Kosuke Matsuzono

A new simple score (ABS) for assessing behavioral and psychological symptoms of dementia

In addition to cognitive impairment, behavioral and psychological symptoms of dementia (BPSD) are another important aspect of most dementia patients. This study was designed for a new simple assessment of BPSD. We first employed a clinical survey for the local community with sending an inquiry letter to all members (n=129) of dementia caregiver society, and then attempted to create a new BPSD score for dementia with 10 BPSD items. This new simple BPSD score was compared to a standard-detailed BPSD score neuropsychiatric inventory (NPI) for a possible correlation (n=792) and a time to complete (n=136). Inter-rater reliability was examined comparing scores between main and second caregivers (n=70) for AD. Based on the clinical survey for local caregivers, a new BPSD score for dementia (ABS, Abes BPSD score) was newly created, in which each BPSD item was allotted by an already-weighted score (maximum 1-9) based on the frequency and severity, and was finalized with taking temporal occurrences into account. ABS was filled by the main caregiver with a full score of 44, was well correlated with NPI (r=0.716, **p<0.01) in 792 AD patients (age 78.6 ± 7.0 years, MMSE 19.0 ± 5.9), and took a shorter time as only 56.8 ± 38.8s (**p<0.01) than NPI score (132.7 ± 94.0 s) with 136 AD patients. A high inter-rater reliability was obtained (r=0.964, **p<0.01) with a little smaller score (0.877 time) of ABS in secondary than the main caregivers. ABS provides a new simple and quick test for BPSD assessment, with a good correlation to NPI but a shorter time, and with a high inter-rater reliability. Thus ABS is useful for evaluating BPSD for mild to moderate dementia patients.

Combination Therapy of Cholinesterase Inhibitor (Donepezil or Galantamine) plus Memantine in the Okayama Memantine Study

BACKGROUND/OBJECTIVE To compare the effectiveness of combination therapy with cholinesterase inhibitors (ChEI) plus memantine in all AD patients and in older AD patients (age >75 years). METHODS The Okayama Memantine Study was used to compare the clinical effects of combination therapy of donepezil plus memantine (n = 61) or galantamine plus memantine (n = 53) in all AD patients, and in older AD patients separately, with six batteries at baseline, at 6 months with ChEI only monotherapy, and at 3, 6, and 12 months after addition of memantine to the treatment schedule (18 months total). RESULTS The addition of memantine resulted in stabilization of the Mini-Mental State Examination scores and Hasegawa dementia rating for 6 months, and then significantly declined at 12 months in both subgroups. Frontal assessment battery (FAB) declined significantly at 12 months after memantine addition in the donepezil subgroup, while the galantamine subgroup significantly improved at 6 months. Affective functions were well preserved after memantine addition until 12 months, except for the apathy scale at 12 months after memantine addition in the galantamine subgroup. The combination therapy of donepezil plus memantine was better for apathy in older AD patients, and galantamine plus memantine was better for cognitive functions. CONCLUSIONS The addition of memantine stabilized cognitive scores for 6 months and affective scores for 12 months in the donepezil subgroup. Additionally, memantine significantly improved FAB at 6 months in the galantamine subgroup although apathy scale became significantly worse at 12 months.

A novel familial prion disease causing pan-autonomic-sensory neuropathy and cognitive impairment.

A 34-year-old Japanese female began to have urinary retention of up to 2 l at the age of 26 years. At age 30 years, she developed syncope for 5 min due to orthostatic hypotension. At age 31 years, she began to show memory disturbances. After the age of 31 years, she suffered from frequent vomiting and diarrhea. Her family tree is shown in Fig. 1a. Her mother developed dementia, urinary disturbance and orthostatic hypotension (from 140/100 mmHg lying to 80/45 mmHg standing) with frequent syncope attacks at the age of 47 years. She had thermoanesthesia in her lower limbs. One year after onset, she died without a final diagnosis. The grandfather of the present case is told to have developed dementia with urinary disturbance and orthostatic hypotension at the age of 52 years, and died at the age of 62 years, but no medical record could be obtained. The present case had a height of 159.5 cm and a body weight of 39.5 kg. Her cognitive function showed mild decline to 27/30 in mini-mental state examination and 21/30 in Montreal cognitive assessment. The muscles in her distal limbs were slightly atrophic, and severe thermoanesthesia and hypoalgesia were present. Her tendon reflexes showed generalized areflexia. Severe orthostatic hypotension was observed from 115/80 mmHg (lying) to 59/35 mmHg (standing). Cerebrospinal flood (CSF) analysis showed an elevated protein level of 141 mg/dl, and otherwise normal data. Other laboratory data are shown in Table 1 and Fig 1b–e. Compound muscle action potentials and sensory action potentials were not evoked in bilateral tibial and sural nerves, respectively. Sural nerve biopsy revealed moderate loss of myelinated fibers (Fig. 1f) with no deposits of amyloid material. Unlike normal sural nerve (Fig. 1g), prion protein staining of the biopsy revealed ragged deposits in myelin (Fig. 1h,i). The serum and CSF neuron-specific enolase levels were elevated at concentrations of 35.2 ng/ml and 134.9 ng/ml, respectively. The CSF levels of 14-3-3 and tau proteins were also elevated at 1125 lg/ml and 2994 pg/ ml, respectively. Thus, the prion gene was analyzed, revealing a 2-bp deletion (CT) in codon 178 that causes additional variable 25 amino acid at C-terminal from the mutation site to the premature stop codon at codon 195 (Fig. 1j). We examined this mutation by polymerase chain reaction-based restriction fragment length polymorphism analysis using BssSI restriction enzyme [2]. The BssSI restriction site detects mutation of the present 2-bp deletion (Fig. 1k). There are no brain autopsy data to confirm prion disease in the proband, therefore she was treated as presumed prion disease. Bi-level positive airway pressure was initiated for her in order to avoid sudden death at night, and the patient is living by herself today.

Cognitive and affective benefits of combination therapy with galantamine plus cognitive rehabilitation for Alzheimer's disease

The aim of the present study was to compare the effects of a galantamine only therapy and a combination therapy with galantamine plus ambulatory cognitive rehabilitation for Alzheimers disease patients.

Combination benefit of cognitive rehabilitation plus donepezil for Alzheimer's disease patients

Alzheimers disease (AD) is one of the most important diseases in aging society, and non‐drug therapy might be an alternative therapeutic approach. Thus, we evaluated the add‐on effect of cognitive rehabilitation on AD patients under donepezil treatment.

Cerebral Embolic Stroke after Disappearing Takotsubo Cardiomyopathy

Takotsubo cardiomyopathy can induce cerebral embolic stroke because of intracardiac thrombosis, but the timing of cardiogenic embolism relating to takotsubo cardiomyopathy has not been well described. We evaluated a 71-year-old woman with takotsubo cardiomyopathy, who developed cardiogenic cerebral embolism after recovery of cardiac wall motion. Nevertheless, we treated her with anticoagulation therapy. The present clinical observation suggests that attention should be paid to the timing when takotsubo cardiomyopathy resolves against risk of cardiogenic cerebral embolism.

C-Terminal-Deleted Prion Protein Fragment Is a Major Accumulated Component of Systemic PrP Deposits in Hereditary Prion Disease With a 2-Bp (CT) Deletion in PRNP Codon 178

Prion protein (PrP) has 2 glycosylated sites and a glycosylphosphatidylinositol (GPI) anchor on the C-terminal. Reports on genetic prion disease with GPI anchorless PrP are very limited. In this study, we characterized the molecular alterations of mutated PrP in a 37-year-old female autopsy case with a recently identified PRNP mutation involving a 2-bp deletion in codon 178 that results in a premature stop codon mutation in codon 203. Postmortem examination revealed numerous irregularly shaped coarse PrP deposits and multicentric plaques in the brain that were mainly comprised of C-terminal deleted abnormal PrP primarily derived from the mutant allele. Additionally, abnormal PrP deposits were detected in almost all other examined organs. PrP was mainly deposited in peripheral nerves, smooth muscles, and blood vessels in non-CNS tissues. Western blot analysis after proteinase K treatment showed protease-resistant PrP (PrPres) signals with a molecular weight of 9 kDa; weak PrPres smear signals of 9 to ∼80 kDa were also noted. Gel filtration revealed that PrPres oligomers were mainly composed of the PrP fragments. In conclusion, the mutated PrP lacking that GPI anchor was truncated shortly and deposited in almost every examined organ.

Estimation of the presence of small dense lipoprotein cholesterol in acute ischemic stroke

Small dense low-density lipoprotein (sdLDL) is an established risk factor in ischemic heart disease. However, its clinical significance in acute ischemic stroke (AIS) is uncertain. This study evaluates the prognostic value of the presence of sdLDL in patients with AIS by determining whether it contributes to clinical outcome or not. We studied 530 consecutive patients admitted within the first 48 hours after onset of ischemic stroke and 50 corresponding controls. Serum lipid parameters were measured on admission by standard laboratory methods. The percentage of AIS patients with sdLDL was significantly higher than the one of matched controls with sdLDL. Concerning comparisons between AIS patients with or without sdLDL, the percentages of males and patients with histories of smoking, hypertension, and cardiovascular disease were significantly higher in AIS patients with sdLDL. Concerning the grade of severity, modified Rankin Scale (mRS) on discharge was significantly higher in AIS patients with sdLDL. On logistic regression analysis, age (OR=2.29, P<0.001), male gender (OR=0.49, P<0.01), history of atrial fibrillation (OR=3.46, P<0.001), and the presence of sdLDL (OR=1.59, P<0.05) were significantly associated with poor prognosis (mRS on discharge >3). Our study showed that the presence of sdLDL might be independently associated with a poor prognosis after AIS.

'PrP systemic deposition disease': clinical and pathological characteristics of novel familial prion disease with 2-bp deletion in codon 178.

A novel TYPE of prion disease associated mainly with autonomic‐sensory polyneuropathy was reported by us previously.

Tumefactive demyelinating disease mimicking malignant tumor in positron emission tomography with 11C‐methionine

Tumefactive demyelination is sometimes difficult differentiate from malignant tumors. Positron emission tomography with 11C‐methionine is useful for diagnosing cerebral malignant tumors, but there are previous reports for tumefactive demyelination. We experienced a 32‐year‐old man who suffered from subacute onset dysarthria and left hemiparesis with magnetic resonance image of a large lesion (5.3 × 4.2 cm) in the right frontal lobe. Positron emission tomography with 18F‐fluorodeoxyglucose showed a high ring‐shaped glucose uptake in the lesion and 11C‐methionine showed a remarkable methionine uptake in the whole lesion. Although a malignant tumor was suspected, the patient was finally diagnosed with tumefactive demyelinating disease based on brain biopsy results, and was treated completely by methylpredonisolone therapy. Although 11C‐methionine uptake with positron emission tomography commonly suggests a malignant tumor, there can still be a possibility of tumefactive demyelinating disease.