Hiroi Tomioka

Detection of hypofrontality in drivers with Alzheimer's disease by near-infrared spectroscopy

It is important to appropriately evaluate the driving performance of elderly persons. In the present study, near-infrared spectroscopy (NIRS) was employed to investigate differences of brain function between individuals with Alzheimers disease (n=12) and healthy elderly controls (n=14) while they were being tested using a driving simulator. Changes of the oxyhemoglobin level in the prefrontal areas of each subject were measured by NIRS during a driving task (collision avoidance). Compared with healthy controls, the Alzheimers disease group showed a less prominent increase of oxyhemoglobin in the prefrontal cortex during the collision avoidance task. The correlation between delay in braking and changes of oxyhemoglobin was positive in the healthy controls and negative in the Alzheimers disease group, suggesting that a task-related prefrontal increase of oxyhemoglobin has different implications under normal and pathological conditions. NIRS is a potentially useful tool for real-time monitoring of prefrontal activity during simulated or actual driving.

Transcranial Magnetic Stimulation of the Parietal Cortex Facilitates Spatial Working Memory: Near-Infrared Spectroscopy Study

The present study investigated whether transcranial magnetic stimulation (TMS) to the parietal cortex improves the performance of healthy persons in a spatial working memory (WM) task. The effect of TMS on the frontal cortex was examined by measuring oxygenated hemoglobin (oxy-Hb) with near-infrared spectroscopy. Fifty-two healthy persons received either 100% resting motor threshold TMS at 5 Hz (real TMS) or sham TMS while engaged in a spatial WM task or a control visuospatial attention task. TMS was applied to either the left or the right parietal cortex during the delay period of the task. Reaction times improved in the spatial WM task, but not in the control task, with real TMS, whereas sham TMS had no effect. This improvement was only observed when TMS was applied to the right parietal cortex. Application of real TMS to the right parietal cortex also significantly increased frontal oxy-Hb levels during the WM task, but reduced oxy-Hb during the control task. These results suggest that TMS to the right parietal cortex may selectively facilitate spatial WM. Hemispheric asymmetry and the frontoparietal network theory may explain the observed effect of right parietal TMS on spatial WM.

Serum Anticholinergic Activity: A Possible Peripheral Marker of the Anticholinergic Burden in the Central Nervous System in Alzheimer’s Disease

We review the utility of serum anticholinergic activity (SAA) as a peripheral marker of anticholinergic activity (AA) in the central nervous system (CAA). We hypothesize that the compensatory mechanisms of the cholinergic system do not contribute to SAA if their system is intact and that if central cholinergic system deteriorates alone in conditions such as Alzheimers disease or Lewy body dementia, CAA and SAA are caused by way of hyperactivity of inflammatory system and SAA is a marker of the anticholinergic burden in CNS. Taking into account the diurnal variations in the plasma levels of corticosteroids, which are thought to affect SAA, it should be measured at noon or just afterward.

A Longitudinal Functional Neuroimaging Study in Medication-Naïve Depression after Antidepressant Treatment

Recent studies have indicated the potential clinical use of near infrared spectroscopy (NIRS) as a tool in assisting the diagnosis of major depressive disorder (MDD); however, it is still unclear whether NIRS signal changes during cognitive task are state- or trait-dependent, and whether NIRS could be a neural predictor of treatment response. Therefore, we conducted a longitudinal study to explore frontal haemodynamic changes following antidepressant treatment in medication-naïve MDD using 52-channel NIRS. This study included 25 medication-naïve individuals with MDD and 62 healthy controls (HC). We performed NIRS scans before and after antidepressant treatment and measured changes of [oxy-Hb] activation during a verbal fluency task (VFT) following treatment. Individuals with MDD showed significantly decreased [oxy-Hb] values during a VFT compared with HC in the bilateral frontal and temporal cortices at baseline. There were no [oxy-Hb] changes between pre- and post-antidepressant treatment time points in the MDD cohort despite significant improvement in depressive symptoms. There was a significant association between mean [oxy-Hb] values during a VFT at baseline and improvement in depressive symptoms following treatment in the bilateral inferior frontal and middle temporal gyri in MDD. These findings suggest that hypofrontality response to a VFT may represent a potential trait marker for depression rather than a state marker. Moreover, the correlation analysis indicates that the NIRS signals before the initiation of treatment may be a biological marker to predict patient’s clinical response to antidepressant treatment. The present study provides further evidence to support a potential application of NIRS for the diagnosis and treatment of depression.

Donepezil abolishes anticholinergic activity in a patient with amnesia.

We report the case of a 74-year-old woman who presented with amnesia and positive serum anticholinergic activity (SAA), which disappeared after treatment with the cholinesterase inhibitor donepezil for 1 year. Her only other regular medications were topical glaucoma preparations. We suggest that mental stress, mild cognitive impairment and Alzheimer’s disease pathology combined to generate SAA in this patient. We also consider that SAA may have subsequently become negative because of upregulation of acetylcholine production by donepezil, and because the patient’s other medications and physical condition (including glaucoma) remained unchanged during the 1-year period.

Differentiating early and late‐onset depression with multichannel near‐infrared spectroscopy

Background:  Individuals with late‐life depression can be divided into two categories, those with early and late‐onset depression (EOD and LOD, respectively). It has been reported that LOD has more accentuated subcortical vascular lesions and frontal lobe dysfunction (hypofrontality). The aim of the present study was to examine whether LOD exhibits more prominent hypofrontality than EOD during performance of the word fluency task (WFT) under multichannel near‐infrared spectroscopy (NIRS), a newly developed non‐invasive functional neuroimaging technique.

Beyond the Hypothesis of Serum Anticholinergic Activity in Alzheimer's Disease: Acetylcholine Neuronal Activity Modulates Brain-Derived Neurotrophic Factor Production and Inflammation in the Brain

The brain of Alzheimers disease (AD) patients is characterized by neurodegeneration, especially an acetylcholine (ACh) neuronal deficit with accumulation of β-amyloid protein, which leads to oxygen stress and inflammation. The active oxygen directly damages the neuron by increasing intracellular Ca2+. The inflammation is due to activation of the microglia, thereby producing cytokines which inhibit the production of brain-derived neurotrophic factor (BDNF). As the BDNF acts by neuronal protection, synaptogenesis and neurogenesis, the reduction of BDNF in the brain of AD patients worsens the symptoms of AD. On the other hand, treatment of AD patients with a cholinesterase inhibitor enhances ACh activity and inhibits inflammation. Then the expression of BDNF is restored and neuroprotection reestablished. However, there are several reports which showed controversial results concerning the relationship between BDNF and AD. We speculate that BDNF is related to some neurocognitive process and reflects neuronal activity in other neurodegenerative and neuropsychiatric disorders and that in the mild cognitive impairment stage, BDNF and choline acetyltransferase (ChAT) activities are hyperactivated because of a compensatory mechanism of AD pathology. In contrast, in the mild stage of AD, BDNF and ChAT activity are downregulated.

Hypothesis of Endogenous Anticholinergic Activity in Alzheimer's Disease.

In this article, we review and repropose our hypothesis of the endogenous appearance of anticholinergic activity (AA) in Alzheimers disease (AD). First, we introduce our previous articles and speculate that, because acetylcholine (ACh) regulates both cognitive function and inflammation, downregulation of this neurotransmitter causes upregulation of the inflammatory system. AA then appears endogenously with the production of cytokines and the downregulation of ACh in AD. To support our hypothesis, we present a female AD patient whose AA was considered to occur endogenously through her AD pathology. Her serum anticholinergic activity (SAA) was positive at her first visit to our memory clinic, was negative at the 1-year and 2-year follow-up visits, and had become positive again by 3 years. We speculate that the initial positive SAA was related to her AD pathology plus mental stress, and that her SAA at 3 years was related to her AD pathology only. Consequently, we believe that 2 patterns of SAA positivity (and therefore AA) exist. One occurs when the downregulation of ACh reaches a critical level, and the other occurs with the addition of some other factor such as medication, induced illness or mental stress that causes AA to affect AD pathology. Finally, we consider the pharmacotherapy of AD based on the proposed hypothesis and conclude that cholinesterase inhibitors can be used to prevent rapid disease progression, whereas N-methyl-D-aspartate receptor antagonists should be reserved for the treatment of AD that is already in a stage of rapid progression. We also propose a staging schema for patients with AD.

Reviews: Serum Anticholinergic Activity: A Biomarker for Rapid Progression of Alzheimer's Disease

We have previously reported the possibilities that anticholinergic activity (AA) appeared endogenously in Alzheimer’s disease (AD) and accelerated AD pathology. In this article we reviewed the reasons why AA endogenously appeared in AD and accelerated AD pathology and that the serum anticholinergic activity (SAA) was suitable as one of the biological marker of AD. We argued firstly that an acethycholine (Ach) played a role to maintain an endogenous anti-inflammatory pathway in the brain and the peripheral tissue. Secondarily, the deficiency of Ach in the brain might trigger the inflammatory process in AD patients by way of the suppression of cholinergic anti-inflammatory pathway and AA might be generated by inflammatory process. At third, AA disturbed not only memory functions but also accelerated AD pathology (increasing of amyloidgenic), and at fourth, we proposed a possibility that the SAA was useful as a marker of rapid progression of AD pathology in the moderate stage. SAA was considered to appear at moderate stage of AD when the symptoms rapidly were progress and an inflammation was occurred in the brain. The activities of N-methyl-D-aspartate (NMDA) receptors were accelerated and it progressed an inflammation in the brain. Memantine should be prescribed to AD patients with positive SAA in order to suppress inflammation by antagonizing the NMDA receptor. Therefore, when SAA was detected in AD, it should be considered to prescribe memantine. Finally, we speculated that down regulation of Ach and up regulation of NMDA receptor were involved in the pathology (increasing of amyloid) of AD disease and commented that cholinesterase inhibitors in mild stage and NMDA receptor antagonist in moderate stage in AD should be prescribed to prevent appearance of AA as well as to ameliorate symptoms by way of the up-regulation of Ach and the suppression of inflammation process.

Anticholinergic Activity and Schizophrenia.

In this article, we review the downregulation of acetylcholinergic activity in schizophrenia and discuss the similarity and difference between Alzheimers disease (AD) and schizophrenia in terms of acetylcholine (ACh) and anticholinergic activity (AA); then, we propose the use of cognition-enhancing therapy for schizophrenia. As ACh regulates an inflammatory system, when the cholinergic system is downregulated to a critical level, the inflammatory system is activated. We consider the possibility that AA appears endogenously in AD and accelerates AD pathology. This hypothesis can also be applied to schizophrenia. In fact, even before the onset of the disorder, in the prodromal phase of schizophrenia, cognitive dysfunction exists, and antibodies against astrocyte muscarinic-1 and muscarinic-2 receptors are present in the serum of patients with the paranoid type of schizophrenia. Then we noted that the prodromal phase in schizophrenia might correspond to the mild stage in AD and the acute phase to moderate stage concerning AA. We also think that we should enhance cognition in schizophrenia even in the prodromal phase because as mentioned above, downregulation of ACh is prominent in schizophrenia even in the prodromal phase.