A case report of platypnea-orthodeoxia syndrome: A rare condition found during diagnostic workup of a patient with embolic stroke of undetermined sources.

Platypnea-orthodeoxia syndrome (POS) is a rare condition wherein the magnitude of the interatrial shunt changes between the sitting and supine positions. We diagnosed POS in a case initially considered to be of embolic stroke of undetermined source and performed emergency foramen ovale closure as definitive management for the patient. In this case, additional risk factors for POS include spinal deformity, meandering of the aorta, and exclusion of the right atrium due to overextension. Transcranial color flow imaging is recommended for the diagnosis of POS because of its sensitivity, specificity, and non-invasiveness. Although POS is an important barrier to effective rehabilitation, early diagnosis and definitive management lead to dramatic clinical improvement.

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.

Stopwatch training improves cognitive functions in patients with Parkinson's disease.

Parkinson's disease (PD) impairs various cognitive functions, including time perception. Dysfunctional time perception in PD is poorly understood, and no study has investigated the rehabilitation of time perception in patients with PD. We aimed to induce the recovery of time perception in PD patients and investigated the potential relationship between recovery and cognitive functions/domains other than time perception. Sixty patients with PD (27 females) and 20 healthy controls (10 females) were recruited. The participants underwent a feedback training protocol for 4 weeks to improve the accuracy of subjective spatial distance or time duration using a ruler or stopwatch, respectively. They participated in three tests at weekly intervals, each comprising 10 types of cognitive tasks and assessments. After duration feedback training for 1 month, performance on the Go/No-go task, Stroop task, and impulsivity assessment improved in patients with PD, while no effect was observed after distance feedback training. Additionally, the effect of training on duration production correlated with extended reaction time and improved accuracy in the Go/No-go and Stroop tasks. These findings suggest that time perception is functionally linked to inhibitory systems. If the feedback training protocol can modulate and maintain time perception, it may improve various cognitive/psychiatric functions in patients with PD. It may also be useful in the treatment of diseases other than PD that cause dysfunctions in temporal processing.

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.

Increased Presence of Cerebral Microbleeds Correlates With Ventricular Enlargement and Increased White Matter Hyperintensities in Alzheimer's Disease.

Objective: To investigate whether the number of cerebral microbleeds (CMB) could be a useful indicator to predict glymphatic system dysfunction in Alzheimer's disease (AD) patients, by comparing the degree of cerebral spinal fluid (CSF) and interstitial fluid (ISF) stasis. Methods: Forty probable AD patients were included, with those exhibiting two or more CMB were included in the multiple CMB group (mCMB, n = 21, mean = 11.1), and none or one CMB included in the non-multiple CMB group (nmCMB, n = 19, mean = 0.84). CMB was defined in axial gradient recalled echo (GRE) T2*-weighted images. Evans index (EI) was calculated to measure lateral ventricle enlargement, Voxel-based Specific Regional Analysis System for Alzheimer's Disease (VSRAD) software was used to determine the extent of gray and white matter atrophy, and Fazekas scale (FS) was used to determine white matter hyperintensities (WMH). Results: EI was significantly larger in mCMB than in nmCMB, while the gray and white matter volume was not different between groups. Thus, the difference in lateral ventricle enlargement between AD with and without multiple CMB reflects a combination of the degree of brain atrophy and the extent of CSF stasis. FS was higher in mCMB than in the nmCMB, suggesting the failure of ISF elimination was more severe in mCMB cases. Conclusion: The difference in lateral ventricle enlargement and WMH between AD with or without multiple CMB may reflect a difference in the degree of CSF/ISF stagnation.

The relationship between thyroid function and cerebral blood flow in mild cognitive impairment and Alzheimer's disease.

The thyroid hormones have been reported to be associated with cognitive decline and Alzheimer's disease. The relationship between thyroid function within the normal range and cerebral blood flow in Alzheimer's disease patients has been shown in a recent study. Mild cognitive impairment is often the first stage of Alzheimer's disease; thus, early diagnosis is important. The present study investigated the relationship between thyroid function and regional cerebral blood flow in patients with mild cognitive impairment and Alzheimer's disease. A total of 122 memory clinic outpatients who underwent thyroid function testing and single photon emission computed tomography were divided into mild cognitive impairment, Alzheimer's disease, and Normal groups. Regional cerebral blood flow was calculated using a three-dimensional stereotactic region of interest template in an automated cerebral perfusion single photon emission computed tomography analysis system. Multiple regression analysis adjusted for age and sex was conducted to examine the relationships between thyroid hormones and regional cerebral blood flow. Thyroid stimulating hormone was significantly associated with regional cerebral blood flow in the bilateral temporal, bilateral pericallosal, and bilateral hippocampal regions in the mild cognitive impairment group. In the Alzheimer's disease group, free triiodothyronine was significantly associated with regional cerebral blood flow in the bilateral parietal, right temporal, and bilateral pericallosal regions. The present study showed the association of thyroid stimulating hormone with regional cerebral blood flow in the mild cognitive impairment group and the association of free triiodothyronine with regional cerebral blood flow in the Alzheimer's disease group. These study findings could contribute to the early diagnosis of mild cognitive impairment at general memory clinics and the prevention of subsequent progression to Alzheimer's disease.

The subjective perception of past, present, and future time in patients with Alzheimer's disease: a qualitative study.

BACKGROUND: The relationship between dementia and time perception impairment is unknown. AIM: This study aims to explore subjective perception of the passage of time in patients with Alzheimer's disease (AD). METHODS: We conducted semi-structured interviews with 11 AD patients. Grounded theory, a qualitative research methodology, was used for data analysis. RESULTS: Based on interview transcripts, five categories were designated: {Live according to a private clock}, {The past comes up}, {Move back and forth between the present and the past}, {Cannot imagine the future}, and {Bid farewell to this world as early as tomorrow}. DISCUSSION: Our results suggest that AD patients alternate past and present without complete awareness and cannot imagine a future other than one ending in death.

Novel clinical features of nonconvulsive status epilepticus.

Nonconvulsive status epilepticus (NCSE) has rapidly expanded from classical features such as staring, repetitive blinking, chewing, swallowing, and automatism to include coma, prolonged apnea, cardiac arrest, dementia, and higher brain dysfunction, which were demonstrated mainly after the 2000s by us and other groups. This review details novel clinical features of NCSE as a manifestation of epilepsy, but one that is underdiagnosed, with the best available evidence. Also, we describe the new concept of epilepsy-related organ dysfunction (Epi-ROD) and a novel electrode and headset which enables prompt electroencephalography.

[Confabulation: From the Aspect of Disturbance in Time Perception].

Confabulation is a false story that amnesic patients make up unintentionally, by recollecting irrelevant memories instead of relevant. Disconnection of a brain network, including the diencephalon, basal forebrain, orbitofrontal, cortex and medial temporal lobe, could be the cause of this neuropsychological symptom. Considering confabulation from the aspect of disturbance in time perception is useful in understanding the mechanism of human time perception and the essence of confabulation.

Autobiographical age awareness disturbance syndrome in autoimmune limbic encephalitis: two case reports.

BACKGROUND: Autobiographical memory is a form of episodic memory characterized by a sense of time and consciousness that enables an individual to subjectively re-experience his or her past. As part of this mental re-enactment, the past is recognized relative to the present. Dysfunction of this memory system may lead to confusion regarding the present perception of time. CASE PRESENTATION: Two Japanese women (42 and 55 years old) temporarily believed they were living in their past during a course of autoimmune limbic encephalitis. Their autobiographical memories and behaviour reflected their self-estimated age, and they could not recall memories experienced beyond that age. More surprisingly, their subjective age estimations and autobiographical memories were transiently corrected when they were made aware of their true age. Disorientation, anterograde amnesia, and retrograde amnesia were common additional symptoms. Neuroimaging suggested disturbances in medial temporal and orbitofrontal brain regions in both cases. CONCLUSIONS: This syndrome is characterized by three elements: 1) failure to subjectively recognize the present; 2) inability to suppress irrelevant past memories; and 3) transient restitution of awareness of the present through realization of the individual's true age. We defined this syndrome as 'autobiographical age awareness disturbance', and focused our investigation on the role of age self-awareness. If recall of relevant and suppression of irrelevant past memories are both necessary to subjectively recognize the present relative to the past, dysfunction of medial temporal and orbitofrontal brain regions is predicted to lead to abnormal subjective placement in time. However, the subjective experience of age tends to be an important informational component for retrieving remote autobiographical memories. This suggests that correct age awareness is essential for the proper recognition of the remote past in relation to the present. This is the first report to focus on the relationship between subjective temporal orientation and age self-awareness. While the role of age awareness in this process is still unclear, investigating autobiographical age awareness disturbance as a part of subjective temporal awareness dysfunction can be useful in understanding the processes underlying human time recognition.

[Association between Elderly Onset Epilepsy and Dementia].

Japan is experiencing an increase in the number of patients with dementia, and the incidence of epilepsy is high among the elderly. A survey of patients with epilepsy who were admitted to our hospital's neurology department showed that new onset epilepsy occurred more frequently in elderly patients. In addition, a greater proportion of elderly patients had dementia as an underlying disease. Although the prevalence of epilepsy in dementia varies, higher brain dysfunctions are known to be related to epilepsy. Because a symptom of epilepsy may be mistaken for dementia, it is important to understand the association between epilepsy and dementia, including their tendencies and characteristics.

[Mental time dysfunction in Parkinson's and Alzheimer's diseases].

Mental time is altered by a number of factors and the underlying neural processing involved is highly complicated. Recent research suggests that mental time in patients with particular neurological diseases is perceptually shorter than in normal individuals. This review introduces mental time dysfunction and a model for processing of mental time in Parkinson's and Alzheimer's disease. Although the two diseases show the same dysfunction of mental time in behavior, we expect the underlying neural mechanism to vary in each disease. It is possible that the dysfunction of mental time in Parkinson's disease is caused by the abnormal striatum acting as a pacemaker, while that in Alzheimer's disease is caused by abnormal hippocampal memory.

[Epilepsy and dementia].

Japan is experiencing an increase in the number of dementia patients, and the incidence of epilepsy is high among the elderly. A survey, from 2007 to 2012, of 279 epilepsy patients admitted to our hospital's neurology department showed that newly-onset epilepsy occurred more frequently in elderly patients. Of 153 elderly patients with epilepsy, aged 65 years and older, 31(20.2%) had dementia as an underlying disease. Although the prevalence of epilepsy in dementia is varied, higher brain dysfunctions are known to occur as a result of epilepsy. Considering such symptoms as epilepsy with higher brain dysfunction (E-HBD) would enable clinical investigation without overlooking higher brain dysfunctions that have effective treatments.

Perceiving "ghost" images: a unique case of visual allesthesia with hemianopsia in mitochondrial disease.

A 49-year-old man with mitochondrial disease presented with visual allesthesia, a rare and puzzling phenomenon. He was admitted for treatment because of convulsions. After the convulsions ceased, he exhibited left homonymous hemianopsia. Brain diffusion-weighted magnetic resonance imaging (MRI) showed a high-intensity area in the right occipital lobe. Both the hemianopsia and the MRI activation in this area disappeared by day 36 of hospitalization. On the morning of day 57, right homonymous hemianopsia emerged in a singular manner. The patient perceived an illusory object (a bottle placed by the bedside) in his left visual field, while the real object was in his blind right field. This case of visual allesthesia was accompanied by palinopsia, ie, perseveration of the image of the bottle. Diffusion-weighted MRI showed a new, high-intensity area in the left occipital lobe. We believe the visual allesthesia resulted from transfer of cortical information obtained by blindsight between hemispheres as a result of epileptic excitation.

[A case of primary erythromelalgia successfully treated with high-dose intravenous immunoglobulin therapy].

Erythromelalgia is a rare condition characterized by constant or paroxysmal burning pain, erythema, and the elevation of skin temperature in the extremities. Recently, the impairment of C-fiber function due to autoimmune system involvement is considered as the primary cause of erythromelalgia. However, a successful treatment has yet not been established. We report a case of a 39-year-old woman with primary erythromelalgia accompanied by high cerebrospinal fluid protein concentration and axonal neuropathy. She received various antiepileptic and anti-inflammatory drugs, but failed to improve. She finally underwent high-dose intravenous immunoglobulin therapy, which dramatically improved her symptoms and normalized cerebrospinal fluid protein concentration. This result demonstrates the effectiveness of high-dose intravenous immunoglobulin therapy for the treatment of primary erythromelalgia and the possibility of autoimmune system involvement.