Thalamic volume and related visual recognition are associated with freezing of gait in non-demented patients with Parkinson’s disease Mun Kyung Sunwoo a , Kyoo H. Cho a , Jin Yong Hong b , Ji E. Lee a , Young H. Sohn a , Phil Hyu Lee a, c, * a Department of Neurology, Yonsei University College of Medicine, Seoul, South Korea b Department of Neurology, Yonsei University Wonju College of Medicine, Wonju, South Korea c Severance Biomedical Science Institute, Seoul, South Korea article info Article history: Received 1 May 2013 Received in revised form 5 July 2013 Accepted 24 July 2013 Keywords: Freezing of gait Parkinson’s disease Thalamus Cholinergic abstract Background: The pathophysiology of freezing of gait (FOG) in non-demented Parkinson’s disease (PD) patients remains poorly understood. Recent studies have suggested that neurochemical alterations in the cholinergic systems play a role in the development of FOG. Here, we evaluated the association between subcortical cholinergic structures and FOG in patients with non-demented PD. Methods: We recruited 46 non-demented patients with PD, categorized into PD with (n ¼ 16) and without FOG (n ¼ 30) groups. We performed neuropsychological test, region-of-interest-based volu- metric analysis of the substantia innominata (SI) and automatic analysis of subcortical brain structures using a computerized segmentation procedure. Results: The comprehensive neuropsychological assessment showed that PD patients with FOG had lower cognitive performance in the frontal executive and visual-related functions compared with those without freezing of gait. The normalized SI volume did not differ significantly between the two groups (1.65  0.18 vs. 1.68  0.31). The automatic analysis of subcortical structures revealed that the thalamic volumes were significantly reduced in PD patients with FOG compared with those without FOG after adjusting for age, sex, disease duration, the Unified PD Rating Scale scores and total intracranial volume (left: 6.71 vs. 7.16 cm 3 , p ¼ 0.029, right: 6.47 vs. 6.91 cm 3 , p ¼ 0.026). Multiple linear regression analysis revealed that thalamic volume showed significant positive correlations with visual recognition memory (left: b ¼ 0.441, p ¼ 0.037, right: b ¼ 0.498, p ¼ 0.04). Conclusions: These data suggest that thalamic volume and related visual recognition, rather than the cortical cholinergic system arising from the SI, may be a major contributor to the development of freezing of gait in non-demented patients with PD. Ó 2013 Published by Elsevier Ltd. Freezing of gait (FOG) is a unique and disabling symptom usually observed in 25% of early Parkinson’s disease (PD) patients and 50% of patients with advanced PD [1]. FOG is an episodic inability to initiate gait and turning, in which the feet appear ‘glued to the floor’ [1]. It has been recognized that FOG is associated with motor dysfunction, cognitive processing and affective symptoms [2]. Although it definitely contributes to worsening the quality of life of patients with PD, the pathophysiology remains poorly understood. A recent review described that FOG induced by gait pattern gen- eration disturbance, motor and cognitive automaticity failure, and frontal executive and perceptual malfunction [3]. And there are several evidences that structural and functional alteration may be involved in FOG. A volumetric analysis demonstrated that FOG is associated with frontal, temporal and inferoposterior parietal cortical atrophy [4]. Functional imaging studies showed that decreased coordinated neural connectivity, such as executive attention and visual network, is related to the development of FOG [5e7]. FOG is an independent motor symptom that is not correlated with parkinsonian motor symptoms of bradykinesia or rigidity, but is well correlated with frontal executive function, suggesting that distinct pathological or neurochemical changes in extra- dopaminergic system may underlie its pathogenesis [4]. Recent studies have suggested that neurochemical alterations in the cholinergic systems might play a role in the FOG development along with cognitive impairment [8,9]. There are two major sources * Corresponding author. Department of Neurology, Yonsei University College of Medicine, 250 Seongsanno, Seodaemun-gu, Seoul 120-752, South Korea. Tel.: þ82 2 2228 1608; fax: þ82 2 393 0705. E-mail address: phisland@chol.net (P.H. Lee). Contents lists available at ScienceDirect Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis 1353-8020/$ e see front matter Ó 2013 Published by Elsevier Ltd. http://dx.doi.org/10.1016/j.parkreldis.2013.07.023 Parkinsonism and Related Disorders 19 (2013) 1106e1109