders that increases oxidative stress and predisposition toward apoptosis. Increased MAO-A levels in prefrontal cortex (PFC) and anterior cingulate cortex (ACC) occur in rodent models of depressive behavior and human studies of depressed moods. Extreme dysphoria is common in borderline personality disorder (BPD), especially when severe, and the molecular underpinnings of severe BPD are largely unknown. We hypothesized that MAO-A levels in PFC and ACC would be highest in severe BPD and would correlate with symptom magnitude.

### METHODS

\[11C\] Harmine positron emission tomography measured MAO-A total distribution volume (MAO-A VT), an index of MAO-A density, in severe BPD subjects (*n* = 14), moderate BPD subjects (*n* = 14), subjects with a major depressive episode (MDE) only (*n* = 14), and healthy control subjects (*n* = 14). All subjects were female.

### RESULTS

Severe BPD was associated with greater PFC and ACC MAO-A VT compared with moderate BPD, MDE, and healthy control subjects (multivariate analysis of variance group effect: *F*6,102 = 5.6, *p* &lt; .001). In BPD, PFC and ACC MAO-A VT were positively correlated with mood symptoms (PFC: *r* = .52, *p* = .005; ACC: *r* = .53, *p* = .004) and suicidality (PFC: *r* = .40, *p* = .037; ACC: *r* = .38, *p* = .046), while hippocampus MAO-A VT was negatively correlated with verbal memory (*r* = −.44, *p* = .023).

### CONCLUSIONS

***These results suggest that elevated MAO-A VT is associated with multiple indicators of BPD severity, including BPD symptomatology, mood symptoms, suicidality, and neurocognitive impairment.***

Psychiatric illnesses are often conceptualized as comprising multiple clusters of target pathologies that co-segregate across different disorders ([1](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4942262/#R1)). Consistent with this perspective, monoamine oxidase-A (MAO-A) is an important target in neurodegenerative illness, due to its role in apoptosis ([2](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4942262/#R2),[3](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4942262/#R3)), and in affect dysregulation, due to the association of elevated MAO-A levels in the prefrontal cortex (PFC) and anterior cingulate cortex (ACC) with depressive symptoms ([4](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4942262/#R4)–[7](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4942262/#R7)). MAO-A is an enzyme located on outer mitochondrial membranes in glia and monoamine-releasing neurons that increases oxidative stress, influences predisposition toward intrinsic apoptosis, and metabolizes monoamines ([3](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4942262/#R3)). In brain tissue, greater MAO-A levels are correlated with elevated MAO-A activity ([8](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4942262/#R8)), and an index of MAO-A density, the MAO-A distribution volume (MAO-A VT), can be measured with \[11C\] harmine positron emission tomography (PET) ([9](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4942262/#R9)). \[11C\] Harmine is a selective, reversible PET radiotracer that binds to the center of the active pocket of the MAO-A enzyme with high affinity ([10](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4942262/#R10)).

Borderline personality disorder (BPD), especially when severe, is a major burden on public health and health care systems due to its high prevalence, occurring in 10% of outpatient psychiatric cases and 20% of psychiatric inpatient cases ([11](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4942262/#R11)). A core feature of BPD is affect dysregulation with accompanying episodes of severe dysphoria that drive expression of other BPD symptoms, including intense anger, dysfunctional interpersonal interactions, and recurrent suicidal behavior ([12](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4942262/#R12),[13](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4942262/#R13)). Severe dysphoria in BPD is highly clinically relevant because it is associated with need for inpatient care ([14](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4942262/#R14)), although other dimensions of the illness, such as neurocognitive impairment, also contribute to BPD severity ([15](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4942262/#R15)). Severe BPD is associated with greater functional impairment ([16](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4942262/#R16),[17](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4942262/#R17)), dysregulated emotional responses to negative stimuli ([18](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4942262/#R18)), and increased suicidality ([17](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4942262/#R17)), which together contribute to the clinical burden of BPD.

The principal aim of the present investigation was to measure MAO-A VT in BPD with moderate or severe symptoms. One model of emotional dysregulation in BPD highlights a deficient regulatory control system localized to the PFC and ACC ([19](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4942262/#R19)) that is based on PET studies showing reduced engagement of these regions ([20](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4942262/#R20)–[24](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4942262/#R24)). In support of this model, meta-analysis of functional neuroimaging studies pinpoints hypoactivity of the ACC and dorsal regions of the PFC as central to the abnormal neurocircuitry underlying negative emotionality in BPD, although specific pathologies therein have not been identified ([25](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4942262/#R25)). Depressive behaviors in rodents, such as those observed in chronic social defeat or chronic restraint stress paradigms, are associated with greater MAO-A messenger RNA and activity in the PFC ([26](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4942262/#R26),[27](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4942262/#R27)). Moreover, depressive and anxious behaviors in rodents, particularly in the context of altered social environments, are associated with increased gene expression and reduced degradation of brain MAO-A ([28](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4942262/#R28),[29](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4942262/#R29)). Since affect dysregulation emerges from impaired social interaction and is core to worsened presentations of BPD ([30](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4942262/#R30),[31](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4942262/#R31)), the primary study hypothesis was that PFC and ACC MAO-A VT would be most elevated in severe BPD, particularly in relation to mood symptoms and suicidality, and elevated to a lesser extent in moderate BPD. Given that several of the functions attributed to MAO-A, including generation of oxidative stress and induction of apoptosis, are processes implicated in neurocognitive impairment ([32](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4942262/#R32)), a secondary aim was to investigate MAO-A VT in functional regions linked to verbal memory ability in BPD. Therefore, the secondary hypothesis was that MAO-A VT would be elevated in the hippocampus when verbal memory impairment is more severe.

**Source:** [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4942262/](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4942262/)