Writing errors in ALS related to loss of neuronal integrity in the anterior cingulate gyrus

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Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by loss of motor neuron and various cognitive deficits including writing errors. 11C-flumazenil (FMZ), the positron emission tomography (PET) GABAA receptor ligand, is a marker of cortical dysfunction. The objective of this study was to investigate the relationship between cognitive deficits and loss of neuronal integrity in ALS patients using 11C-FMZ PET. Ten patients with ALS underwent both neuropsychological tests and 11C-FMZ-PET. The binding potential (BP) of FMZ was calculated from 11C-FMZ PET images. There were no significant correlations between the BP and most test scores except for the writing error index (WEI), which was measured by the modified Western Aphasia Battery — VB (WAB-IVB) test. The severity of writing error was associated with loss of neuronal integrity in the bilateral anterior cingulate gyrus with mild right predominance (n = 9; x = 4 mm, y = 36 mm, z = 4 mm, Z = 5.1). The results showed that writing errors in our patients with ALS were related to dysfunction in the anterior cingulate gyrus.

Introduction

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive muscular atrophy and weakness with upper motor neuron impairment. It has traditionally been believed that intelligence is spared except in a small proportion of patients. Mitsuyama [1] described patients with dementia as having memory difficulty, global intellectual impairment, personality change, emotional disorder and loss of spontaneous speech. These deficits are consistent with fronto-temporal lobar degeneration (FTLD).

Recent studies have shed light on the mild cognitive impairment of ALS patients who do not meet the criteria of FTLD [2]. The published rate of ALS patients with cognitive impairment varies from 3% to 52% [3], [4], [5], [6]. As a result of intensive explorations of frontal lobe function, impairment of verbal fluency and executive function have been identified as specific deficits in ALS [4], [7], [8], [9], [10], [11]. Some Japanese investigators described that ALS patients frequently had agraphia without aphasia regardless of whether they had dementia [12], [13], [14], [15]. Omission of a Japanese kana letter was the most frequent error, and substitution, displacement, and incorrect letters were also often observed. The pattern of errors looked like they occurred from a frontal lobe lesion, which was supported by the finding of a reduction in cerebral blood flow in the frontal lobe in a single photon emission computed tomography (SPECT) study of a few cases. An autopsied case with progressive agraphia and ALS-D showed marked degeneration of the left middle frontal gyrus including Exner's area [16]. Thus, dysfunction of the frontal lobe was suspected as being responsible for the writing error in patients with ALS; however, because the number of reported cases was small, the pathological locus has not been conclusively identified.

The GABAA receptor ligand 11C-flumazenil (FMZ) is a probe used in positron emission tomography (PET) for the central-type benzodiazepine receptor (BZR) [17]. In vitro studies of specimens obtained from patients with epileptogenic brain lesions demonstrated altered GABAergic neurotransmission in the perilesional epileptic cortex [18], [19]. Therefore, FMZ PET is a sensitive, noninvasive method for visualizing focal cortical dysfunction that may represent epileptogenic zones. Because GABA receptors are abundant in the cortex, cerebral BZRs co-located with GABAA receptors can also be used as a marker of neuronal viability [20].

In this study, we performed several cognitive screening tests in non-demented ALS patients and identified the locus of their cognitive symptoms using FMZ PET.

Section snippets

Subjects

Ten patients with sporadic ALS agreed to participate in this study from September 2007 to June 2008. At the time of the examination, the patients were in the following categories of the revised El Escorial Criteria: 2 patients definite, 4 probable, 3 possible, and 1 suspected. All patients deteriorated in the following year, developing probable or definite ALS by 2010 [21]. The lesion at onset was located in the brainstem in 7 cases, cervical region in 2 cases and lumbosacral region in 1 case.

Results

The neuropsychological test scores are shown in Table 2. As reported in a previous study, patients with ALS performed poorly at picture arrangements and writing (the average WEI of the patients was 6.0 while that of 16 normal controls was 2.9) [15]. In the present study, there were no significant correlations between BP and scores except for the WEI. Various regions showed a correlation between BP and the WEI including the bilateral anterior cingulate gyrus (e.g., bilateral middle frontal

Discussion

11C-flumazenil PET studies in ALS patients by Wicks et al. [1] revealed that the binding potential of 11C-FMZ in the inferior frontal gyrus, superior temporal gyrus, and anterior insula was decreased in patients with impaired verbal fluency and that the score in a confrontation naming test was correlated with the binding potential in the left middle frontal gyrus and left cuneus. Turner et al. [11], [26] reported that ALS patients had decreased binding potential in the left fronto-temporal

Conflict of interest

None.

Acknowledgements

We thank all patients and control subjects for their active cooperation. This work was supported in part by a Grant-in-Aid for the Research Committee of CNS Degenerative Diseases of the Research on Measures for Intractable Diseases from the Ministry of Health, Welfare and Labor, Japan, and by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, Sports, and Culture, Japan.

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