Daisuke Yanase

Partial volume effect-corrected FDG PET and grey matter volume loss in patients with mild Alzheimer’s disease

PurposeAlthough 18F-fluorodeoxyglucose (FDG) PET is an established imaging technique to assess brain glucose utilisation, accurate measurement of tracer concentration is confounded by the presence of partial volume effect (PVE) due to the limited spatial resolution of PET, which is particularly true in atrophic brains such as those encountered in patients with Alzheimer’s disease (AD). Our aim was to investigate the effects of PVE correction on FDG PET in conjunction with voxel-based morphometry (VBM) in patients with mild AD.MethodsThirty-nine AD patients and 73 controls underwent FDG PET and MRI. The PVE-corrected grey matter PET images were obtained using an MRI-based three-compartment method. Additionally, the results of PET were compared with grey matter loss detected by VBM.ResultsBefore PVE correction, reduced FDG uptake was observed in posterior cingulate gyri (PCG) and parieto-temporal lobes (PTL) in AD patients, which persisted after PVE correction. Notably, PVE correction revealed relatively preserved FDG uptake in hippocampal areas, despite the grey matter loss in medial temporal lobe (MTL) revealed by VBM.ConclusionFDG uptake in PCG and PTL is reduced in AD regardless of whether or not PVE correction is applied, supporting the notion that the reduced FDG uptake in these areas is not the result of atrophy. Furthermore, FDG uptake by grey matter tissue in the MTL, including hippocampal areas, is relatively preserved, suggesting that compensatory mechanisms may play a role in patients with mild AD.

Epidemiology of familial amyloid polyneuropathy in Japan: Identification of a novel endemic focus.

BACKGROUND Familial amyloid polyneuropathy (FAP) is distributed worldwide with several endemic foci including two major foci in Japan. OBJECTIVE To elucidate a nationwide epidemiology of FAP in Japan. DESIGN, SETTING, AND PATIENTS (i) We analyzed the data of FAP patients registered by the Ministry of Health, Labour, and Welfare, Japan, during 2003-2005. (ii) As Ishikawa prefecture was found to be a novel endemic focus, we examined 27 FAP patients in Ishikawa to characterize their clinical and genetic features in comparison with other endemic foci. RESULTS (i) The prevalence of familial amyloidosis in Japan was estimated to be 0.87-1.1 per 1,000,000 persons. Nagano prefecture had the highest prevalence (11-15.5), followed by Kumamoto (10.1-10.3), and then Ishikawa (3.5-4.2). (ii) All the FAP patients in Ishikawa had transthyretin (TTR) type FAP; all the families had a TTR Val30Met mutation except one family with a Leu58Arg mutation. FAP with Val30Met mutation in Ishikawa was characterized by late onset, high penetrance, and moderate autonomic dysfunction. CONCLUSIONS Ishikawa prefecture is the third endemic focus of FAP in Japan. FAP with TTR Val30Met mutation in Japan can be classified to (i) early-onset and endemic (Nagano and Kumamoto), (ii) late-onset and endemic (Ishikawa), and (iii) late-onset and non-endemic types.

Effect of sample size for normal database on diagnostic performance of brain FDG PET for the detection of Alzheimerʼs disease using automated image analysis

ObjectiveTo investigate the relationship between the sample size for a normal database (NDB) and diagnostic performance of FDG PET using three-dimensional stereotactic surface projection for the detection of Alzheimers disease. MethodsWe generated nine NDB sets consisting of 4, 6, 8, 10, 20, 30, 40, 50 and 60 normal subjects. In order to assess the diagnostic performance using these NDBs to distinguish Alzheimers disease patients from normal subjects, we recruited 52 patients with probable Alzheimers disease (25 males, 27 females; mean age, 66.8±8.1 years) and 50 normal subjects (24 males, 26 females; mean age, 65.7±9.4 years). A receiver operating characteristic (ROC) analysis was performed for comparison of diagnostic accuracy among NDB sets. ResultsSmall NDBs (n≤10) yielded poor quality of mean and SD images as compared with large NDBs (n≥20). The ROC curves of the smaller group varied inconsistently, whereas those of the larger group were nearly superimposable. The area under the ROC curve (AUC) of the NDBs with sample size 6 (0.911) or 8 (0.929) was significantly smaller than that of the largest NDB (n=60, 0.956). The AUCs of the larger group did not fall below 0.950, whereas AUCs of the smaller subgroup never exceeded 0.950. ConclusionsOur data indicate that the sample size for an NDB affects the diagnostic performance of FDG PET using automated statistical approach, and that inclusion of at least 10 subjects is recommended, and 20 seems to be preferable for generating NDBs, although even a small NDB may provide clinically relevant results.

Blood-Brain Barrier Permeability Correlates with Medial Temporal Lobe Atrophy but Not with Amyloid-β Protein Transport across the Blood-Brain Barrier in Alzheimer’s Disease

Background/Aims: Alterations in the blood-brain barrier (BBB) may play an important role in the pathogenesis and treatment of Alzheimer’s disease (AD). We investigated BBB disturbance and its influence on the equilibrium of amyloid-β protein (Aβ) between plasma and cerebrospinal fluid (CSF) in AD patients. Methods: We analyzed albumin ratio as a marker of the BBB permeability and correlated it with the severity of dementia, brain atrophy on MRI, apolipoprotein E isoform, CSF levels of total tau, CSF and plasma levels of Aβ 1–40 (Aβ40) and 1–42 (Aβ42), and CSF/plasma ratios of Aβ40 and Aβ42 in 42 AD patients. Results: The albumin ratio was positively correlated with the severity of medial temporal lobe atrophy but not with the other parameters including CSF/plasma ratios of Aβ40 or Aβ42. Conclusion: Our results suggest that progression of medial temporal lobe atrophy is associated with increased BBB permeability and that the transport of Aβ across the BBB is not influenced by the BBB alteration in AD.

A Comparison of the Diagnostic Sensitivity of MRI, CBF-SPECT, FDG-PET and Cerebrospinal Fluid Biomarkers for Detecting Alzheimer's Disease in a Memory Clinic

Background/Aim: Magnetic resonance imaging (MRI), cerebral blood flow single photon emission computed tomography (CBF-SPECT), fluorodeoxyglucose-positron emission tomography (FDG-PET) and cerebrospinal fluid (CSF) biomarkers are used for the diagnosis of Alzheimer’s disease (AD). We aimed to reveal the relative sensitivity of these tools in a memory clinic setting. Methods: In 207 patients with probable AD in our memory clinic, medial temporal lobe atrophy on MRI, hypoperfusion/hypometabolism of the parietotemporal lobe and posterior cingulate gyrus in ethylcysteinate dimer-CBF-SPECT/FDG-PET, and abnormalities of CSF amyloid β-protein 1–42, total tau and phosphorylated tau were evaluated as findings characteristic of AD. Results: The AD findings were observed in 77.4% of all AD patients with MRI, 81.6% with CBF-SPECT, 93.1% with FDG-PET and 94.0% with CSF biomarkers. At the stage of Clinical Dementia Rating (CDR) 0.5, CSF biomarkers were the most sensitive (90.0%); at the stage of CDR 1, FDG-PET (96.7%) and CSF biomarkers (95.5%) were highly sensitive. At the stage of CDR 2, all tools showed high positive percentages. Conclusion: The diagnosis of AD was most often supported by CSF biomarkers and FDG-PET at the early stage of dementia (CDR 1) and by CSF biomarkers at the earlier stage (CDR 0.5).

Cerebrospinal fluid of Alzheimer patients promotes β-amyloid fibril formation in vitro

Cerebral deposition of amyloid beta-peptide (Abeta) is an invariant feature of Alzheimers disease (AD). To answer why soluble Abeta does not aggregate to beta-amyloid fibrils (fAbeta) in the brain of normal humans, we examined the influence of cerebrospinal fluid (CSF) obtained from AD and non-AD patients on the formation of fAbeta(1-40) and fAbeta(1-42) in vitro, by using fluorescence spectroscopy with thioflavin T and electron microscopy. Although the CSF obtained from both groups inhibited the formation of both fAbeta(1-40) and fAbeta(1-42), the CSF from non-AD patients inhibited the formation of fAbetas more strongly than that from AD patients. In AD patients, the final levels of fAbetas formation showed a significant negative correlation with the Abeta(1-42) level in CSF. These results indicate that fAbeta deposition in the brain of AD may be enhanced by the decrease of specific inhibitory factors and/or by the increase of specific accelerating factors in CSF.

Effect of Cognitive and Aerobic Training Intervention on Older Adults with Mild or No Cognitive Impairment: A Derivative Study of the Nakajima Project

Background: An increasing elderly population in Japan requires effective cognitive intervention programs for dementia. This study demonstrates the effectiveness of such programs for older adults. Methods: The participants were local community-dwelling non-demented older adults and adults with mild cognitive impairment who underwent executive function and group aerobic training. In addition, a non-intervention group participated in activity sessions involving handicraft, Skutt ball matches, and cooking. The four criteria for assessment were cognitive function, instrumental activities of daily living, human relationships, and physical function. Results: The participants in both intervention groups showed a significant improvement in their memory function compared with the non-intervention group. Conclusion: Early rehabilitation intervention using executive function and aerobic training programs may improve memory.

Posterior cingulate atrophy and metabolic decline in early stage Alzheimer's disease

To test the hypothesis that Alzheimers disease (AD) patients with posterior cingulate/precuneus (PCP) atrophy would be a distinct disease form in view of metabolic decline. Eighty-one AD patients underwent (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET) and structural magnetic resonance imaging (MRI). Positron emission tomography and voxel-based morphometry (VBM) Z-score maps were generated for the individual patients using age-specific normal databases. The patients were classified into 3 groups based on atrophic patterns (no-Hipp-PCP, atrophy in neither hippocampus nor PCP; Hipp, hippocampal atrophy; PCP, PCP atrophy). There were 16 patients classified as no-Hipp-PCP, 55 as Hipp, and 10 as PCP. The Mini Mental State Examination (MMSE) score was similar among the groups. The greater FDG decline than atrophy was observed in all groups, including the no-Hipp-PCP. The PCP group was younger, and was associated with a greater degree of FDG decline in PCP than the others. There are diverse atrophic patterns in a spectrum of AD. In particular, a subset of patients show PCP atrophy, which is associated with greater metabolic burden.

Glucose metabolism and gray-matter concentration in apolipoprotein E ε4 positive normal subjects

Apolipoprotein E (ApoE) ε4 is known as a genetic risk factor for Alzheimers disease (AD). This study investigated the prevalence of imaging abnormalities suggestive of AD in cognitively normal ApoE ε4 carriers using (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET) and voxel-based morphometry (VBM). Forty-five cognitive normal ApoE ε4 allele carriers and 45 noncarriers underwent both FDG positron emission tomography and magnetic resonance imaging (MRI). A total of 90 normal database sets were generated for the individual 45 ε4 carriers and 45 noncarriers. Mean z-scores in the predefined AD-specific regions of interest (ROI) were calculated for each ε4 carrier and noncarrier using the individually defined normal database. The prevalence of AD-like hypometabolism and atrophy in the ε4 carriers was 8.9% and 17.7%, respectively, and did not differ significantly from those in the noncarriers (8.9%, 8.8%). The majority of ε4 carriers showed preserved FDG uptake or gray matter concentration.

Inclusion body myopathy with paget disease of bone and frontotemporal dementia associated with a novel G156s mutation in the VCP gene

1. Rosen DR, Siddique T, Patterson D, Figlewicz DA, Sapp P, Hentati A, et al. Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 1993;362:59–62. 2. Andersen PM, Al-Chalabi A. Clinical genetics of amyotrophic lateral sclerosis: what do we really know? Nat Rev Neurol 2011;7:603–615. 3. Saccon R, Bunton-Stasyshyn RKA, Fisher EMC, Fratta P. Is SOD1 loss of function involved in amyotrophic lateral sclerosis? Brain 2013;136: 2342–2358. 4. Suthers G, Laing N, Wilton S, Dorosz S, Waddy H. ‘Sporadic’ motoneuron disease due to familial SOD1 mutation with low penetrance. Lancet 1994;344:1773. 5. Juneja T, Pericak-Vance MA, Laing NG, Dave S, Siddique T. Prognosis in familial amyotrophic lateral sclerosis: progression and survival in patients with glu100gly and ala4val mutations in Cu,Zn superoxide dismutase. Neurology 1997;48:55–57. 6. Katz JS, Katzberg HD, Woolley SC, Marklund SL, Andersen PM. Combined fulminant frontotemporal dementia and amyotrophic lateral sclerosis associated with an I113T SOD1 mutation. Amyotroph Lateral Scler 2012;13:567–569. 7. Salameh JS, Atassi N, David WS. SOD1 (A4V)-mediated ALS presenting with lower motor neuron facial diplegia and unilateral vocal cord paralysis. Muscle Nerve 2009;40:880–882.