Association between longitudinal changes in striatal dopamine transporter uptake and clinical features of dementia with Lewy bodies.

BACKGROUND: It is widely known that there is low striatal 123 I-2ß-Carbomethoxy-3ß-(4-iodophenyl)-N-(3- fluoropropyl) nortropane (123 I-FP-CIT) dopamine transporter single photon emission tomography (DaT-SPECT) uptake in patients with dementia with Lewy bodies (DLB). No studies to date have analyzed the association between longitudinal changes of clinical features and DaT uptake in patients with Parkinson syndrome, particularly those with DLB. The aim of this study was to investigate the association between the longitudinal changes in DaT uptake and the severity of parkinsonism and cognitive function in DLB patients. METHODS: A total of 35 outpatients with probable DLB who underwent DaT-SPECT twice (at the initial examination and the follow-up period) in the Memory Disorder Clinic at the Department of Geriatric Medicine, Tokyo Medical University, were enrolled in this study between April 2014 and September 2020. The correlation between annual changes in DaT uptake and clinical features (cognitive function decline and parkinsonism) of the patients was analyzed. RESULTS: A significant correlation was detected between annual changes in parkinsonism symptom severity and DaT uptake in the left posterior putamen (r = -0.39, P = 0.03), and between Mini-Mental State Examination scores and DaT uptake in all regions except the right posterior putamen (P < 0.05) in patients with DLB. CONCLUSIONS: Our results suggested that the pathway from the ventrolateral tier of the substantia nigra to the putamen might be more crucial for motor function than other pathways, not only in Parkinson's disease but also in DLB.

Effects of 12-month exercise intervention on physical and cognitive functions of nursing home residents requiring long-term care: a non-randomised pilot study.

AIMS: We performed a 12-month exercise intervention for 'nursing home for the elderly' residents requiring long-term care. We evaluated changes in their muscular strength, muscle mass, and cognitive function. METHODS: Thirty-seven nursing home residents (Mini-Mental State Examination (MMSE): 14.7 ± 7.0, Barthel Index: 44.2 ± 18.9) were enrolled. We divided the participants into the exercise intervention group (n = 19) and non-intervention group (n = 18) ensuring no significant difference in the participants' characteristics at baseline. For the exercise intervention group, exercise was performed for about 40 min twice a week for 12 months. Skeletal Mass Index and grip force were determined to evaluate muscle mass and muscle strength, respectively. MMSE, Trail Making Test (TMT) part A, and Geriatric Depression Scale 15 (GDS15) were used for cognitive function evaluation, with their changes investigated. RESULTS: After 12 months, the MMSE scores were significantly improved in the exercise intervention group compared with the non-intervention group (change from baseline to 12 months: Non-intervention: -1.0 ± 2.8, Intervention: 1.2 ± 3.0; P = 0.04). Moreover, the grip force of the dominant arm was significantly improved in the exercise intervention group compared with the non-intervention group (change from baseline to 12 months: Non-intervention: -1.3 ± 2.8 kg, Intervention: 1.4 ± 4.6 kg; P = 0.007). The prevalence of sarcopenia was significantly increased after 12 months compared with baseline in the non-intervention group (Non-intervention: 61.1% → 75.0%, Intervention: 77.8% → 71.4%; P < 0.02). There were no significant changes in GDS15, Barthel Index and TMT after 12 months in intervention and non-intervention groups. CONCLUSION: Exercise intervention may be effectively used for improving the physical and cognitive functions of nursing home residents requiring long-term care.

Utility of neuromelanin-sensitive MRI in the diagnosis of dementia with Lewy bodies.

OBJECTIVE: Dementia with Lewy bodies (DLB) is recognized as the second most common cause of degenerative dementia in older people with Alzheimer's disease (AD), and distinguishing between these 2 diseases may be challenging in clinical practice. However, accurate differentiation is important because these 2 diseases have different prognoses and require different care. Recently, several studies have reported that neuromelanin-sensitive MRI can detect neurodegeneration in the substantia nigra pars compacta (SNc). DLB patients are considered to demonstrate degeneration and a reduction of dopaminergic neurons in the SNc. Therefore, neuromelanin-sensitive MRI may be useful for the diagnosis of DLB. Therefore, in this study, we aimed to investigate the usefulness of neuromelanin-sensitive MRI in the distinguishing DLB from AD. METHODS: A total of 21 probable DLB and 22 probable AD patients were enrolled. All participants underwent both DaT-SPECT and neuromelanin-sensitive MRI. A combined model of neuromelanin-sensitive MRI and Dopamine transporter single-photon emission computed tomography (DaT-SPECT) was created using logistic regression analysis (forced entry method). RESULTS: There was no difference in the diagnostic utility of neuromelanin-sensitive MRI and DaT-SPECT in distinguishing DLB from AD. There was no significant correlation between the results of neuromelanin-sensitive MRI and DaT-SPECT in DLB patients. The combination of neuromelanin-sensitive MRI and DaT-SPECT demonstrated higher diagnostic performance in distinguishing between DLB and AD compared with neuromelanin-sensitive MRI alone. Additionally, although the combination of both modalities showed a larger AUC compared with DaT-SPECT alone, the difference was not statistically significant. CONCLUSIONS: Neuromelanin-sensitive MRI may be equally or even more useful than DaT-SPECT in the clinical differentiation of DLB from AD. Furthermore, the combination of neuromelanin-sensitive MRI and DaT-SPECT may be a highly sensitive imaging marker for distinguishing DLB from AD.

Characterization of Alzheimer's Disease Subtypes Based on Magnetic Resonance Imaging and Perfusion Single-Photon Emission Computed Tomography.

BACKGROUND: Alzheimer's disease (AD) is a biologically heterogenous disease. Previous studies have reported the existence of various AD subtypes, and the various clinical features of the subtypes. However, inconsistent results have been obtained. OBJECTIVE: To clarify the clinical characteristics of the various AD subtypes, by classifying probable AD into subtypes based on magnetic resonance imaging (MRI) and single-photon emission computed tomography (SPECT) findings. METHODS: A total of 245 patients with probable AD were classified into the typical AD (TAD) subtype, limbic-predominant (LP) subtype, hippocampal-sparing (HS) subtype, and minimal-change (MC) subtype, based on the presence of medial temporal lobe atrophy on MRI and posterior cerebral hypoperfusion on SPECT. Demographics, including age, sex, body mass index, disease duration, education years, comorbidities, frailty, leisure activity, and neuropsychological findings were compared between the AD subtypes. RESULTS: he frequency of TAD, LP, HS, and MC subtypes was 49%, 20%, 18%, and 13%, respectively. Patients with the LP subtype were older and characterized by fewer major comorbidities, higher frailty, and slower progression of disease. Patients with the HS subtype were younger and characterized by shorter disease duration, lower frailty, and preserved memory, but had prominent constructional dysfunction. Patients of the MC subtype were characterized by shorter disease duration, lower education level, less leisure activity, less impaired memory and orientation, and slower progression. CONCLUSION: Patients with different AD subtypes differed in their demographic and clinical features. The characterization of patients' AD subtypes may provide effective support for the diagnosis, treatment, and care of AD patients.

Differentiating Mild Cognitive Impairment, Alzheimer's Disease, and Dementia With Lewy Bodies Using Cingulate Island Sign on Perfusion IMP-SPECT.

The cingulate island sign (CIS) on fludeoxyglucose (FDG)-positron emission tomography (PET) is a supporting biomarker of dementia with Lewy bodies (DLB). Its diagnostic accuracy has only been investigated in FDG-PET, however. The present prospective study compared the CIS on I-iodoamphetamine-single photon emission computed tomography (SPECT) among patients with mild cognitive impairment (MCI), AD, or DLB. Fifty-eight patients with MCI, 42 with probable AD, and 58 with probable DLB were enrolled. The "CIScore" used to evaluate the CIS was defined as the ratio of volume of interest (VOI)-1 (indicating posterior cingulate gyrus [PCG]) to VOI-2 (area of significantly reduced regional cerebral blood perfusion [rCBF] in DLB patients compared with in healthy controls). It was calculated using eZIS software. The CIScore for MCI, DLB, and AD was 0.22, 0.23, and 0.28, respectively. The CIScore in the AD group was significantly higher than that in the DLB or MCI groups (AD vs. DLB: p < 0.001, AD vs. MCI: p < 0.005). This suggests that the CIScore can discriminate DLB from AD, if the decrease in rCBF in the PCG is similar between them. We believe that it is difficult to identify MCI based on the CIScore, as the decrease in rCBF in the PCG is not severe. The diagnostic accuracy of the CIScore may be low as it often shows an increase in elderly DLB patients, in whom the pathologically common form is most prevalent (1). Further study should include assessment of multiple components such as symptom classification and age.

Awareness of the COVID-19 Outbreak and Resultant Depressive Tendencies in Patients with Severe Alzheimer's Disease.

The ongoing coronavirus disease 2019 (COVID-19) pandemic has substantially affected patients with dementia and their caregivers. However, we found not all Alzheimer's disease (AD) patients were afraid of COVID-19 infection. Therefore, we investigated the association between rate of awareness of COVID-19 and depressive tendency in AD. 126 consecutive outpatients with AD were enrolled in this study from May 25, on the day when the declaration of emergency was lifted in Japan, through June 30, 2020. In addition to routine psychological tests, the participants were asked the following two questions: "Do you know COVID-19?" and "Why are you wearing a face mask?". Moderate to severe AD patients were found to have a low COVID-19 recognition rate and did not fully understand why they were wearing face masks. In addition, because they did not understand the seriousness of the COVID-19 outbreak, their Geriatric Depression Scale scores were also substantially lower. These results may appear to simply indicate that people with severe dementia are unaware of current events. However, these results provide insights into how to care for patients with dementia and how to allocate the time and support of our limited staff during the COVID-19 outbreak.

Positive Association Between Cognitive Function and Cerebrospinal Fluid Orexin A Levels in Alzheimer's Disease.

BACKGROUND: Recently, many studies have investigated the association between orexin A and Alzheimer's disease (AD). However, it remains to be determined whether the observed changes in orexin A levels are associated with pathological changes underlying AD, or cognitive function. In particular, a direct association between cerebrospinal fluid (CSF) orexin A levels and cognitive function has not been reported to date. OBJECTIVE: The aim of this study was to identify whether there is a direct association between the orexinergic system and cognitive function in AD. METHODS: For this study, we included 22 patients with AD and 25 control subjects who underwent general physical, neurological, and psychiatric examinations, neuroimaging, and CSF collection by lumbar puncture were enrolled. Correlations between CSF orexin A levels and CSF AD biomarker levels (i.e., levels of phosphorylated tau [p-tau], Aß42, and Aß42/Aß40) were assessed to confirm the results of previous studies. Moreover, the correlation between CSF orexin A levels and Mini-Mental State Examination (MMSE) and Japanese version of the Montreal Cognitive Assessment (MoCA-J) scores were analyzed. RESULTS: There was a significant positive correlation between CSF orexin-A levels and cognitive function (MMSE scores: r = 0.591, p = 0.04, MoCA score: r = 0.571, p = 0.006) in AD patients. CONCLUSION: This is the first study to our knowledge demonstrating an association between cognitive function and CSF orexin A levels in AD. Our results suggest the possibility that orexinergic system overexpression is not always a negative factor for cognitive function In AD.

Classification of Clinically Diagnosed Alzheimer's Disease Associated with Diabetes Based on Amyloid and Tau PET Results.

BACKGROUND/OBJECTIVE: Although type 2 diabetes mellitus (DM) is a risk factor for the development of dementia, the underlying brain pathologies and mechanisms vary among patients. In this study, we classified patients with clinically diagnosed Alzheimer's disease (AD) associated with DM into subgroups based on their amyloid and tau accumulation patterns on positron emission tomography (PET), and analyzed the differences in clinical features and brain imaging findings between the subgroups. METHODS: Sixty-four patients with probable or possible AD associated with DM were classified using PiB (detects amyloid, A) and PBB3 (detects tau, T) PET studies. Patients were classified into the A+/T+ group (n = 35, AD pathology), the A- /T+ group (n = 19, tauopathy), and the A- /T- group (n = 10, non-amyloid/non-tau neuronal damage). RESULTS: Compared with the A+/T+ group, the A- /T+ group showed less-well controlled glycemia, longer duration of diabetes, more glucose variability, higher frequency of insulin therapy and biochemical hypoglycemia, and greater impairment of frontal lobe function, slower progression of cognitive decline, fewer APOE4 carriers, less severe medial temporal lobe atrophy, and lower frequency of posterior cerebral hypoperfusion. This subgroup showed different clinical and radiological features from AD. CONCLUSION: Among patients with clinically diagnosed AD with DM, there are subgroups with neuronal damage independent of AD pathology. A subgroup of dementia patients suspected of having tauopathy is strongly associated with DM-related metabolic abnormalities. This study highlights the identification of a novel dementia subgroup (diabetes-related dementia), which is important for considering appropriate therapies and care in clinical practice.

Neuroimaging Characteristics of Frailty Status in Patients with Alzheimer's Disease.

BACKGROUND/OBJECTIVE: Although frailty is closely linked to dementia, particularly Alzheimer's disease (AD), underlying pathophysiology of frailty associated with AD remains uncertain. This study aimed to investigate differences in structural and functional brain imaging abnormalities between AD with and without frailty. METHODS: A total of 191 outpatients with probable AD (men: 91; women: 100; age: 80.7±6.3 years) who underwent both magnetic resonance imaging (MRI) and single-photon emission computed tomography (SPECT) were enrolled in this study. Frailty was determined in accordance with the Obu study Health Promotion for the Elderly. We compared numbers of small infarctions in the subcortical gray and white matter and severity of white matter abnormalities (periventricular hyperintensity [PVH] and deep white matter hyperintensity [DWMH]) on MRI, and regional cerebral blood flow (rCBF) changes on SPECT between AD with and without frailty. RESULTS: The prevalence of frailty was 43.4% in patients with AD. PVH and DWMH scores were significantly higher in AD with frailty compared to those without frailty. AD with frailty had a trend of decreased rCBF in the bilateral anterior cingulate gyrus, whereas those without frailty tend to have decreased rCBF in the left dominant parietal lobe and precuneus. CONCLUSION: Our MRI and SPECT imaging studies suggest different underlying pathophysiology in the brain between AD with frailty and without frailty.

Role of Neuroimaging as a Biomarker for Neurodegenerative Diseases.

It has recently been recognized that neurodegenerative diseases are caused by common cellular and molecular mechanisms including protein aggregation and inclusion body formation. Each type of neurodegenerative disease is characterized by the specific protein that aggregates. In these days, the pathway involved in protein aggregation has been elucidated. These are leading to approaches toward disease-modifying therapies. Neurodegenerative diseases are fundamentally diagnosed pathologically. Therefore, autopsy is essential for a definitive diagnosis of a neurodegenerative disease. However, recently, the development of various molecular brain imaging techniques have enabled pathological changes in the brain to be inferred even without autopsy. Some molecular imaging techniques are described as biomarker in diagnostic criteria of neurodegenerative disease. Magnetic resonance imaging (MRI), single photon emission computed tomography (SPECT), positron emission tomography (PET), and amyloid imaging are described in the diagnostic guidelines for Alzheimer's disease in the National Institute on Aging-Alzheimer's Association. MRI, dopamine transporter (DAT) imaging, and 123I-metaiodobenzyl-guanidine (MIBG) myocardial scintigraphy listed in the guidelines for consensus clinical diagnostic criteria for dementia with Lewy bodies are described as potential biomarkers. The Movement Disorder Society Progressive Supranuclear Palsy Study Group defined MRI, SPECT/PET, DAT imaging, and tau imaging as biomarkers. Other diagnostic criteria for neurodegenerative disease described neuroimaging findings as only characteristic finding, not as biomarker. In this review, we describe the role of neuroimaging as a potential biomarker for neurodegenerative diseases.

Amyloid and Tau Positron Emission Tomography in Suggested Diabetesrelated Dementia.

BACKGROUND: Type 2 diabetes mellitus (DM) has been shown to increase the risk for cognitive decline and dementia, such as Alzheimer disease (AD) and vascular dementia (VaD). In addition to AD and VaD, there may be a dementia subgroup associated with specific DM-related metabolic abnormalities rather than AD pathology or cerebrovascular disease, referred to as diabetes-related dementia (DrD). METHOD: We studied 11C-PiB and 11C-PBB3 positron emission tomography (PET) in 31 subjects with DrD and 5 subjects with AD associated with DM to assess amyloid and tau deposits in the brain. RESULTS: All subjects with AD showed both positive PiB and PBB3. However, only 12 out of 31 subjects (39%) with DrD showed positive PiB, whereas 17 out of 21 subjects (81%) who underwent PBB3 PET showed positive PBB3. Depending on the positivity of PiB and PBB3, we classified 21 subjects into a negative PiB and a positive PBB3 pattern (11 cases, 52%), indicating tauopathy, a positive PiB and a positive PBB3 pattern (6 cases, 29%), indicating AD pathology, or a negative PiB and a negative PBB3 pattern (4 cases, 19%). Among 11 subjects showing a negative PiB and a positive PBB3 pattern, there were 2 PBB3 deposit patterns, including the medial temporal lobe only and extensive neocortex beyond the medial temporal lobe. CONCLUSION: DrD showed variable amyloid and tau accumulation patterns in the brain. DrD may be associated predominantly with tau pathology, in addition to AD pathology and non-amyloid/non-tau neuronal damage due to DM-related metabolic abnormalities.

Decreased Muscle Strength and Quality in Diabetes-Related Dementia.

BACKGROUND/AIMS: Diabetes-related dementia (DrD), a dementia subgroup associated with specific diabetes mellitus (DM)-related metabolic abnormalities, is clinically and pathophysiologically different from Alzheimer disease (AD) and vascular dementia. We determined whether skeletal muscle strength, quality, and mass decrease in individuals with DrD. METHODS: We evaluated grip and knee extension strength, muscle mass, and gait speed in 106 patients with probable AD and without type 2 DM (AD[-DM] group), 74 patients with probable AD and with DM (AD[+DM] group), and 36 patients with DrD (DrD group). Muscle quality was defined as the ratio of muscle strength to muscle mass. RESULTS: Both female and male subjects with DrD showed significantly decreased muscle strength and quality in the upper extremities compared with the subjects with AD[-DM] or AD[+DM]. Female subjects with DrD showed significantly decreased muscle quality in the lower extremities compared with the subjects with AD[-DM]. Both female and male subjects with DrD had a significantly lower gait speed compared with the subjects with AD[-DM]. However, there were no significant differences in muscle mass and the prevalence of sarcopenia between the groups. CONCLUSION: Subjects with DrD showed decreased muscle strength and quality, but not muscle mass, and had a low gait speed.

Comparison of diagnostic utility of semi-quantitative analysis for DAT-SPECT for distinguishing DLB from AD.

PURPOSE: It is widely known that there is low striatal 123I-FP-CIT dopamine transporter single photon emission computed tomography (DAT-SPECT) uptake in patients with dementia with Lewy bodies (DLB). However, a consistent quantitative evaluation method for DAT-SPECT has not yet been established. There are two semi-quantitative software packages for DAT-SPECT available in Japan, namely, DaTView and DaTQUANT. The aim of this study was to identify which of these is superior for distinguishing DLB from AD. Moreover, we aimed to identify which region of the striatum is more suitable for distinguishing DLB from AD. METHODS: Patients with Alzheimer's disease (AD) (n=95) and patients with DLB (n=133) who underwent DAT-SPECT were enrolled. DaTView and DaTQUANT were used as semi-quantitative analysis tools for DAT-SPECT. RESULTS: There were significant correlations in DAT uptake between DaTView and entire regions by DaTQUANT. There was no significant difference in diagnostic accuracy between DaTView and DaTQUANT except in the posterior putamen by DaTQUANT. CONCLUSIONS: For distinguishing DLB from AD, both of DaTView and DaTQUANT software are useful. Moreover, assessing the DAT uptake in entire striatum by DaTView might be sufficient for distinguishing DLB from AD.

Correlation between clinical symptoms and striatal DAT uptake in patients with DLB.

OBJECTIVE: It is widely known that there is low striatal 123I-FP-CIT dopamine transporter-single photon emission tomography (DAT-SPECT) uptake in patients with dementia with Lewy bodies (DLB). We assessed the correlation between symptom and regional low DAT uptake in the striatum. METHODS: Patients with Alzheimer's disease (AD) (n = 95) and patients with DLB (n = 133) who underwent DAT-SPECT were enrolled. We examined the correlation between symptoms [cognitive function decline, fluctuations, visual hallucinations, parkinsonism, and REM sleep behavior disorder (RBD)] and regional striatal DAT uptake in the patients with DLB. RESULTS: When comparing the DLB patients with or without fluctuations, visual hallucinations, or RBD, there were no significant differences in DAT uptake in any regions of the striatum. DLB patients with parkinsonism had significantly lower DAT uptake in entire striatum, entire putamen, and anterior putamen compared to DLB patients without parkinsonism. Moreover, there was weak but significant correlation between severity of parkinsonism and DAT uptake in entire regions of the striatum in patients with DLB. There was no significant correlation between cognitive function and DAT uptake in any regions of the striatum in patients with DLB. CONCLUSIONS: In patients with DLB, only parkinsonism is associated with a reduction in striatal DAT uptake.