Subacute meningoencephalitis in a subset of patients with AD after Abeta42 immunization.

BACKGROUND: AD is characterized by cerebral deposition of beta-amyloid plaques with amyloid beta-peptide (Abeta) 42 as the major peptide constituent, along with neurofibrillary tangles and neuronal loss. In transgenic mice, active immunization against Abeta42 removes these plaques and improves cognitive function. A Phase I study in AD patients demonstrated good safety and tolerability of multiple injections of aggregated Abeta42 (AN1792) with QS-21 as adjuvant. METHODS: Three hundred seventy-two patients with mild to moderate AD were randomized to receive IM injections of AN1792 or placebo (4:1) at baseline and at months 1, 3, 6, 9, and 12 in a multicenter Phase II safety, tolerability, and pilot efficacy study. Dosing was terminated after four early reports of meningoencephalitis, but follow-up continued. The study remains blinded, and further results will be reported after its termination. RESULTS: Symptoms and laboratory findings consistent with meningoencephalitis occurred in 18 of 298 (6%) patients treated with AN1792 compared with 0 of 74 on placebo (p = 0.020). Sixteen of the 18 had received two doses, one had received one dose, and one had received three doses of the study drug before symptoms occurred. The median latency from the first and last injections to symptoms was 75 and 40 days. No case occurred later than 6 months after the first immunization. Anti-Abeta42 antibody titers were not correlated with the occurrence or severity of symptoms or relapses. Twelve patients recovered to or close to baseline within weeks, whereas six remain with disabling cognitive or neurologic sequelae. All 18 patients remain alive to date (December 31, 2002), 6 months to >1 year after symptom onset. CONCLUSIONS: Postvaccination meningoencephalitis occurred without clear relation to serum anti-Abeta42 antibody titers. Potential mechanisms such as T-cell and microglial activation may be responsible and are under consideration to develop a safer anti-Abeta immunotherapy for AD.

Assessment of low-flow CSF drainage as a treatment for AD: results of a randomized pilot study.

OBJECTIVE: This prospective, randomized, controlled study was designed to investigate the safety, feasibility, and preliminary efficacy of long-term CSF drainage via a low-flow ventriculoperitoneal shunt in subjects suffering from AD. METHODS: Twenty-nine subjects selected for probable AD (National Institute of Neurological and Communicative Diseases and Stroke-Alzheimer's Disease and Related Dementias Association criteria) were screened to exclude normal pressure hydrocephalus or other etiologies of dementia and randomized to treatment (shunt) or no treatment groups. The study endpoint was the comparison of group performance on psychometric testing at quarterly intervals for 1 year. Shunted subjects had CSF withdrawn for MAP-tau and Abeta((1-42)) assays at the same time intervals. RESULTS: There was no mortality from the surgical procedure, and no patient sustained a subdural hematoma. Five notable postoperative adverse events, which resolved without permanent neurologic deficit, were reported in the shunt group. Group mean Mattis Dementia Rating Scale total scores showed little change over the year in the shunt-treatment group, in contrast to a decline in the control group (p = 0.06). Mini-Mental State Examination mean scores supported a trend in favor of shunt treatment (p = 0.1). There was a concomitant decrease in ventricular CSF concentrations of AD biomarkers MAP-tau and Abeta((1-42)). CONCLUSIONS: The surgical procedure and the device are reasonably safe. Adverse events were consistent with shunt procedures for hydrocephalus in this older population. The endpoint data show a trend in favor of the treated group. A larger, randomized, double-blinded, controlled, clinical trial is underway.

Toward neuroanatomical models of analogy: a positron emission tomography study of analogical mapping.

Several brain regions associated with analogical mapping were identified using (15)O-positron emission tomography with 12 normal, high intelligence adults. Each trial presented during scanning consisted of a source picture of colored geometric shapes, a brief delay, and a target picture of colored geometric shapes. Analogous pictures did not share similar geometric shapes but did share the same system of abstract visuospatial relations. Participants judged whether each source-target pairing was analogous (analogy condition) or identical (literal condition). The results of the analogy-literal comparison showed activation in the dorsomedial frontal cortex and in the left hemisphere; the inferior, middle, and medial frontal cortices; the parietal cortex; and the superior occipital cortex. Based on these results as well as evidence from relevant cognitive neuroscience studies of reasoning and of executive working memory, we hypothesize that analogical mapping is mediated by the left prefrontal and inferior parietal cortices.

The calculating brain: an fMRI study.

To explore brain areas involved in basic numerical computation, functional magnetic imaging (fMRI) scanning was performed on college students during performance of three tasks; simple arithmetic, numerical magnitude judgment, and a perceptual-motor control task. For the arithmetic relative to the other tasks, results for all eight subjects revealed bilateral activation in Brodmann's area 44, in dorsolateral prefrontal cortex (areas 9 and 10), in inferior and superior parietal areas, and in lingual and fusiform gyri. Activation was stronger on the left for all subjects, but only at Brodmann's area 44 and the parietal cortices. No activation was observed in the arithmetic task in several other areas previously implicated for arithmetic, including the angular and supramarginal gyri and the basal ganglia. In fact, angular and supramarginal gyri were significantly deactivated by the verification task relative to both the magnitude judgment and control tasks for every subject. Areas activated by the magnitude task relative to the control were more variable, but in five subjects included bilateral inferior parietal cortex. These results confirm some existing hypotheses regarding the neural basis of numerical processes, invite revision of others, and suggest productive lines for future investigation.

Tranquilizers, stimulants, and enhancers of cognition.

For patients with cognitive dysfunction, the appropriate use of neurotransmitter specific medication may permit independent living. This article examines a variety of tranquilizers, stimulants, and enhancers of cognition and evaluates which may be most effective given their side effect profiles.

Linguistic processing during repetitive transcranial magnetic stimulation.

To determine if linguistic processing could be selectively disrupted with repetitive transcranial magnetic stimulation (rTMS), rTMS was performed during a picture-word verification task. Seven right-handed subjects were trained in two conditions: picture-word verification, which required the subject to verify whether the picture of an object matched the subtitle name on the same page, and frame verification, which required subjects to verify whether there was a rectangular frame around the combined object picture and subtitle. Half of the trials were performed during rTMS. The effects of rTMS on performance were evaluated at the following four scalp positions: left anterior (the area where rTMS produced speech arrest), a mirror site on the right, and two positions in the left and right parietal region. Stimulation over the left deltoid muscle served as a control. Subjects had less difficulty in making picture-word matching decisions during unstimulated compared with stimulated trials at the left anterior and posterior positions. No significant difference in accuracy was detected in the frame verification condition, but response times in the frame verification condition were longer with stimulation at the left anterior position. Because rTMS of the dominant hemisphere affected linguistic processing independent of speech motor output, we confirm that rTMS may be used to investigate language and other cognitive functions.

PET imaging of maze processing.

Covered maze traversal models nonverbal planning, involving sequential execution of moves using learned spatial maps. To determine the neural substrate involved in maze processing, eleven adults underwent [H(2)15O]-PET while performing motor control, following the computer; visual control, choosing the wall with more dead-ends; uncovered maze, traversing fully visible mazes; covered maze, traversing mazes only locally visible. Maze processing lateralizes to the right hemisphere: uncovered maze versus controls revealed area 23 and 29 activation; covered maze versus controls activated areas 8, 10 and 19. The extrastriate region may store path information, evoked by prefrontal areas for spatial planning and navigation.

Prevalence of tremor and Parkinson's disease.

To determine the prevalence of essential tremor (ET) and Parkinson's disease (PD) in a retirement community, all residents of Carefree, Arizona, aged over 65 years were contacted. All participants completed validated questionnaires for PD and ET, and were examined using the Unified Parkinson's Disease Rating Scale. Of 356 individuals evaluated, 155 (43.5%) had tremor; 73 (20.5%) had ET; 26 (7.3%) had PD; and 56 (15.7%) had postural tremor (PT). Thus, a large percentage of individuals were found to have tremor, in the plurality of whom it could be classified as ET. The number of individuals with Parkinson's disease exceeded our expectations.

Brain activation during script event processing.

Regional cerebral blood flow was measured with positron emission tomography in seven normal volunteers while they performed various script event verification tasks. The left frontal lobe, left anterior cingulate and the anterior part of the left superior temporal gyrus were more activated in the script event membership and action categorization conditions, whereas the right frontal lobe, left superior temporal gyrus and the middle temporal gyrus bilaterally were more activated in the script event temporal order verification condition. These results indicate that the temporal ordering of script events and determining whether an event belongs to a particular script or action category are processed by distinctive distributed neuronal networks.