Perfusion fMRI detects deficits in regional CBF during memory-encoding tasks in MCI subjects.

OBJECTIVE: To determine how memory-encoding tasks elicit functional perfusion change in subjects with amnestic mild cognitive impairment (aMCI). METHODS: Twelve subjects with aMCI and 14 age-matched cognitively normal (CN) subjects were recruited for this study. Arterial spin-labeling perfusion MRI (ASL-MRI) was employed to measure regional cerebral blood flow (CBF) during both control and encoding task conditions. RESULTS: Experimental results demonstrated that hypoperfusion occurred in the right precuneus and cuneus in the aMCI group, and not the CN group, during the control state. During the memory-task performance, the difference in these regional hypoperfusion areas extended to the posterior cingulate. These regional perfusion rates correlated with the Mini-Mental State Examination and the Rey Auditory Verbal Learning Test scores. In addition, a CBF percentage increase (22.7%) occurred in the right parahippocampus region during the memory-encoding task performance in the CN group, with approximately no change in the aMCI group. CONCLUSION: Subjects with amnestic mild cognitive impairment had significant regional cerebral hypoperfusion and lacked the dynamic capability to modulate their regional cerebral blood flow responses to the challenge of the functional tasks.

Decreased glutamate + glutamine in Alzheimer's disease detected in vivo with (1)H-MRS at 0.5 T.

OBJECTIVE: To determine whether glutamate + glutamine (GLX) levels in the brain as measured in vivo with proton MRS at 0.5 tesla (T) distinguish between probable Alzheimer's disease and normal aging. BACKGROUND: Glutamatergic markers had been measured previously in postmortem brain tissue. Conventional proton MRS at 1.5 T cannot reliably detect the GLX resonance in vivo. The authors developed a technique at 0.5 T that is sensitive to the GLX resonance. METHODS: Metabolite ratios using creatine and phosphocreatine resonance as an internal standard were acquired from the cingulate region of 18 patients with AD and 12 healthy controls. The major resonances in the spectrum were examined: N-acetylaspartate (NAA), choline-containing compounds, myo-inositol, and GLX. The Mini-Mental State Examination (MMSE) was used to assess cognitive status. The Instrumental Activities of Daily Living Scale (Instrumental ADL) was used to assess functional status. RESULTS: Reduced ratios of GLX (-10%, p = 0.001) and NAA (-12%, p = 0.000) were found in patients with AD. Increased ratios of myo-inositol in patients with AD approached significance (+14%). GLX ratios of patients with AD were correlated with MMSE (r = 0.61, p = 0.007) and Instrumental ADL (r = 0.59, p = 0.01) scores. The combined sensitivity of NAA and myo-inositol in correctly diagnosing AD was 78%. The addition of GLX to NAA and myo-inositol increased the sensitivity to 89%. Overall diagnostic accuracy improved from 80 to 83% with the addition of GLX. CONCLUSIONS: Glutamate + glutamine reduction may be a biologic marker for AD and may be a potential aid in the early clinical diagnosis of AD.

A treatment and withdrawal trial of besipirdine in Alzheimer disease.

Besipirdine hydrochloride (HP 749) is an indole-substituted analog of 4-aminopyridine. Besipirdine enhances both cholinergic and adrenergic neurotransmission in the central nervous system. The present study examined the efficacy and tolerability of two doses of besipirdine (5 and 20 mg b.i.d.) in 275 patients with Alzheimer disease during 3 months of treatment and for 3 months after withdrawal of treatment. Assessment after withdrawal of treatment was used in an effort to distinguish persistent efficacy attributable to a neuroprotective mechanism from reversible symptomatic efficacy. Besipirdine was generally well tolerated. The level of performance on the cognitive subscale of the Alzheimer Disease Assessment Scale (ADAS-Cog) was sustained during 3 months of treatment with besipirdine, whereas some deterioration in the performance of patients treated with placebo was observed over the same period. The small difference between active and placebo treatment groups approached, but did not reach statistical significance in the primary intent-to-treat analysis (p = 0.067); analysis of patients who completed all assessments was supportive (p = 0.031). Global ratings using the Clinician Interview-Based Impression of Change did not detect a besipirdine treatment benefit, possibly because of an adverse effect on mood and behavior in some patients. A high ratio of adrenergic to cholinergic potency may have resulted in the adverse effects of besipirdine and hence its failure to support the hypothesis that multiple neurotransmitter treatment may be more efficacious than monotherapy. The efficacy apparent on the ADAS-Cog after 3 months of treatment did not persist 3 months after withdrawal of treatment, suggesting that the benefit was symptomatic. This study provides a practical example of the use of treatment withdrawal assessment to distinguish neuroprotective from symptomatic efficacy.

Effectiveness and safety of velnacrine for the treatment of Alzheimer's disease. A double-blind, placebo-controlled study. Mentane Study Group.

BACKGROUND: Alzheimer's disease is characterized by cognitive and behavioral disturbances that are mediated in part by cholinergic brain deficits. OBJECTIVE: To evaluate the long-term effectiveness and safety of an investigational cholinesterase inhibitor, that is, velnacrine maleate, in treating patients with clinically probable Alzheimer's disease (according to the criteria of the National Institute of Neurological Disorders and Stroke [Washington, DC]-Alzheimer Disease and Related Disorders Association [Chicago, Ill]). METHODS: This was a double-blind, placebo-controlled study. After a single-blind washout period, patients were randomized to receive placebo (n = 152), velnacrine maleate, 150 mg/d (n = 149), or velnacrine maleate, 225 mg/d (n = 148) for 24 weeks. Primary end points were cognitive behavior and memory components of the Alzheimer's Disease Assessment Scale and the Clinical Global Impression of Change scale. Secondary end points were caregiver-rated scales. RESULTS: The scores for the cognitive behavior and memory components of the Alzheimer's Disease Assessment Scale deteriorated in the placebo-treated group (P < .05) but not in the velnacrine-treated groups. Between-group comparisons favored velnacrine maleate, 225 mg over 150 mg (P < .05). Findings were similar for the Clinical Global Impression of Change scale and three of the four caregiver-rated scales. Treatment-related adverse clinical events occurred in 36%, 28%, and 30% of patients in the groups that received placebo, velnacrine maleate (150 mg), and velnacrine maleate (225 mg), respectively. The most common adverse clinical event was diarrhea, which rarely interrupted therapy. Treatment was stopped because of reversible abnormal liver function test results (five or more times the upper limits of normal) in 3%, 30%, and 24% of the patients who received placebo, velnacrine maleate (150 mg), and velnacrine maleate (225 mg), respectively. CONCLUSIONS: Velnacrine produces modest but significant benefits in patients with Alzheimer's disease. Velnacrine maleate (225 mg) is more effective than 150 mg of velnacrine. Both dosages have acceptable safety profiles.

Leukocyte hexokinase activity in aging and Alzheimer disease.

We determined the effects of clinical variables on hexokinase (HK) activity in leukocytes from Alzheimer's disease (AD) patients and controls. Age accounted for 51% of the variance in HK activity in the young and 23% in the old. Duration of illness in both familial and sporadic AD accounted for HK levels by 32 and 38%, respectively. Hexokinase activity increases with age and does not discriminate between familial and sporadic AD.

Correlation of neuronal cell body size in motor cortex and hippocampus with body height, body weight, and axonal length.

This study examined the comparative effects of body height and body weight on the neuronal cell size in humans and investigated their possible mechanisms. A total of 21 cases between the ages of 20 and 40 years were studied. Data on body height, body weight, and neuropathology were obtained from autopsy records. Mean cross sectional areas of cell bodies for 30 normal neurons were determined for the motor cortex projecting to lumbar spinal cord segments (L) 1-4 (Betz cells) as well as various regions of the hippocampus. Approximate axonal length of the motor neuron studied was measured from motor cortex to L2. We found that only motor cortex neuronal cell body size was significantly proportional to body height and the respective axonal length (p < .05). The findings indicate that: 1) body height has a greater effect than body weight on the motor neuron cell size, probably because of its association with axonal length; 2) the effect is regional (motor cortex) rather than general.

Correlation of computed tomography and postmortem findings of a diffuse astrocytoma: a case report.

Diffusely infiltrating astrocytomas often present diagnostic difficulties. We herein correlate the radiologic and postmortem findings of a diffuse astrocytoma and conclude that recognition of abnormal bilateral and fairly symmetric enlargement and increased density of normal structures in CT scans may lead to an antemortem diagnosis of the tumor.

Alzheimer disease: quantitative analysis of I-123-iodoamphetamine SPECT brain imaging.

To enable a more quantitative diagnosis of senile dementia of the Alzheimer type (SDAT), the authors developed and tested a semiautomated method to define regions of interest (ROIs) to be used in quantitating results from single photon emission computed tomography (SPECT) of regional cerebral blood flow performed with N-isopropyl iodine-123-iodoamphetamine. SPECT/IMP imaging was performed in ten patients with probable SDAT and seven healthy subjects. Multiple ROIs were manually and semiautomatically generated, and uptake was quantitated for each ROI. Mean cortical activity was estimated as the average of the mean activity in 24 semiautomatically generated ROIs; mean cerebellar activity was determined from the mean activity in separate ROIs. A ratio of parietal to cerebellar activity less than 0.60 and a ratio of parietal to mean cortical activity less than 0.90 allowed correct categorization of nine of ten and eight of ten patients, respectively, with SDAT and all control subjects. The degree of diminished mental status observed in patients with SDAT correlated with both global and regional changes in IMP uptake.

The development of daytime rearing behavior in methylazoxymethanol-treated rats: methodological considerations.

The development of daytime rearing behavior was studied in the offspring of pregnant rats which received injections of methylaxymethanol acetate (MAM) or saline during the 15th day of gestation. MAM and control rats were tested at 10, 15, 20, 25, and 30 days of age. The results indicated that the onset of rearing for both groups appeared at approximately 15 days of age, with no significant differences found between sexes. No rearing deficits were seen in MAM rats through 25 days of age despite the fact that these animals sustained greater than a 50% reduction in telencephalic mass. However, at 30 days of age MAM rats reared for significantly longer periods of time during each episode than did their control counterparts, although the actual number of rears did not differ between groups. The results are discussed in terms of neuroplastic events which follow MAM-induced damage and the need for multivariate research when analyzing rearing behavior.

Methylazoxymethanol acetate cortical hypoplasia alters the pattern of stimulation-induced behavior in neonatal rats.

In an attempt to identify a neural basis for the developmental progression in the organization of behavior evidenced in responses to lateral hypothalamic electrical stimulation, the responses to medial forebrain bundle (MFB) stimulation of pups whose mothers had been treated with saline or the antimitotic agent methylazoxymethanol acetate (MAM) on gestational Day 15 were measured. Administration of MAM at this age produces a severe and lasting cortical hypoplasia. Monopolar stainless-steel electrodes aimed at the MFB at the level of the lateral hypothalamus were implanted in pups 3, 10, 15 and 20 days of age and responses to 500 ms trains of stimulation were recorded. At 3 and 10 days of age, the number of behavioral responses increased with increasing frequency of stimulation in both MAM and saline-treated pups. Ten-day-old MAM-treated pups, however, displayed 'significantly less behavioral organization in their pattern of responding to stimulation. MAM pups, unlike saline-treated pups, continued to respond to stimulation at Day 15. Even at postnatal Day 20 some MAM-treated pups responded to stimulation. Neurochemical analysis of the brains of littermates demonstrated a significant increase in choline acetyltransferase levels indicating a relative hyperinnervation of afferent cholinergic terminals, confirming the cortical hypoplasia and replicating earlier work. These results suggest a role for the developing neocortex in organizing the behavioral responses to stimulation. The onset of cortical inhibitory mechanisms may channel behavioral responses in normally developing pups and prevent the characteristic activational responses to stimulation in Day-15 pups.

Nicotinic acetylcholine binding sites in Alzheimer's disease.

In Alzheimer's disease (AD), there is a loss of presynaptic cholinergic markers in the cerebral cortex, but the nature of cholinergic receptor changes is unclear. In this study, [3H]acetylcholine and [3H]nicotine were used to label nicotinic cholinergic binding sites in cerebral cortical tissues obtained at autopsy from patients with AD and from matched controls. A consistent and severe loss of nicotinic receptors was found in AD.

Regional heterogeneity of choline acetyltransferase activity in primate neocortex.

Choline acetyltransferase activity in precentral and temporal regions of primate neocortex is 2.5-fold higher than in occipital cortex. These results suggest large differences in the density of innervation in different regions of primate neocortex by the nucleus basalis of Meynert.