Masahiro Shigeta

Intracerebroventricular Infusion of Nerve Growth Factor in Three Patients with Alzheimer’s Disease

Nerve growth factor (NGF) is important for the survival and maintenance of central cholinergic neurons, a signalling system impaired in Alzheimer’s disease. We have treated 3 patients with Alzheimer’s disease with a total of 6.6 mg NGF administered continuously into the lateral cerebral ventricle for 3 months in the first 2 patients and a total of 0.55 mg for 3 shorter periods in the third patient. The patients were extensively evaluated with clinical, neuropsychological, neurophysiological and neuroradiological techniques. Three months after the NGF treatment ended, a significant increase in nicotine binding was found in several brain areas in the first 2 patients and in the hippocampus in the third patient as studied by positron emission tomography. A clear cognitive amelioration could not be demonstrated, although a few neuropsychology tests showed slight improvements. The amount of slow-wave cortical activity as studied by electroencephalography was reduced in the first 2 patients. Two negative side effects occurred with NGF treatment: first, a dull, constant back pain was observed in all 3 patients, which in 1 patient was aggravated by axial loading resulting in sharp, shooting pain of short duration. When stopping the NGF infusion, the pain disappeared within a couple of days. Reducing the dose of NGF lessened the pain. Secondly, a marked weight reduction during the infusion with a clear weight gain after ending the infusion was seen in the first 2 patients. We conclude from this limited trial that, while long-term intracerebroventricular NGF administration may cause certain potentially beneficial effects, the intraventricular route of administration is also associated with negative side effects that appear to outweigh the positive effects of the present protocol. Alternative routes of administration, and/or lower doses of NGF, perhaps combined with low doses of other neurotrophic factors, may shift this balance in favor of positive effects.

Quantitative electroencephalography in mild cognitive impairment: longitudinal changes and possible prediction of Alzheimer's disease

The present study evaluated the clinical course of patients with mild cognitive impairment (MCI), the pattern of electroencephalography (EEG) changes following cognitive deterioration, as well as the potential of neurophysiological measures in predicting dementia. Twenty-seven subjects with MCI were followed for a mean follow up period of 21 months. Fourteen subjects (52%) progressed (P MCI) to clinically manifest Alzheimers disease (AD), and 13 (48%) remained stable (S MCI). The two MCI subgroups did not differ in baseline EEG measures between each other and the healthy controls (n = 16), but had significantly lower theta relative power at left temporal, temporo-occipital, centro-parietal, and right temporo-occipital derivation when compared to the reference AD group (n = 15). The P MCI baseline alpha band temporo-parietal coherence, alpha relative power values at left temporal and temporo-occipital derivations, theta relative power values at frontal derivations, and the mean frequency at centro-parietal and temporo-occipital derivations overlapped with those for AD and control groups. After the follow-up, the P MCI patients had significantly higher theta relative power and lower beta relative power and mean frequency at the temporal and temporo-occipital derivations. A logistic regression model of baseline EEG values adjusted for baseline Mini-Mental Test Examination showed that the important predictors were alpha and theta relative power and mean frequency from left temporo-occipital derivation (T5-O1), which classified 85% of MCI subjects correctly.

Quantitative Electroencephalography Power and Coherence in Alzheimer's Disease and Mild Cognitive Impairment

In this study the best combination of quantitative electroencephalographic variables (qEEG) for the discrimination of groups with mild to moderate Alzheimers disease (AD), mild cognitive impairment and healthy subjects was defined and related to neuropsychological performance. The study population included 18 patients with mild to moderate probable AD, 19 subjects with objective memory disturbance, 17 subjects with subjective memory complaints who did not have clinical evidence of memory disturbance, and 16 healthy controls. AD patients had significantly increased theta and decreased alpha relative power, mean frequency, and temporoparietal coherence. There was no significant difference in the mean frequency in the left temporal region between AD patients and subjects with objective memory disturbances. Temporoparietal coherence appeared as a discriminant variable together with alpha and theta relative power only between AD patients and controls giving 77.8% sensitivity and 100% specificity. Significant correlations between regional changes in qEEG variables and cognitive functions were found.

Apolipoprotein E ε4 allele decreases functional connectivity in Alzheimer’s disease as measured by EEG coherence

OBJECTIVES The ε4 allele of apolipoprotein E (APOE) represents a major biological risk factor for late onset Alzheimer’s disease. However, it is still not known whether the APOE genotype affects the progression of the disease, assessed by different functional methods. METHODS The study sample included 41 patients with probable Alzheimer’s disease. Subjects had similar severity of disease, age of onset, and duration of illness, and were subcategorised according to their APOE genotypes: 17 with no ε4 allele, 14 with one ε4 allele, and 10 with two ε4 alleles. The control group consisted of 18 healthy subjects comparable with the patients in age and education. Analysed quantitive EEG (qEEG) variables were the ratio of alpha and theta absolute power and EEG coherence in alpha frequency band, representing major cortical association pathways. RESULTS There was pronounced EEG slowing in all three patient subgroups compared with the controls for the alpha/theta ratio, but there was no significant difference across the patient subgroups. Patients homozygous for the APOE ε4 allele had reduced right and left temporoparietal, right temporofrontal, and left occipitoparietal coherence. Patients without and with one ε4 allele showed an overlap between the control group and group with two ε4 alleles in coherence measures. CONCLUSIONS APOE ε4 does not influence EEG slowing, an index which reflects severity of the disease in patients with Alzheimer’s disease, but seems to be associated with selective decreases in functional connectivity as assessed by EEG coherence. This finding might be of clinical importance when considering different pathogenetic mechanisms.

Long-term tacrine treatment in three mild Alzheimer patients: effects on nicotinic receptors, cerebral blood flow, glucose metabolism, EEG, and cognitive abilities.

The effect of long-term treatment with tacrine (tetrahydroaminoacridine) was studied in three Alzheimer patients (aged 57, 64, and 68 years) with mild dementia. All three patients had a Mini-Mental State Examination score of 24/30 and carried at least one apolipoprotein E (ApoE) epsilon4 allele. Tacrine was given in doses between 80 and to 160 mg daily for 13-31 months. A lower tacrine concentration was observed generally in cerebrospinal fluid (CSF) compared with plasma. The acetylcholinesterase activity in CSF tended to be increased following longer periods of tacrine treatment, whereas the butyrylcholinesterase activity was decreased. The three patients repeatedly underwent positron emission tomography investigation of cerebral blood flow, nicotinic receptors, cerebral glucose metabolism, and electroencephalogram (EEG) and cognitive tests. Positive influences on these parameters were observed following both short-term and long-term treatment with tacrine. Improvement of nicotinic receptors (measured as 11C-nicotine binding), cerebral blood flow, EEG, and some cognitive tests (trail making test, block design test) occurred earlier after initiation of tacrine treatment compared with the glucose metabolism, which was increased after several months of tacrine treatment. An improvement in attention (trail making test) was observed following tacrine as sign for frontal lobe activation (EEG). The functional effects of tacrine in Alzheimer patients appeared to be related to both dose and length of cholinesterase inhibitor treatment.

Donepezil treatment of patients with severe Alzheimer's disease in a Japanese population: results from a 24-week, double-blind, placebo-controlled, randomized trial.

Background/Aims: A 24-week, randomized, parallel-group, double-blind placebo-controlled study was conducted to evaluate the efficacy and tolerability of donepezil in severe Alzheimer’s disease (AD). Methods: Patients with severe AD (Mini-Mental State Examination score 1–12; modified Hachinski Ischemic Score ≤6; Functional Assessment Staging ≧6) were enrolled in this study in Japan. A total of 325 patients were randomized to donepezil 5 mg/day (n = 110), donepezil 10 mg/day (n = 103) or placebo (n = 112). Primary outcome measures were change from baseline to endpoint in the Severe Impairment Battery (SIB) and Clinician’s Interview-Based Impression of Change-plus caregiver input (CIBIC-plus) at the endpoint visit. Results: Donepezil 5 mg/day and 10 mg/day were significantly superior to placebo on the SIB, with a least-squares mean treatment difference of 6.7 and 9.0, respectively (p < 0.001 compared with placebo). CIBIC-plus analyses showed significant differences in favor of donepezil 10 mg/day over placebo at endpoint (p = 0.003). A statistically significant dose-response relationship was demonstrated with the SIB and CIBIC-plus. Donepezil was well tolerated. Conclusion: This study confirmed the effectiveness of donepezil 10 mg/day in patients with severe AD and demonstrated a significant dose-response relationship. Donepezil at dosages of both 5 mg/day and 10 mg/day is safe and well tolerated in Japanese patients with severe AD.

Spatial organization of EEG activity from alertness to sleep stage 2 in old and younger subjects.

In order to elucidate brain mechanisms that contribute to the increased tendency for vigilance dysregulation in the elderly, we examined the spatial organization of brain electric activity [electroencephalogram (EEG)] during decreasing vigilance from alertness to onset of sleep stage 2, comparing 7 old and 10 younger, healthy subjects (60–79 and 18–41 years old, respectively). Two features were analyzed: (1) change of location of the brain electric source gravity centers of the EEG frequency bands, and (2) magnitude of fluctuation of these locations over time. Multichannel EEG was analyzed into source gravity center localizations for seven EEG frequency bands, using fast Fourier transform (FFT) Dipole Approximation (first principal component‐single source modeling in the frequency domain). Multivariate analysis of covariance (MANCOVA) showed: source localizations were more anterior in old than younger subjects for beta‐1 and more superior for all three beta bands; from alertness to sleep, delta and theta EEG sources (inhibitory activity) changed to more posterior and superior areas, and alpha‐1 and ‐2 (routine activity) and beta‐1 and ‐2 sources (excitatory activity) towards anterior and superior areas. Fluctuations of the source locations of delta and beta‐2 were larger on the superior–inferior axis, and of beta‐2 smaller on the left–right axis in the old than younger subjects. The results suggest functional specifications (inhibitory, routine, excitatory) of cortical positron emission tomography (PET) changes reported in sleep. In sum, aging exhibits changes in spatial organization of EEG‐generating neuronal assemblies; during the transition wakefulness‐to‐sleep, aging affects the spatial‐temporal dynamics of this organization. The latter is suggested to contribute to the increased risk for consciousness disturbances in the elderly.

A Follow-Up Study of the Family with the Swedish APP 670/671 Alzheimer’s Disease Mutation

Objective: To study the progression of Alzheimer’s disease (AD) at a very early stage and to evaluate clinical markers of presymptomatic AD. Setting: Longitudinal study at a university hospital. Subjects: A Swedish family harboring a double mutation at codons 670/671 of the APP gene on chromosome 21 was followed longitudinally for 3 years. Both mutation carriers and noncarriers participated. Outcome Measurements: Results from clinical investigations, electroencephalography, neuropsychological and neuroradiological examinations including magnetic resonance imaging, single-photon emission computed tomography and positron emission tomography were assessed and compared on two or more occasions. Main Outcome: During follow-up, 1 initially asymptomatic mutation carrier who was near the expected age of onset for this family, developed cognitive symptoms, and at the end of the follow-up fulfilled the diagnostic criteria for AD. One mutation carrier with cognitive symptoms at the first examination showed clinical deterioration and was diagnosed with AD. One demented mutation carrier died and was shown to have typical AD neuropathology at autopsy. The two remaining asymptomatic mutation carriers, as well as all the noncarriers were asymptomatic. These mutation carriers who were near the expected age of onset of AD but without clinical signs of the disease, did not show changes in either electrophysiological parameters or volumes of the temporal lobes. However, in these 2 individuals the blood flow in the temporal lobe showed intermediate values between the symptomatic mutation carriers and healthy noncarriers. Two neuropsychological tests showed a deterioration that paralleled clinical symptoms in 1 of the mutation carriers who was close to the expected age of onset and who at the end of the follow-up had clinical signs of AD. In the same subject, brain glucose metabolism was pathologically reduced in the temporal lobes before other clinical symptoms were obvious. Conclusion: In this familial form of AD a reduced temporal lobe glucose metabolism was indicative of AD before the expected clinical onset. Reduced glucose metabolism even preceded the development of subjective or objective cognitive dysfunction and might therefore serve as a clinical marker for AD before the onset of clinical symptoms. Reduced cerebral blood flow in the temporal lobes and cognitive deterioration paralleled the clinical decline in the early stage of the disease.

Global dimensional complexity of multichannel EEG in mild Alzheimer's disease and age-matched cohorts.

Multichannel EEG as sequence of momentary brain field maps constitutes a trajectory through K-dimensional state space (K = number of channels); the complexity of this trajectory is assessed by the nonlinear measure of global correlation dimension (Global Dimensional Complexity, GDC) with the number of electrodes as embedding dimension. We analyzed eyes-closed EEG of three age-matched subject groups: mild Alzheimers disease (AD; n = 21), mild cognitive impairment (29) and subjective memory complaint (29). Kruskal-Wallis statistics showed an overall effect between groups. AD patients differed significantly (GDC = 4.56) from mild cognitive impairments (GDC = 4.98) and from subjective memory complaints (GDC = 4.93). GDC also had significant positive correlations with mental condition and performance (MMSE and WAIS-R scores). Thus, the dynamics of brain state development over time in mild AD differs from that in mild cognitive impairment and in subjective memory complaint cases.

EEG slowing and cerebrospinal fluid tau levels in patients with cognitive decline.

WE explored the relationship between cerebrospinal fluid (CSF) tau levels as indirect markers of tau-related pathology in Alzheimers disease (AD) and EEG slowing, a typical neurophysiological finding in the disease. A positive correlation between CSF tau levels and ratio of alpha/delta global field power was found in 14 AD patients (r = 0.65, p = 0.01). This relationship was better approximated by polynomial fit of 2nd degree (p = 0.002). A subgroup of AD patients (n = 7) with higher tau levels and shorter duration of illness showed a strong relationship between CSF tau levels and alpha/theta (r = 0.83, p = 0.02), and alpha/delta (r = 0.87, p = 0.01) ratios of the global field power. There were no significant correlations between EEG slowing and CSF tau levels in 12 patients with mild cognitive dysfunction or in 14 healthy control subjects. That a strong inverse linear correlation exists in AD patients with higher levels of tau and shorter duration of illness may imply that with longer illness duration CSF tau levels decrease due to neuronal death.