Yoshiyuki Nishio

Severe olfactory dysfunction is a prodromal symptom of dementia associated with Parkinson's disease: a 3 year longitudinal study

Dementia is one of the most debilitating symptoms of Parkinsons disease. A recent longitudinal study suggests that up to 80% of patients with Parkinsons disease will eventually develop dementia. Despite its clinical importance, the development of dementia is still difficult to predict at early stages. We previously identified olfactory dysfunction as one of the most important indicators of cortical hypometabolism in Parkinsons disease. In this study, we investigated the possible associations between olfactory dysfunction and the risk of developing dementia within a 3-year observation period. Forty-four patients with Parkinsons disease without dementia underwent the odour stick identification test for Japanese, memory and visuoperceptual assessments, (18)F-fluorodeoxyglucose positron emission tomography scans and magnetic resonance imaging scans at baseline and 3 years later. A subgroup of patients with Parkinsons disease who exhibited severe hyposmia at baseline showed more pronounced cognitive decline at the follow-up survey. By the end of the study, 10 of 44 patients with Parkinsons disease had developed dementia, all of whom had severe hyposmia at baseline. The multivariate logistic analysis identified severe hyposmia and visuoperceptual impairment as independent risk factors for subsequent dementia within 3 years. The patients with severe hyposmia had an 18.7-fold increase in their risk of dementia for each 1 SD (2.8) decrease in the score of odour stick identification test for Japanese. We also found an association between severe hyposmia and a characteristic distribution of cerebral metabolic decline, which was identical to that of dementia associated with Parkinsons disease. Furthermore, volumetric magnetic resonance imaging analyses demonstrated close relationships between olfactory dysfunction and the atrophy of focal brain structures, including the amygdala and other limbic structures. Together, our findings suggest that brain regions related to olfactory function are closely associated with cognitive decline and that severe hyposmia is a prominent clinical feature that predicts the subsequent development of Parkinsons disease dementia.

Distinct patterns of regional cerebral glucose metabolism in Parkinson's disease with and without mild cognitive impairment.

There is no consensus with regard to the clinical and neuroimaging characteristics of prodromal dementia in Parkinsons disease (PD). To delineate functional neuroimaging features of PD with mild cognitive impairment (PDMCI) and with no cognitive impairment (PDNC), we compared regional cerebral glucose metabolism (CMRglc) amongst 13 patients with PDMCI, 27 with PDNC, and 13 healthy controls. The PDNC patients had limited areas of hypometabolism in the frontal and occipital cortices. In the PDMCI patients, there were extensive areas of hypometabolism in the posterior cortical regions, including the temporo‐parieto‐occipital junction, medial parietal, and inferior temporal cortices. The present results suggest that posterior cortical dysfunction is the primary neuroimaging feature of PD patients at risk for dementia.

Diagnostic accuracy of 123I-meta-iodobenzylguanidine myocardial scintigraphy in dementia with Lewy bodies: a multicenter study.

Background and Purpose Dementia with Lewy bodies (DLB) needs to be distinguished from Alzheimer’s disease (AD) because of important differences in patient management and outcome. Severe cardiac sympathetic degeneration occurs in DLB, but not in AD, offering a potential system for a biological diagnostic marker. The primary aim of this study was to investigate the diagnostic accuracy, in the ante-mortem differentiation of probable DLB from probable AD, of cardiac imaging with the ligand 123I-meta-iodobenzylguanidine (MIBG) which binds to the noradrenaline reuptake site, in the first multicenter study. Methods We performed a multicenter study in which we used 123I-MIBG scans to assess 133 patients with clinical diagnoses of probable (n = 61) or possible (n = 26) DLB or probable AD (n = 46) established by a consensus panel. Three readers, unaware of the clinical diagnosis, classified the images as either normal or abnormal by visual inspection. The heart-to-mediastinum ratios of 123I-MIBG uptake were also calculated using an automated region-of-interest based system. Results Using the heart-to-mediastinum ratio calculated with the automated system, the sensitivity was 68.9% and the specificity was 89.1% to differentiate probable DLB from probable AD in both early and delayed images. By visual assessment, the sensitivity and specificity were 68.9% and 87.0%, respectively. In a subpopulation of patients with mild dementia (MMSE ≥ 22, n = 47), the sensitivity and specificity were 77.4% and 93.8%, respectively, with the delayed heart-to-mediastinum ratio. Conclusions Our first multicenter study confirmed the high correlation between abnormal cardiac sympathetic activity evaluated with 123I-MIBG myocardial scintigraphy and a clinical diagnosis of probable DLB. The diagnostic accuracy is sufficiently high for this technique to be clinically useful in distinguishing DLB from AD, especially in patients with mild dementia.

Association of olfactory dysfunction and brain. Metabolism in Parkinson's disease

Hyposmia is one of the cardinal early symptoms of Parkinson disease (PD). Accumulating clinical and pathological evidence suggests that dysfunction of the olfactory‐related cortices may be responsible for the impaired olfactory processing observed in PD; however, there are no clear data showing a direct association between altered brain metabolism and hyposmia in PD. In this study, we evaluated brain glucose metabolism and smell‐identification ability in 69 Japanese patients with nondemented PD. Olfactory function was assessed using the Odor Stick Identification Test for Japanese. The regional cerebral metabolic rate of glucose consumption at rest was measured using 18F‐fluorodeoxyglucose positron emission tomography and was analyzed using SPM‐based group comparisons and the brain–behavior partial least‐squares method. We found that olfactory dysfunction was closely related to cognitive dysfunction, including memory impairment. Moreover, brain–behavior partial least‐squares analysis revealed that odor‐identification performance was closely associated with broad cortical dysfunction, including dysfunction of the piriform cortex and amygdala. Our results suggest that the cognitive deficit in olfactory perception is an important aspect of hyposmia in PD and that this deficit is caused by altered brain metabolism in the amygdala and piriform cortex.

Corticolimbic gray matter loss in Parkinson’s disease without dementia

Background:  The relationship between corticolimbic involvement and cognitive dysfunction in non‐demented Parkinson’s disease (PD) patients has not yet been elucidated.

White matter involvement in idiopathic normal pressure hydrocephalus: a voxel-based diffusion tensor imaging study

The aim of this study was to characterise the white matter damage involved in idiopathic normal pressure hydrocephalus (INPH) using diffusion tensor imaging (DTI) and the relationship between this damage and clinical presentation. Twenty patients with INPH, 20 patients with Alzheimer’s disease and 20 patients with idiopathic Parkinson’s disease (as disease control groups) were enrolled in this study. Mean diffusivity (MD) and fractional anisotropy (FA) were determined using DTI, and these measures were analysed to compare the INPH group with the control groups and with certain clinical correlates. On average, the supratentorial white matter presented higher MD and lower FA in the INPH group than in the control groups. In the INPH group, the mean hemispheric FA correlated with some of the clinical measures, whereas the mean hemispheric MD did not. On a voxel-based statistical map, white matter involvement with high MD was localised to the periventricular regions, and white matter involvement with low FA was localised to the corpus callosum and the subcortical regions. The total scores on the Frontal Assessment Battery were correlated with the FA in the frontal and parietal subcortical white matter, and an index of gait disturbance was correlated with the FA in the anterior limb of the left internal capsule and under the left supplementary motor area. DTI revealed the presence of white matter involvement in INPH. Whereas white matter regions with high MD were not related to symptom manifestation, those with low FA were related to motor and cognitive dysfunction in INPH.

Do parkinsonian patients have trouble telling lies? The neurobiological basis of deceptive behaviour

Parkinsons disease is a common neurodegenerative disorder with both motor symptoms and cognitive deficits such as executive dysfunction. Over the past 100 years, a growing body of literature has suggested that patients with Parkinsons disease have characteristic personality traits such as industriousness, seriousness and inflexibility. They have also been described as ‘honest’, indicating that they have a tendency not to deceive others. However, these personality traits may actually be associated with dysfunction of specific brain regions affected by the disease. In the present study, we show that patients with Parkinsons disease are indeed ‘honest’, and that this personality trait might be derived from dysfunction of the prefrontal cortex. Using a novel cognitive task, we confirmed that patients with Parkinsons disease (n = 32) had difficulty making deceptive responses relative to healthy controls (n = 20). Also, using resting-state 18F-fluorodeoxyglucose PET, we showed that this difficulty was significantly correlated with prefrontal hypometabolism. Our results are the first to demonstrate that the ostensible honesty found in patients with Parkinsons disease has a neurobiological basis, and they provide direct neuropsychological evidence of the brain mechanisms crucial for human deceptive behaviour.

Pareidolias: complex visual illusions in dementia with Lewy bodies

Patients rarely experience visual hallucinations while being observed by clinicians. Therefore, instruments to detect visual hallucinations directly from patients are needed. Pareidolias, which are complex visual illusions involving ambiguous forms that are perceived as meaningful objects, are analogous to visual hallucinations and have the potential to be a surrogate indicator of visual hallucinations. In this study, we explored the clinical utility of a newly developed instrument for evoking pareidolic illusions, the Pareidolia test, in patients with dementia with Lewy bodies—one of the most common causes of visual hallucinations in the elderly. Thirty-four patients with dementia with Lewy bodies, 34 patients with Alzheimer’s disease and 26 healthy controls were given the Pareidolia test. Patients with dementia with Lewy bodies produced a much greater number of pareidolic illusions compared with those with Alzheimer’s disease or controls. A receiver operating characteristic analysis demonstrated that the number of pareidolias differentiated dementia with Lewy bodies from Alzheimer’s disease with a sensitivity of 100% and a specificity of 88%. Full-length figures and faces of people and animals accounted for >80% of the contents of pareidolias. Pareidolias were observed in patients with dementia with Lewy bodies who had visual hallucinations as well as those who did not have visual hallucinations, suggesting that pareidolias do not reflect visual hallucinations themselves but may reflect susceptibility to visual hallucinations. A sub-analysis of patients with dementia with Lewy bodies who were or were not treated with donepzil demonstrated that the numbers of pareidolias were correlated with visuoperceptual abilities in the former and with indices of hallucinations and delusional misidentifications in the latter. Arousal and attentional deficits mediated by abnormal cholinergic mechanisms and visuoperceptual dysfunctions are likely to contribute to the development of visual hallucinations and pareidolias in dementia with Lewy bodies.

Cognitive Profile of Idiopathic Normal Pressure Hydrocephalus

Background/Aims: Frontal lobe dysfunction is believed to be a primary cognitive symptom in idiopathic normal pressure hydrocephalus (iNPH); however, the neuropsychology of this disorder remains to be fully investigated. The objective of this study was to delineate a comprehensive profile of cognitive dysfunction in iNPH and evaluate the effects of cerebrospinal fluid (CSF) shunt surgery on cognitive dysfunction. Methods: A total of 32 iNPH patients underwent neuropsychological testing of memory, attention, language, executive function, and visuoperceptual and visuospatial abilities. Of these 32 patients, 26 were reevaluated approximately 1 year following CSF shunt surgery. The same battery of tests was performed on 32 patients with Alzheimer’s disease (AD) and 30 healthy elderly controls. Results: The iNPH patients displayed baseline deficits in attention, executive function, memory, and visuoperceptual and visuospatial functions. Impairments of attention, executive function, and visuoperceptual and visuospatial abilities in iNPH patients were more severe than in those with AD, whereas the degree of memory impairment was comparable to that in AD patients. A significant improvement in executive function was observed following shunt surgery. Conclusion: Patients with iNPH are impaired in various aspects of cognition involving both ‘frontal’ executive functions and ‘posterior cortical’ functions. Shunt treatment can ameliorate executive dysfunction.

Attentional set-shifting deficit in Parkinson's disease is associated with prefrontal dysfunction: an FDG-PET study.

The attentional set-shifting deficit that has been observed in Parkinson’s disease (PD) has long been considered neuropsychological evidence of the involvement of meso-prefrontal and prefrontal-striatal circuits in cognitive flexibility. However, recent studies have suggested that non-dopaminergic, posterior cortical pathologies may also contribute to this deficit. Although several neuroimaging studies have addressed this issue, the results of these studies were confounded by the use of tasks that required other cognitive processes in addition to set-shifting, such as rule learning and working memory. In this study, we attempted to identify the neural correlates of the attentional set-shifting deficit in PD using a compound letter task and 18F-fluoro-deoxy-glucose (FDG) positron emission tomography during rest. Shift cost, which is a measure of attentional set-shifting ability, was significantly correlated with hypometabolism in the right dorsolateral prefrontal cortex, including the putative human frontal eye field. Our results provide direct evidence that dysfunction in the dorsolateral prefrontal cortex makes a primary contribution to the attentional set-shifting deficit that has been observed in PD patients.