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Impaired neurocognitive functioning in acromegaly--case report.


GH is an anabolic hormone and recently its involvement in the development of the central nervous system, in the process of myelination, differentiation of glial cells and cognitive functions have been proven. Research conducted on animal model highlights the role of GH / IGF-1 axis in regulating brain growth, development and myelination processes (1). IGF1 improves cerebral circulation, increases neuronal activity and inhibits neuronal apoptosis. (2, 3, 4, 5, 6).

Based on anatomical findings, it was postulated the GH and IGF 1 role concerning higher cognitive functions such as short term memory, long term memory and spatial orientation.

While normal GH- IGF1 axis has a neuroprotective role, on the contrary, the excess of those hormones may have negative effects. Cognitive dysfunctions associated with acromegaly may be justified by the fact that changes in structure and function occur in time and they are not fully reversible even if GH and IGF1 values normalize under treatment. Moreover, secondary complications of acromegaly triggered by the specific hormonal profile such as diabetes and arterial hypertension might be additional factors for cognitive impairment (7, 8, 9).

Acromegalic patients have a deficient activation of brain areas associated with memory, in this case, the temporal and prefrontal region. Both short-term memory and long-term memory are impaired. The severity of these dysfunctions is correlated probably directly with circulating levels of GH, IGF-1 and the duration of active disease (10).

Electroencephalography (EEG) and Low-Resolution Electromagnetic Tomography (LORETA) can provide a functional imaging of brain and were used in order to appreciate the neurophysiologic state of acromegalic patients. Decreased beta activity in left medial temporal cortex and a decreased alpha activity in the right prefrontal cortex was found in naive acromegalic patients compared to healthy subjects (11). LORETA revealed a significant decreased activity in prefrontal and middle temporal cortex, which in healthy brain are proved to be areas that are responsible for cognitive functions, namely executive functions and memory (12).

We describe a case of acromegaly with a long history disease (33 years) that exhibits an attention deficit and an impaired executive function that might be the consequences of long term exposure to high levels of GH and IGF1 on prefrontal and temporal cortex.


We present the case of a 66 year old woman known with acromegaly, since 1983 (pituitary GH macroadenoma).

At the moment of diagnosis, the patient showed acromegalic signs: enlargements of hands, feet and nasal pyramid. Investigations confirmed the presence of pituitary macroadenoma with excessive GH production. The patient refused surgery so she received two cycles of cobalt therapy (1984 and 1987) and subsequent treatment with bromocriptine with a good control of the disease.

Symptoms like sadness, anhedonia, loss of appetite, insomnia, and fatigue have increased over the last 15 years. The patient was diagnosed with major depressive disorder accompanied by panic attacks. The diagnosis was confirmed by the Hamilton Depression Rating Scale as the patient obtained a score of 16 points.

On the basis of anterior studies that have already emphasized the deficit of activation of the prefrontal cortex, whose main role concerns the executive function of the brain, our case report focuses on investigation of this aspect in acromegalic patient.

We have decided to further investigate this patient because she complained of suffering from memory loss, decreased attention, physical and mental fatigue, tearfulness. In order to obtain a more specific self-estimated disease perception, we applied the AcroQol (Acromegaly Quality of Live Questionnaire). Table number I reveals the scores the patient obtained.

On Trail Making Test well-known instrument to psychologists that can detect difficulties in attention and cognitive inflexibility (13, 14, 15) our patient scored 106 seconds in the first sample (Trail Making Test A) and 160 seconds on the Trail Making Test part B. These results are below average in comparison to age, sex and education level matches.

Verbal fluency tests were used to estimate the executive function. The patient obtained a total score of 17 which is below average.

For StroopTest (measuring the specific components of executive function, referring in particular to the prepotent response inhibition), the patient achieved the ratio inference score (Ir) of 0.417 which is also below average.

All test results are synthesised in table no. II.


Our case report shows an impaired attention and executive function in an acromegalic patient that has suffered from this disease for 33 years. Our patient had no other complications of the disease that might have an impact on cognitive function as diabetes or arterial hypertension.

The term of executive function covers a wide range of cognitive processes and behavioural skills such as mental flexibility, working memory, inhibitory control, cognition and emotion (16, 17).

Attention, cognitive flexibility, and impulse control are the attribute of executive function and can be tested using tests such as: Stroop Test, Trail Making Test A and B, Wisconsin Card Sorting Test, phonematic fluency test (18).

Trail Making Test is a very useful and easy to apply instrument that provides important information concerning attention and executive function. The fact that the patient needed 106 seconds for part A and 160 seconds for part B which are certainly below average and reveals cognitive deficits. According to Tombaugh for the 65-69 year age group with less than 12 years of study the normal average score is 39 for the first sample and 86 for the second (19). These below-average results of our patient obtained are in accordance with the results of

Ashendorf (20). The number of seconds required to solve the part A task for her age and educational category (55-77) was on average between 25-42s, which means that the patient obtained aborderline result, as she is on 3-8% percentile. As for Part B, the patient shows a significant decline in executive function. According to the authors, values higher than 154 seconds place the subject in this category, the average being 57 101 (20). Thus, we can conclude that during this test, the patient experienced a dramatic decrease in attention and executive function.

Verbal fluency test is also particularly important for predicting lesions in adults in the prefrontal brain area (21, 22, 23). Our patient scored 17, which is under the normal range according to the results obtained by Machado in 2009 on 345 healthy elderly persons (24). The average score for her age and education match control group was 26.13, which revealed serious deficits.

Stroope Test is a wide spread instrument that can be used on healthy persons but also in the case of cognitive dysfunctions. It can investigate the selective attention, cognitive flexibility and processing speed. As our acromegalic patient achieved an IR of 0.417, that shows difficulties. Mean ratio interference scores across 19 studies were 0.64 for control (25).

Also, an interesting result was the lower score obtained at her personal relationships and a better result concerning her own appearance in comparison with other studies, where the result is opposite. This result might be explained by the fact that elderly people tend not to give so much importance to their physical appearance. The global score was of 65 which places the patient among the general results obtained by acromegalic patients.

Tiemensma et al. (26) studied 68 patients who underwent a long-term treatment for acromegaly and 60 control individuals, using a scale of apathy, a scale of irritability, depression and anxiety and a scale assessing cognitive function through 11 tests. The results testify that acromegalic patients had a worse score on all questionnaires, but not in cognitive tests.

On the other hand, Yedinak and Fleseriu evaluated the cognitive dysfunction of 10 patients with active acromegaly, 17 with controlled disease and 14 pituitary adenomas with no secretion. The results confirm hat the patients with non secreting pituitary adenoma scored worse than the acromegalic patients and that there is no significant difference between patients with controlled and active acromegaly (30).

Martin-Rodriguez et al. highlights the fact that long-term exposure to high levels of GH / IGF1 may affect the brain function on long-term (11). The conclusion was that acromegalic patients have a neurocognitive impairment and the specific treatment cannot provide the complete recovery of neurocognitive function.

A connection between the anatomical changes and the neurocognitive disfunctions in acromegalic patients is possible, MRI showing an increased global grey matter and white matter (9).

Memory presents a negative correlation with GH and IGF-1 (12). Pathophysiological basis of such an effect would be that there are many GH and IGF1 receptors in choroid plexus, hypothalamus, hippocampus, neocortex and the grooved area.


The pathophysiological basis of cognitive dysfunction in acromegaly is not completely explained, and the studies are contradictory. Focusing not only on biochemical parameters but also on improving the cognitive functions we can increase the chances for a better quality of life. An early diagnosis of neurocognitive disorders can be the basis for pharmacologic and behavioural interventions with improvement of life quality in acromegalic patients.


The authors declare that they have no potential conflicts of interest to disclose.


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Emilia GHIJA--Ph. D. Student, No. 16 "Gr. T. Popa" University of Medicine and Pharmacy, Str. Universita{:ii, zip code 700115, Iasi, Romania

Cristina PREDA--Associated Professor, Department of Endocrinology, No. 16 "Gr. T. Popa" University of Medicine and Pharmacy, Str. Universitatii, zip code 700115, Iasi, Romania

Cezara BOTEZATU--M. D., Ph. D., Senior Psychiatrist, "Socola" Institute of Psychiatry, No. 36, Soseaua Bucium, zip code 700282, Iasi, Romania

Andrei DUMBRAVA--Lecturer, Faculty of Psychology, "Alexandru Ioan Cuza" University, No. 11, Carol I Blvd, zip code 700506, Ia?i, Romania

Carmen VULPOI--Professor, Department of Endocrinology, "Gr. T. Popa" University of Medicine and Pharmacy, No. 16 Str. Universitatii, zip code 700115, Iasi, Romania



Department of Endocrinology, "Grigore T. Popa" University of Medicine and Pharmacy, No. 16 Str. Universitatii, zip code 700115, Iasi, Romania

Tel.: +40 745 374 258, Fax: +40 232 229 940


Submission: March, 3rd, 2016

Acceptance: April, 27th, 2016
Table I. The scores obtained by patient in AcroQol

                       Physical   Appearance     Personal
                        scale      subscale    relationships

The patience's score      18          26            25
The maximum score         40          35            35

Table no. II. The scores the patient obtained to the performed tests.

                     Cognitive    The patient   The median
                    evaluation       score        score

Trail Making Test   Attention     106 s         39 s
Part A (time in

Trail Making Test   Executive     160 s         86 s
Part B (time in     functioning

Stroop Test-ratio   Executive     0,417         0,64
inference score     functioning

Verbal Fluency      Executive     17            26,13
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Title Annotation:Case Reports
Author:Ghita, Emilia; Preda, Cristina; Botezatu, Cezara; Dumbrava, Andrei; Vulpoi, Carmen
Publication:Bulletin of Integrative Psychiatry
Article Type:Report
Date:Jun 1, 2016
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