1 Introduction
Bipolar disorder (BD) is a recurrent mental disorder with unclear
etiology, often causing severe disability among people who suffer from
it (Kessing et al., 2017). Despite evidence that bipolar disorder is
highly heritable(Sandstrom et al., 2019; YANG et al., 2018), the
specific pathogenic mechanism involving a complex combination of genetic
and external environmental variables remains unknown(Breuer et al.,
2018). Endophenotypes are disease-related signatures that are strongly
heritable and independent of the patient’s clinical condition(McGue. et
al., 2017). Detecting the endophenotype of bipolar disorder can provide
us with important information about the etiology of this complicated
disease, as well as a useful target for early diagnosis, prevention, and
individualized therapy. Working as an endophenotype requires meeting
certain requirements, such as disease-related, state independence,
familial association, and co-segregation within families, according to
prior studies(Gottesman. et al., 2003). Several studies have found that
bipolar disorder patients suffer cognitive abnormalities, particularly
in sustained attention, verbal learning, and executive
functioning(Douglas et al., 2017; Van Rheenen et al., 2017; Luperdi et
al., 2021; Ceylan et al.,2020).
These cognitive deficiencies are more noticeable during the disease’s
exacerbation phase, but recent discoveries have indicated that patients
still exhibit chronic cognitive impairment following symptom remission,
albeit to a smaller extent than during the exacerbation period (Cardenas
et al., 2016). The endurance of these abnormalities suggests that they
may be a defining feature of the condition rather than merely a symptom
of its start. Furthermore, if the cognitive deficiencies of a bipolar
patient’s unaffected first-degree relative manifest as an intermediate
condition, i.e., less severe than the patient but more severe than the
healthy control, the cognitive deficits are most likely an underlying
endophenotype of bipolar disorder. The endophenotypes linked with
cognitive deficits in bipolar disorder are contentious, with some
research proposing that verbal memory deficits(Rodriguez et al., 2012;
Kulkarni et al., 2010), executive function deficits, and selective
attention deficits were endophenotypes of cognitive deficits in bipolar
disorder(Normala et al., 2012; Bauer et al., 2016). There was, however,
research that contradicts these findings (Daban et al., 2016). For
example, except for the ability to recognize surprising facial
expressions, cognitive deficiencies did not fit the features of the
bipolar illness endophenotype in a study of 172 individuals with bipolar
disorder in remission and 52 first-degree relatives of patients without
the disorder(Kjaerstad et al., 2020). Exploratory investigations on the
endophenotypes linked with cognitive deficits in bipolar disorder are
still relevant due to the disparity in the results of earlier studies.
Furthermore, the majority of prior studies used Caucasians as the study
sample, and there are few studies on domestic Han Chinese.
Neurological soft signs (NSS) are small neurological abnormalities in
motor coordination, sensory integration, and disinhibition. These
defects are associated with changes in cortical and subcortical
structures in patients with mental disorders, which can be objectively
stimulated and effectively evaluated(Ciufolini et al., 2018; Rathod et
al., 2020). NSS in mental diseases partly reflects the developmental
abnormalities of the nervous system caused by genetic and non-genetic
processes(Nasab et al., 2017). 20 The
majority of recent studies on psychiatric diseases’ neurological soft
signals have used schizophrenia patients as the study sample(Yingying et
al., 2020; Yingying et al., 2017). The aberrant neurodevelopmental
theory of schizophrenia is supported by increased NSS(Bora et al.,
2015), and some items in the NSS have been identified as probable
endophenotypes of schizophrenia(Yingying et al., 2020; Yingying et al.,
2017). Patients with bipolar disorder, for example, displayed much more
motor coordination and sensory integration symptoms than healthy
controls, according to case-control research(Sagheer et al., 2018).
Additionally, patients with bipolar disorder experienced much more NSS
than healthy controls, per the results of a 2018 meta-analysis(Bora et
al., 2018). However, when opposed to the literature on schizophrenia,
NSS in bipolar disorder is a comparatively understudied area. Numerous
studies, on the other hand, have discovered significant neurological and
genetic similarities between schizophrenia and bipolar disorder(Bora et
al., 2016; Gotra et al., 2020; Chrobak et al., 2021). As a result, it’s
acceptable to assume that, similar to schizophrenia, several items in
the NSS fit the requirements for a bipolar disorder endophenotype. Given
that both cognitive deficits and NSS are associated with
neurodevelopmental problems in psychiatric disorders, combining the two
endophenotypes of the disorder may result in a more effective
endophenotype. Because numerous risk variables for psychiatric disorders
frequently cluster together to represent a genetic risk for the same
disorder, it has been suggested that these risk factors be combined to
create a composite or multivariate endophenotype to better identify
genetic risk(Turetsky et al., 2007).
The goal of this study was twofold: first, to find cognitive deficits
and NSS-related items that met the endophenotypic criteria for bipolar
disorder by assessing cognitive function and NSS in euthymic patients
with bipolar disorder (EBP), their unaffected first-degree relatives
(FDR), and healthy controls (HC); and second, to see if a composite
endophenotype of bipolar disorder can be created using cognitive
deficiencies and NSS items that meet endophenotypic criteria and verify
it.