Metabolic changes in the plasma of mild Alzheimer's disease patients treated with Hachimijiogan.

Background: Alzheimer's disease (AD), the most prevalent form of dementia, is a debilitating, progressive neurodegeneration. Amino acids play a wide variety of physiological and pathophysiological roles in the nervous system, and their levels and disorders related to their synthesis have been related to cognitive impairment, the core feature of AD. Our previous multicenter trial showed that hachimijiogan (HJG), a traditional Japanese herbal medicine (Kampo), has an adjuvant effect for Acetylcholine estelase inhibitors (AChEIs) and that it delays the deterioration of the cognitive dysfunction of female patients with mild AD. However, there are aspects of the molecular mechanism(s) by which HJG improves cognitive dysfunction that remain unclear. Objectives: To elucidate through metabolomic analysis the mechanism(s) of HJG for mild AD based on changes in plasma metabolites. Methods: Sixty-seven patients with mild AD were randomly assigned to either an HJG group taking HJG extract 7.5 g/day in addition to AChEI or to a control group treated only with AChEI (HJG:33, Control:34). Blood samples were collected before, 3 months, and 6 months after the first drug administration. Comprehensive metabolomic analyses of plasma samples were done by optimized LC-MS/MS and GC-MS/MS methods. The web-based software MetaboAnalyst 5.0 was used for partial least square-discriminant analysis (PLS-DA) to visualize and compare the dynamics of changes in the concentrations of the identified metabolites. Results: The VIP (Variable Importance in Projection) score of the PLS-DA analysis of female participants revealed a significantly higher increase in plasma metabolite levels after HJG administration for 6 months than was seen in the control group. In univariate analysis, the aspartic acid level of female participants showed a significantly higher increase from baseline after HJG administration for 6 months when compared with the control group. Conclusion: Aspartic acid was a major contributor to the difference between the female HJG and control group participants of this study. Several metabolites were shown to be related to the mechanism of HJG effectiveness for mild AD.

Cerebral white matter lesions and regional blood flow are associated with reduced cognitive function in early-stage cognitive impairment.

Background: Differences in the extent of cerebral white matter lesions (WML) and regional cerebral blood flow (rCBF) in early-stage cognitive impairment (ESCI) contribute to the prognosis of cognitive decline; however, it is unclear precisely how WML and rCBF affect cognitive decline in ESCI. Objective: We examined the association between WML, rCBF, and cognitive impairment in the ESCI, using path analysis to clarify how these variables affect each other. Methods: Eighty-three patients who consulted our memory clinic regarding memory loss were included in this study based on the Clinical Dementia Rating. Participants underwent the Mini-Mental State Examination (MMSE), brain magnetic resonance imaging (MRI) for voxel-based morphometry analysis, and brain perfusion single-photon emission computed tomography (SPECT) for rCBF evaluation in cortical regions, using 3D stereotactic surface projection (3D-SSP) analysis. Results: Path analysis was performed on the MRI voxel-based morphometry and SPECT 3D-SSP data, showing a significant correlation between both and MMSE scores. In the most suitable model (GFI = 0.957), correlations were observed between lateral ventricular (LV-V) and periventricular WML (PvWML-V) volumes [standardized coefficient (SC) = 0.326, p = 0.005], LV-V and rCBF of the anterior cingulate gyrus (ACG-rCBF; SC = 0.395, p < 0.0001), and ACG-rCBF and PvWML-V (SC = 0.231, p = 0.041). Furthermore, a direct relationship between PvWML-V and MMSE scores was identified (SC = -0.238, p = 0.026). Conclusion: Significant interrelationships were observed among the LV-V, PvWML-V, and ACG-rCBF that directly affected the MMSE score in the ESCI. The mechanisms behind these interactions and the impact of PvWML-V on cognitive function require further investigation.

An exploratory, open-label, randomized, multicenter trial of hachimijiogan for mild Alzheimer's disease.

Background: Alzheimer's disease (AD) is a progressive neurodegeneration and is the most prevalent form of dementia. Intervention at an early stage is imperative. Although three acetylcholinesterase inhibitors (AChEIs) are currently approved for the treatment of mild AD, they are not sufficiently effective. Novel treatments for mild AD are of utmost importance. Objective: To assess the effectiveness of hachimijiogan (HJG), a traditional Japanese herbal medicine (Kampo), in the treatment of mild AD. Methods: This exploratory, open-label, randomized, multicenter trial enrolled patients with mild AD whose score on the Mini Mental State Examination (MMSE) was over 21points. All participants had been taking the same dosage of AChEI for more than 3 months. The participants were randomly assigned to an HJG group taking HJG extract 7.5 g/day in addition to AChEI or to a control group treated only with AChEI. The primary outcome was the change from baseline to 6 months post treatment initiation on the Alzheimer's Disease Assessment Scale-cognitive component- Japanese version(ADAS-Jcog). The secondary outcomes were change from baseline of the Instrumental Activity of Daily Life (IADL), Apathy scale, and Neuropsychiatric Inventory (NPI) -Q score. Results: Among the 77 enrollees, the data of 69(34 HJG and 35 control)were available for analysis. The difference in the change of ADAS-Jcog from baseline to 6 months of the HJG and control groups was 1.29 (90% Confidence interval (CI), -0.74 to 3.32 p = 0.293). In the subgroup analysis, the differences in the change from baseline to 3 and 6 months for women were 3.70 (90% CI ,0.50 to 6.91, p = 0.059) and 2.90 (90% CI,0.09 to 5.71, p = 0.090), respectively. For patients over 65 years, the difference at 3 months was 2.35 (90%CI, 0.01 to 4.68 p = 0.099). No significant differences were found between the HJG and control groups in IADL score, Apathy scale, or NPI-Q score. Conclusion: Although not conclusive, our data indicate that HJG has an adjuvant effect for acetylcholinesterase inhibitors and that it delays the deterioration of the cognitive dysfunction of mild Altzheimer's disease patients. Clinical Trial Registration: http://clinicaltrials.gov Japan Registry of clinical trials, identifier jRCTs 071190018.

White Matter Lesions May Aid in Differentiating Idiopathic Normal Pressure Hydrocephalus and Alzheimer's Disease.

BACKGROUND: Idiopathic normal pressure hydrocephalus (iNPH) is often misdiagnosed as Alzheimer's disease (AD) due to overlapping pathophysiology and similar imaging characteristics, including ventricular enlargement and increased white matter lesions (WMLs). OBJECTIVE: To compare the extent and distribution of WMLs directly between iNPH and AD and examine the association with underlying pathophysiology. METHODS: Twelve patients with iNPH (mean age: 78.08 years; 5 females), 20 with AD (mean age: 75.40 years; 13 females), and 10 normal cognition (NC) participants (mean age: 76.60 years; 7 females) were recruited. The extent and distribution of WMLs and the lateral ventricular volume (LV-V) were evaluated on MRI using voxel-based morphometry analysis. Concentrations of cerebrospinal fluid biomarkers, such as amyloid-ß protein (Aß)42, Aß40, Aß38, and tau species, were also measured. Risk factors for small vessel disease (SVD) were assessed by blood examination and medical records. RESULTS: The periventricular WML volume (PWML-V) and deep WML volume (DWML-V) were significantly larger in iNPH than in AD and NC. The DWML-V was dominant in iNPH, while the PWML-V was dominant in AD and NC. GM-V was significantly smaller in AD than in iNPH and NC. The LV-V positively correlated with WML-V in all participants. There was a significant negative correlation between LV-V and Aß38 in iNPH. Furthermore, there was no significant difference in SVD risk factors between the groups. CONCLUSION: The differences in the extent and distribution of WMLs between iNPH and AD, especially predominance of DWML-V over PWML-V in iNPH, may reflect decreased fluid and Aß clearance.

Serum BDNF as a Potential Biomarker of Alzheimer's Disease: Verification Through Assessment of Serum, Cerebrospinal Fluid, and Medial Temporal Lobe Atrophy.

There is an urgent need to establish blood biomarkers for Alzheimer's disease (AD). Although it has been speculated that brain-derived neurotrophic factor (BDNF) is associated with AD, whether it can be used as a blood biomarker has yet to be determined. We used serum, cerebrospinal fluid (CSF), and medial temporal lobe atrophy from patients with AD to evaluate the association of BDNF with AD and assess its severity. For the blood analysis, 66 participants [21 normal controls (NCs) with normal cognitive function, 22 patients with mild cognitive impairment (MCI) due to AD, and 23 patients with AD] were included. For the CSF analysis, 30 participants were included. Magnetic resonance imaging, including a voxel-based specific regional analysis system for AD, and a Mini Mental State Examination were performed. Serum levels of BDNF and CSF levels of amyloid-ß42, total tau, and phosphorylated tau were measured using ELISA. Serum BDNF levels were significantly lower in the MCI due to AD group than in the NC group (p = 0.037). Although there was no significant difference in the AD group, there was a downward trend compared to the NC group. Serum BDNF levels were positively correlated with CSF Aß42 levels (r = 0.49, p = 0.005). There was a significant correlation between serum BDNF levels and medial temporal lobe atrophy. Decreased serum BDNF can potentially be used as a biomarker for early AD detection. Early detection of AD with a less invasive blood test is very beneficial, as it allows for intervention before dementia progresses.

Sex Differences in the Relationship of Serum Vitamin B1 and B12 to Dementia Among Memory Clinic Outpatients in Japan.

Dementia and cognitive impairment are considered to be one of the biggest social and medical problems. While there is a definite relationship between vitamin B and cognitive decline, this has yet to be fully assessed with regard to sex differences. Thus, the present study investigated the relationship of vitamin B1 or vitamin B12 with dementia in accordance with the sex in 188 patients who visited the Memory Clinic at Showa University Hospital in Japan from March 2016 to March 2019. Cognitive function was tested by the Japanese version of the Mini-Mental State Examination (MMSE) and Hasegawa Dementia Scale-Revised (HDS-R). Blood tests were performed to measure the vitamin levels. Logistic regression analysis was used to calculate the odds ratio (OR) for dementia and the 95% confidence interval (CI). Compared to the highest vitamin group (third tertile), the lowest vitamin group (first tertile) exhibited a significantly increased OR for dementia defined by MMSE for vitamin B1 (OR:3.73, 95% CI:1.52-9.16) and vitamin B12 (2.97, 1.22-7.28) among women. In contrast, vitamin levels were not significantly associated with dementia determined by MMSE in men. These findings were similar even when dementia was defined by HDS-R. The present study suggests that vitamin B1 plays a role in preventing development of dementia in women. Future longitudinal studies will need to be undertaken in order to examine whether decreasing vitamin levels occur before or after cognitive impairment, and whether maintaining a higher vitamin level can prevent a worsening of cognitive function and the development of dementia.

Early diagnosis of prodromal dementia with Lewy bodies using clinical history of probable REM sleep behaviour disorder and cardiac 123 I-MIBG scintigraphy in memory clinics.

BACKGROUND: Rapid eye movement sleep behaviour disorder (RBD) is associated with reduced cardiac 123 I-metaiodobenzylguanidine (MIBG) uptake and often precedes the onset of Lewy body (LB) disorders. We investigated the role of cardiac 123 I-MIBG scintigraphy in relation to probable RBD for the clinical diagnosis of prodromal dementia with Lewy bodies (DLB) in memory clinics. METHODS: We reviewed clinical profiles of 60 consecutive patients who underwent cardiac 123 I-MIBG scintigraphy in our memory clinics. The diagnostic threshold of 2.20 was used as the cut-off for the heart-to-mediastinum ratio at the delayed phase. RESULTS: Cardiac 123 I-MIBG abnormality was identified in 28 patients at baseline; six were cognitively unimpaired, six had mild cognitive impairment (MCI)-LB, and 16 had probable DLB based on the National Institute on Aging and Alzheimer's Association Research Framework. Although the number of core features increased in accordance with the progression of three cognitive categories, there were no differences in the prevalence of probable RBD and the cardiac MIBG scintigraphy indices among them. During the observation period, two cognitively unimpaired patients with probable RBD progressed to MCI-LB, and three MCI-LB patients with probable RBD developed DLB. The prevalence of final diagnosis of probable MCI-LB or DLB was significantly higher in these patients (85%) than the remaining 32 patients without (9%). Of 25 patients with probable RBD, 22 (88%) had a cardiac 123 I-MIBG abnormality regardless of cognitive conditions. Only one patient consulted a sleep centre for the abnormal sleep behaviour before visiting our memory clinics. Regarding the gender differences, male predominance was not identified and sleep-related injury more frequently occurred in men (7/12, 58%) than in women (1/10, 10%). CONCLUSIONS: Proactive detection of probable RBD plus cardiac 123 I-MIBG abnormality provides the opportunity for an early diagnosis of prodromal DLB in memory clinics. This approach warrants further follow-up studies with polysomnographic and pathological verification.

Toxic Amyloid-ß42 Conformer May Accelerate the Onset of Alzheimer's Disease in the Preclinical Stage.

BACKGROUND: Toxic amyloid-ß protein (Aß) conformers play an important role in the progression of Alzheimer's disease (AD). The ratio of toxic conformer to total Aß42 in cerebrospinal fluid (CSF) was significantly high in AD and mild cognitive impairment (MCI) due to AD using an enzyme-linked immunosorbent assay kit with a 24B3 antibody. OBJECTIVE: We compared the toxic Aß42, conformer at different stages of AD to identify its contribution to AD pathogenesis. METHODS: We compared 5 patients with preclinical AD, 11 patients with MCI due to AD, 21 patients with AD, and 5 healthy controls to measure CSF levels of total Aß42, total tau, tau phosphorylated at threonine 181 (p-tau), and toxic Aß conformers. All were classified using the Clinical Dementia Rating. Cognitive function was assessed using the Japanese version of the Mini-Mental State Examination (MMSE-J). RESULTS: Toxic Aß conformer level was insignificant between groups, but its ratio to Aß42 was significantly higher in AD than in preclinical AD (p < 0.05). Toxic Aß42 conformer correlated positively with p-tau (r = 0.67, p < 0.01) and p-tau correlated negatively with MMSE-J (r = -0.38, p < 0.05). CONCLUSION: Toxic Aß conformer triggers tau accumulation leading to neuronal impairment in AD pathogenesis.

Cingulate Island Sign in Single Photon Emission Computed Tomography: Clinical Biomarker Correlations in Lewy Body Disease and Alzheimer's Disease.

We compared 'CIScore' determined by quantitative single photon emission computed tomography studies of the cingulate island sign to cerebrospinal fluid (CSF) biomarkers in Lewy body disease (LBD) and Alzheimer's disease (AD) to assess its usefulness and pathological background. Among the 16 each age-matched LBD and AD patients, the CIScore differed significantly but was not correlated with CSF biomarkers. In LBD, hippocampal atrophy significantly correlated with Clinical Dementia Rating and CSF p-tau and t-tau levels. Our results showed CIS was not related to CSF biomarkers in LBD and high CSF tau levels were related to clinical disease severity and hippocampal atrophy.

Eosinophilic meningitis caused by primary angiitis of the central nervous system.

Eosinophilic meningitis is defined as the presence of 10 eosinophils/mm(3) in the cerebrospinal fluid (CSF) or eosinophils accounting for more than 10% of CSF leukocytes. A 76-year-old man who developed cognitive dysfunction and consciousness disturbance had eosinophilic meningitis (his CSF contained 19.0% eosinophils). Because the etiology was unknown, we performed a brain biopsy. The pathological findings showed inflammatory infiltration in the small-sized arteries of the meninges. The patient was ultimately diagnosed as having primary angiitis of the central nervous system (PACNS). Eosinophilic meningitis occurring in a patient with PACNS is extremely rare, and this is the first report of this condition in Japan.

Picture agnosia as a characteristic of posterior cortical atrophy.

BACKGROUND: Posterior cortical atrophy (PCA) is a degenerative disease characterized by progressive visual agnosia with posterior cerebral atrophy. We examine the role of the picture naming test and make a number of suggestions with regard to diagnosing PCA as atypical dementia. METHODS: We investigated 3 cases of early-stage PCA with 7 control cases of Alzheimer disease (AD). The patients and controls underwent a naming test with real objects and colored photographs of familiar objects. We then compared rates of correct answers. RESULTS: Patients with early-stage PCA showed significant inability to recognize photographs compared to real objects (F = 196.284, p = 0.0000) as measured by analysis of variants. This difficulty was also significant to AD controls (F = 58.717, p = 0.0000). CONCLUSION: Picture agnosia is a characteristic symptom of early-stage PCA, and the picture naming test is useful for the diagnosis of PCA as atypical dementia at an early stage.

Cerebral microbleeds and dilative remodeling of the basilar artery: a magnetic resonance imaging study.

This study was conducted to examine the relationship between cerebral microbleeds (CMBs), one of the manifestations of small-vessel diseases (SVDs), and basilar artery (BA) dilatation on magnetic resonance imaging (MRI). Clinical information and MRI images were reviewed for 149 outpatients aged 46-90 years, excluding those who had a previous symptomatic cerebrovascular event. CMBs were evaluated on T2∗-weighted MRI, and BA diameters were measured as the maximal width of the flow void on axial T2-weighted MRI to assess dilatation. Patients were divided into 2 groups, with CMBs and without CMBs, and clinical information and BA diameters were compared between the groups. Regression analyses of the data also were performed. The 2 groups had significant differences in mean blood pressure (MBP), low-density lipoprotein (LDL) and uricemic acid levels, and BA diameter. Adjusted logistic regression analysis showed that MBP (odds ratio [OR], 1.059 per 1 mm Hg; 95% confidence interval [CI], 1.019-1.101; P = .0035), LDL (OR, 0.976 per 1 mg/dL; 95% CI, 0.960-0.994; P = .0072), and BA diameter (OR, 3.266 per 1 mm; 95% CI, 1.504-7.103; P = .0028) each had an independent association with the presence of CMB. Adjusted multiple regression analysis showed that only BA diameter (ß coefficient, 0.240; 95% CI, 0.775-3.734; P = .0031) was independently associated with the number of CMBs. Our data indicate that CMB, a manifestation of SVD, shows a strong association with BA dilatation.

Kana versus kanji in amyotrophic lateral sclerosis: a clinicoradiological study of writing errors.

The frequency of writing errors in samples from 14 patients with amyotrophic lateral sclerosis without manifest aphasia were compared with clinical background and indices from X-ray computed tomography, including the Evans' index (EI) and the cella media index (CMI). The inferior horn index (IHI) was measured as the maximal width of the short axis of the bilateral inferior horn of the lateral ventricles/the maximum transverse distance between the two internal laminae. Overt dementia and disinhibitive behavioral changes were significantly associated with frequency of total errors (p = 0.0280) and kanji errors (p = 0.0025). Significant associations were found for the EI with kana errors (p = 0.0481) and for the IHI with kanji errors (p = 0.0052). Preferential involvement of kana and kanji may reflect involvement of language-related areas in the frontotemporal lobes with frontal lobe or temporal lobe predominance.

[Germinoma presenting with personality and socio-behavioral abnormalities may challenge differential diagnoses].

We described the major diagnostic difficulties encountered in the case of a 25-year-old man with the pathological diagnosis of a germinoma. The patient initially developed an eating disorder at the end of 2003 and a character change ensued since the beginning of 2004. On admission in August 2004, his cardinal symptoms and signs included marked apathy, depersonalization, generalized muscle wasting, and decreased tendon reflexes. Brain T2-weighted (T2-WI) MR and FLAIR images showed high signal intensities in the suprasellar region and at the genu of the corpus callosum that extended along the sub-pia mater of the right anterior horn. These lesions showed mild enhancement on gadolinium-enhanced T1-WI. CSF examination revealed a mildly elevated level of protein and increased cell counts but did not show any malignant cells on repeated spinal tap. The patient's status remained practically unchanged till December 2004 when he developed diabetes insipidus. Soon afterward, the patient collapsed into akinetic mutism and developed corresponding new lesions at the tegmentum of the midbrain. These new lesions disappeared spontaneously and akinetic mutism regressed without any specific therapy. We tentatively diagnosed of neurosarcoidosis based on a characteristic progressive-regressive clinical course, CSF data, and radiological findings. Clinical symptoms and the enhanced masses on MRI were highly responsive to steroid therapy after which the patient was able to return home. However, disturbances in consciousness and tenacious vomiting recurred in September. Brain MRI revealed a markedly re-enlarged and easily enhanced mass at the right anterior horn, which extended into the cerebral aqueduct and resulted in obstructive hydrocephalus. On surgery, histopathological investigation revealed germinoma. This case highlights the need for careful discrimination between a slow growing germinoma and chronic granulomatous diseases of the brain such as neurosarcoidosis. Early histological investigation may be warranted in patients who present difficulties during differential diagnoses.