Development of a Novel Nutrition-Related Multivariate Biomarker for Mild Cognitive Impairment Based on the Plasma Free Amino Acid Profile.

Nutritional epidemiology has shown the importance of protein intake for maintaining brain function in the elderly population. Mild cognitive impairment (MCI) may be associated with malnutrition, especially protein intake. We explored blood-based biomarkers linking protein nutritional status with MCI in a multicenter study. In total, 219 individuals with MCI (79.5 ± 5.7 year) from 10 institutions and 220 individuals who were cognitively normal (CN, 76.3 ± 6.6 year) in four different cities in Japan were recruited. They were divided into the training (120 MCI and 120 CN) and validation (99 MCI and 100 CN) groups. A model involving concentrations of PFAAs and albumin to discriminate MCI from CN individuals was constructed by multivariate logistic regression analysis in the training dataset, and the performance was evaluated in the validation dataset. The concentrations of some essential amino acids and albumin were significantly lower in MCI group than CN group. An index incorporating albumin and PFAA discriminated MCI from CN participants with the AUC of 0.705 (95% CI: 0.632-0.778), and the sensitivities at specificities of 90% and 60% were 25.3% and 76.8%, respectively. No significant association with BMI or APOE status was observed. This cross-sectional study suggests that the biomarker changes in MCI group may be associated with protein nutrition.

Decreased circulating branched-chain amino acids are associated with development of Alzheimer's disease in elderly individuals with mild cognitive impairment.

Background: Nutritional epidemiology has shown that inadequate dietary protein intake is associated with poor brain function in the elderly population. The plasma free amino acid (PFAA) profile reflects nutritional status and may have the potential to predict future changes in cognitive function. Here, we report the results of a 2-year interim analysis of a 3-year longitudinal study following mild cognitive impairment (MCI) participants. Method: In a multicenter prospective cohort design, MCI participants were recruited, and fasting plasma samples were collected. Based on clinical assessment of cognitive function up to 2 years after blood collection, MCI participants were divided into two groups: remained with MCI or reverted to cognitively normal ("MCI-stable," N = 87) and converted to Alzheimer's disease (AD) ("AD-convert," N = 68). The baseline PFAA profile was compared between the two groups. Stratified analysis based on apolipoprotein E ε4 (APOE ε4) allele possession was also conducted. Results: Plasma concentrations of all nine essential amino acids (EAAs) were lower in the AD-convert group. Among EAAs, three branched-chain amino acids (BCAAs), valine, leucine and isoleucine, and histidine (His) exhibited significant differences even in the logistic regression model adjusted for potential confounding factors such as age, sex, body mass index (BMI), and APOE ε4 possession (p < 0.05). In the stratified analysis, differences in plasma concentrations of these four EAAs were more pronounced in the APOE ε4-negative group. Conclusion: The PFAA profile, especially decreases in BCAAs and His, is associated with development of AD in MCI participants, and the difference was larger in the APOE ε4-negative population, suggesting that the PFAA profile is an independent risk indicator for AD development. Measuring the PFAA profile may have importance in assessing the risk of AD conversion in the MCI population, possibly reflecting nutritional status. Clinical trial registration: [https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000025322], identifier [UMIN000021965].

Analysis of incidence and risk factors for progression in patients with intracranial steno-occlusive lesions by serial magnetic resonance angiography.

OBJECTIVES: Conventional angiography and transcranial Doppler ultrasonography have usually been used for serial observation of cerebral atherosclerotic diseases. This study used magnetic resonance (MR) angiography to monitor serial changes in steno-occlusive lesions of the major intracranial arteries to elucidate the incidence of progression and investigate the risk factors for progression. PATIENTS AND METHODS: The 151 consecutive patients, 78 males and 73 females aged 42-92 years (mean 71.1+/-10.2 years), were followed up by serial MR angiography for 5-34 months (mean 14.4+/-5.78 months). Progression was defined as increased stenosis or occlusion, or new stenotic lesion. Age, sex, duration of MR angiography follow up, hypertension, diabetes mellitus, hyperlipidemia, hyperuricemia, current smoking, and atrial fibrillation were chosen as risk factors for multiple logistic analysis. RESULTS: Twenty-three of the patients (15.2%) had progression, caused by total occlusion in 10, increased stenosis in 10, and new stenosis in 3, 15 patients had regression, and 113 patients had no change. Diabetes (odds ratio: 6.771, p value: 0.0004) and current smoking (odds ratio: 7.574, p value: 0.0019) were determined as significant risk factors for progression. CONCLUSIONS: Patients with intracranial steno-occlusive lesion and either diabetes or smoking habit should be carefully followed up by serial MR angiography.

Creutzfeldt-Jakob Disease Mimicking Alzheimer Disease and Dementia With Lewy Bodies-Findings of FDG PET With 3-Dimensional Stereotactic Surface Projection.

A 78-year-old man received a diagnosis of sporadic Creutzfeldt-Jakob disease based on symptoms and findings of MRI, FDG PET, and cerebrospinal fluid markers. PET with 3-dimensional stereotactic surface projection (3D-SSP) showed that the distribution of hypometabolism mimicked that of Alzheimer disease. A 68-year-old woman was treated under a diagnosis of convulsion. Findings of MRI, PET, familial history, and cerebrospinal fluid markers revealed familial Creutzfeldt-Jakob disease. FDG PET with 3D-SSP disclosed that the hypometabolic pattern mimicked that of dementia with Lewy bodies. FDG PET with 3D-SSP can demonstrate similar patterns in various neurodegenerative disorders.

Perfusion CT investigation of chronic internal carotid artery occlusion: comparison with SPECT.

This study investigated the usefulness of perfusion computed tomography (CT) for the evaluation of patients with chronic internal carotid artery (ICA) occlusion by comparing the findings with those of iodine-123 iodoamphetamine ([(123)I]IMP) single photon emission computed tomography (SPECT). Twenty five patients with chronic ICA occlusion were investigated on the same day by perfusion CT to measure the cerebral blood flow (CBF), cerebral blood volume (CBV), and mean transient time (MTT), and [(123)I]IMP SPECT to measure the regional CBF, significant correlations were observed between regional CBF measured by SPECT and CBF measured by perfusion CT (r = 0.659, R(2) = 0.434, p < 0.001), regional CBF and CBV (r = -0.406, R(2) = 0.165, p < 0.001) and regional CBF and MTT (r = -0.592, R(2) = 0.350, p < 0.001). Significant correlations were also observed between CBF and CBV (r = -0.153, R(2) = 0.023, p < 0.001), CBF and MTT (r = -0.580, R(2) = 0.337, p < 0.001) and MTT and CBV (r = 0.763, R(2) = 0.582, p < 0.001). Perfusion CT is useful to evaluate the hemodynamic state of patients with chronic major cerebral artery occlusive disorders.

Quantitative measurement of regional cerebral blood flow with flow-sensitive alternating inversion recovery imaging: comparison with [iodine 123]-iodoamphetamin single photon emission CT.

BACKGROUND AND PURPOSE: Flow-sensitive alternating inversion recovery (FAIR) MR imaging is a technique for depicting cerebral perfusion without contrast enhancement. Our purpose was to determine whether quantification at FAIR imaging can be used to assess regional cerebral blood flow (rCBF) in a manner similar to [iodine 123]-iodoamphetamin ((123)I-IMP) single photon emission CT (SPECT). METHODS: Nine patients with internal carotid or major cerebral arterial stenosis underwent (123)I-IMP SPECT and FAIR imaging (single section, different TIs, 1.5 T) at rest and after acetazolamide (Diamox) stress. FAIR and (123)I-IMP rCBF values were compared and correlated. Receiver operating characteristic analysis was conducted to detect hypoperfused segments on FAIR images. RESULTS: rCBF values of normally perfused segments were 41.53 and 51.91 mL/100 g/min for pre- and post-acetazolamide (123)I-IMP studies, respectively. Corresponding values for pre- and post-acetazolamide FAIR images, respectively, were 46.64 and 59.60 mL/100 g/min with a TI of 1200 milliseconds and 53.23 and 68.17 mL/100 g/min with a TI of 1400 milliseconds. (123)I-IMP and FAIR results were significantly correlated, with both pre- and post-acetazolamide images. Sensitivity (86%) in detecting hypoperfused segments was significantly higher with post-acetazolamide images (TI, 1400 milliseconds), and specificity (82-85%) and accuracy (80-82%) were higher with all pre- and post-acetazolamide images (all TIs). CONCLUSIONS: The significant correlation, high specificity and accuracy in detecting hypoperfused segments, similar increases in flow on both post-acetazolamide images, and absence of the need for contrast enhancement suggest that FAIR imaging, like nuclear medicine study, is complementary to routine MR imaging in the assessment of cerebral perfusion.

Supernumerary phantom limbs associated with left hemispheric stroke: case report and review of the literature.

OBJECTIVE AND IMPORTANCE: Supernumerary phantom limb (SPL) is extremely rare. Literature reports noted 17 cases that occurred after right cerebral hemispheric stroke and 2 cases that occurred after left cerebral hemispheric stroke, but without imaging diagnoses. CLINICAL PRESENTATION: A 45-year-old male patient complained of SPLs on the right side after recurrent left thalamic hemorrhage. Computed tomography and magnetic resonance imaging demonstrated the lesion causing the left hemispheric stroke. INTERVENTION: The patient was treated conservatively. Computed tomographic scans demonstrated that the lesion had disappeared by 15 days after admission. The sensation of SPLs disappeared after 28 days. CONCLUSION: SPL may occur among patients with left hemispheric stroke, especially those with lesions in the thalamus, spastic paresis on the right side immediately after stroke, and psychiatric disorders such as alcohol and tobacco intoxication.

Surgical management of aneurysms of the bifurcation of the internal carotid artery.

Internal carotid artery (ICA) bifurcation aneurysms are rare and easily bleed in younger patients, but are difficult to treat surgically, due to perforators surrounding and adherent to the aneurysm. A series of 25 patients treated by clipping under the operating microscope are analyzed and compared with previous cases. Twenty-five patients, 11 men and 14 women (mean age 51 years), were treated by the same neurosurgeon. Seventeen patients presented with subarachnoid hemorrhage (Hunt & Kosnik Grade I in three, II in five, III in two, IV in seven), five with unruptured ICA bifurcation aneurysms, and three with unruptured ICA bifurcation aneurysms but another ruptured aneurysm. There were 23 small, one large, and one giant ICA bifurcation aneurysms. The projection was superior in 12, anterior in seven, and posterior in six cases. Pterional approach was employed for all cases. Outcomes were evaluated at discharge with the Glasgow Outcome Scale. Favorable outcomes (good recovery (GR) and moderate disability (MD)) were obtained in ten of 17 patients with ruptured ICA bifurcation aneurysm. Favorable outcomes were significantly greater in Grades I and II (three in I, four in II) than in Grades III and IV (one in III, two in IV; P=0.0498). Seven of eight patients with unruptured ICA bifurcation aneurysm had favorable outcomes. Temporary clipping and projection of the aneurysm did not affect the outcome. Causative factors of unfavorable outcomes were primary brain damage in cases of small and large aneurysms and perforator damage in the case of giant aneurysm. Poor clinical grade and vasospasm are the causative factors of poor outcome in patients with ruptured ICA bifurcation aneurysm. Preservation of perforators is crucial in cases of giant aneurysm. Clipping of unruptured ICA bifurcation aneurysms is recommended since they tend to bleed at a lower age than other aneurysms.

Velocity-coded colour magnetic resonance angiography and perfusion-weighted magnetic resonance imaging for the evaluation of extracranial-to-intracranial arterial bypass surgery.

BACKGROUND AND PURPOSE: Velocity-coded colour magnetic resonance angiography (VCCMRA) and perfusion magnetic resonance imaging (pMRI) were evaluated as methods for investigating the efficacy of extracranial-to-intracranial arterial bypass (EC-IC bypass) by comparing the findings of VCCMRA and those of cerebral angiography and by measuring the improvement ratio after EC-IC bypass by pMRI compared to that by single photon emission computed tomography (SPECT) using the autoradiographic technique. METHODS: Thirteen patients who underwent VCCMRA, angiography, SPECT, and pMRI before and after surgery were analyzed. Findings of VCCMRA were compared to those of angiography. Improvement ratio was calculated compared to the cerebellum for cerebral blood volume, mean transit time (MTT), and regional cerebral blood flow (rCBF) as measured by pMRI and quantitative SPECT. RESULTS: Findings of VCCMRA were in good agreement with those of angiography and clearly showed the direction of bypass flow. No statistically significant correlation was observed between the improvement ratios in CBF in the hemisphere and middle cerebral artery territory on the surgical and non-surgical sides and in rCBF in the same regions of interest (ROIs) (r=-0.574, 0.09). However, a statistically significant correlation was observed between the cerebrovascular reserve capacity (CVRC) in the hemisphere on the surgical side and in MTT in the same ROIs (r=0.955, P<0.001). CONCLUSION: VCCMRA may clearly show the direction of flow in the EC-IC bypass. MIT measured by pMRI may indicate the postoperative state of CVRC. These techniques could replace angiography and positron emission tomography or SPECT in patients undergoing EC-IC bypass.

[Clinical and radiological study of ossification of the anterior longitudinal ligament in the cervical spine].

Twenty-seven patients with ossification of the anterior longitudinal ligament (OALL) in diffuse idiopathic skeletal hyperostosis (DISH) in the cervical region were diagnosed among 2000 individuals during 10 months and analyzed clinically and radiologically by two neurosurgeons. Sex distribution was 20 men and 7 women with ages ranging from 57 to 82 years (average: 72.3 y.o.). Main signs and symptoms were dysesthesia of the upper extremities, stiff neck, dizziness and dysphagia (33%). Three patients had diabetes mellitus, 14 had hypertension, and 15 had hyperuremia. Ossification of the posterior longitudinal ligament (OPLL) co-existed in 18 patients (66%). Number of vertebral bodies with cervical OALL ranged from 4 to 6 (average: 4.8) and thickness of ossification of the anterior longitudinal ligament was from 2 to 6 (average: 3.1) mm. Originally we divided OALL in the cervical region into 3 types, nodular-type; 16 cases, continuous-type; 7 cases, and mixed-type; 4 cases. Small OPLL can be diagnosed by either cervical CT or myelo-CT. DISH is thought to be a benign clinical entity, but patients with OALL in DISH, accompanied by OPLL and those accompanied by dysphasia are frequently encountered and sometimes may be treated surgically.

[A case of multiple mycotic intracranial aneurysms].

A patient with multiple mycotic aneurysms associated with infective endocarditis is reported. A 45-year-old man was admitted on February 16, 2001 under the diagnosis of infective endocarditis. After alpha-streptococcus was identified by a blood culture, he was treated with high doses of antibiotics. However, 2 weeks after admission, he suddenly suffered from headache and mild left hemiparesis. A CT showed a parenchymal hematoma in the right parietal lobe. Cerebral angiography demonstrated aneurysms of the bilateral middle cerebral artery and the left posterior cerebral artery. At first, we trapped and resected the ruptured right middle cerebral aneurysm. After the surgery, we tried to treat two unruptured aneurysms by endovascular treatment. During the provocation test for the posterior cerebral artery, the arterial wall was perforated by a guide wire. The parent artery was occluded by coils at this site. Although the aneurysm was still filled by retrograde blood flow, it finally disappeared six months after treatment. The left middle cerebral artery aneurysm could not be treated because the provocation test showed cognitive deficits. The patient recovered from infective endocarditis after four-months of antibiotic therapy; and the unruptured aneurysm had not changed in size for 11 months. Recently, the outcome of patients with intracranial mycotic aneurysm is improved by development of multimodality management. Especially, endovascular therapy may become an effective treatment for unruptured aneurysms, but it is necessary to take risks, such as arterial perforation into consideration.

Hypermetabolism in patients with dementia with Lewy bodies.

PURPOSE: Detection of hyperperfusion by I-123 N-isopropyl-p-iodoamphetamine single photon emission computed tomography can be helpful to diagnose dementia with Lewy bodies (DLB). This study characterized hypermetabolism in DLB. MATERIALS AND METHODS: A total of 22 probable cases of DLB were examined by F-18 2-fluoro-2-deoxy-D-glucose positron emission tomography. RESULTS: Hypermetabolism was found in the peri-motor area, basal ganglia, and cerebellum. Eleven patients had hypermetabolism in all 3 areas, 6 in 2 areas, 4 in 1 area, and 1 in no area. Hypermetabolism was most frequent in the cerebellum. Comparison of the 11 patients with hypermetabolism in all 3 areas to the other 11 cases found no significant differences in age (P = 0.2555), sex (P = 0.1889), Mini-Mental State Examination score (P = 0.0897), and Parkinsonism. However, visual hallucinations were significantly more frequent in the patients with hypermetabolism in all 3 areas (P = 0.0018). CONCLUSIONS: Hypermetabolism is common in patients with DLB and may be related to visual hallucinations.

Diffuse idiopathic skeletal hyperostosis associated with risk factors for stroke: a case-control study.

STUDY DESIGN: The incidence of risk factors for cerebrovascular diseases was investigated in patients with diffuse idiopathic skeletal hyperostosis (DISH) and patients with cervical spondylosis. OBJECTIVES: To investigate the association between DISH and cerebrovascular disease. SUMMARY OF BACKGROUND DATA: DISH is a common skeletal disease mainly affecting the anterior and lateral spinal longitudinal ligaments. The principal clinical features are nonradicular pain, stiffness, dysphagia (cervical portion), and associated ossification of the posterior longitudinal ligament. METHODS: Age- and sex-matched patients were divided into three groups: 45 patients with DISH, 45 patients with cervical spondylosis Grade I and II, and 45 patients with cervical spondylosis Grade III and IV. Anthropometric, laboratory, and magnetic resonance (MR) imaging findings were analyzed. RESULTS: The values of uric acid (P = 1.60 x 10) and alkaline phosphatase (P = 2.00 x 10) were significantly greater in patients with DISH than in the other groups. Patients with DISH had a significantly higher incidence of ossification of the posterior longitudinal ligament (P = 5.21 x 10). Stiffness was significantly more common in patients with DISH and patients with spondylosis Grade III and IV than in patients with spondylosis Grade I and II (P = 0.000232). The incidence of infarction on MR imaging was significantly higher in patients with DISH than in the other groups (P = 0.0120). The incidence of stenosis or occlusion of a major cerebral artery on MR angiography was significantly higher in patients with DISH than in the other groups (P = 0.00264). CONCLUSIONS: DISH is associated with increased incidences of risk factors for stroke and cerebrovascular disease.

Risk factors for growth of unruptured intracranial aneurysms: follow-up study by serial 0.5-T magnetic resonance angiography.

OBJECTIVE: The independent risk factors for aneurysm growth were retrospectively investigated in 130 patients with unruptured aneurysms who were followed up by 0.5-T serial magnetic resonance angiography with stereoscopic images. METHODS: Age, sex, site of aneurysm, size of aneurysm, multiplicity of aneurysms, type of circle of Willis, length of follow-up period, cerebrovascular event, hypertension, diabetes, hyperlipidemia, smoking habit, and family history of subarachnoid hemorrhage were investigated using multiple logistic analysis. RESULTS: Fourteen patients (16 aneurysms) among the 130 patients (159 aneurysms) showed aneurysm growth (10.8%) during follow-up of 10 to 69 months (mean 29.3 +/- 10.5 mo). Multiple logistic analysis disclosed that location on the middle cerebral artery (odds ratio [OR] 0.08, P < 0.01), multiplicity of aneurysms (OR 68.5, P < 0.01), aneurysm size of 5 mm or larger (OR 1.17, P = 0.05), and family history of subarachnoid hemorrhage (OR 10.9, P < 0.01) were independent risk factors. CONCLUSION: Location on the middle cerebral artery, multiplicity, aneurysm size of 5 mm or larger, and family history of subarachnoid hemorrhage are independent risk factors for aneurysm growth. These results may help to determine the treatment choice for unruptured aneurysms.

COL6A1, the candidate gene for ossification of the posterior longitudinal ligament, is associated with diffuse idiopathic skeletal hyperostosis in Japanese.

STUDY DESIGN: Genetic screening of collagen 6A1 gene (COL6A1) in patients with diffuse idiopathic skeletal hyperostosis (DISH) recruited in Japan and the Czech Republic. OBJECTIVE: To investigate allelic associations between DISH and nucleotide variants of COL6A1. SUMMARY OF BACKGROUND DATA: DISH is a skeletal hyperostotic disease characterized by ligamentous ossification of the anterolateral side of the spine. Ossification of the posterior longitudinal ligament (OPLL) is a related disorder with DISH, and COL6A1 was identified as a susceptibility gene to OPLL. COL6A1 was examined for susceptibility in DISH patients from Japan and the Czech Republic. METHODS: Seven single nucleotide polymorphisms of COL6A1 were genotyped by direct sequencing. The allele frequencies were compared between 97 Japanese DISH patients and 298 Japanese controls, and between 96 Czech DISH patients and 96 Czech controls by chi2 test. RESULTS: The intron 32 (-29) single nucleotide polymorphisms of COL6A1 was significantly associated with the Japanese DISH patients (chi2 = 9.33; P = 0.0022), but not with the Czech DISH patients. CONCLUSIONS: Because COL6A1 could be a susceptibility to the occurrence of DISH and OPLL in the Japanese population, we consider that COL6A1 could be responsible for the hyperostotic state, leading to ectopic bone formation in the spinal ligament.

Optimal inversion time for acquiring flow-sensitive alternating inversion recovery images to quantify regional cerebral blood flow.

The purpose of this study was to correlate regional cerebral blood flow (rCBF) measured by I-123-IMP and flow-sensitive alternating inversion recovery (FAIR) studies with different inversion time (TI) values to find out the optimum TI that gives comparable rCBF and images on FAIR study. Nine patients with symptoms and signs of internal carotid or major cerebral arterial stenosis were enrolled in this study. Both I-123-IMP single photon emission computed tomography (SPECT) and FAIR images were acquired in all patients. Single-slice FAIR images (with different TI values) were acquired using a 1.5-T MRI unit. The rCBF was calculated from all I-123-IMP and FAIR images. Receiver operating characteristics (ROC) analysis was performed to detect hypoperfused segments on FAIR images. The rCBF calculated from FAIR and I-123-IMP studies were compared and correlated with each other. The ROC analysis showed no significant differences among the readers or TI values, but a trend of higher sensitivity, specificity, and accuracy was observed with TI of 1400 ms. The rCBF values of FAIR and I-123-IMP studies significantly correlated with each other. The FAIR images with TI value of 1400 ms gave more comparable CBF. A TI value of 1400 ms might be optimum for 1.5-T MR strength to get high quality FAIR images and comparable CBF.