Hitoshi Shimada

Mapping of brain acetylcholinesterase alterations in Lewy body disease by PET

Objective: To characterize brain cholinergic deficits in Parkinson disease (PD), PD with dementia (PDD), and dementia with Lewy bodies (DLB). Methods: Participants included 18 patients with PD, 21 patients with PDD/DLB, and 26 healthy controls. The PD group consisted of nine patients with early PD, each with a disease duration of less than 3 years, five of whom were de novo PD patients, and nine patients with advanced PD, each with a disease duration greater than or equal to 3 years. The PDD/DLB group consisted of 10 patients with PDD and 11 patients with DLB. All subjects underwent PET scans with N-[11C]-methyl-4-piperidyl acetate to measure brain acetylcholinesterase (AChE) activity. Brain AChE activity levels were estimated voxel-by-voxel in a three-compartment analysis using the arterial input function, and compared among our subject groups through both voxel-based analysis using the statistical parametric mapping software SPM5 and volume-of-interest analysis. Results: Among patients with PD, AChE activity was significantly decreased in the cerebral cortex and especially in the medial occipital cortex (% reduction compared with the normal mean = −12%) (false discovery rate–corrected p value <0.01). Patients with PDD/DLB, however, had even lower AChE activity in the cerebral cortex (% reduction = −27%) (p < 0.01). There was no significant difference between early PD and advanced PD groups or between DLB and PDD groups in the amount by which regional AChE activity in the brain was reduced. Conclusions: Brain cholinergic dysfunction occurs in the cerebral cortex, especially in the medial occipital cortex. It begins in early Parkinson disease, and is more widespread and profound in both Parkinson disease with dementia and dementia with Lewy bodies.

Cholinergic imaging in corticobasal syndrome, progressive supranuclear palsy and frontotemporal dementia.

Corticobasal syndrome, progressive supranuclear palsy and frontotemporal dementia are all part of a disease spectrum that includes common cognitive impairment and movement disorders. The aim of this study was to characterize brain cholinergic deficits in these disorders. We measured brain acetylcholinesterase activity by [11C] N-methylpiperidin-4-yl acetate and positron emission tomography in seven patients with corticobasal syndrome (67.6+/-5.9 years), 12 with progressive supranuclear palsy (68.5+/-4.1 years), eight with frontotemporal dementia (59.8+/-6.9 years) and 16 healthy controls (61.2+/-8.5 years). Two-tissue compartment three-parameter model and non-linear least squares analysis with arterial input function were performed. k3 value, an index of acetylcholinesterase activity, was calculated voxel-by-voxel in the brain of each subject. The k3 images in each disease group were compared with the control group by using Statistical Parametric Mapping 2. Volume of interest analysis was performed on spatially normalized k3 images. The corticobasal syndrome group showed decreased acetylcholinesterase activity (k3 values) in the paracentral region, frontal, parietal and occipital cortices (P<0.05, cluster corrected). The group with progressive supranuclear palsy had reduced acetylcholinesterase activity in the paracentral region and thalamus (P<0.05, cluster corrected). The frontotemporal dementia group showed no significant differences in acetylcholinesterase activity. Volume of interest analysis showed mean cortical acetylcholinesterase activity to be reduced by 17.5% in corticobasal syndrome (P<0.001), 9.4% in progressive supranuclear palsy (P<0.05) and 4.4% in frontotemporal dementia (non-significant), when compared with the control group. Thalamic acetylcholinesterase activity was reduced by 6.4% in corticobasal syndrome (non-significant), 24.0% in progressive supranuclear palsy (P<0.03) and increased by 3.3% in frontotemporal dementia (non-significant). Both corticobasal syndrome and progressive supranuclear palsy showed brain cholinergic deficits, but their distribution differed somewhat. Significant brain cholinergic deficits were not seen in frontotemporal dementia, which may explain the unresponsiveness of this condition to cholinergic modulation therapy.

Reconstruction magnetic resonance neurography in chronic inflammatory demyelinating polyneuropathy.

To study distribution and patterns of nerve hypertrophy in chronic inflammatory demyelinating polyneuropathy (CIDP), magnetic resonance neurography with 3‐dimensional reconstruction of short tau inversion recovery images was performed in 33 patients. This technique clearly showed longitudinal morphological changes from the cervical roots to the nerve trunks in the proximal arm. Nerve enlargement was detected in 88% of the patients. According to the clinical subtype of CIDP, typical CIDP patients showed symmetric and root‐dominant hypertrophy, whereas Lewis–Sumner syndrome patients had multifocal fusiform hypertrophy in the nerve trunks. The patterns of nerve hypertrophy presumably reflect the different pathophysiology of each CIDP subtype. Ann Neurol 2014.

β-Amyloid in Lewy body disease is related to Alzheimer's disease-like atrophy.

The aim of this study was to investigate whether amyloid deposition is associated with Alzheimers disease (AD)‐like cortical atrophy in Lewy body (LB) disease (LBD). Participants included 15 LBD with dementia patients (8 with dementia with Lewy bodies [DLB] and 7 with Parkinsons disease [PD] with dementia [PDD]), 13 AD patients, and 17 healthy controls. Age, gender, and Mini–Mental State Examination scores were matched between patient groups. All subjects underwent PET scans with [11C]Pittsburgh Compound B to measure brain amyloid deposition as well as three‐dimensional T1‐weighted MRI. Gray‐matter volumes (GMVs) were estimated by voxel‐based morphometry. Volumes‐of‐interest analyses were also performed. Forty percent of the 15 DLB/PDD patients were amyloid positive, whereas all AD patients and none of the healthy controls were amyloid positive. Amyloid‐positive DLB/PDD and AD patients showed very similar patterns of cortical atrophy in the parahippocampal area and lateral temporal and parietal cortices, with 95.2% of cortical atrophy distribution being overlapped. In contrast, amyloid‐negative DLB/PDD patients had no significant cortical atrophy. Compared to healthy controls, parahippocampal GMVs were reduced by 26% in both the amyloid‐positive DLB/PDD and AD groups and by 10% in the amyloid‐negative DLB/PDD group. The results suggest that amyloid deposition is associated with AD‐like atrophy in DLB/PDD patients. Early intervention against amyloid may prevent or delay AD‐like atrophy in DLB/PDD patients with amyloid deposition.

Apathy correlates with prefrontal amyloid β deposition in Alzheimer's disease

Objective Neuropsychiatric symptoms affect many patients with Alzheimers disease (AD). (11C)Pittsburgh Compound-B (PIB) positron emission tomography (PET) has enabled the in vivo visualisation of brain amyloid-β (Aβ) deposition. This study exploratively investigated the correlation between brain Aβ deposition measured by (11C)PIB PET and neuropsychiatric symptoms in AD. Methods Participants were 28 patients (15 women, 13 men) with PIB-positive AD. Clinical assessments included Mini-Mental State Examination, Clinical Dementia Rating scale, neuropsychiatry inventory (NPI) and frontal assessment battery. All patients underwent three-dimensional T1-weighted MRI and (11C)PIB PET. The distribution volume ratio (DVR), an index of (11C)PIB retention and, thus, Aβ deposition, was estimated voxel by voxel from (11C)PIB PET data with partial volume correction. Voxel-based correlation analysis was performed to assess the relationships between DVR and each NPI subscale. Additionally, voxel-based analysis of covariance (ANCOVA) of the DVR images was performed between Patients with AD with and without each neuropsychiatric symptom. Voxel-based morphometry analysis of MRI was also performed. Results Apathy subscale was correlated with (11C)PIB retention in the bilateral frontal and right anterior cingulate. (11C)PIB retention was greater in the bilateral frontal cortex of patients with AD with apathy than those of without apathy. Overlapping areas between the two analyses were the bilateral orbitofrontal gyrus and left superior frontal gyrus. Other NPI subscales were not correlated with (11C)PIB retention. Voxel-based morphometry analysis of MRI showed no significant cluster of correlation between grey matter volume and NPI subscales. Conclusions This study revealed that prefrontal Aβ deposition correlates with apathy.

Reduced perfusion in the anterior cingulate cortex of patients with pure autonomic failure: an 123I-IMP SPECT study

Background: Pure autonomic failure (PAF) is a selective peripheral disorder in which Lewy bodies form within the autonomic ganglia. Patients with this disorder usually have no central lesions; however, chronic autonomic failure may secondarily affect the central nervous system. This study evaluated brain perfusion in patients with PAF by using N-isopropyl-p-123I iodoamphetamine (123I-IMP) single photon emission computed tomography (SPECT). Methods: Six patients with PAF (all men; mean (SD) age 68±5 years) who had experienced autonomic symptoms for more than 5 years and six age-matched healthy control subjects (all men; mean (SD) age 67±5 years) were included in this study. The regions of interest (ROI) on spacially normalized 123I-IMP SPECT images were automatically computed for both groups. Results: Perfusion of the dorsal anterior cingulate cortex was decreased in the PAF group compared with the healthy control group (0.93 vs 1.01; p<0.001). In the other brain regions measured, there was no significant difference in regional perfusion between the two groups. Conclusions: The dorsal anterior cingulate cortex is poorly perfused and may be functionally altered in patients with PAF. The reduced perfusion in such individuals may be a secondary change that results from chronic autonomic failure.

Potassium channel antibody-associated encephalitis with hypothalamic lesions and intestinal pseudo-obstruction

A subgroup of limbic encephalitis is associated with antibodies against voltage-gated potassium channels (VGKC), and responds well to immuno-modulating therapies. Anti-VGKC antibodies are also found in Isaacs syndrome and Morvans syndrome, both of which are sometimes complicated by thymoma. We describe a 52-years-old man with limbic encephalitis, thymoma, and anti-VGKC antibodies, who presented with autonomic dysfunctions such as severe intestinal pseudo-obstruction, hyperhidrosis and hypertension. Thymectomy and corticosteroid therapy remarkably improved his symptoms. Brain magnetic resonance imaging showed hypothalamic lesions, in addition to the bilateral involvement of the medial temporal lobes. This patient had severe autonomic dysfunctions resembling those of Morvans syndrome. This case may represent a subgroup of VGKC-antibody associated syndromes with a wide spectrum of symptoms, including Isaacs syndrome, Morvans syndrome, and limbic encephalitis.

Noninvasive k3 estimation method for slow dissociation PET ligands: application to [11C]Pittsburgh compound B.

BackgroundRecently, we reported an information density theory and an analysis of three-parameter plus shorter scan than conventional method (3P+) for the amyloid-binding ligand [11C]Pittsburgh compound B (PIB) as an example of a non-highly reversible positron emission tomography (PET) ligand. This article describes an extension of 3Pu2009+u2009analysis to noninvasive ‘3P++’ analysis (3Pu2009+u2009plus use of a reference tissue for input function).MethodsIn 3P++ analysis for [11C]PIB, the cerebellum was used as a reference tissue (negligible specific binding). Fifteen healthy subjects (NC) and fifteen Alzheimers disease (AD) patients participated. The k3 (index of receptor density) values were estimated with 40-min PET data and three-parameter reference tissue model and were compared with that in 40-min 3Pu2009+u2009analysis as well as standard 90-min four-parameter (4P) analysis with arterial input function. Simulation studies were performed to explain k3 biases observed in 3P++ analysis.ResultsGood model fits of 40-min PET data were observed in both reference and target regions-of-interest (ROIs). High linear intra-subject (inter-15 ROI) correlations of k3 between 3P++ (Y-axis) and 3Pu2009+u2009(X-axis) analyses were shown in one NC (r2u2009=u20090.972 and slopeu2009=u20090.845) and in one AD (r2u2009=u20090.982, slopeu2009=u20090.655), whereas inter-subject k3 correlations in a target region (left lateral temporal cortex) from 30 subjects (15 NCu2009+u200915 AD) were somewhat lower (r2u2009=u20090.739 and slopeu2009=u20090.461). Similar results were shown between 3P++ and 4P analyses: r2u2009=u20090.953 for intra-subject k3 in NC, r2u2009=u20090.907 for that in AD and r2u2009=u20090.711 for inter-30 subject k3. Simulation studies showed that such lower inter-subject k3 correlations and significant negative k3 biases were not due to unstableness of 3P++ analysis but rather to inter-subject variation of both k2 (index of brain-to-blood transport) and k3 (not completely negligible) in the reference region.ConclusionsIn [11C]PIB, the applicability of 3P++ analysis may be restricted to intra-subject comparison such as follow-up studies. The 3P++ method itself is thought to be robust and may be more applicable to other non-highly reversible PET ligands with ideal reference tissue.

Obstructive factors of the physical rehabilitation in elderly patients with cognitive decline

subjects reported emotional and sexual estrangement in terms of sharing thoughts and feelings with others, failure to meet emotional needs, reduced participation in social activities, less hand-holding and kissing, and increased concerns about their partner’s ability to engage in sexual activity (p-values 0.001, 0.03, 0.02, 0.008, 0.02, 0.0003, respectively). Conclusions: Sexuality and emotional intimacy are an important part of life irrespective of age or cognitive status. While the development of cognitive decline sufficient to meet criteria for MCI or dementia does not affect the emotional or sexual well-being of the person affected, it has negative consequences for the cognitively normal partner’s emotional and sexual needs. Consideration of a spousal caregiver’s needs should include an assessment of sexuality and emotional intimacy.

Lewy body disease with dementia can be well-differentiated from Alzheimer's disease by measurement of cerebral cortical acetylcholinesterase activity by PET

IC-P-017 LEWY BODY DISEASE WITH DEMENTIA CAN BE WELL-DIFFERENTIATED FROM ALZHEIMER’S DISEASE BY MEASUREMENT OF CEREBRAL CORTICAL ACETYLCHOLINESTERASE ACTIVITY BY PET Hitoshi Shimada, Hitoshi Shinotoh, Shigeki Hirano, Michie Miyoshi, Koichi Sato, Noriko Tanaka, Tsuneyoshi Ota, Masato Asahina, Akiyo Aotsuka, Kiyoshi Fukushi, Hiroshi Ito, Satoshi Kuwabara, Toshiaki Irie, Tetsuya Suhara, Molecular Neuroimaging Group, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan; Section for Human Neurophysiology, Research Center for Frontier Medical Engineering, Chiba University, Chiba, Japan; Asahi Hospital for Neurological Diseases and Rehabilitation, Chiba, Japan; Department of Neurology, JR Tokyo General Hospital, Tokyo, Japan; Department of Clinical Neuroscience and Therapeutics, Hiroshima University, Hiroshima, Japan; Department of Psychiatry, Ichihara Hospital, Teikyo University School of Medicine, Chiba, Japan; Department of Neurosurgery, Tokyo Women’s Medical University Medical Center East, Tokyo, Japan; Department of Psychiatry, Juntendo University School of Medicine, Tokyo, Japan; Department of Neurology, Graduate School of Medicine, Chiba University, Chiba, Japan; Molecular Probe Group, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan; Department of Rehabilitation Medicine, Chiba Aoba Municipal Hospital, Chiba, Japan. Contact e-mail: shim@alpha.ocn.ne.jp