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.

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.

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.

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.

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.

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.

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.

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.

Discrepancy Between the Degree of Cognitive Impairment and Brain Imaging Abnormalities in Alzheimer's Disease Patients Is Associated with Cognitive Reserve.

BACKGROUND: In Alzheimer's disease (AD) patients, the severity of cognitive impairment is thought to correlate with the degree of brain imaging abnormalities. However, some patients show only mild cognitive deficit, despite severe brain atrophy on magnetic resonance imaging (MRI) or marked hypoperfusion in the cerebral cortices on single-photon emission computed tomography (SPECT). This suggests that cognitive reserve (CR) can compensate for the clinical manifestations of AD in patients with extensive brain pathology. OBJECTIVE: We aimed to determine whether this discrepancy between cognitive and imaging findings is associated with CR. METHODS: Factors associated with the discrepancy between the degree of cognitive impairment and MRI (medial temporal lobe atrophy) and SPECT (posterior cerebral hypoperfusion) findings were analyzed in 135 patients with probable AD. Factors as proxies for CR included education, occupation, leisure activity, comorbidities, frailty, and other demographics. The discrepancy index (DI) was calculated as the difference between the degree of imaging abnormalities and the degree of cognitive dysfunction. RESULTS: Multiple regression analysis showed that leisure activity and education were significantly associated with the discrepancy between cognitive and imaging findings. When the level of CR was determined based on leisure activity and education, the high-CR group showed a significantly larger DI than the moderate- and low-CR groups. CONCLUSION: The discrepancy between cognitive and imaging findings in patients with AD is associated with CR, measured using a combination of two indicators, i.e., leisure activity and education. Therefore, lifestyle interventions may delay the appearance of clinical symptoms resulting from underlying AD pathology, by increasing CR.

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.

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.

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.

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.

Efficacy of Olfactory and Pareidolia Tests Compared With That of Indicative Biomarkers in Diagnosis of Dementia With Lewy Bodies.

Purpose: Although olfactory decline and visual hallucinations are useful in distinguishing dementia with Lewy bodies (DLB) from Alzheimer's disease (AD) in a clinical setting, neither is easy to evaluate objectively. The pareidolia test is used to assess susceptibility to visual hallucinations, while in Japan, the Odor Stick Identification Test for the Japanese (OSIT-J) is used to objectively quantify olfactory decline. The present study investigated the efficacy of these olfactory and pareidolia tests in differentiating AD from DLB. Their usefulness was then compared with that of the indicative biomarkers in neuroimaging for a clinical diagnosis of DLB listed in the Fourth Consensus Report of the Dementia with Lewy Bodies Consortium. Methods: A total of 24 probable DLB and 22 probable AD patients were enrolled. All underwent 4 diagnostic procedures: uptake of dopamine transporter in single photon emission computed tomography (DaT-SPECT) and meta-iodobenzylguanidine (MIBG) in myocardial scintigraphy, the pareidolia test, and OSIT-J. The sensitivity, specificity, and accuracy of these methods in differentiating DLB from AD were compared. Results: Sensitivity and specificity in differentiating DLB from AD were 86 and 100% by the heart-to-mediastinum ratio of MIBG uptake; 82 and 96% by the specific binding ratio on DaT-SPECT; 77 and 67% by the combination of OSIT-J and pareidolia test scores; 73 and 62% by the pareidolia test scores; and 77 and 58% by the OSIT-J scores, respectively. Conclusions: The present results suggest that the pareidolia and OSIT-J tests may be considered before resorting to nuclear neuroimaging in the diagnosis of DLB.

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.

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.