Associations of depressive symptoms with white matter abnormalities and regional cerebral blood flow in patients with amnestic mild cognitive impairment.

AIM: Depressive symptoms are one of the most common neuropsychiatric symptoms in patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD), although the pathophysiologies of the depressive symptoms that occur in these diseases have not been elucidated to date. In this study, we therefore investigated the associations between depressive symptoms and cognitive performance, white matter abnormalities, and regional cerebral blood flow (rCBF) in amnestic MCI patients. METHODS: Thirty-eight patients with amnestic MCI were analyzed. The volumes of periventricular hyperintensities (PVH) and deep white matter hyperintensities (DWMH) were measured on T2-fluid-attenuated inversion recovery magnetic resonance imaging using the imaging software 3D-slicer. Associations between the Geriatric Depression Scale (GDS) score and other neuropsychological test scores on the one hand and the PVH and DWMH volumes on the other were analyzed. Voxel-wise correlations of rCBF with GDS score, after controlling for the effects of age, were investigated using SPM8 software. RESULTS: Significant correlations were identified between GDS score, Trail Making Test B and apathy scale scores on the one hand and PVH volume on the other. A significant negative association between GDS score and rCBF was identified in the right dominant bilateral dorsolateral prefrontal cortex (DLPFC). CONCLUSIONS: Depressive symptoms are significantly associated with PVH volume in MCI patients. The rCBF of the DLPFC was significantly associated with depressive symptoms, suggesting that this area might be closely involved in the pathogenesis of the depressive symptoms observed in MCI patients. Geriatr Gerontol Int 2022; 22: 846-850.

Association of regional white matter hyperintensity volumes with cognitive dysfunction and vascular risk factors in patients with amnestic mild cognitive impairment.

AIM: White matter hyperintensities (WMH) obtained by magnetic resonance imaging (MRI) have been reported to promote neurodegeneration and cognitive decline in patients with mild cognitive impairment (MCI). However, little is known about the association between regional WMH (rWMH) and cognitive dysfunction in MCI. We hence investigated the associations between rWMH volumes and cognitive dysfunction in MCI. METHODS: Thirty-eight subjects with amnestic MCI were analysed. The volumes of periventricular hyperintensities (PVH) and deep WMH (DWMH) were measured on a T2-FLAIR MRI using a 3D-slicer, and regional PVH and DWMH (rPVH and rDWMH) volumes were calculated. The associations of rPVH and rDWMH volumes with cognition and blood levels of various molecules were investigated. Furthermore, rPVH and rDWMH volumes were compared between MCI with vascular risk factors, such as hypertension, diabetes mellitus (DM), and dyslipidemia, and those without these risk factors. RESULTS: rPVH volume (bilateral cornu frontale, pars parietalis, and cornu occipitale) positively correlated with Trail Making Test-A/B scores and CysC level, whereas rDWMH volume did not correlate with any of the items. rPVH volumes (right cornu frontale, bilateral pars parietalis and cornu occipitale, and right pars temporalis) and rDWMH volumes (left frontal and parietal lobes) were significantly larger in MCI patients with DM than in those without. CONCLUSIONS: PVH volumes (bilateral areas of cornu frontale, pars parietalis, and cornu occipitale) were closely associated with attention and executive dysfunction. Serum CysC level and DM were associated with WMH volume, suggesting that CysC level and DM might be important markers for determining treatment strategies for white matter abnormalities in MCI. Geriatr Gerontol Int 2021; 21: 644-650.

Association of White Matter Hyperintensity Progression with Cognitive Decline in Patients with Amnestic Mild Cognitive Impairment.

BACKGROUND: White matter hyperintensities (WMH) on MRI have been reported to increase the risk of conversion from mild cognitive impairment (MCI) to Alzheimer's disease (AD). However, effects of the progression of WMH on the cognition of patients with MCI remains unclear to date. OBJECTIVE: To investigate the association between WMH progression and cognitive decline in amnestic MCI patients. METHODS: Thirty-eight subjects with amnestic MCI were analyzed prospectively every year for 2 years. Fourteen MCI subjects dropped out on the final visit, and therefore 24 subjects with MCI were analyzed for the entire duration. The volumes of periventricular hyperintensities (PVH) and deep WMH (DWMH) were measured on T2 FLAIR using the 3D-slicer. The associations between PVH/DWMH progression and cognitive decline were investigated. RESULTS: An increase in DWMH volume significantly correlated with changes in Mini-Mental State Examination and category verbal fluency scores, whereas an increase in PVH volume did not correlate with changes in any item. CONCLUSION: DWMH progression was closely associated with a decline in frontal lobe function and semantic memory, suggesting that WMH progression might affect some AD pathophysiologies in amnestic MCI patients.

Phosphorylated TDP-43 localizes to chronic cerebral infarctions in human brains.

The transactivation response DNA-binding protein of 43 kDa (TDP-43) is a nuclear protein pivotal in RNA processing. Because phosphorylated TDP43 (pTDP-43) has been identified as a component of the ubiquitin-positive and tau-negative inclusions observed in the brains of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) patients, it is considered to play a major role in neurodegenerative processes. We previously reported that pTDP-43 is located in macrophages of atherosclerotic lesions of human carotid and major cerebral arteries. We hence hypothesized that pTDP-43 might be localized in the macrophages of other human brain lesions. Therefore, we investigated the immunolocalization of pTDP-43 in human brains with chronic cerebral infarction. Furthermore, we investigated the colocalization of pTDP-43 and the 14-3-3 eta isoform and found that pTDP-43 was localized in many macrophages located in chronic cerebral infarctions, in 6 out of the 15 human brains analyzed. pTDP-43 colocalized with the 14-3-3 eta isoform in these lesions. This is the first demonstration of pTDP-43 immunolocalization in chronic cerebral infarctions in human brains. We believe that our findings may be useful towards further understanding the pathophysiological roles of TDP-43 in various neurological disorders.

Essential autophagic protein Beclin 1 localizes to atherosclerotic lesions of human carotid and major intracranial arteries.

Macrophage autophagy has been shown to exert a protective role in atherosclerosis. Beclin 1 is an essential autophagic protein, and the Beclin-1-interacting complex promotes the formation of autophagosomes. However, the localization of Beclin 1 in human atherosclerotic lesions has not been clarified to date. We hence investigated the immunolocalization of Beclin 1 in atherosclerotic lesions of human carotid and major intracranial arteries. Furthermore, we investigated the colocalization of Beclin 1 with the 14-3-3 eta isoform and high mobility group box 1 (HMGB1). Beclin 1 was observed in the cytoplasm of many foamy macrophages located near to or in the periphery of lipid-rich necrotic cores. Beclin 1 colocalized with the 14-3-3 eta isoform in carotid plaques, and also colocalized with HMGB1 in carotid plaques. This is the first demonstration of Beclin 1 immunolocalization in human carotid and main cerebral artery plaques. We believe that our results will contribute towards understanding the role of autophagy in atherosclerosis and towards the prevention of stroke.

Frontotemporal dementia-associated protein "phosphorylated TDP-43" localizes to atherosclerotic lesions of human carotid and main cerebral arteries.

The transactivation response DNA binding protein (TARDP) of 43 kDa (TDP-43) is a nuclear protein pivotal in RNA processing. Because phosphorylated (p) TDP-43 has been identified as a component of ubiquitin-positive and tau-negative inclusions in frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS), it is considered to play a major role in neurodegenerative processes. We investigated the immunolocalization of pTDP-43 in atherosclerotic lesions of human carotid and main cerebral arteries. Furthermore, we investigated the co-localization between pTDP-43 and 14-3-3 eta isoform or high mobility group box 1 (HMGB1). pTDP-43 localized in the cytoplasm of many foamy macrophages located in the periphery of lipid-rich necrotic cores, and in the cytoplasm of infiltrated smooth muscle cell-like cells. pTDP-43 co-localized the 14-3-3 eta isoform in carotid plaques. pTDP-43 also co-localized HMGB1. This is the first demonstration of pTDP-43 immunolocalization in human carotid and main cerebral artery plaques. We believe that demonstration of the localization of pTDP-43 in atherosclerotic lesions is important as this may contribute to the establishment of the clinical diagnostic imaging of FTLD and ALS using the pTDP-43 epitope. Moreover, this finding may be useful for further understanding the role of TDP in cell death.

Association of serum cystatin C with white matter abnormalities in patients with amnestic mild cognitive impairment.

AIM: White matter hyperintensities (WMH) on MRI have been reported to be a risk factor for the conversion from mild cognitive impairment (MCI) to Alzheimer's disease, although the reason remains unclear. In the present study, we hence investigated the associations between WMH volumes and cognitive function, blood levels of various molecules, and the presence of lifestyle-associated diseases in patients with amnestic MCI. METHODS: The initial data of 38 patients with amnestic MCI and 10 normal control individuals were analyzed. The volumes of periventricular hyperintensities (PVH) and deep WMH (DWMH) were measured on T2 fluid-attenuated inversion recovery using the imaging software, 3D Slicer; and the association between PVH/DWMH volumes and cognitive function, blood levels of molecules (such as cystatin C [CysC], 25-hydroxyvitamin D and homocysteine) and the presence of lifestyle-associated diseases (such as hypertension, hyperlipidemia and diabetes mellitus) were analyzed. RESULTS: In the MCI group, the PVH volume : intracranial volume ratio significantly correlated with Trail Making Test-A/B scores and CysC level by Pearson's analysis, and the PVH volume : intracranial volume ratio significantly correlated with only CysC levels, whereas the DWMH volume : intracranial volume ratio did not correlate with any items at all by linear multiple regression analysis. CONCLUSIONS: PVH volume was closely associated with frontal lobe dysfunction, particularly with attention and executive dysfunction. Serum CysC level was associated with PVH volume, which suggests that CysC might be a useful marker for determining treatment strategies for white matter abnormalities in amnestic MCI. Geriatr Gerontol Int 2019; 19: 1036-1040.

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.

Caregivers' education decreases depression symptoms and burden in caregivers of patients with dementia.

OBJECTIVE: To determine whether providing education to caregivers of patients with dementia decreases their depression symptoms and burden. METHODS: Eighty-three outpatients with dementia being treated at the Memory Clinic of Tokyo Medical University Hospital and their caregivers were enrolled. Forty-seven caregivers were enrolled in the caregivers' education (EDU) group and 36 were enrolled in the control (CTL) group. Caregivers were assessed for depression, burden, and quality of life (QoL). Patients were assessed for cognition, psychological symptoms, and QoL. Assessments were carried out at baseline and at 3 months (3M). Caregivers in the EDU group received lectures on symptoms and progression of dementia, management of symptoms, use of social resources etc. RESULTS: At 3M, prevalence of depression symptoms in the EDU group significantly decreased from 36% to 17%, whereas it significantly increased from 22% to 50% in the CTL group. Depression and burden were significantly improved at 3M in the EDU group, whereas they significantly worsened in the CTL group. Psychological symptoms showed a lower tendency at 3M for the EDU group. No significant changes in QoL of caregivers and patients were found in either group. CONCLUSIONS: Providing education to caregivers of patients with dementia improves their depression symptoms and sense of burden, and tends to improve the behaviour and psychological symptoms of dementia in the patients. Providing education to caregivers of dementia patients may hence result in beneficial effects for both the patients and their caregivers, and should be widely used in dementia care.

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.

14-3-3 protein sigma isoform co-localizes with phosphorylated α-synuclein in Lewy bodies and Lewy neurites in patients with Lewy body disease.

α-Synuclein shares structural homology with 14-3-3 proteins. Seven 14-3-3 protein isoforms have been identified in mammals. Among them, the 14-3-3 sigma isoform was initially considered absent in the mammalian brain. However, we previously identified immunohistochemical association of 14-3-3 sigma with Pick bodies. Because 14-3-3 isoforms other than sigma isoform have been identified in Lewy bodies, we were prompted to look for this 14-3-3 sigma-like immunoreactivity (IR) in Lewy bodies in the brainstem, cerebral cortex, and Lewy neurites in seven patients with Lewy body disease. Unexpectedly, 14-3-3 sigma-like IR was consistently found in various types of Lewy pathologies in all cases examined. Double labeling studies confirmed its colocalization with alpha-synuclein. In general, 14-3-3 proteins can trap and hold some phosphorylated proteins in the cytoplasm and they can prevent or mediate apoptosis and survival of some cells. More precisely, the 14-3-3 sigma isoform is unique in its multiple cellular functions such as facilitating cell cycle arrest in the G2 phase, positively regulating p53, and suppressing tumor growth. Although the precise role of 14-3-3 sigma in the development of Lewy pathology remains elusive, its consistent association to Lewy pathology may expand our understanding of Lewy pathogenesis.

Time-dependent and lesion-dependent HMGB1-selective localization in brains of patients with cerebrovascular diseases.

High mobility group box 1 protein (HMGB1) has multiple functions, including the maintenance of nucleosomes and the regulation of gene transcription. HMGB1 is released from activated macrophages, resulting in the induction of inflammatory cytokines. Recently, much research about the role of HMGB1 in cerebrovascular disease (CVD) has been reported. In an animal model, HMGB1 neutralization ameliorates brain infarction, there is an early release of HMGB1 from neurons, and HMGB1 antibody attenuates delayed cerebral vasospasm in experimental subarachnoid hemorrhage. It was also reported that elevation of HMGB1 in serum correlates with severity of acute intracerebral hemorrhage. However, the evidence of HMGB1 localization in brains of patients with CVD is very limited. Therefore, we investigated at autopsy the immunolocalization of HMGB1 in brains of patients with CVD (acute and chronic cerebral infarction, acute cerebral hemorrhage, subarachnoid hemorrhage). In 3 out of 10 acute cerebral infarction cases, the cytoplasm of neurons located around the ischemic core (i.e., penumbra) was positive for HMGB1. In the chronic stage of cerebral infarction, macrophages located in some ischemic regions were positive for HMGB1. Around the hematoma in the basal ganglia, HMGB1-like immunoreactivity (IR) was intense in macrophages. However, around the subarachnoid hematoma, HMGB1-like IR was not seen in the cortex. In arteries surrounded by subarachnoid hematoma, HMGB1-like IR was located in the cytoplasm of vascular smooth muscle cells. These findings, which partially differ from animal model results, may provide translational research and a basis for understanding the role of HMGB1 in brains of patients with CVD.

Calmodulin-like skin protein is downregulated in human cerebrospinal fluids of Alzheimer's disease patients with apolipoprotein E4; a pilot study using postmortem samples.

OBJECTIVE: Calmodulin-like skin protein (CLSP) is a secreted peptide that inhibits neuronal cell death, linked to Alzheimer's disease (AD), by binding to the heterotrimeric humanin receptor and activating an intracellular survival pathway. CLSP is only expressed in skin keratinocytes and related epithelial cells, circulates in the blood stream, and passes the blood-cerebrospinal fluid (CSF) barrier. In the current study, we addressed the issues as to whether CLSP functions in the central nervous system and whether the concentration of CLSP is reduced in the CSFs of AD patients. METHODS: Mice were intraperitoneally injected with 5 nmol of recombinant human CLSP. At 1h after the injection, the mice were sacrificed for the analysis of the existence of human CLSP in blood and interstitial fluid (ISF)-containing brain samples. Using postmortem CSF samples, we next determined the concentrations of CLSP in CSFs of human AD and control cases. RESULTS: Intraperitoneally administered recombinant human CLSP circulated in the blood stream and reached the brain interstitial fluid. The concentrations of CLSP in CSFs of human AD and control cases are sufficient to exhibit the CLSP activity. Although the concentrations of CLSP in CSFs were not significantly different between AD and control cases, the concentrations of CLSP are lower in the AD cases with the apolipoprotein E4 genotype than in the AD cases without the apolipoprotein E4 genotype. DISCUSSION: The first result indicates that CLSP enters the central nervous system through the blood-brain barrier. The second result suggests that CLSP functions in the human brains. The third result may exclude the possibility that the downregulation of the CLSP level is involved in the AD pathogenesis. The last result may contribute to the better understanding of the AD pathogenesis from the standpoint of the apolipoprotein E genotype.

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.

Neuroimaging for diagnosing dementia with Lewy bodies: What is the best neuroimaging technique in discriminating dementia with Lewy bodies from Alzheimer's disease?

AIM: We compared the diagnostic value of four neuroimaging techniques, namely, 123 I-2ß-Carbomethoxy-3ß-(4-iodophenyl)-N-(3-fluoropropyl) nortropane (123 I-FP-CIT) dopamine transporter single-photon emission computed tomography (DAT-SPECT), magnetic resonance imaging, perfusion SPECT and 123 I-metaiodobenzyl-guanidine myocardial scintigraphy in differentiating dementia with Lewy bodies (DLB) from Alzheimer's disease (AD). METHODS: A total of 32 patients with probable AD and 32 patients with probable DLB were enrolled in the present study. For the comparison study, we used the specific binding ratio for DAT-SPECT, the heart-to-mediastinum ratio in the delay phase for 123 I-metaiodobenzyl-guanidine myocardial scintigraphy, z-scores in the medial occipital lobe for perfusion SPECT and z-scores of hippocampal atrophy using a voxel-based specific regional analysis system for AD for magnetic resonance imaging. RESULTS: DAT-SPECT enabled more accurate differentiation of DLB from AD than other methods. 123 I-metaiodobenzyl-guanidine myocardial scintigraphy enabled more accurate differentiation of DLB from AD than magnetic resonance imaging and perfusion SPECT. CONCLUSIONS: In agreement with the recent consensus clinical diagnostic criteria for DLB, we confirmed that the diagnostic accuracy of DAT-SPECT imaging is significantly higher than other neuroimaging techniques. Geriatr Gerontol Int 2017; 17: 819-824.