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.

A Novel LRRK2 Variant p.G2294R in the WD40 Domain Identified in Familial Parkinson's Disease Affects LRRK2 Protein Levels.

Leucine-rich repeat kinase 2 (LRRK2) is a major causative gene of late-onset familial Parkinson's disease (PD). The suppression of kinase activity is believed to confer neuroprotection, as most pathogenic variants of LRRK2 associated with PD exhibit increased kinase activity. We herein report a novel LRRK2 variant-p.G2294R-located in the WD40 domain, detected through targeted gene-panel screening in a patient with familial PD. The proband showed late-onset Parkinsonism with dysautonomia and a good response to levodopa, without cognitive decline or psychosis. Cultured cell experiments revealed that p.G2294R is highly destabilized at the protein level. The LRRK2 p.G2294R protein expression was upregulated in the patient's peripheral blood lymphocytes. However, macrophages differentiated from the same peripheral blood showed decreased LRRK2 protein levels. Moreover, our experiment indicated reduced phagocytic activity in the pathogenic yeasts and α-synuclein fibrils. This PD case presents an example wherein the decrease in LRRK2 activity did not act in a neuroprotective manner. Further investigations are needed in order to elucidate the relationship between LRRK2 expression in the central nervous system and the pathogenesis caused by altered LRRK2 activity.

Usefulness of texture analysis in 123I-FP-CIT for the differentiation of AD and DLB subtypes.

OBJECTIVE: I-2ß-carbomethoxy-3ß-(4-iodophenyl)-N-(3-fluoropropyl) nortropane (123I-FP-CIT) is well known to be a useful tracer for differentiating dementia with Lewy bodies (DLB) and Alzheimer disease (AD). However, clinically, there are some cases in which these diseases cannot be differentiated by ordinary quantitative methods. Therefore, in this study, we established an index that reflects not only the total count but also the distribution and heterogeneity of tracer uptake. We investigated whether assessment of the heterogeneous depletion of 123I-FP-CIT is useful for the differentiation of various types of dementia, i.e., probable DLB, possible DLB, and AD, using texture analysis. MATERIALS AND METHODS: A total of 122 patients with either probable DLB (n=35), possible DLB (n=23), AD (n=44), and normal controls (n=20) were analyzed. Summated single photon emission computed tomography (SPECT) images (7 to 10 slices) of the patients, including the bilateral striatum, were analyzed using the gray-level histogram method (GLHM) of texture analysis. Mean, variance, skewness, and kurtosis of GLHM were compared with the specific binding ratio by Livia Tossici-Bolt's method (SBR). RESULTS: The sensitivity and specificity for differentiating probable DLB from possible DLB, AD, and normal controls were 97.1% and 77.0%, respectively, for skewness, using a cut-off point of 6.8%, and 97.1% and 81.6%, respectively, for kurtosis, using a cut-off point of 53.4%. The sensitivity and specificity for differentiating probable and possible DLB from AD and normal controls was 65.5% and 98.4%, respectively, for skewness, using a cut-off point of 6.4%, and 79.3% and 93.8%, respectively, for kurtosis, using a cut-off point of 53.4%. CONCLUSION: In the assessment of the efficacy of 123I-FP-CIT to differentiate AD and DLB subtypes, mean, variance, skewness, and kurtosis by GLHM was as useful as the SBR method. Moreover, possible DLB and probable DLB could be differentiated by skewness and kurtosis. Our results demonstrate that texture analysis is more useful than conventional quantitative methods for obtaining valuable information of the brain. Textural features as such may have considerable potential as imaging biomarkers of DLB progression.

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.

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.

Utility of the combination of DAT SPECT and MIBG myocardial scintigraphy in differentiating dementia with Lewy bodies from Alzheimer's disease.

PURPOSE: (123)I-2ß-Carbomethoxy-3ß-(4-iodophenyl)-N-(3-fluoropropyl) nortropane ((123)I-FP-CIT) dopamine transporter single photon emission computed tomography (DAT SPECT) and (123)I-metaiodobenzylguanidine (MIBG) myocardial scintigraphy can be used to assist in the diagnosis of patients with dementia with Lewy bodies (DLB). We compared the diagnostic value of these two methods in differentiating DLB from Alzheimer's disease (AD). Furthermore, we evaluated whether a combination of DAT SPECT and MIBG myocardial scintigraphy would provide a more useful means of differentiating between DLB and AD. METHODS: Patients with AD (n = 57) and patients with DLB (n = 76) who underwent both DAT SPECT and MIBG myocardial scintigraphy were enrolled. The sensitivity, specificity, and accuracy of both methods as well as their combination for differentiating DLB from AD were calculated. Moreover, we examined whether symptoms of the patients with DLB were associated with the patterns of the abnormalities displayed on DAT SPECT and MIBG myocardial scintigraphy. RESULTS: The sensitivity and specificity of differentiating DLB from AD were 72.4 and 94.4 % by the heart to mediastinum ratio of MIBG uptake, 88.2 and 88.9 % by the specific binding ratio on DAT SPECT, and 96.1 and 90.7 % by their combination, respectively. The combined use of DAT SPECT and MIBG myocardial scintigraphy enabled more accurate differentiation between DLB and AD compared with either DAT SPECT or MIBG myocardial scintigraphy alone. There was a significantly higher frequency of parkinsonism in the abnormal DAT SPECT group than the normal DAT SPECT group. On the other hand, there was a higher frequency of the appearance of rapid eye movement (REM) sleep behavior disorder in the abnormal MIBG uptake group than the normal MIBG uptake group. CONCLUSION: These results suggested that using a combination of these scintigraphic methods is a useful and practical approach to differentiate DLB from AD.

CCR8 regulates contact hypersensitivity by restricting cutaneous dendritic cell migration to the draining lymph nodes.

Allergic contact dermatitis (ACD) is a typical occupational disease in industrialized countries. Although various cytokines and chemokines are suggested to be involved in the pathogenesis of ACD, the roles of these molecules remain to be elucidated. CC chemokine receptor 8 (CCR8) is one such molecule, of which expression is up-regulated in inflammatory sites of ACD patients. In this study, we found that Ccr8(-/-) mice developed severer contact hypersensitivity (CHS) responses to 2,4-dinitrofluorobenzene, a murine model of ACD, compared with wild-type mice. T cells from Ccr8(-/-) mice showed enhanced proliferative recall responses and Th1 and Th17 cell populations were expanded in these mice. However, CHS responses were similar between SCID mice adoptively transferred with Ccr8(-/-) and wild-type T cells, suggesting that CCR8 in T cells is not responsible for the exacerbation of CHS. Notably, skin-resident dendritic cells (DCs), such as Langerhans cells and dermal DCs, and inflammatory DCs were highly accumulated in lymph nodes (LNs) of Ccr8(-/-) mice after sensitization. Consistent with this, Ccr8(-/-) antigen-presenting cells readily migrated from the skin to the draining LNs after sensitization. These observations suggest that CCR8 negatively regulates migration of cutaneous DCs from the skin to the draining LNs in CHS by keeping these cells in the skin.

[Mild cognitive impairment].

Mild cognitive impairment(MCI) is considered to be a transition state between normal cognition and dementia. The subtypes of MCI are highly heterogeneous in terms of etiology, presentation, and prognosis. Patients with the amnestic subtype of MCI are at a high risk of progression to Alzheimer disease (AD); this subtype may represent the prodromal stage of AD. Moreover, patients with MCI who are not aware of their memory deficits and in whom practice effects are not observed exhibit parietotemporal hypoperfusion on single photon emission CT, indicating that these findings are predictors of progression to AD. In this review, I have discussed the most current aspects related to the concept and clinical presentation of MCI.

Subgroups of Alzheimer's disease associated with diabetes mellitus based on brain imaging.

BACKGROUND/AIMS: We attempted to define possible subgroups of Alzheimer's disease (AD) associated with diabetes mellitus (DM) based on brain imaging. METHODS: We classified 175 patients with clinically diagnosed AD and type 2 DM into 4 subgroups on the basis of the presence or absence of cerebrovascular disease (CVD) on MRI (CVD or no CVD) and posterior cerebral hypoperfusion on SPECT (AD pattern or no AD pattern). Differences in the clinical characteristics among the subgroups were examined. RESULTS: The subgroup showing neither a CVD pattern nor an AD pattern had significantly older age, higher hemoglobin A1c level, longer duration of diabetes, higher frequency of insulin therapy, lower frequency of apolipoprotein E4 carriers, less severe medial temporal lobe atrophy, more impaired attention, less impaired word recall, and slower progression of cognitive impairment than the subgroup showing an AD pattern. We found no characteristic features of other subgroups. CONCLUSION: The clinical features of subjects with AD associated with DM may differ depending on brain imaging patterns. Among them, there may be a dementia subgroup with characteristics predominantly associated with DM-related metabolic abnormalities.

Posterior spinal artery syndrome showing marked swelling of the spinal cord: a clinico-pathological study.

OBJECTIVE: To describe a rare autopsy case of posterior spinal artery syndrome with marked swelling of the spinal cord, an unusually subacute onset and short clinical course. METHODS: Case report. FINDINGS: An 84-year-old Japanese woman presented with bilateral muscle weakness of the lower legs and sensory disturbance 1 week after head contusion. Neurological findings worsened gradually. She developed phrenic nerve paralysis and died of respiratory failure 6 weeks after the onset of neurological symptoms. On pathological examination, the spinal cord was markedly swollen in the cervical and upper thoracic segments. Microscopically, there was loss of myelin sheath in the bilateral posterior columns and neuronal loss of the posterior horns in all of the spinal segments. However, findings were unremarkable in the bilateral anterior columns and bilateral anterior horns in most of the spinal segments. Posterior spinal arteries had no stenosis, occlusion, or thrombosis. We considered that pathogenesis was infarction associated with head injury. CONCLUSION: To our knowledge, this is the first report of a case of posterior spinal artery syndrome with a markedly swollen spinal cord and poor prognosis.

Detection of BRAF V600E mutation in radiological Langerhans cell histiocytosis-associated neurodegenerative disease using droplet digital PCR analysis.

Langerhans cell histiocytosis-associated neurodegenerative disease (LCH-ND) is the most serious late complication secondary to LCH and is gradually progressive, destructive, and irreversible. Detection of the BRAF V600E mutation in peripheral blood mononuclear cells (PBMCs), even in the absence of active LCH lesions, is considered a sign of clinical LCH-ND, presenting with both abnormal imaging findings and neurological symptoms. However, the detection of the BRAF V600E mutation in PBMCs of patients with asymptomatic radiological LCH-ND (rLCH-ND) without active LCH lesions who present only with abnormal imaging findings is unknown. In this study, we analyzed the BRAF V600E mutations in PBMCs and cell-free DNA (cfDNA) of patients with rLCH-ND without active LCH lesions (n = 5) using a droplet digital polymerase chain reaction (ddPCR) assay. The BRAF V600E mutation in PBMCs was detected in three out of five (60%) cases. The mutant allele frequencies in the three positive cases were 0.049%, 0.027%, and 0.015%, respectively. However, the cfDNA BRAF V600E mutation remained undetected in all patients. Detection of the BRAF V600E mutant allele in PBMCs may be helpful in identifying asymptomatic rLCH-ND in patients at high risk for developing LCH-ND, including those with relapses at CNS risk sites or central diabetes insipidus.

Longitudinal patterns of Alzheimer's disease subtypes: A follow-up magnetic resonance imaging and single-photon emission computed tomography study.

AIM: Alzheimer's disease (AD) is a biologically heterogenous disease. In a previous study, we classified 245 patients with probable AD into the typical AD (TAD), limbic-predominant (LP), hippocampal-sparing (HS) and minimal-change (MC) subtypes based on their medial temporal lobe atrophy on magnetic resonance imaging and posterior hypoperfusion on single-photon emission computed tomography, and described differences in clinical features among the patients with different AD subtypes. This study aimed to clarify the longitudinal patterns of changes in patients with the various AD subtypes by follow-up brain imaging analyses. METHODS: Follow-up magnetic resonance imaging or single-photon emission computed tomography data obtained 12-48 months after the first brain imaging were investigated in 79 patients with probable AD, comprising 25 of the TAD subtype, 19 of the LP subtype, 17 of the HS subtype and 18 of the MC subtype. RESULTS: All patients of the TAD subtype remained as the same subtype at follow up. Approximately 37% of patients of the LP subtype and 29% of patients of the HS subtype progressed to the TAD subtype, and 17%, 33% and 6% of the MC subtype progressed to the TAD, LP and HS subtypes, respectively. The group of patients showing subtype progression was associated only with a longer follow-up duration. CONCLUSIONS: There might be different progression patterns and progression rates of changes among the atypical AD subtypes. Further longitudinal brain imaging studies might provide information regarding the pathophysiological association between the various AD subtypes, and might be helpful for determining appropriate therapies and management methods. Geriatr Gerontol Int 2023; 23: 919-924.

The clinical application of optimized AT(N) classification in Alzheimer's clinical syndrome (ACS) and non-ACS conditions.

We aimed to assess the utility of AT(N) classification in clinical practice. We measured the cerebrospinal fluid levels of amyloid-ß (Aß) 42, Aß40, phosphorylated tau, total tau, and neurofilament light chain (NfL) in samples from 230 patients with Alzheimer's clinical syndrome (ACS) and 328 patients with non-ACS. The concordance of two A-markers (i.e., Aß42 alone and the Aß42/Aß40 ratio) was not significantly different between the ACS (87.4%) and non-ACS (74.1%) groups. However, the frequency of discordant cases with AAß42-alone+/AAß-ratio- was significantly higher in the non-ACS (23.8%) than in the ACS group (7.4%). The concordance of two N-markers (i.e., total tau and NfL) was 40.4% in the ACS group and 24.4% in the non-ACS group. In the ACS samples, the frequency of biological Alzheimer's disease (i.e., A+T+) in Ntau+ cases was 95% while that in NNfL+ cases was 65%. Reflecting Aß deposition and neurodegeneration more accurately, we recommend the use of AT(N) classification defined by cerebrospinal fluid AAß-ratioTNNfL in clinical practice.

Discrepancy Between Cognitive Test and Brain Imaging Results in Alzheimer's Disease Associated with Diabetes.

BACKGROUND/OBJECTIVE: Although a large number of studies have been performed on the association between Alzheimer's disease (AD) and type 2 diabetes mellitus (DM), the underlying pathophysiology of AD associated with DM has not been fully elucidated to date. We compared cognitive functions and brain imaging findings between AD patients with and without DM to characterize the association between cognition and imaging findings in AD patients with DM. METHODS: Cognitive functions and brain imaging findings, including medial temporal lobe atrophy analyzed by magnetic resonance imaging, and hypoperfusion in the parietal, posterior cingulate, and frontal regions analyzed by single-photon emission computed tomography were compared between 126 AD patients without DM ([AD-DM]) and 51 AD patients with DM ([AD+DM]). Factors associated with cognitive-imaging associations, including education, occupation, leisure activity, comorbidity, frailty, and other demographics, were analyzed. RESULTS: The [AD+DM] group showed significantly more severe cognitive dysfunction than the [ADDM] group, despite a similar degree of brain imaging abnormalities. Among the factors associated with cognitive-imaging associations, the level of leisure activity was significantly lower in the [AD+DM] group than in the [AD-DM] group, but no significant differences in other factors were observed between the 2 groups. CONCLUSION: The cognitive-imaging discrepancy observed in AD patients with DM may be associated with their low cognitive reserve, possibly caused by their low amount of leisure activities. Our findings suggest that lifestyle interventions, including physical, cognitive, and social activities, may reduce cognitive decline in AD patients with DM.

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.

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.