Factors and brain imaging features associated with cognition in oldest-old patients with Alzheimer-type dementia.

BACKGROUND: The underlying pathophysiology of cognitive dysfunction in oldest-old patients with Alzheimer-type dementia (AD) has not been clarified to date. We aimed to determine the factors and brain imaging features associated with cognition in oldest-old patients with AD. METHODS: We enrolled 456 consecutive outpatients with probable AD (145 men and 311 women, age range: 51-95 years). Demographic factors, such as education level, disease duration at initial visit, body mass index, comorbidities, frailty, and leisure activity, and brain imaging features, including severity of medial temporal lobe (MTL) atrophy, white matter lesions and infarcts, and frequency of posterior cerebral hypoperfusion were compared among pre-old (≤ 74 years), old (75 to 84 years), and oldest-old (≥ 85 years) subgroups. RESULTS: The oldest-old subgroup showed significantly longer disease duration, lower education level, more severe frailty, less leisure activity, worse cognitive impairment, a tendency of slower progression of cognitive decline, greater MTL atrophy, more severe white matter hyperintensities and infarcts, and lower frequency of posterior hypoperfusion than the younger age subgroups. Regarding the brain imaging subtypes, there were significantly more patients with the limbic-predominant subtype and fewer patients with the hippocampal-sparing subtype in the oldest-old AD group than the pre-old AD group. CONCLUSIONS: Oldest-old patients with AD show different factors and brain imaging features associated with cognition from pre-old and old patients. Our results are expected to provide useful information towards understanding the pathophysiology of oldest-old patients with AD, and for determining their clinical diagnosis and appropriate management methods.

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.

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.

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.

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.

A Nationwide Survey and Multicenter Registry-Based Database of Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy in Japan.

OBJECTIVES: Clinical characteristics of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) include migraine, recurrent stroke, white matter lesions, and vascular dementia. CADASIL is one of the most common hereditary cerebral small vessel diseases. Clinical presentation of CADASIL varies and a racial gap may exist between the Asian and Caucasian populations. This is the first nationwide epidemiological survey which aimed to elucidate the clinical features of CADASIL in Japan. Moreover, the registration database of CADASIL was constructed. METHODS: Subjects included CADASIL patients who visited the hospitals (totally 1,448 hospitals) certified by the Japanese Society of Neurology and/or Japan Stroke Society in 2016. This study consisted of a two-step survey; patients with CADASIL were identified genetically by the first questionnaire, and their clinical features were assessed by the second questionnaire. Selected 6 hospitals registered the data of all CADASIL patients using a Research Electronic Data Capture (REDCap) system for the second questionnaire. RESULTS: Based on the criteria, 88 patients (50 male and 38 female) with CADASIL were enrolled. The mean age of symptom onset was 49.5 years. Sixteen (18.2%) patients had an elderly onset (>60 years). Thirteen patients (13.6%) had history of migraine with aura and 33 patients (37.5%) had vascular risk factor(s). From among the 86 patients who were examined using magnetic resonance imaging, abnormal deep white matter lesions were detected in 85 patients (98.8%), WMLs extending to anterior temporal pole in 73 patients (84.9%), and cerebral microbleeds in 41 patients (47.7%). Anti-platelet therapy was received by 65 patients (73.9%). Thirty-eight patients (43.2%) underwent treatment with lomerizine hydrochloride. Thirty-four different mutations of NOTCH3 were found in exons 2, 3, 4, 5, 6, 8, 11, 14, and 19. Most of the mutations existed in exon 4 (n = 44, 60.3%). The prevalence rate of CADASIL was 1.20 to 3.58 per 100,000 adults in Japan. CONCLUSION: This questionnaire-based study revealed clinical features and treatment status in Japanese CADASIL patient, although it may not be an exhaustive search. We have constructed the REDCap database for these CADASIL 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.

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.

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.

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.