The impact of awareness of deficits on emotional status in fragile x-associated tremor/ataxia syndrome (FXTAS)

Material Information

The impact of awareness of deficits on emotional status in fragile x-associated tremor/ataxia syndrome (FXTAS)
Gangemi, Alanna Lee
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viii, 40 leaves : ; 28 cm

Thesis/Dissertation Information

Master's ( Master of Arts)
Degree Grantor:
University of Colorado Denver
Degree Divisions:
Department of Psychology, CU Denver
Degree Disciplines:


Subjects / Keywords:
Fragile X syndrome -- Patients ( lcsh )
Ataxia -- Patients ( lcsh )
Awareness ( lcsh )
Depression, Mental ( lcsh )
bibliography ( marcgt )
theses ( marcgt )
non-fiction ( marcgt )


Includes bibliographical references (leaves 31-40).
General Note:
Department of Psychology
Statement of Responsibility:
by Alanna Le Gangemi.

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|University of Colorado Denver
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Auraria Library
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Resource Identifier:
656255905 ( OCLC )
LD1193.L645 2010m G36 ( lcc )

Full Text
Alanna Lee Gangemi
B.A., Texas Lutheran University, 2008
A thesis submitted to the
University of Colorado Denver
in partial fulfillment
of the requirements for the degree of
Master of Arts

The thesis for the Master of Arts
degree by
Alanna Lee Gangemi
has been approved
5 Apr: V U i Q

Gangemi, Alanna Lee (M.A., Clinical Psychology)
The Impact of Awareness of Deficits on Emotional Status in fragile X-associated
tremor/ataxia syndrome (FXTAS)
Thesis directed by Professor James P. Grigsby
Fragile X-associated tremor/ataxia syndrome (FTXAS) is a late-onset
neurodegenerative disorder affecting a subset of individuals with the fragile X
premutation. The major symptoms include intention tremor, cerebellar ataxia,
cognitive impairment, parkinsonism, peripheral neuropathy, and autonomic disorders.
The objectives of the study were to assess the role of awareness, or insight, in this
population and to examine the effects of awareness on the relationship between
impairment and symptoms of depression. Awareness of deficits was not found to
moderate the relationship between impairment and depressive symptoms. The
regression models did suggest, however, that awareness of deficits was a significant
predictor of depressive symptoms in men with FXTAS. Future research should focus
on examining the associations between awareness and the disorders additional
This abstract accurately represents the content of the candidates thesis. I recommend
its publication.
James P./Grigsby

I dedicate this thesis to my parents, who instilled the value of education and a love of
learning in me. I also dedicate this thesis to my sister, Alicia, for her unwavering
belief in me and to Ryan, for all of his devotion and support.

I would like to thank my advisor, Jim, for his guidance and teachings during my
research. I would also like to thank my committee members, Kevin and Angela, for
their contributions and support.

1. INTRODUCTION................................................1
Clinical Phenotype of FXTAS..............................3
Neurological Findings.............................3
Neuropsychological Findings.......................5
Neuropsychiatric Findings.........................6
Etiology of FXTAS........................................7
Toxic Gain-of-Function Effect.....................7
Purpose of the Study.....................................8
2. METHOD.....................................................11
Data Analysis...........................................14
3. RESULTS....................................................18
4. DISCUSSION............................................... 27

3.1 Variable means before and after missing data imputation.................20
3.2 Correlation matrix of study variables...................................21
3.3 Summary of regression models assessing the moderating role of awareness
(N = 50)...............................................................22

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset
neurodegenerative disorder that affects individuals with the fragile X premutation.
The major symptoms of FXTAS are intention tremor and cerebellar ataxia (Hagerman
et al., 2001). Patients that develop the syndrome will typically experience onset of
neurological symptoms in their 50s or 60s. Associated clinical features include
executive cognitive dysfunction, Parkinsonism, peripheral neuropathy, autonomic
disorders, psychiatric features, and general cognitive deficits (Bacalman et ah, 2006;
Bourgeois et ah, 2007; Grigsby et ah, 2007a; Grigsby et ah, 20066; Grigsby et ah,
20076; Hagerman et ah, 2001; Hagerman, Greco, & Hagerman, 2003; & Jacquemont
et ah, 2003). Magnetic resonance imaging shows increased signal intensity in white
matter of the middle cerebellar peduncles (MCP) and adjacent white matter on T2-
weighted images, global brain atrophy, and enlarged ventricle size (Brunberg et ah,
2002, Hagerman et ah, 2001; Hagerman, Greco, & Hagerman, 2003; Jacquemont et
ah, 2003). The most notable histological abnormality includes the presence of
eosinophilic, intranuclear inclusions observed in neuronal and astrocytic nuclei of the
cortex, cerebrum, and brainstem, with the most numerous found in the hippocampus
(Greco et ah, 2002). A loss of cerebellar Purkinje cells is also commonly seen. The

discovery of elevated levels of FMR1 mRNA in male premutation carriers provides
evidence for an additional molecular phenotypic abnormality affecting males with the
premutation, and this has led to the theory that FXTAS represents a toxic gain of
function in response to high levels of messenger RNA; the formation of inclusions
may be a reaction to the elevated message (Greco et al., 2002; Hagerman, 2001;
Hagerman & Hagerman, 2004a; Tassone et al., 2000a; Tassone et al., 20006).
Although a good deal has been learned about FXTAS in the ten years since its
identification, there is much yet to leam, including the disorders natural history and
specific mechanistic bases for its etiology. This paper is intended to discuss what has
been learned about this neurodegenerative disorder thus far and examine the
relationship between levels of awareness into deficits, impairment, and depressive
symptomatology associated with FXTAS.
The prevalence of the FMR1 premutation in the general population has been
reported to be 1 per 259 females and 1 per 813 males (Dombrowski et al., 2002;
Rousseau, Rouillard, Morel, Khandjian, & Morgan, 1995). More recent data suggest
that the true prevalence may be as high as 1 per 125 women and 1 per 250 males
(Femandez-Carvajal et al., 2009; Hagerman & Hagerman, 2004). According to the
standards set forth by the American College of Medical Genetics, normal FMR1
alleles have a CGG repeat length of 5-44, premutation alleles are considered to have

55-200 repeats, and full mutation alleles have a repeat length of >200 (Maddalena et
al., 2001). Approximately one-third of premutation male carriers will develop
FXTAS and incidence increases with age. Jacquemont and colleagues (20046)
estimate that FXTAS affects 17% of male carriers aged 50-59, 39% aged >50, and
75% aged >80. These results were based on self-reports of tremor and ataxia in a
premutation carrier population. Although the mean age of onset is approximately 60,
younger premutation carriers (<55) may have the propensity to exhibit minor clinical
manifestations of FXTAS (Loesch et ah, 2008).
Clinical Phenotype of FXTAS
Neurological Findings
Prior to the discovery of FXTAS, patients were offered a variety of different
diagnoses falling under such categories as Parkinsonism, tremor, ataxia, and dementia
(Hall et ah, 2005; Leehey et ah, 2003). The neurological features of FXTAS have
now been well documented in the literature (Berry-Kravis et ah, 2003; Hagerman et
ah, 2001; Hagerman, Greco, & Hagerman, 2003; Jacquemont et ah, 2004a;
Jacquemont et ah, 2003; Leehey et ah, 2003; Leehey et ah, 2007). Leehey and
colleagues (2007) report that the progression of motor signs indicate tremor usually
occurs before gait difficulties, with a median delay of two years after onset of tremor.

Tremor is most commonly kinetic, but a percentage of patients may also experience a
mild degree of resting tremor, as seen in Parkinsons disease. Patients generally
report that tremor begins in the dominant hand and progresses to the contralateral
hand over the course of a few years (Jacquemont et ah, 2003). Intention tremor is
progressive in the case of FXTAS and can become moderately to severely disabling.
Patients may experience functional impairment in daily activities and motor tasks
including writing, eating, dressing, shaving and driving (Brega et al., 2009). The
inability to perform basic activities of daily living increases with the progression of
the syndrome (Leehey et al., 2007). Gait disturbances manifest as poor balance,
falling, wide-based gait, and difficulty with tandem walking. Patients become
increasingly dependent on walking aids and wheelchairs as neurological symptoms
advance (Leehey et al., 2007).
Parkinsonism features are often related to motor difficulties and commonly
manifest as rigidity and resting tremor. In their review, Jacquemont et al. (2004a)
document that bradykinesia, increased tone, postural instability, and a reduction in
facial expressions are usually mild to moderate in most cases. Peripheral neuropathy
and autonomic dysfunction are also seen in patients affected by FXTAS (Hagerman et
al., 2001; Jacquemont et al., 2003; Leehey 2003). Abolished reflexes, abnormal
pinprick discrimination, and impaired vibration sense in the distal lower extremities

are signs of peripheral neuropathy reported by some patients. Autonomic dysfunction
is also variable and can include impotence and urinary and/or bowel incontinence.
Neuropsychological Findings
Perhaps the most substantial cognitive deficits in men diagnosed with FXTAS
are those of an executive nature. Compared to controls, symptomatic carriers perform
worse on executive functioning tasks involving behavioral self-regulation in the
context of goal-directed activity, control of attention, working memory, verbal
fluency, speed of information processing, and insight (Bourgeois et al., 2007; Brega
et al., 2008; Grigsby et al., 2007a; Grigsby et al., 2006a; Grigsby et al., 20076; &
Grigsby et al., 20066). Some evidence suggests that asymptomatic premutation
carriers also struggle with executive deficits and working memory, with researchers
postulating that subtle cognitive changes may occur prior to the onset of neurological
symptoms (Grigsby et al., 2006a; Loesch et al., 2003; & Moore et al., 2004). This is
yet to be confirmed, however, because the natural history of the disease has not been
outlined. The neuropsychological findings are generally concordant with MRI results
and the behavior reported by spouses and caregivers of men with FXTAS (Brega et
al., 2008 & Grigsby et al., 20066). For example, some patients behaviors have been
described as disinhibited, lacking initiation and distractible. Grigsby et al. (2006a)
proposed that widespread atrophy and neurodegeneration interrupt critical networks

responsible for complex cognitive abilities. Additionally, the impairments in memory
and speed of information processing observed in FXTAS are consistent with the
presence of inclusions located in the hippocampus (Greco et al., 2002). Findings
suggest that speech and language are relatively unaffected and remain intact during
the progression of the disease (Grigsby et ah, 2007a & Grigsby et ah, 2006b). Men
with FXTAS perform significantly worse on measures of overall intellectual
functioning compared to controls (Grigsby et ah, 2007a & Grigsby et ah, 20076).
Neuropsychiatric Findings
FXTAS has been associated with a range of neuropsychiatric features
including depression (Bacalman et ah, 2006 & Bourgeois et ah, 2007). Although
mood symptoms are common in elderly men with cognitive decline, Bacalman and
colleagues (2006) found that psychiatric symptoms of depression were more common
in men with FXTAS than in men without the disease. The relationship between
FXTAS and psychopathology must be viewed as correlative rather than causal
because the psychiatric features seen in FXTAS are common in asymptomatic
premutation carriers (Cornish et ah, 2005 & Hessl et ah, 2005). It is unknown
whether the depression seen in FXTAS patients can be partly or wholly attributed to
the cognitive deficits of FXTAS, brain abnormalities related to the disease, or to
psychosocial adjustment issues brought on by the diseases progression. The mood

problems experienced by patients with FXTAS may be related to the high frequency
of inclusion formations located in the hippocampus, a limbic structure known to have
significant involvement in psychiatric problems such as depression and anxiety
(Greco et al., 2006). Future longitudinal research will be necessary to reveal if
psychological symptoms progress along with other aspects of the disease as well.
Etiology of FXTAS
Toxic Gain-of-Function Effect
An intriguing link has been proposed between the formation of intranuclear
inclusions and elevated FMR1 mRNA levels found in carriers of premutation alleles.
It is hypothesized that the formation of inclusions and subsequent development of
FXTAS is caused by a toxic RNA gain-of-function effect (Greco et al., 2002;
Hagerman et al., 2001; & Jacquemont et al., 2003). In addition to an elevation of
mRNA levels, premutation carriers also possess a slight reduction of FMR1 protein
(FMRP). This model suggests that the deficit of FMRP is compensated for through
increased levels of mRNA that disrupt the expression of other proteins leading to
inclusion formation. The gain of function effect is one possible molecular
mechanism accounting for the basis of FXTAS. In order to test this hypothesis,
Willemsen et al. (2003) developed an animal model consisting of mice that were

genetically altered to carry premutation alleles of the FMR1 gene. After 72 weeks the
mice exhibited intranuclear inclusions similar to the inclusions studied in FXTAS.
The presence of inclusions in light of normal FMRP levels in the mice provides
evidence for a gain-of-function effect and against a protein deficiency model. Other
genetic and environmental factors should not be discounted in the discussion of
possible causes of FXTAS. The presentation of symptoms is highly variable and
premutation carriers fall along a continuum of involvement in the case of onset,
severity, and progression of the disease (Loesch, Churchyard, Brotchie, Marot, &
Tassone, 2005). It is unlikely that a single factor is responsible for the development
of a complex neurodegenerative disorder such as FXTAS.
Purpose of the Study
The purpose of this current study is to examine if awareness of deficits in
FXTAS moderates the relationship between impairment and depression. As
discussed above, the primary cognitive deficits in FXTAS comprise impairment of
different facets of executive functioning, which include insight and the capacity to
monitor ones own behavior. An examination of the varying levels of awareness
found in this syndrome may lead to an understanding of how these individuals
experience symptoms and may therefore provide valuable information to the health
care professionals that treat them. The impact of awareness, or insight, has not

currently been systematically studied in this population but has been examined in
other clinical populations.
The following literature provides evidence that an individuals accurate
appraisal of deficits related to his or her mental status is associated with greater
distress compared to individuals with an inaccurate appraisal. A study examining
awareness of deficits in a group of patients with multiple sclerosis found that
individuals with impaired awareness exhibited lower neuropsychological functioning
and appeared less distressed than patients with intact awareness (Sherman, Rapport,
& Ryan, 2008). MS patients with acute awareness into their deficits were found to
feel more distressed by their deficits than patients with impaired awareness. Research
regarding survivors of acquired brain injury found that high rates of distress were
associated with a higher degree of awareness of impairment and more intact cognitive
and/or executive functioning (Cooper-Evans, Alderman, Knight, & Oddy, 2008).
Alternatively, survivors with limited awareness and more cognitive impairment
reported lower levels of distress. In a sample of outpatient males with schizophrenia,
depression was linked to a greater understanding ones own mind (Lysaker et al.,
2005). In another study, cognitive reserve was found to moderate the relationship
between depressive symptoms and lack of awareness of deficits in dementia
(Sptiznagel, Tremont, Brown, & Gunstad, 2006). Premorbid cognitive functioning

was defined as cognitive reserve in this particular study. Increased awareness of
cognitive deficits was related to greater depressive symptoms in individuals with
higher cognitive reserve. Therefore, persons with higher premorbid functioning and
intact awareness appeared more distressed about their deficits than persons with
lower premorbid functioning and intact awareness. This suggests that individuals that
were aware of a substantial loss in functioning due to their illness were more likely to
feel distressed than those that were aware of a minimal loss in functioning.
Determining the relationship between awareness of deficits, impairment, and
symptoms of depression in FXTAS will contribute important knowledge to the
existing body of literature. I hypothesize that awareness will moderate the
relationship between impairment and symptoms of depression among a sample of
men diagnosed with FXTAS so that the positive relationship between impairment and
depressive symptoms is stronger under the condition of high versus low awareness.
Elaborating on this general hypothesis, awareness of ADLs will be a stronger
moderator between motor impairment and depressive symptoms and awareness of
IADLs will be a stronger moderator between cognitive impairment and depressive

The protocol for this study was reviewed and approved by the institutional
review boards of the University of Colorado at Denver and Health Sciences Center
and the University of California, Davis, Medical Center. Prior to participating, all
subjects provided written informed consent and Health Insurance Portability and
Accountability Act (HIPPA) authorization prior to participating. Funding was
provided by the National Institute of Neurological Disorders and Stroke (NINDS
grant number NS044299).
The 128 men that participated in the study were recruited through a variety of
channels. Many were identified through their involvement in earlier pedigree studies
conducted at the participating institutions, through their participation in meetings of
the National Fragile X Foundation, through their membership status in fragile X-
support groups, or through clinical practices of study co investigators. Participants
were 41-89 years of age and were native English speakers. The majority of subjects
were White (93.4%). One subject was African American, 1 was American
Indian/Alaska Native, and 3.7% of subjects reported their ethnicity as Hispanic or

Latino. Each participant was categorized into one of three groups: (a) premutation
carriers without FXTAS (asymptomatic carriers); (b) FXTAS; or (c) control (i.e.,
normal allele). The asymptomatic, FXTAS, and control groups comprised of 36, 50,
and 42 males, respectively. Due to the nature of the research question, the FXTAS
subgroup will comprise this studys sample, bringing the total N= 50.
All participants were administered a thorough battery of cognitive and
neuropsychological tests, a neurological evaluation, and assays related to Fragile X
genetic status. In this paper, performance was measured with instruments designed to
capture motor functioning, cognitive functioning, psychological functioning, and
functional status.
Symptom Checklist-90-Revised (SCL-90-R): A broad evaluation of
psychological symptoms comprised of a 90-item, 5-point rating scale (Derogatis &
Lazarus, 1994). This instrument was designed to measure a patients symptoms and
their intensity at a specific time point. It measure symptoms that align on 9 scales, or
domains, including depression, somatization, obsessive-compulsive, interpersonal
sensitivity, anxiety, hostility, phobic anxiety, paranoid ideation, and psychoticism.

Scores from the depression domain of the SCL-90-R represent the criterion variable
in this study (depressive symptoms).
Letter Number Sequencing (LNS): A subtest of the Wechsler Adult
Intelligence Scale-Third Edition (WAIS-III) used as a measure of working memory
and attention (Wechsler, 1997). It tests the ability to hold letters and numbers in mind
and then sequence the numbers in order followed by the letters in alphabetical order.
In this study, the LNS measure comprises the degree of cognitive impairment
experienced by the participants. Although the LNS may be considered a measure of
working memory, for the purpose of this study it is generalized to reflect impairment
in cognition.
Purdue Pegboard: An instrument used to measure motor dexterity (Tiffin &
Asher, 1948). It was designed to measure gross and fine movements of hands,
fingers, arms, and fingertip dexterity. Therefore, this measure is suited to represent
participants motor impairment.
Measures of Activities of Daily Living (ADLs) and Instrumental Activities of
Daily Living (IADLs): Brief questionnaire designed to measure overall performance
in ADLs and IADLs (Katz, Ford, Moskowitz, Jackson, & Jaffe, 1963; Duke
University, 1988). Participants and informants both completed the questionnaire,

answering items regarding the participants performance on a variety of daily
activities. The index of ADLs includes activities such as bathing or showering,
dressing, eating, using the toilet, etc. IADLs are generally more complex activities
and the index includes items such as preparing meals, driving a car, shopping for
groceries, etc. The two variables of awareness originate from the ADL and IADL
measures. Awareness of functional status was determined by calculating the inter-
rater agreement between patient and caregiver of the patients performance of ADLs
and IADLs.
Data Analysis
All statistical procedures were performed using the SPSS 18.0 software
package. Statistical significance was evaluated using 1-tailed tests. Because the
sample was relatively small, a was set at .05 for all analyses. Frequencies and
descriptive statistics were computed for all variables to explore the data. A missing
value analysis (MVA) was performed for each variable and missing continuous data
were imputed via regression estimation. In this case, MVA was preferable over list-
wise deletion because of the small sample size. Variable means before and after
imputation were compared to assess the validity of the procedure. A statistical power
level of .80 was achieved to detect large effects in the models (Miles & Shevlin,

2001). A substantial increase in sample size would have been necessary for the
regression models to detect medium and small effects.
Standardized scores were computed from the participants Letter
Number Sequencing, Purdue Pegboard, and SCL-90-R depression raw scores.
Instead of using the patients reports of depressive symptoms in the SCL-90-R, the
caregivers reports of the patients symptoms were used. The rationale behind this is
that for many of the patients, executive functioning is impaired, and hence their
reports may not represent an accurate appraisal of symptoms. Cohens kappa
coefficients were calculated for the variables of awareness. The inter-rater agreement
between patient and caregiver of the patients performance of ADLs and IADLs was
the best proxy for awareness because it was assumed that the caregivers reports were
more accurate than the patients reports. Subsequently, the level of concordance or
discordance between the two raters can be substituted as a patients level of
awareness of their performance in daily activities.
Descriptive statistics were computed to describe the sample and a Pearson
product-moment correlation matrix was extracted to examine correlation coefficients.
All variables except for the criterion variable were centered to increase
interpretability of interactions and to control for multicollinearity (Aiken & West,
1991). Four 2-step linear hierarchical multiple regression analyses were conducted to

examine the hypothesized moderating role of awareness in the relationship of
impairment and depressive symptoms. The hypotheses and the nature of the
symptoms in FXTAS were the driving reasons behind the implementation of 4
regression models. Model 1 examined the potential interaction between cognitive
impairment and ADL awareness. In model 2, the interaction of interest was between
cognitive impairment and IADL awareness. Model 3 aimed to examine a potential
interaction between motor impairment and ADL awareness and model 4 looked at the
relationship between motor impairment and IADL awareness. First of all, the two
types of impairment (cognitive and motor), were examined separately in the
regression models because they are quite distinct from each other. Not only does
impairment in cognitions and motor status impact patients in different ways, but the
symptoms experienced by men affected with FXTAS are quite variable. It follows
reason that awareness of performance of complex activities (IADLs) is more likely to
have an effect on the relationship between cognitive impairment (which plays a role
in the execution of complex activities) and depression than motor impairment and
depression. As such, awareness of concrete activities (ADLs) is more likely to have
an effect on the relationship between motor impairment (which influences the
likelihood of fulfilling the physical demands of many of the ADLs) and depression
than cognitive impairment and depression. At step 1 of each model, covariates, type
of impairment, and type of awareness were entered. At step 2 of each model, all

variables in step 1 were entered in addition to the product of type of impairment and
type of awareness in question.
Cognitive impairment, £)(50) = .17,p< .05, motor impairment, D{50) = .17,
p < .05, ADL awareness, D{50) = .29, p < .05, and IADL awareness, D{50) = .33,
p < .05 were all significantly non-normal, thus violating the assumption of normality.
The assumption of normality was still violated after transformations of the data were
attempted. Log transformations were successful in creating normal data for the
criterion variable and the covariate of duration of illness. The log transformations for
the latter two variables were used in the analyses. All remaining assumptions and
regression diagnostics were met.

According to Table 3.1, missing data imputation did not seem to modify the
data considerably. Therefore, it is unlikely that the procedure confounded the
following results. The mean age was 67.78 years (SD = 8.24) and mean education
was 15.38 years (SD = 3.16). Unadjusted Pearson product-moment correlation
coefficients (r) showed that cognitive impairment (r = -.33, P < .05), ADL awareness
(r = -.34, P < .05), and IADL awareness (r -.43, P < .05) were negatively correlated
with symptoms of depression, indicating that lower levels of these variables were
associated with more depressive symptoms. In addition, CGG repeat length (r = .26,
P <.05) was positively correlated with symptoms of depression, indicating that longer
lengths are associated with more depressive symptoms Table 3.2 lists the complete
correlation matrix.
In the four regression models, awareness did not interact with impairment to
influence depressive symptoms (see Table 3.3). However, ADL awareness, t = -2.25,
p < .05, t = -2.34, p < .05, was a significant predictor of depression in models 1 and 3,
respectively. Awareness of IADLs, t = -2.21 ,p< .05, t = -2.52,p< .05, was also a
significant predictor of depressive symptoms in models 2 and 4, respectively. The

analyses of variance, F(7, 42) = 2.32, p < .05, F(7, 42) = 2.25, p < .05), suggest
models 2 and 3 fit the data and are significantly good predictors of depression. The
analysis of variance of regression model 1 approached the level of significance, F(7,
42) = 2.22, p > .05.

Table 3.1 Variable means before and after missing data imputation
Variable Before imputation After imputation
n X SD n X SD
Age 50 67.78 8.24 50 67.78 8.24
Education 48 15.38 3.22 50 15.38 3.16
Duration of illness 21 .76 .32 50 .73 .31
CGG repeat 50 94.78 17.44 50 94.78 17.44
Cognitive 44 -.41 1 50 -.42 1.01
Motor impairment 47 -.80 .89 50 -.81 .95
ADL awareness 46 .63 .41 50 .61 .42
IADL awareness 46 .66 .40 50 .67 .39
Depressive 44 1.73 .08 50 1.73 .08

Table 3.2 Correlation matrix of study variables
Variable 1 2 3 4 5 6 7 8 9
1. Age 1 -.05 -.29* .14 -.08 -.24* -.16 -.21 .01
2. Education -.05 1 .17 .08 .00 .18 -.08 -.16 .07
3. CGG repeat -.29* .17 1 .20 -.12 -.21 -.04 -.27* .26*
4. Duration of .14 .08 .20 1 -.09 -.05 .06 -.06 .09
5. Cognitive -.08 .00 -.12 -.09 1 .31* .27* .30* -.33*
impairment 6. Motor -.24* .18 -.21 -.05 .31* 1 .30* .28* -.18
impairment 7. ADL -.11 -.08 -.04 .06 .27* .30* 1 .57* -.37*
8. IADL -.21 -.16 -.27* -.06 .30* .28* .57* 1 -.43
9. Depression .01 .07 .26* .09 -.33* -.18 -.37* -.43* 1
*P< .05

Table 3.3 Summary of regression models assessing the moderating role of awareness
(N = 50)
Variable R2 Adj. R2 B SE B P />value
Model 1
Step 1 .25 .14
Age .00 .00 .02 .88
Education .00 .00 .00 .99
CGG .00 .00 .22 .13
Duration of illness .01 .03 .04 .73
Cognitive impairment .01 .01 -.21 .12
ADL .06 .02 -.30 .03*
Step 2 .27 .14
Age .00 .00 .04 .75
Education .00 .00 .00 .98
CGG .00 .00 .23 .11
Duration of illness .02 .03 .08 .57
Cognitive impairment -.02 .01 -.23 .10
ADL -.06 .02 -.31 .02*

Table 3.3 (Cont.)
Variable R2 Adj. R2 B SE B P
Cognitive impairment -.02 .02 -.14
Model 2
Step 1 .25 .15
Age .00 .00 -.04
Education .00 .00 -.01
CGG .00 .00 .12
Duration of illness .01 .03 .03
Cognitive impairment -.01 .01 -.21
I ADL -.07 .03 -.34
Step 2 .27 .15
Age .00 .00 -.08
Education .00 .00 -.04
CGG .00 .00 .06
Duration of illness .00 .04 -.01
Cognitive impairment -.01 .01 -.19

Table 3.3 (Cont.)
Variable R2 Adj. R2 B SE B p /7-value
IADL -.07 .03 -.33 .03*
Cognitive impairment .03 .03 .18 .27
Model 3
Step 1 .20 .09
Age .00 .00 .03 .81
Education .00 .00 .00 .95
CGG .00 .00 .24 .12
Duration of illness .01 .03 .06 .65
Motor .00 .01 .00 .96
ADL -.07 .03 -.36 .01*
Step 2 .27 .15
Age .00 .00 .07 .63
Education .00 .00 .03 .78
CGG .00 .00 .24 .12

Table 3.3 (Cont.)
Variable R2 Adj. R2 B SE B P />value
Duration of illness .00 .04 -.01 .91
Motor .00 .01 .06 .67
impairment ADL -.06 .02 -.33 .02*
Motor .06 .03 .28 .06
impairment x ADL
Model 4
Step 1 .21 .10
Age .00 .00 -.05 .71
Education .00 .00 -.01 .93
CGG .00 .00 .11 .49
Duration of illness .01 .03 .05 .71
Motor .00 .01 -.05 .71
impairment IADL -.08 .03 -.39 .01*

Table 3.3 (Cont.)
Variable R2 Adj. R2 B SE B P p-\alue
Step 2 .23 .11
Age .00 .00 -.03 .80
Education .00 .00 .00 .97
CGG .00 .00 .12 .45
Duration of illness .00 .04 .00 .98
Motor .00 .01 .00 .98
impairment IADL -.08 .03 -.38 .01*
Motor .03 .03 .16 .28
impairment x IADL
*p < .05

The primary goal of this study was to examine the role of awareness in the
relationship between impairment and depressive symptoms in a sample of individuals
with FXTAS. Contrary to previous findings on the topic and counter to the
hypothesis, awareness did not moderate the relationship between impairment and
symptoms of depression. Awareness was found to predict depression above and
beyond all other study variables. Not only do the results of this study pose more
questions, but they also suggest that depression in this population be explored with a
broad lens.
As a significant predictor of depression, awareness may serve as a protective
factor for the development of depressive symptoms. Depression was found to
decrease as the level of awareness increased. Although this finding does not support
the hypothesis, it does suggest that the relationship between awareness and depression
is more complex than previously thought. One possible explanation for this is that
individuals with intact awareness that are slightly to moderately impaired may feel
less distressed by knowing they still wield a sense of control over their thoughts. In
our culture, the losing of ones mind is considered quite distressful and is

stigmatized to a certain extent. Despite the uncontrollable events taking place within
them, such as the development of tremor, ataxia, and other disease symptoms, they
are able to seek relief in knowing they are still aware of internal and external events.
Furthermore, the contained ability to relate their thoughts to more positive and
optimistic aspects of their lives may serve to protect against depressive symptoms.
While impairment was not found to be a significant predictor of depression,
a difference was noted between the effects of cognitive and motor impairment. Loss
of cognitive impairment, or working memory in this case, had a more profound
impact on depressive symptoms than motor impairment. The degree of depressive
symptoms increased as cognitive ability declined. Perhaps this speaks to the value
placed on cognitive functioning and the participants difficulty accepting a decline of
this nature compared to a decline in motor functioning. On the other hand, this
finding could be a reflection of the convoluted relationship surrounding the cause of
cognitive deficits of FXTAS and symptoms of depression. In other words, the
problems with cognitive functioning could be attributed to depressive symptomology
or to the disorder itself.
Limitations of this study should be noted. The study used a correlational
design and causal inferences must be interpreted with caution. The results are unable
to address directionality or causality. This study utilized secondary data and did not

include the most ideal, direct measurements of variables. While the variables were
justified for the study, a validated measure of awareness, such as the Behavioural
Assessment of the Dysexecutive Syndrome, (BADS, Wilson, Alderman, Burgess,
Emslie, & Evans, 1996) may have positively impacted content validity. Aside from
violating the assumption of normality, all remaining regression diagnostics and
assumptions were achieved. This lends almost complete support for the accuracy and
generalizability of the model. A moderate amount of shrinkage was also linked to the
regression models. Lastly, the model achieved enough statistical power to only detect
large effects.
Future research should focus on the inclusion of validated measures of
impairment and awareness. Expanding on this, an in-depth examination of the
relationship between awareness and other variables may refine the nature of
interactions associated with depressive symptoms. It would not be unprecedented to
find that a variety of factors, such as physiological, biological, psychological, and
social factors, influences the relationship between awareness and depressive
symptoms. Awareness may also be found to have an impact on other psychiatric
conditions that people with FXTAS experience, since comorbidity is commonly seen
in this population.

In conclusion, the results indicate that awareness failed to moderate the
relationship between impairment and depressive symptoms in a subset of individuals
with FXTAS. Awareness may serve to protect against symptoms of depression,
however. It appears that the mood symptoms experienced in this group of individuals
are complex and are a result of numerous influential factors. The untangling of the
role of awareness will help serve to better treat individuals and further classify the
disorder known as FXTAS.

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