Brain Volume Alterations Using 3tesla Magnetic Resonance and Neuropsychological Findings in Gaucher Disease Patients

Gaucher Disease (GD) is a metabolic inherited disorder, that classically includes three clinical phenotypes. Type I GD (GD1) is considered as a non-neuronopathic variant and can mimic a hematologic disease; type II (GD2) is classified as an acute neuropathic form and type III (GD3) is characterized by a slower and progressive neurological involvement. A protective role of N370S mutation against neurological impairment had been previously hypothesized in GD1, however, increasing data and our experience show that patients with GD1 may present clinical signs of parkinsonism, frequently combined with cognitive impairment and behavioral alterations. Structural brain changes associated with cognitive impairments in GD patients, especially type I, has not yet been reported.

The prospective study, called SENOPRO_GAUCHER, has investigated in depth, the neurological status in GD patients using a multidisciplinary approach, including 3Tesla magnetic resonance (3T MR). This study was approved by our Ethics Committee. Baseline data on neurological, psychological, psychiatric, somatosensory, and motor evaluations, and electroencephalography (EEG) surprisingly revealed two, or more, clinical and/or instrumental, neurological signs in all GD1 patients, and a wide spectrum of neurological abnormalities in all GD3 patients.

We, hereby, report the results of investigations on brain structure of GD patients, compared to that of healthy subjects, using 3T MR, in order to evaluate whether brain alterations can predict neurocognitive impairment in GD patients, especially GD1. Out of 22 GD patients, assessed for neuropsychological and psychiatric functions, 19 (17 GD1, 2 GD3, median age = 44, range 17 - 68 years) underwent 3T MR examination. Regarding genotyping, all but one of the 17 GD1 patients was N370S mutation heterozygous.

A Voxel-based Morphometry (VBM) analysis was performed to investigate brain structure in the 19 GD patients and in 19 healthy subjects with no neurological or neuropsychiatric disease. The healthy subjects, matched to patients by age, sex, and education, in addition to 3T MR, underwent neuropsychological assessment using Mini-Mental State Exam and Mental Deterioration Battery, to evaluate cognitive functions and mental deterioration, respectively. Qualitative MR examinations revealed unspecific abnormalities in 7/17 GD1 patients. In particular, cortical and/or subcortical areas of gliosis (4 patients), vascular ectasia extended from the left frontal surface of the brain to the lateral ventricle (1 patient), dilation of perivascular spaces in the sub-cortical and nucleus-basal area (1 patient), diffuse suffering of the brain white matter due to a chronic ischemic vascular damage (1 patient) were found. Concurrently, results of the VBM analysis revealed that a set of regions, mostly located in the prefrontal and parieto-occipital cortex, were significantly reduced in GD patients, compared to healthy subjects. The most affected regions included the frontal eye fields, the dorso-lateral prefrontal cortex, the posterior cingulate cortex, and the V3B area. Psychological and psychiatric evaluations underlined anxiety, depression, and somatic concerns in 10/17 GD1 patients, combined with cognitive impairments in two of them. Moreover, 1/2 GD3 and 5/17 GD1 patients showed cognitive impairments in attention, language, short-term memory, and executive cognitive functions. The local brain volume reductions, detected in GD1 patients, were in line with the cognitive impairments resulted in the neuropsychological assessment. Cortical reductions of fronto-parietal regions, responsible for the planning and execution of movements, are compatible with impairments in executive functions (digit-span) and visuo-spatial memory, found in GD1 patients. Moreover, impairments in short-term memory observed in GD1 patients are compatible with cortical reductions in the frontal cortex found by the VBM analysis.

In conclusion, focal brain differences found between GD1 patients and healthy subjects may predict and clarify the cognitive impairments and behavioural alterations observed in GD patients. The brain structural analyses, associated with neuropsychological assessment, suggest that a multidisciplinary approach is necessary in evaluating GD1 patients.