Efficacy and safety of donepezil in patients with dementia with Lewy bodies: results from a 12-week multicentre, randomised, double-blind, and placebo-controlled phase IV study.

BACKGROUND: Donepezil has been approved in Japan for the treatment of dementia with Lewy bodies (DLB) based on clinical trials showing its beneficial effects on cognitive impairment. This phase IV study evaluated the efficacy of donepezil by focusing on global clinical status during a 12-week double-blind phase. METHODS: Patients with probable DLB were randomly assigned to the placebo (n = 79) or 10 mg donepezil (n = 81) groups. The primary endpoint was changes in global clinical status, assessed using the Clinician's Interview-Based Impression of Change plus Caregiver Input (CIBIC-plus). We also assessed four CIBIC-plus domains (general condition, cognitive function, behaviour, and activities of daily living) and changes in cognitive impairment and behavioural and neuropsychiatric symptoms measured using the Mini-Mental State Examination (MMSE) and the Neuropsychiatric Inventory (NPI), respectively. RESULTS: Although donepezil's superiority was not shown in the global clinical status, a significant favourable effect was detected in the cognitive domain (P = 0.006). MMSE scores improved in the donepezil group after adjustments in post hoc analysis (MMSE mean difference, 1.4 (95% confidence interval (CI), 0.42-2.30), P = 0.004). Improvements in NPIs were similar between the groups (NPI-2: -0.2 (95% CI, -1.48 to 1.01), P = 0.710; NPI-10: 0.1 (95% CI, -3.28 to 3.55), P = 0.937). CONCLUSION: The results support the observation that the efficacy of 10 mg donepezil in improving cognitive function is clinically meaningful in DLB patients. The evaluation of global clinical status might be affected by mild to moderate DLB patients enrolled in this study. No new safety concerns were detected.

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.

Early diagnosis of prodromal dementia with Lewy bodies using clinical history of probable REM sleep behaviour disorder and cardiac 123 I-MIBG scintigraphy in memory clinics.

BACKGROUND: Rapid eye movement sleep behaviour disorder (RBD) is associated with reduced cardiac 123 I-metaiodobenzylguanidine (MIBG) uptake and often precedes the onset of Lewy body (LB) disorders. We investigated the role of cardiac 123 I-MIBG scintigraphy in relation to probable RBD for the clinical diagnosis of prodromal dementia with Lewy bodies (DLB) in memory clinics. METHODS: We reviewed clinical profiles of 60 consecutive patients who underwent cardiac 123 I-MIBG scintigraphy in our memory clinics. The diagnostic threshold of 2.20 was used as the cut-off for the heart-to-mediastinum ratio at the delayed phase. RESULTS: Cardiac 123 I-MIBG abnormality was identified in 28 patients at baseline; six were cognitively unimpaired, six had mild cognitive impairment (MCI)-LB, and 16 had probable DLB based on the National Institute on Aging and Alzheimer's Association Research Framework. Although the number of core features increased in accordance with the progression of three cognitive categories, there were no differences in the prevalence of probable RBD and the cardiac MIBG scintigraphy indices among them. During the observation period, two cognitively unimpaired patients with probable RBD progressed to MCI-LB, and three MCI-LB patients with probable RBD developed DLB. The prevalence of final diagnosis of probable MCI-LB or DLB was significantly higher in these patients (85%) than the remaining 32 patients without (9%). Of 25 patients with probable RBD, 22 (88%) had a cardiac 123 I-MIBG abnormality regardless of cognitive conditions. Only one patient consulted a sleep centre for the abnormal sleep behaviour before visiting our memory clinics. Regarding the gender differences, male predominance was not identified and sleep-related injury more frequently occurred in men (7/12, 58%) than in women (1/10, 10%). CONCLUSIONS: Proactive detection of probable RBD plus cardiac 123 I-MIBG abnormality provides the opportunity for an early diagnosis of prodromal DLB in memory clinics. This approach warrants further follow-up studies with polysomnographic and pathological verification.

Dementia with Lewy bodies presenting as frontotemporal dementia phenotype.

We herein report two patients with dementia with Lewy bodies (DLB) presenting characteristic symptoms suggestive of the behavioural variant of frontotemporal dementia (bvFTD). Patient 1 presented behavioural and personality changes from the onset, such as restlessness, compulsive behaviours, and stereotypical speech. A neuroimaging study showed preferential frontal involvement, and this patient fulfilled the diagnostic criteria for bvFTD. However, 123 I-metaiodobenzylguanidine cardiac scintigraphy revealed a markedly lowered uptake, suggesting the diagnosis of possible DLB. Patient 2 fulfilled the criteria for probable DLB, but later presented bvFTD-like symptoms similar to those in patient 1. These patients suggest that DLB can be a candidate for differential diagnosis of bvFTD in the clinical setting.

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.

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.

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.

Prevalence and Clinical Implications of the Mirror and TV Signs in Advanced Alzheimer's Disease and Dementia with Lewy Bodies.

OBJECTIVE: To explore the prevalence and clinical implications of the mirror and TV signs in the moderate to advanced stages of Alzheimer's disease (AD) and dementia with Lewy bodies (DLB). METHODS: We retrospectively examined the prevalence of clinical and psychiatric symptoms including the mirror and TV signs in 200 subjects with AD and 200 with DLB and evaluated the relationships among the symptoms. RESULTS: The mirror sign was found in 3.0% of AD and 4.5% of DLB subjects. The TV sign was found in 1.5% of AD and 4.0% of DLB subjects. The prevalence of the mirror and TV signs was not significantly different between the AD and DLB groups. Visual hallucination, visual illusion, misidentification of person, and sleep talking were significantly more frequent in DLB than in AD subjects. The mirror sign was significantly associated with lower Mini-Mental State Examination scores, whereas the TV sign was significantly associated with the misidentification of person. CONCLUSIONS: Both the mirror and TV signs were rare even in the moderate to advanced stages of AD and DLB. The mirror sign may be independent from other delusional misidentification syndromes (DMSs). Being associated mainly with global cognitive decline, the mirror sign is unlikely attributed to any specific cognitive impairment or the dysfunction of localized brain areas. In contrast, the TV sign was significantly more often coexistent with the misidentification of person, suggesting that the TV sign may partly share common neuropsychological mechanisms with DMSs.

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.

[Delusions in Dementia].

Delusion is a common neuropsychiatric symptom in dementia, especially in Alzheimer disease and dementia with Lewy bodies. Persecutory delusions are the most common, and include delusions of theft, jealousy, and abundant. Patients with persecutory delusions have impairment of the psychological processes mediating the formation and maintenance of normal social beliefs. Several disordered psychological processes such as attentional bias, attributional bias, jumping-to-conclusions reasoning bias, and theory of mild deficit may contribute to the delusion formation. Cognitive processes involving information about self, others, and social interaction are required in social cognition. Damage of the neural circuitry involved in social cognition ("social brain"), such as the medial prefrontal cortex, may be a neuroanatomical basis for persecutory delusions in dementia.

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.

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.

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.

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.

[Clinical Neuropsychology of Dementia with Lewy Bodies].

Dementia with Lewy bodies (DLB) shows lesser memory impairment and more severe visuospatial disability than Alzheimer disease (AD). Although deficits in both consolidation and retrieval underlie the memory impairment, retrieval deficit is predominant in DLB. Visuospatial dysfunctions in DLB are related to the impairments in both ventral and dorsal streams of higher visual information processing, and lower visual processing in V1/V2 may also be impaired. Attention and executive functions are more widely disturbed in DLB than in AD. Imitation of finger gestures is impaired more frequently in DLB than in other mild dementia, and provides additional information for diagnosis of mild dementia, especially for DLB. Pareidolia, which lies between hallucination and visual misperception, is found frequently in DLB, but its mechanism is still under investigation.

Neuronal nitric oxide has a role as a perfusion regulator and a synaptic modulator in cerebellum but not in neocortex during somatosensory stimulation--an animal PET study.

To clarify a role of neuronal nitric oxide in neurovascular coupling, we performed cerebral blood flow (CBF) and cerebral metabolic rate of glucose (CMR(glc)) measurements with positron emission tomography in somatosensory-stimulated cats using a specific neuronal nitric oxide synthase inhibitor, 7-nitroindazole (7-NI). The effect on flow-metabolism coupling were tested by global and regional-specific changes on CBF and CMR(glc), and the regional-specific effect was estimated both by regions of interest (ROI) and voxel-based (VB) analysis using globally-normalized CBF and CMR(glc) changes. The electrical somatosensory stimulation in the unilateral forepaw elicited coupled increase in CBF and CMR(glc) in the contralateral somatosensory cortex (7%) and the ipsilateral cerebellum (8%). 7-NI induced 20% decrease in global CBF both during rest and activation, but not in global CMR(glc) at simulation. Both ROI and VB analysis showed that 7-NI induced an increase in CMR(glc) (13%) in the ipsilateral cerebellum compared to control under vehicle alone, but it was accompanied by only 8% increase in CBF, suggesting uncoupling of flow-metabolism while it induced any perturbations in the contralateral somatosensory cortex. These observations suggest that neuronal nitric oxide has an important role for a mediator of regional neurovascular coupling as well as synaptic modulator in the cerebellum, but less so in the neocortex.