New objective simple evaluation methods of amyloid PET/CT using whole-brain histogram and Top20%-Map.

OBJECTIVE: This study aims to assess the utility of newly developed objective methods for the evaluation of intracranial abnormal amyloid deposition using PET/CT histogram without use of cortical ROI analyses. METHODS: Twenty-five healthy volunteers (HV) and 38 patients with diagnosed or suspected dementia who had undergone 18F-FPYBF-2 PET/CT were retrospectively included in this study. Out of them, 11C-PiB PET/CT had been also performed in 13 subjects. In addition to the conventional methods, namely visual judgment and quantitative analyses using composed standardized uptake value ratio (comSUVR), the PET images were also evaluated by the following new parameters: the skewness and the mode-to-mean ratio (MMR) obtained from the histogram of the brain parenchyma; Top20%-map highlights the areas with high tracer accumulation occupying 20% volume of the total brain parenchymal on the individual's CT images. We evaluated the utility of the new methods using histogram compared with the visual assessment and comSUVR. The results of these new methods between 18F-FPYBF-2 and 11C-PiB were also compared in 13 subjects. RESULTS: In visual analysis, 32, 9, and 22 subjects showed negative, border, and positive results, and composed SUVR in each group were 1.11 ± 0.06, 1.20 ± 0.13, and 1.48 ± 0.18 (p < 0.0001), respectively. Visually positive subjects showed significantly low skewness and high MMR (p < 0.0001), and the Top20%-Map showed the presence or absence of abnormal deposits clearly. In comparison between the two tracers, visual evaluation was all consistent, and the ComSUVR, the skewness, the MMR showed significant good correlation. The Top20%-Maps showed similar pattern. CONCLUSIONS: Our new methods using the histogram of the brain parenchymal accumulation are simple and suitable for clinical practice of amyloid PET, and Top20%-Map on the individual's brain CT can be of great help for the visual assessment.

Neuropsychological basis of impaired gesture imitations in patients with Alzheimer's disease and dementia with Lewy bodies.

INTRODUCTION: The aim of this study was to examine the neuropsychological factors that may be related to the impaired gesture imitations in patients with dementia. METHODS: The imitation of unilateral finger and bimanual gestures was evaluated in 162 patients with Alzheimer's disease (AD) and 103 patients with dementia with Lewy bodies (DLB). The relationships of gesture imitation performance to global cognition, semantic fluency, phonemic fluency, figure copying, clock drawing, and trail-making test part A (TMT-A) scores were examined. RESULTS: Mean scores for unilateral finger imitation were significantly lower in DLB patients than in AD patients, and significantly more DLB patients showed impaired performance in unilateral finger imitation than AD patients. In contrast, the percentage of patients with impaired bimanual gesture imitation was not significantly different between AD and DLB patients. Unilateral finger imitation performance was predicted by pentagon copying in the AD patients, and was predicted by cube copying in the DLB patients. Bimanual gesture imitation performance was predicted by TMT-A scores and phonemic fluency in the AD patients but was predicted by TMT-A scores, cube copying, and parkinsonism severity in the DLB patients. DISCUSSION: Our study suggested that bimanual gesture imitation is a complex task that is supported by a wide range of neuropsychological processes, such as visuospatial attention, executive function, and visuomotor control, and therefore, it was easily impaired in early dementia. Unilateral finger imitation was more similar to constructional tasks, such as figure drawing, and was impaired more often in DLB patients than in AD patients.

18F-FPYBF-2, a new F-18-labelled amyloid imaging PET tracer: first experience in 61 volunteers and 55 patients with dementia.

OBJECTIVE: Recently, we developed a benzofuran derivative for the imaging of ß-amyloid plaques, 5-(5-(2-(2-(2-18F-fluoroethoxy)ethoxy)ethoxy)benzofuran-2-yl)-N-methylpyridin-2-amine (18F-FPYBF-2) (Ono et al., J Med Chem 54:2971-9, 2011). The aim of this study was to assess the feasibility of 18F-FPYBF-2 as an amyloid imaging PET tracer in a first clinical study with healthy volunteers and patients with various dementia and in comparative dual tracer study using 11C-Pittsburgh Compound B (11C-PiB). METHODS: 61 healthy volunteers (age: 53.7 ± 13.1 years old; 19 male and 42 female; age range 24-79) and 55 patients with suspected dementia [Alzheimer's Disease (AD); early AD: n = 19 and moderate stage AD: n = 8, other dementia: n = 9, mild cognitive impairment (MCI): n = 16, cognitively normal: n = 3] for first clinical study underwent static head PET/CT scan using 18 F - FPYBF-2 at 50-70 min after injection. 13 volunteers and 14 patients also underwent dynamic PET scan at 0-50 min at the same instant. 16 subjects (volunteers: n = 5, patients with dementia: n = 11) (age: 66.3 ± 14.2 years old; 10 males and 6 females) were evaluated for comparative study (50-70 min after injection) using 18F-FPYBF-2 and 11C-PiB on separate days, respectively. Quantitative analysis of mean cortical uptake was calculated using Mean Cortical Index of SUVR (standardized uptake value ratio) based on the established method for 11C-PiB analysis using cerebellar cortex as control. RESULTS: Studies with healthy volunteers showed that 18F-FPYBF-2 uptake was mainly observed in cerebral white matter and that average Mean Cortical Index at 50-70 min was low and stable (1.066 ± 0.069) basically independent from age or gender. In patients with AD, 18F-FPYBF-2 uptake was observed both in cerebral white and gray matter, and Mean Cortical Index was significantly higher (early AD: 1.288 ± 0.134, moderate AD: 1.342 ± 0.191) than those of volunteers and other dementia (1.018 ± 0.057). In comparative study, the results of 18F-FPYBF-2 PET/CT were comparable with those of 11C-PiB, and the Mean Cortical Index (18F-FPYBF-2: 1.173 ± 0.215; 11C-PiB: 1.435 ± 0.474) showed direct proportional relationship with each other (p < 0.0001). CONCLUSIONS: Our first clinical study suggest that 18F-FPYBF-2 is a useful PET tracer for the evaluation of ß-amyloid deposition and that quantitative analysis of Mean Cortical Index of SUVR is a reliable diagnostic tool for the diagnosis of AD.

18F-FPYBF-2, a new F-18 labelled amyloid imaging PET tracer: biodistribution and radiation dosimetry assessment of first-in-man 18F-FPYBF-2 PET imaging.

OBJECTIVE: Recently, a benzofuran derivative for the imaging of ß-amyloid plaques, 5-(5-(2-(2-(2-18F-fluoroethoxy)ethoxy)ethoxy)benzofuran-2-yl)- N-methylpyridin-2-amine (18F-FPYBF-2) has been validated as a tracer for amyloid imaging and it was found that 18F-FPYBF-2 PET/CT is a useful and reliable diagnostic tool for the evaluation of AD (Higashi et al. Ann Nucl Med, https://doi.org/10.1007/s12149-018-1236-1 , 2018). The aim of this study was to assess the biodistribution and radiation dosimetry of diagnostic dosages of 18F-FPYBF-2 in normal healthy volunteers as a first-in-man study. METHODS: Four normal healthy volunteers (male: 3, female: 1; mean age: 40 ± 17; age range 25-56) were included and underwent 18F-FPYBF-2 PET/CT study for the evaluation of radiation exposure and pharmacokinetics. A 10-min dynamic PET/CT scan of the body (chest and abdomen) was performed at 0-10 min and a 15-min whole-body static scan was performed six times after the injection of 18F-FPYBF-2. After reconstructing PET and CT image data, individual organ time-activity curves were estimated by fitting volume of interest data from the dynamic scan and whole-body scans. The OLINDA/EXM version 2.0 software was used to determine the whole-body effective doses. RESULTS: Dynamic PET imaging demonstrated that the hepatobiliary and renal systems were the principal pathways of clearance of 18F-FPYBF-2. High uptake in the liver and the gall bladder, the stomach, and the kidneys were demonstrated, followed by the intestines and the urinary bladder. The ED for the adult dosimetric model was estimated to be 8.48 ± 1.25 µSv/MBq. The higher absorbed doses were estimated for the liver (28.98 ± 12.49 and 36.21 ± 15.64 µGy/MBq), the brain (20.93 ± 4.56 and 23.05 ± 5.03µ Gy/MBq), the osteogenic cells (9.67 ± 1.67 and 10.29 ± 1.70 µGy/MBq), the small intestines (9.12 ± 2.61 and 11.12 ± 3.15 µGy/MBq), and the kidneys (7.81 ± 2.62 and 8.71 ± 2.90 µGy/MBq) for male and female, respectively. CONCLUSIONS: The ED for the adult dosimetric model was similar to those of other agents used for amyloid PET imaging. The diagnostic dosage of 185-370 MBq of 18F-FPYBF-2 was considered to be acceptable for administration in patients as a diagnostic tool for the evaluation of AD.

Neuropsychological Differences Related to Age in Dementia with Lewy Bodies.

BACKGROUND/AIMS: To examine the influence of age on neuropsychological performances in dementia with Lewy bodies (DLB) and Alzheimer disease (AD) patients. METHODS: We examined memory, executive, and visuo-constructional performances in 202 DLB patients and 236 AD patients. We divided the subjects into three age groups (65-74, 75-84, and 85-95 years old), and evaluated the differences in neuropsychological performances. RESULTS: Recent memory in the DLB group was significantly better than that in the age-matched AD group when comparing the age groups 65-74 years and 75-84 years; however, memory impairment in the DLB patients in the age group 85-95 years was comparable with that in the age-matched AD patients. In contrast to recent memory, the other assessed neuropsychological performances, such as visuospatial and executive functions, showed no significant change in differences between the DLB and AD groups with advancing age. CONCLUSION: Our study revealed that the nature of memory impairment in DLB patients changes according to age. DLB patients in the young-old and old-old age groups showed significantly better memory performance than the age-matched AD patients, whereas memory performance of the DLB patients in the oldest-old age group was similar to that of the age-matched AD patients. This may be associated with the increased rate of coexisting AD pathology in DLB patients with older age.

Impaired imitation of gestures in mild dementia: comparison of dementia with Lewy bodies, Alzheimer's disease and vascular dementia.

INTRODUCTION: To examine whether imitation of gestures provided useful information to diagnose early dementia in elderly patients. METHODS: Imitation of finger and hand gestures was evaluated in patients with mild dementia; 74 patients had dementia with Lewy bodies (DLB), 100 with Alzheimer's disease (AD) and 52 with subcortical vascular dementia (SVaD). RESULTS: Significantly, more patients with DLB (32.4%) compared with patients with AD (5%) or SVaD (11.5%) had an impaired ability to imitate finger gestures bilaterally. Also, significantly, more patients with DLB (36.5%) compared with patients with AD (5%) or SVaD (15.4%) had lower mean scores of both hands. In contrast, impairment of the imitation of bimanual gestures was comparable among the three patient groups (DLB 50%, AD 42%, SVaD 42.3%). DISCUSSION: Our study revealed that imitation of bimanual gestures was impaired non-specifically in about half of the patients with mild dementia, whereas imitation of finger gestures was significantly more impaired in patients with early DLB than in those with AD or SVaD. Although the sensitivity was not high, the imitation tasks may provide additional information for diagnosis of mild dementia, especially for DLB.

Neural correlates of psychotic symptoms in dementia with Lewy bodies.

The aim of this study was to investigate the association between psychotic symptoms in dementia with Lewy bodies and brain perfusion on single photon emission tomography. Based on factor analysis in 145 patients, psychotic symptoms were classified into five symptom domains (factor 1 to 4-related symptoms and delusions). The relationship between each symptom domain and brain perfusion was assessed in 100 patients with dementia with Lewy bodies, while accounting for the effects of age, sex, dementia severity, parkinsonism and dysphoria. Factor 1 symptoms (Capgras syndrome, phantom boarder, reduplication of person and place and misidentification of person) represented misidentifications, and were significantly related to hypoperfusion in the left hippocampus, insula, ventral striatum and bilateral inferior frontal gyri. Factor 3 symptoms (visual hallucination of person and feeling of presence) represented hallucinations of person and were related to hypoperfusion in the left ventral occipital gyrus and bilateral parietal areas. Delusions of theft and persecution were associated with relative hyperperfusion in the right rostral medial frontal cortex, left medial superior frontal gyrus and bilateral dorsolateral frontal cortices. This study revealed that different psychotic symptoms in dementia with Lewy bodies were associated with distinguishable cerebral networks. Visual hallucinations were related to dysfunction of the parietal and occipital association cortices, misidentifications were related to dysfunction of the limbic-paralimbic structures and delusions were related to dysfunction of the frontal cortices. Our findings provide important insights into the pathophysiological mechanisms underlying psychotic symptoms in dementia with Lewy bodies.

Cerebral substrates related to impaired performance in the clock-drawing test in dementia with Lewy bodies.

AIMS: To identify the neural correlates of impaired performance in the clock-drawing test (CDT) in patients with dementia with Lewy bodies (DLB). METHODS: Cerebral blood flow was measured by single photon emission computed tomography in patients with clinically diagnosed DLB, and was compared between impaired CDT (n = 30) and normal CDT (n = 30) subgroups. RESULTS: DLB patients with impaired CDT performance showed significantly lower cerebral blood flow in the bilateral frontal eye fields, supplementary eye fields, right posterior putamen and the right ventrolateral part of the thalamus relative to the normal CDT subgroup. Performance in other visuospatial/attentional tasks (trail making test part A, copying a cube, semantic fluency, and block design) was also poorer in the impaired CDT group than the normal CDT group. CONCLUSIONS: This study indicates that impaired performances on the CDT and some visuospatial/attentional tasks by DLB patients are closely related to dysfunctions of the frontal-subcortical network relevant to control of visuospatial attention and arousal, involving the frontal eye fields, supplementary eye fields and the thalamus. Our findings provide evidence that cognitive performance in DLB reflects the pathological involvement of both cortical and subcortical regions, and suggest that the neurophysiological basis underlying impaired CDT in DLB may be different from that in Alzheimer disease.

Classification of psychotic symptoms in dementia with Lewy bodies.

OBJECTIVE: The aim of this study is to determine empirically a possible classification of psychotic symptoms, and identify the frequency of such symptoms in dementia with Lewy bodies (DLB). METHODS: This was a clinical study of prospectively observed patients from the memory clinic at Shiga Medical Center. The authors conducted a factor analysis of psychotic symptoms in 96 probable DLB and 4 possible DLB patients, clinically diagnosed according to the consensus criteria, were included. RESULTS: Four factors were obtained. Factor 1 was closely akin to misidentifications, including Capgras syndrome, phantom boarder, and reduplication of people and places. Factor 2 consisted of reduplication of people, the belief that deceased relatives are still alive, and the belief that absent relatives are in the house, which was classified as a type of misidentification or paramnesia. Factor 3 was akin to visual hallucinations of nonhuman objects, and factor 4 mirrored the hallucination of people and feeling of presence. Delusions were independent of these factors. Following the results of factor analysis, the rates of each symptom group were identified. Hallucinations were the most frequent psychotic symptom in DLB (78%), followed by misidentifications (56%) and delusions (25%). CONCLUSION: This study suggested that hallucinations, misidentifications, and delusions should be separately considered in understanding of underlying pathophysiology or psychopathology of DLB.

The Cambridge Behavioral Inventory: validation and application in a memory clinic.

The authors examined the validity of the Cambridge Behavioral Inventory (CBI), a questionnaire investigating broad neuropsychiatric symptoms and everyday functional ability in dementia. Test-retest reliability of the CBI was acceptable. Cross-validation with the Neuropsychiatric Inventory showed good concurrent validity of the CBI. The CBI reliably demonstrated that disinhibition, stereotypic behavior, elation, anxiety, poor self-care, and changes in eating habits occurred more commonly in patients with frontotemporal lobar degeneration than those with Alzheimer's disease. The authors concluded that the CBI is a reliable informant-based assessment of neuropsychiatric symptoms and everyday functioning and may be a suitable tool for use in general clinical practice settings.

Neural correlates of impaired performance on the clock drawing test in Alzheimer's disease.

To identify the neural correlates for impaired performance on the clock drawing test (CDT) in patients with Alzheimer's disease (AD), we examined the relationship between the CDT performances and the regional cerebral blood flow (rCBF) in 100 AD patients. The patients were equally divided into a mildly impaired CDT group, a severely impaired CDT group, and two normal CDT groups, with age and dementia severity matched. Between-group comparisons revealed that rCBF reduction in the posterolateral region of the left temporal lobe was consistently associated with mild to severe impairment of the CDT in AD. Correlation analysis also showed that the rCBF in the left posterolateral temporal cortex was linearly correlated with CDT performance. The CDT scores in AD were significantly improved for the copy condition relative to the drawing-to-command condition. These findings suggest that CDT performance has a close relationship with the left posterior temporal function, and that semantic memory deficit may at least partly contribute to impaired CDT performance in AD.

Factor structure of a modified version of the wisconsin card sorting test: an analysis of executive deficit in Alzheimer's disease and mild cognitive impairment.

In order to explore the factor structure of a modified version of the Wisconsin Card Sorting Test (mWCST) and to identify the dimensions of deficit in patients with Alzheimer's disease (AD) and mild cognitive impairment (MCI), conventional mWCST scores in 55 AD patients, 17 MCI patients, and 22 controls were subjected to factor analysis. Three factors, perseveration, inefficient sorting, and nonperseverative error, were obtained. Perseveration score was significantly poorer in both AD and MCI than in controls. By contrast, the MCI group showed significantly poorer scores on the nonperseverative error factor than did the AD patients, and the controls yielded intermediate values between the two patient groups. The perseveration factor was significantly correlated with the other estimates of executive function. This study suggested that the many mWCST scores could be reduced to three major factors, and that the perseveration score may effectively represent an aspect of executive dysfunction in AD and MCI patients.

Cerebral correlates of the progression rate of the cognitive decline in probable Alzheimer's disease.

OBJECTIVE: To evaluate the possible relation between the rate of cognitive deterioration in patients with probable Alzheimer's disease (AD) and the distribution pattern of neural dysfunction. METHODS: The regional cerebral blood flow (rCBF) was measured in rapidly and slowly progressing groups of AD patients using single-photon emission computed tomography and was compared between the groups. While controlling for demographic and clinical factors that could be associated with the stage and prognosis of the illness, the deterioration rate of the Mini Mental State Examination (MMSE) score was significantly greater in the rapidly progressing group than that in the slowly progressing group. RESULTS: The rCBF in the right posterodorsal, anterior and superior prefrontal cortices and the inferior parietal cortex was significantly lower in the rapidly progressing patients. Moreover, lower perfusion in these regions correlated significantly with rapid deterioration in the MMSE. CONCLUSIONS: These findings suggest that the rCBF values in these cortical regions could be useful in predicting which AD patients will show a relatively rapid cognitive decline.