Daisuke Hirose

Differential effects of acetylcholinesterase inhibitors on clinical responses and cerebral blood flow changes in patients with Alzheimer's disease: a 12-month, randomized, and open-label trial.

Background/Aims: The present study evaluated the differences in treatment outcomes and brain perfusion changes among 3 types of acetylcholinesterase inhibitors (AchEIs, i.e. donepezil, rivastigmine, and galantamine). Methods: This was a prospective, longitudinal, randomized, open-label, 3-arm (donepezil, rivastigmine, or galantamine), parallel-group, 12-month clinical trial carried out in 55 patients with AD. Results: At 6 months, the results of the Mini-Mental State Examination (MMSE) and the Trail Making Test (TMT)-Part A showed an improvement versus baseline in the donepezil treatment group. All groups showed a significant increase in regional cerebral blood flow (rCBF), mainly in the frontal lobe. Significant rCBF reduction was observed in the temporal lobe and cingulate gyrus in all 3 groups. Conclusion: AchEI treatment prevents the progression of cognitive impairment and increases the relative rCBF in the frontal lobe.

Oxidative stress and inflammation are associated with physical frailty in patients with Alzheimer's disease

Dementia is closely connected with frailty, and these two conditions are common in older adults. However, the biological mechanism that causes frailty in patients with Alzheimers disease (AD) is not fully understood. We determined whether oxidative stress and inflammatory mechanisms could be associated with physical frailty in patients with AD.

Guidelines for the Clinical Diagnosis of Diabetes Mellitus-Related Dementia.

ties in the context of poor glycemic control. Diabetic striatopathy is a well-recognized but rare cause of hemiballism-hemichorea, associated with contralateral basal ganglia hyperdensity on CT and hyperintensity on T1weighted MRI. The cause of clinical and imaging abnormalities is unclear. Several mechanisms attributed to hyperglycemia have been proposed: transient ischemic injury with microhemorrhage resulting in hyperviscosity caused by hyperosmotic state, calcium deposition, gemistocytosis, altered GABAergic and dopaminergic neurotransmission, paramagnetic mineral deposition including zinc-containing metallothionein expressed in swollen astrocytes, and autoimmunity-mediated inflammation. This was the first case, to the authors’ knowledge, of contemporary occurrence of hyperglycemia-related hemichorea and stroke. Two possible diagnostic hypothesis were taken into account: the first considered stroke to have played a central role in diabetes mellitus decompensation, which, in a context of cerebral frailty due to stroke, led to the development of hyperglycemia-related hemiballismhemichorea; the second considered hyperglycemia as the trigger of stroke through an ischemic injury due to hyperviscosity. The available anamnestic data did not help identify which of the two disorders first appeared. The proximity of the stroke lesion to the altered basal ganglia, both in the right middle cerebral artery area, is interesting; although this strengthens the hypothesis of the ischemic mechanism for imaging abnormalities associated to hyperglycemia, it seems in accord with the second hypothesis. It could also be related to the first hypothesis, if the abnormal basal ganglia is considered to enter the ischemic penumbra of the documented stroke. Moreover, a participating direct role of the documented ischemic stroke to the abnormal movements cannot be excluded given the existence also of vascular hemichorea-hemiballism typically associated with lesions of the basal ganglia and, as in this case, of the adjacent white matter. Difficulties in optimal glycemic control probably contributed to the persistence for several months of basal ganglia abnormalities accompanied by recurrence of hemichorea, both finally disappearing 24 months later when diabetes mellitus compensation was also evident. Hyperglycemia-related hemiballism-hemichorea and the occurrence of four ischemic strokes during a 24-month period are rare in clinical practice. This man’s case raises doubts also about the possible predictive role of hyperglycemiarelated hemiballism-hemichorea for recurrence of stroke.

Diabetes-related dementia is associated with dynapenia, but not with sarcopenia

injury in Korea. Seoul: Korea Health Promotion Foundation, 2009. 3 FinnN. Fall-related injuries amongst elderly in Sweden: still an emerging risk? DISSERTATION Karlstad University Studies 2014; 20: 1–79. 4 Stevens JA, Mahoney JE, Ehrenreich H. Circumstances and outcomes of falls among high risk community-dwelling older adults. Injury Epidemiology 2014; 1: 1–9. 5 Cho H, Shin H, Baek M. A study on the establishment and revitalization measures of international safe community – based on samcheok in Gangwon-do. J Korean Soc Disaster 2013; 9: 339–346. 6 Sun ML, Kim SC, Jung HS et al. Injury data comparison between national and local emergency centers in Korea. J Koran Soc Emerg Med 2012; 23: 181–188. 7 Park SS, Choi SE. Analysis on relationship between the accident and injury occurrence and the absence appearance of adults in South Korea. Technol Health Care 2014; 22: 369–377. 8 Kang CH, Kang HA, Park JH. Students injuries and injury surveillance system in cheonan. J Korean Soc Sch Health 2009; 22: 157–167. 9 Lee HW, Park JH, Kang SH et al.A study on self-sufficiency for hospital injury inpatients in Korea. Korea Acad Industr Coop Soc 2011; 12: 5779–5788.

Comparison of diagnostic utility of semi-quantitative analysis for DAT-SPECT for distinguishing DLB from AD

PURPOSE It is widely known that there is low striatal 123I-FP-CIT dopamine transporter single photon emission computed tomography (DAT-SPECT) uptake in patients with dementia with Lewy bodies (DLB). However, a consistent quantitative evaluation method for DAT-SPECT has not yet been established. There are two semi-quantitative software packages for DAT-SPECT available in Japan, namely, DaTView and DaTQUANT. The aim of this study was to identify which of these is superior for distinguishing DLB from AD. Moreover, we aimed to identify which region of the striatum is more suitable for distinguishing DLB from AD. METHODS Patients with Alzheimers disease (AD) (n=95) and patients with DLB (n=133) who underwent DAT-SPECT were enrolled. DaTView and DaTQUANT were used as semi-quantitative analysis tools for DAT-SPECT. RESULTS There were significant correlations in DAT uptake between DaTView and entire regions by DaTQUANT. There was no significant difference in diagnostic accuracy between DaTView and DaTQUANT except in the posterior putamen by DaTQUANT. CONCLUSIONS For distinguishing DLB from AD, both of DaTView and DaTQUANT software are useful. Moreover, assessing the DAT uptake in entire striatum by DaTView might be sufficient for distinguishing DLB from AD.

Frailty in diabetes-related dementia

In older adults, delirium is a frequent cause for hospitalization and is a length misleading condition. Aseptic meningitis might be related to specific leukemia CNS involvement, usually in end-stage treated disease. We showed that aseptic meningitis might reveal AML with no blast cells in blood samples. Therefore, a bone marrow examination should be considered in unexplained aseptic meningitis.

Circulating Levels of Advanced Glycation End Products in Diabetes Mellitus–Related Dementia

but remains underappreciated in the community. Because HCNs spend much time with patients in their homes, they can uniquely identify readmission factors. HCNs identified worsening symptoms, poor home environments, challenging patient priorities, and inappropriate self-management strategies that PCPs did not identify. The lack of relationships between PCPs and HCNs prevents community providers from addressing these concerns collaboratively. These results support the need for explicit agreement on roles and responsibilities and coordination among all providers caring for a patient, concepts that accountable care organizations and patient-centered medical homes espouse. Recently introduced care transitions and care coordination payments by the Centers for Medicare and Medicaid Services may provide incentives to improve communication and coordination among outpatient providers. Because readmissions represent a marker of poor care, improving the delivery of outpatient care may strengthen overall care. This study highlights a fragmented system of community providers and calls for new community provider–focused initiatives to improve the care of this vulnerable population.

Frailty and sarcopenia in subjects with Alzheimer's disease with or without cerebrovascular disease

Madoka Yanagawa, Hiroyuki Umegaki, Taeko Makino, Hirotaka Nakashima and Masafumi Kuzuya Department of Community Healthcare and Geriatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan 3 McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology 1984; 34: 939–944. 4 Fazekas F, Chawluk JB, Alavi A, Hurtig HI, Zimmerman RA. Mr.signal abnormalities at 1.5T in Alzheimer’s dementia and normal aging. AJR Am J Roentgenol 1987; 149: 351–356. 5 Folstein MF, Folstein SE, McHugh PR. Mini-mental state – practical method for grading cognitive state of patients for clinician. J Psychiatr Res 1975; 12: 189–198. 6 Honma A, Fukuzawa K, Tsukada Y, Ishii T, Hasegawa K, Mohs RC. Preparation of the Japanese version of the Alzheimer’s Disease Assessment Scale (ADAS). J Jpn Psychogeriatr Soc 1992; 3: 647–655. 7 Wechsler D. The Wechsler Memory Scale-Revised Manual. San Antonio, TX: The Psychological Corporation, 1987. 8 Berri MS, Silverman JM, Davis KL, Marin D, Grossman HZ, Schmeidler J. Type 2 diabetes is negatively associated with Alzheimer’s disease neuropathology. J Gerontol A Biol Sci Med Sci 2005; 60: 471–475. 9 Kadoi Y, Hinohara H, Kunimoto F et al. Diabetic patients have an impaired cerebral vasodilatory response to hypercapnia under propofol anesthesia. Stroke 2003; 34: 2399– 2403. Letters to the Editor

An Individual with Cerebral Amyloid Angiopathy–Related Inflammation Who Displayed Involuntary Movements

Myoclonus is characterized by a sudden, brief (most often <100 ms), jerky, shock-like involuntary movement. It is uncommon in AD and vascular dementia and can be present in DLB, although typically in later stages of the disease. The temporal sequence of development of myoclonus after initiation of memantine, exclusion of other differential diagnoses, and persistence of resolution of symptoms after cessation of memantine and subsequent withdrawal of clonazepam supports the diagnosis of memantineinduced myoclonus. The Naranjo probability score is 6, suggesting that myoclonus is a “probable” adverse drug reaction of memantine. Memantine is an amino-adamantane that is chemically similar to amantadine. There are case reports of amantadine-induced myoclonus in Parkinson’s disease, with the mechanism of action postulated to be due to alterations in dopamine, serotonin, or glutamate release. When used in therapeutic doses, memantine has fewer side effects than other NMDA antagonists, including amantadine—it binds to the channel in a pseudo-first-order manner and dissociates from the receptor quickly, but when given at high anti-excitotoxic neuroprotective doses of 30–100 mg/kg, memantine exacerbates myoclonic jerks in rat models in a dose-dependent manner. In the current case, drug interactions may have arisen from concomitant use of dextromethorphan (a NMDA antagonist) and chlorpheniramine (an antihistamine with serotonin-norepinephrine reuptake inhibitor properties). Memantine is primarily renally excreted through the organic cation transporter-2 (OCT-2). Dose adjustment is recommended for individuals with renal impairment, with a target dose of 10 mg daily recommended in individuals with CrCl less than 30 mL/min. Thus, the memantine dose of 20 mg/d in the man described above was inappropriately high and could have resulted in gradual accumulation, leading to onset of myoclonus after 2 months. Moreover, interactions with drugs that use the OCT-2 system for excretion, such as fluoroquinolones in this instance, can also lead to high plasma memantine levels. Literature review yielded only four prior case reports of memantine-induced myoclonus and no reported cases in randomized controlled trials (Table 1). The onset of myoclonus after memantine exposure ranged from 6 days to 2 months, with complete resolution of myoclonus upon cessation of memantine. The limbs were typically involved, and there may be concomitant worsening of other symptoms such as agitation and confusion. All subjects were elderly (≥75), and three reported concomitant use of donepezil. Identified precipitants included renal impairment and drug–memantine interactions; many of the offending drugs were newly prescribed. There does not appear to be a predilection for any specific type of dementia. This case, together with previous reports, highlights the importance of considering memantine as a differential diagnosis for new-onset myoclonus when clinically relevant. Prescribers of memantine should keep in mind the need for dose adjustment in renal impairment and potential drug interactions with centrally acting agents (e.g., donepezil, antihistamines) and drugs excreted by the OCT2 transporter.

Role of Neuroimaging as a Biomarker for Neurodegenerative Diseases

It has recently been recognized that neurodegenerative diseases are caused by common cellular and molecular mechanisms including protein aggregation and inclusion body formation. Each type of neurodegenerative disease is characterized by the specific protein that aggregates. In these days, the pathway involved in protein aggregation has been elucidated. These are leading to approaches toward disease-modifying therapies. Neurodegenerative diseases are fundamentally diagnosed pathologically. Therefore, autopsy is essential for a definitive diagnosis of a neurodegenerative disease. However, recently, the development of various molecular brain imaging techniques have enabled pathological changes in the brain to be inferred even without autopsy. Some molecular imaging techniques are described as biomarker in diagnostic criteria of neurodegenerative disease. Magnetic resonance imaging (MRI), single photon emission computed tomography (SPECT), positron emission tomography (PET), and amyloid imaging are described in the diagnostic guidelines for Alzheimer’s disease in the National Institute on Aging-Alzheimer’s Association. MRI, dopamine transporter (DAT) imaging, and 123I-metaiodobenzyl-guanidine (MIBG) myocardial scintigraphy listed in the guidelines for consensus clinical diagnostic criteria for dementia with Lewy bodies are described as potential biomarkers. The Movement Disorder Society Progressive Supranuclear Palsy Study Group defined MRI, SPECT/PET, DAT imaging, and tau imaging as biomarkers. Other diagnostic criteria for neurodegenerative disease described neuroimaging findings as only characteristic finding, not as biomarker. In this review, we describe the role of neuroimaging as a potential biomarker for neurodegenerative diseases.