Superficial small cerebellar infarcts in cerebral amyloid angiopathy on 3 T MRI: A preliminary study.

BACKGROUND: Strictly superficial cerebellar microbleeds and cerebellar superficial siderosis have been considered markers of advanced cerebral amyloid angiopathy (CAA), but there are few studies on cerebellar ischemic lesions in CAA. We investigated the presence of superficial small cerebellar infarct (SCI) ≤15 mm and its relation to magnetic resonance imaging (MRI) markers in patients with probable CAA. METHODS: Eighty patients with probable CAA were retrospectively evaluated. The presence of superficial SCIs was examined, along with cerebellar microbleeds and cerebellar superficial siderosis, using 3-T MRI. Lobar cerebral microbleeds, cortical superficial siderosis (cSS), enlargement of the perivascular space in the centrum semiovale, and white matter hyperintensity were assessed and the total CAA-small vessel disease (SVD) score was calculated. RESULTS: Nine of the 80 patients (11.3%) had a total of 16 superficial SCIs. By tentatively defining SCI <4 mm as cerebellar microinfarcts, 8 out of 16 (50%) superficial SCIs corresponded to cerebellar microinfarcts. The total CAA-SVD score was significantly higher in patients with superficial SCIs (p = 0.01). The prevalence of cSS (p = 0.018), cortical cerebral microinfarct (p = 0.034), and superficial cerebellar microbleeds (p = 0.006) was significantly higher in patients with superficial SCIs. The number of superficial cerebellar microbleeds was also significantly higher in patients with superficial SCIs (p = 0.001). CONCLUSIONS: Our results suggest that in patients with CAA, superficial SCIs (including microinfarcts) on MRI may indicate more severe, advanced-stage CAA. These preliminary findings should be verified by larger prospective studies in the future.

Pulvinar quantitative susceptibility mapping predicts visual hallucinations post-deep brain stimulation in Parkinson's disease.

PURPOSE: We have reported the relationship between low pulvinar nuclei (PN) intensity in susceptibility-weighted imaging and the appearance of visual hallucinations and cognitive function. The aim of the study was to examine the changes in the quantitative susceptibility mapping (QSM) in patients with Parkinson's disease (PD) who underwent deep brain stimulation (DBS) and verify whether the PN susceptibility value (SV) on QSM can predict visual hallucination and cognitive changes after DBS. METHODS: This study examined 24 patients with PD who underwent DBS along with QSM imaging on magnetic resonance imaging (MRI). All MRIs were performed within 3 months before surgery. The PN SV was further assessed based on the QSM. Then, associations were examined among cognitive changes, hallucination, and PN SV. The cognitive function of the patient was compared immediately before surgery and at 1 year postoperatively. RESULTS: Visual hallucinations were observed in seven patients during the follow-up period. The PN SV was ≥0.045 ppm in nine patients with PD, and six of them had visual hallucinations, whereas only one of 15 patients with PD with SV of <0.045 ppm had visual hallucinations (Fisher's exact test, p = .0037). CONCLUSIONS: The SV of >0.045 ppm at the PN in QSM in patients with PD may provide useful information suggesting visual hallucination and cognitive deterioration after DBS treatment.

Association of thyroid peroxidase antibody with the RNF213 p.R4810K variant in ischemic stroke/transient ischemic attack.

BACKGROUND AND AIMS: RNF213 is a susceptibility gene for moyamoya disease and vasospastic angina, with a second hit considered necessary for their development. Elevated thyroid peroxidase antibody (TPO-Ab) levels have been observed in both diseases, suggesting a possible role of TPO-Ab as a second hit for developing RNF213-related vasculopathy. We investigated the association of TPO-Ab levels with RNF213-related ischemic stroke (IS)/transient ischemic attack (TIA), other than moyamoya disease. METHODS: From the National Cerebral and Cardiovascular Center Genome Registry, a multicenter, prospective, observational study, we enrolled patients with IS/TIA who were admitted within 1 week of onset. Patients with IS/TIA due to definite moyamoya disease or hemorrhagic stroke were excluded. Participants underwent genotyping for RNF213 p. R4810K, and baseline characteristics and TPO-Ab levels were compared between RNF213 p. R4810K variant carriers and non-carriers. RESULTS: In total, 2090 IS/TIA patients were analyzed [733 women (35.1%); median age 74 (interquartile range, 63-81) years, baseline NIHSS score 3 (2-6)], and 85 (4.1%) of them carried the variant. Median TPO-Ab levels were significantly higher in variant carriers (8.5 IU/mL vs. 2.1 IU/mL, p < 0.01), who also showed a higher frequency of elevated TPO-Ab levels (>16 IU/mL) (27.1% vs. 4.4%). In the multivariate analysis, presence of the RNF213 p. R4810K variant (adjusted odds ratio, 12.42; 95% confidential interval, 6.23-24.75) was significantly associated with elevated TPO-Ab levels. CONCLUSIONS: Elevated TPO-Ab levels may be significantly associated with presence of the RNF213 p. R4810K variant in IS/TIA patients. Thus, TPO-Ab may inherently modify IS/TIA development in RNF213 p. R4810K variant carriers.

Magnetic resonance imaging and neuropsychological findings for predicting of cognitive deterioration in memory clinic patients.

Objective: The severity of cerebral small vessel disease (SVD) on magnetic resonance imaging (MRI) has been assessed using hypertensive arteriopathy SVD and cerebral amyloid angiopathy (CAA)-SVD scores. In addition, we reported the modified CAA-SVD score including cortical microinfarcts and posterior dominant white matter hyperintensity. Each SVD score has been associated with cognitive function, but the longitudinal changes remain unclear. Therefore, this study prospectively examined the prognostic value of each SVD score, imaging findings of cerebral SVD, and neuropsychological assessment. Methods: This study included 29 patients diagnosed with mild cognitive impairment or mild dementia at memory clinic in our hospital, who underwent clinical dementia rating (CDR) and brain MRI (3D-fluid attenuated inversion recovery, 3D-double inversion recovery, and susceptibility-weighted imaging) at baseline and 1 year later. Each SVD score and neuropsychological tests including the Mini-Mental State Examination, Japanese Raven's Colored Progressive Matrices, Trail Making Test -A/-B, and the Rivermead Behavioral Memory Test were evaluated at baseline and 1 year later. Results: Twenty patients had unchanged CDR (group A), while nine patients had worsened CDR (group B) after 1 year. At baseline, there was no significant difference in each SVD score; after 1 year, group B had significantly increased CAA-SVD and modified CAA-SVD scores. Group B also showed a significantly higher number of lobar microbleeds than group A at baseline. Furthermore, group B had significantly longer Japanese Raven's Colored Progressive Matrices and Trail Making test-A times at baseline. After 1 year, group B had significantly lower Mini-Mental State Examination, Japanese Raven's Colored Progressive Matrices, and Rivermead Behavioral Memory Test scores and significantly fewer word fluency (letters). Conclusion: Patients with worsened CDR 1 year after had a higher number of lobar microbleeds and prolonged psychomotor speed at baseline. These findings may become predictors of cognitive deterioration in patients who visit memory clinics.

Association between behavioral and psychological symptoms and cerebral small vessel disease MRI findings in memory clinic patients.

Objectives: Cerebral small vessel disease (SVD) is commonly observed among elderly individuals with cognitive impairment and has been recognized as a vascular contributor to dementia and behavioral and psychological symptoms (BPS), however, the relationship between BPS and SVD burden remains unclear. Methods: We prospectively recruited 42 patients with mild cognitive impairment (MCI) or mild dementia from the memory clinic in our hospital, who were assigned to either a clinical dementia rating (CDR) of 0.5 or 1.0, respectively. The presence of BPS was determined through interviews with caregivers. The patients underwent brain MRI and three types of SVD scores, total, cerebral amyloid angiopathy (CAA), and modified CAA, were assigned. Patients were also evaluated through various neuropsychological assessments. Results: The CDR was significantly higher in patients with BPS (p = 0.001). The use of antihypertensive agents was significantly higher in patients without BPS (p = 0.038). The time taken to complete trail making test set-A was also significantly longer in patients with BPS (p = 0.037). There was no significant difference in total SVD and CAA-SVD score (p = 0.745, and 0.096) and the modified CAA-SVD score was significantly higher in patients with BPS (p = 0.046). In addition, the number of total CMBs and lobar CMBs was significantly higher in patients with BPS (p = 0.001 and 0.001). Receiver operating characteristic curves for BPS showed that for modified CAA-SVD, a cutoff score of 3.5 showed 46.7% sensitivity and 81.5% specificity. Meanwhile, for the total number of cerebral microbleeds (CMBs), a cut-off score of 2.5 showed 80.0% sensitivity and 77.8% specificity and for the number of lobar CMBs, a cut-off score of 2.5 showed 73.3% sensitivity and 77.8% specificity. Conclusion: Overall, patients with BPS showed worse CDRs, reduced psychomotor speed, higher modified CAA-SVD scores, larger numbers of total and lobar CMBs. We propose that severe modified CAA scores and higher numbers of total and lobar CMBs are potential risk factors for BPS in patients with mild dementia or MCI. Therefore, by preventing these MRI lesions, the risk of BPS may be mitigated.

Sporadic Myotonic Dystrophy Type 2 in a Japanese Patient.

We herein report a Japanese patient with myotonic dystrophy type 2 (DM2), which is rare in Japan. A 64-year-oldman had proximal muscle weakness and grip myotonia. Electromyography showed myotonic discharges, but dystrophia-myotonica protein kinase (DMPK) was negative for CTG repeats. A muscle biopsy revealed increased central nuclei, pyknotic nuclear clumps and muscle fiber atrophy, mainly in type 2 fibers, raising the possibility of DM2. The diagnosis was genetically confirmed by the abnormal CCTG repeat size in cellular nucleic acid-binding protein (CNBP) on repeat-primed polymerase chain reaction, which was estimated to be around 4,500 repeats by Southern blotting.

Correlation between Serum Zinc Levels and Levodopa in Parkinson's Disease.

Long-term intake of potential zinc-chelating drugs may cause zinc deficiency. We postulated that zinc deficiency in Parkinson's disease (PD) patients was related to the intake of drugs such as levodopa. We investigated the relationship between zinc levels and levodopa administration period, dosage, and symptoms of zinc deficiency in PD patients. We measured serum zinc levels and analyzed correlations between serum zinc levels, the levodopa oral administration period, dosage, dosing frequency, and zinc deficiency symptoms including taste disorders. Data analyses were performed using Spearman's rank correlation coefficient. The mean serum zinc level was 60.5 ± 11.6 µg/dL. The mean administration period for levodopa was 8.0 ± 5.5 years, mean administration frequency 3.4 ± 0.9 times/d, and mean administration dose 420.6 ± 237.1 mg/d. Negative correlations between zinc levels and levodopa dosage and dosing frequency were found. Multiple regression analysis showed a significant correlation with the frequency of levodopa (ß = -0.360, p = 0.007). No significant change in clinical symptoms was observed after zinc administration, but anxiety tended to improve. Our results indicated that frequent levodopa administration strongly influenced serum zinc levels which may have alleviating effects on psychiatric symptoms; therefore, preventing zinc deficiency can be important during PD treatment.

Miller Fisher syndrome following BNT162b2 mRNA coronavirus 2019 vaccination.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), began in late 2019. One of the vaccines approved against COVID-19 is the BNT162b2 mRNA COVID-19 vaccine (Pfizer/BioNTech). CASE PRESENTATION: We present the case of a 71-year-old man with no history of the SARS-CoV-2 infection or any recent viral or bacterial illnesses who presented with bilateral oculomotor palsy and limb ataxia after BNT162b2 mRNA COVID-19 vaccination. The diagnosis of Miller Fisher syndrome (MFS) was established based on physical examination, brain magnetic resonance imaging (MRI), cerebrospinal fluid analysis (CSF), and positron emission tomography (PET). There was no evidence of other predisposing infectious or autoimmune factors, and the period from COVID-19 vaccination to the appearance of neurological symptoms was similar to that of other vaccines and preceding events, such as infection. CONCLUSION: Guillain-Barré syndrome (GBS) and its variants after COVID-19 vaccination are extremely rare. Note that more research is needed to establish an association between MFS and COVID-19 vaccines. In our opinion, the benefits of COVID-19 vaccination largely outweigh its risks.

Cerebral Embolism Associated with Calcified Amorphous Tumor: A Review of Cerebral Infarction Cases.

Calcified amorphous tumor (CAT) is a non-neoplastic tumor composed of calcified nodules consisting of amorphous fibrous material, and it may eventually cause cerebral infarction (CI). We experienced a 67-year-old woman with CAT who had recurrent CI. After excision of the CAT, the CI did not show recurrence. A review of previous papers on CI due to CAT in Pubmed revealed that 7 of 13 studies originated in Japan and that CI can occur even with small CAT. Surgical treatment is recommended to prevent CI recurrence, especially when CAT is accompanied by mitral annular calcification or has marked mobility.

Association between cortical microinfarcts and total small vessel disease burden in cerebral amyloid angiopathy on 3-Tesla magnetic resonance imaging.

BACKGROUND AND PURPOSE: Cortical microinfarcts (CMIs) are frequently found in the brains of patients with advanced cerebral amyloid angiopathy (CAA) at autopsy. The small vessel disease (SVD) score for CAA (i.e., the CAA-SVD score) has been proposed to evaluate the severity of CAA-associated vasculopathic changes by a combination of magnetic resonance imaging (MRI) markers. The aim of this study was to examine the association between total CAA-SVD score and features of CMIs on in vivo 3-Tesla MRI. METHODS: Eighty patients with probable CAA were retrospectively analyzed. Lobar cerebral microbleeds, cortical superficial siderosis, enlargement of perivascular space in the centrum semiovale and white matter hyperintensity were collectively assessed, and the total CAA-SVD score was calculated. The presence of CMI was also examined. RESULTS: Of the 80 patients, 13 (16.25%) had CMIs. CMIs were detected more frequently in the parietal and occipital lobes. A positive correlation was found between total CAA-SVD score and prevalence of CMI (ρ = 0.943; p = 0.005). Total CAA-SVD score was significantly higher in patients with CMIs than in those without (p = 0.009). In a multivariable logistic regression analysis, the presence of CMIs was significantly associated with total CAA-SVD score (odds ratio 2.318 [95% confidence interval 1.228-4.376]; p = 0.01, per each additional point). CONCLUSIONS: The presence of CMIs with a high CAA-SVD score could be an indicator of more severe amyloid-associated vasculopathic changes in patients with probable CAA.

A Case of Miyazaki Syndrome Caused by Arachnoid Cyst-Peritoneal Shunt.

BACKGROUND: Miyazaki syndrome is overshunting-associated myelopathy, which is a rare complication of ventriculoperitoneal shunt. We present the first case of Miyazaki syndrome caused by cystoperitoneal (CP) shunt for an arachnoid cyst (AC) in this report. CASE DESCRIPTION: We report a case of a 42-year-old man with 12-year progressive spastic paraplegia, who underwent CP shunt for an AC at the age of 15 years. Although few findings suggested overshunting on symptoms and head computed tomography, contrast-enhanced magnetic resonance imaging revealed the engorgement of the cervical spinal epidural venous plexus compressing the spinal cord. Shunt valve replacement with a pressure-adjustable valve was performed. Postoperatively, the cervical cord compression by the enlarged spinal epidural venous plexus was completely improved, but, possibly due to delayed diagnosis and treatment, the patient's symptoms only partially improved. CONCLUSIONS: When patients with a history of any kind of shunt surgery develop myelopathy, Miyazaki syndrome should be suspected and, for early diagnosis, cervical and/or contrast-enhanced magnetic resonance imaging should be performed.

Hypertensive Arteriopathy and Cerebral Amyloid Angiopathy in Patients with Cognitive Decline and Mixed Cerebral Microbleeds.

BACKGROUND: Hypertensive arteriopathy (HA) and cerebral amyloid angiopathy (CAA) may contribute to the development of mixed cerebral microbleeds (CMBs). Recently, the total small vessel disease (SVD) scores for HA and CAA were proposed, which are determined by a combination of MRI markers to reflect overall severity of these microangiopathies. OBJECTIVE: We investigated whether or not total HA-SVD and CAA-SVD scores could be used to predict overlap of HA and CAA in patients with mixed CMBs. METHODS: Fifty-three subjects with mixed CMBs were retrospectively analyzed. MRI markers (CMBs, lacunes, perivascular space, white matter hyperintensity [WMH] and cortical superficial siderosis [cSS]) were assessed. The HA-SVD score and CAA-SVD score were obtained for each subject. Anterior or posterior WMH was also assessed using the age-related white matter changes scale. RESULTS: The two scores were positively correlated (ρ= 0.449, p < 0.001). The prevalence of lobar dominant CMB distribution (p < 0.001) and lacunes in the centrum semiovale (p < 0.001) and the severity of WMH in the parieto-occipital lobes (p = 0.004) were significantly higher in the high CAA-SVD score group. cSS was found in four patients with high CAA-SVD score who showed lobar-dominant CMB distribution and severe posterior WMH. CONCLUSION: Mixed CMBs are mainly due to HA. Assessing both two scores may predict the overlap of HA and CAA in individuals with mixed CMBs. Patients with a high CAA-SVD score may have some degree of advanced CAA, especially when lobar predominant CMBs, severe posterior WMH, lobar lacunes, or cSS are observed.

Myasthenia gravis with anti-muscle-specific tyrosine kinase antibodies during therapy for multiple myeloma: a case report.

BACKGROUND: The onset of myasthenia (MG) gravis with anti-muscle-specific tyrosine kinase (MuSK) antibodies most commonly peaks in the fourth decade of life, and MG with MuSK antibodies (MuSK-MG) rarely coexists with a malignant tumor. To date, MuSK-MG has not been reported in multiple myeloma (MM). CASE PRESENTATION: A 60-year-old male with MM who was receiving treatment with bortezomib and thalidomide presented diplopia, ptosis, and limb weakness. A diagnosis of MM with Bence-Jones proteinuria was established when he was 56 years old, and he received chemotherapy with four courses of bortezomib and dexamethasone. Although he received thalidomide as maintenance therapy, it was discontinued a year before hospital admission because of sensory neuropathy as a side effect. Six months before hospital admission, he developed mild diplopia. One month before admission, his chemotherapy was interrupted because of viral infection and fatigability. Then he developed neck weakness and bilateral ptosis. A diagnosis of MuSK-MG was made based on neurological and serological examinations. According to the previous relevant literature, this is the first report of MuSK-MG in a patient with MM. CONCLUSIONS: In patients with MM, the possibility of co-existing of autoimmune disease, including MuSK-MG, should be considered. This case emphasizes the need to still consider testing for anti-MuSK antibodies in older MM patients where there is clinical suspicion for possible MG despite negative anti-acetylcholine receptor antibodies and lacking classic MuSK MG phenotype at onset.

Chronic cerebral hypoperfusion activates AIM2 and NLRP3 inflammasome.

Inflammation plays an important role in acute and chronic cerebral ischemia. Recent reports indicate that the inflammatory response triggered by tissue damage is mediated by a multiple-protein complex called the inflammasome. The NOD-like receptor family, pyrin domain containing 3 (NLRP3) and absent in melanoma 2 (AIM2) inflammasome complex triggers caspase 1-mediated maturation of interleukin (IL)-1ß and IL-18. This study tested the hypothesis that chronic cerebral hypoperfusion activates inflammasomes in the white matter of the brain. To induce cerebral hypoperfusion, C57BL/6J mice were subjected to a sham or bilateral common carotid artery stenosis (BCAS) operation using microcoils with an internal diameter of 0.18 mm. At 2 and 4 weeks after BCAS, the mice were sacrificed (n = 5 in each group). Coronal sections were stained with anti-NLRP3 and anti-AIM2 antibodies. Activation of the inflammasome and cytokines was assessed using immunohistochemistry and cell counting. IL-18 and IL-1ß levels were determined by ELISA. Cell counting revealed an increase in NLRP3 and AIM2 inflammasomes at 2 and 4 weeks after BCAS. Immunoreactivity was observed in glial cells in the white matter and corpus callosum. IL-18 and IL-1ß concentrations were significantly increased compared with those in the sham operation group. Expression of NLRP3 and AIM2 was upregulated in glial cells in the autopsied brains of patients with cerebral infarction in the chronic phase. These results suggest that chronic cerebral hypoperfusion induces upregulation of NLRP3 and AIM2 inflammasomes; therefore, inflammasomes may play an important role in the sterile inflammatory response in astrocytes and microglia during chronic cerebral hypoperfusion.

Symptomatic Characteristics of Parkinson's Disease Induced by Neuroleptic Drugs, Based on a Functional Neuroimaging Diagnosis.

Objective When patients take neuroleptics, the distinction between Parkinson's disease (PD) and drug-induced parkinsonism (DIP) based solely on clinical features can become difficult. At present, 123I-FP-CIT SPECT (DAT-SPECT) and 123I-metaiodobenzylguanidine (MIBG) myocardial scintigraphy are widely used to supplement the differential diagnosis of parkinsonism. This study assessed the clinical symptoms and neurological findings in the patients suspected of having DIP based on DAT-SPECT findings. Methods Twenty-three patients (11 men, 12 women, age: 52-81 years old) presenting with DIP were recruited. All patients underwent neurological examinations, including brain magnetic resonance imaging and DAT-SPECT. Patients who showed abnormal DAT-SPECT results underwent MIBG myocardial scintigraphy. Results Eleven patients showed a reduction in the ligand uptake on DAT-SPECT (DAT-positive group), and nine of these patients showed a low delayed heart-to-mediastinum (H/M) ratio on MIBG myocardial scintigraphy. The remaining 12 patients showed normal results on DAT-SPECT (DAT-negative group). All patients in the DAT-positive group had asymmetric motor symptoms, whereas only 4 in the DAT-negative group exhibited this clinical feature (p=0.001). A detailed medical history showed that 7 of the 11 patients in the DAT-positive group had prodromal symptoms for PD. However, only 1 patient in the DAT-negative group exhibited these symptoms (p= 0.009). Although two patients in the DAT-negative group showed poor improvement, they showed a normal H/M ratio on MIBG and no response to levodopa. Conclusion The patients in the DAT-positive group might have prodromal symptoms that were worsened by neuroleptic drugs. The results of detailed history-taking and neurological findings seem to indicate cases of compromised dopaminergic transmission before the administration of neuroleptic drugs.

Cortical Microinfarcts Detected by 3-Tesla Magnetic Resonance Imaging: Differentiation Between Cerebral Amyloid Angiopathy and Embolism.

Background and Purpose- Cortical microinfarcts (CMIs) are small ischemic lesions found in cerebral amyloid angiopathy (CAA) and embolic stroke. This study aimed to differentiate CMIs caused by CAA from those caused by microembolisms, using 3-Tesla magnetic resonance imaging. Methods- We retrospectively investigated 70 patients with at least 1 cortical infarct <10 mm on 3-dimensional double inversion recovery imaging. Of the 70 patients, 43 had an embolic stroke history (Emboli-G) while 27 had CAA-group. We compared the size, number, location, and distribution of CMIs between groups and designed a radiological score for differentiation based on the comparisons. Results- CAA-group showed significantly more lesions <5 mm, which were restricted to the cortex (P<0.01). Cortical lesion number was significantly higher in Emboli-G than in CAA-group (4 versus 2; P<0.01). Lesions in CAA-group and Emboli-G were disproportionately located in the occipital lobe (P<0.01) and frontal or parietal lobe (P=0.04), respectively. In radiological scoring, ≥3 points strongly predicted microembolism (sensitivity, 63%; specificity, 92%) or CAA (sensitivity, 63%; specificity, 91%). The areas under the receiver operating characteristic curve were 0.85 and 0.87 for microembolism and CAA, respectively. Conclusions- Characteristics of CMIs on 3T-magnetic resonance imaging may differentiate CMIs due to CAA from those due to microembolisms.

MEFV gene mutations in neuro-Behçet's disease and neuro-Sweet disease.

Mediterranean fever (MEFV) gene mutations are associated with familial Mediterranean fever (FMF). Recent studies have suggested that MEFV gene mutations may act as disease modifiers in neuro-Behçet's (NBD) disease and neuro-Sweet disease (NSD). We investigated MEFV genes and clinical features in 17 patients with NBD or NSD. MEFV gene mutations were frequently observed (70.6%). Headaches and exertional leg pain were associated with MEFV gene mutations (P < 0.05). Moreover, higher frequency of white matter lesions without sites predilection (P < 0.05) and non-parenchymal lesions (P < 0.05) were also observed. MEFV gene mutations may be associated with particular findings and lesion sites.

Chronic cerebral hypoperfusion upregulates leptin receptor expression in astrocytes and tau phosphorylation in tau transgenic mice.

Alzheimer's disease (AD) is the most common type of dementia in aging adults. Increasing evidence has revealed that vascular risk factors influence the midlife development of AD and that diet-induced obesity accelerates tau phosphorylation in tau transgenic mice and increases the level of serum leptin receptor (leptin-R). Leptin-R is upregulated in the peri-infarct cortices after acute cerebral ischemia. Leptin may be protective against the development of AD as it can inactivate GSK-3ß through the phosphorylation of Ser-9, leading to the reduction of tau phosphorylation. Using tau transgenic mice, the present study examined whether chronic cerebral hypoperfusion affects leptin-R signaling and tau phosphorylation. Eight-month-old tau transgenic mice (T44) overexpressing the shortest human tau isoform were subjected to chronic cerebral hypoperfusion with bilateral common carotid artery stenosis (BCAS) using microcoils or sham surgery. Their brains were analyzed four weeks later to evaluate the expression of phosphorylated tau and leptin-R via immunohistochemistry and Western blot analysis. In addition, expression of leptin-R was examined in the rat primary astrocyte cultures subjected to prolonged chemical hypoxic stress, as well as in autopsied brains. BCAS upregulated leptin-R expression and promoted the expression of phosphorylated tau in T44 Tg mice. In primary astrocyte cultures, leptin-R was upregulated under hypoxic conditions via the phosphorylated AKT/pAKT pathway, possibly suppressing the expression of caspase 3. Leptin-R was also strongly expressed in autopsied brains with AD and cerebrovascular diseases. These results collectively indicate that chronic cerebral hypoperfusion promotes leptin-R signaling and tau phosphorylation.