Release of Alzheimer amyloid precursor derivatives stimulated by activation of muscarinic acetylcholine receptors.

Altered processing of the amyloid precursor protein (APP) is a central event in the formation of amyloid deposits in the brains of individuals with Alzheimer's disease. To investigate whether cellular APP processing is controlled by cell-surface neurotransmitter receptors, human embryonic kidney (293) cell lines were transfected with the genes for human brain muscarinic acetylcholine receptors. Stimulation of m1 and m3 receptor subtypes with carbachol increased the basal release of APP derivatives within minutes of treatment, indicating that preexisting APP is released in response to receptor activation. Receptor-activated APP release was blocked by staurosporine, suggesting that protein kinases mediate neurotransmitter receptor-controlled APP processing.

Iofetamine I 123 single photon emission computed tomography is accurate in the diagnosis of Alzheimer's disease.

To determine the diagnostic accuracy of iofetamine hydrochloride I 123 (IMP) with single photon emission computed tomography in Alzheimer's disease, we studied 58 patients with AD and 15 age-matched healthy control subjects. We used a qualitative method to assess regional IMP uptake in the entire brain and to rate image data sets as normal or abnormal without knowledge of subjects'clinical classification. The sensitivity and specificity of IMP with single photon emission computed tomography in AD were 88% and 87%, respectively. In 15 patients with mild cognitive deficits (Blessed Dementia Scale score, less than or equal to 10), sensitivity was 80%. With the use of a semiquantitative measure of regional cortical IMP uptake, the parietal lobes were the most functionally impaired in AD and the most strongly associated with the patients' Blessed Dementia Scale scores. These results indicated that IMP with single photon emission computed tomography may be a useful adjunct in the clinical diagnosis of AD in early, mild disease.

Putamen-midbrain functional connectivity is related to striatal dopamine transporter availability in patients with Lewy body diseases.

Prior work has shown that functional connectivity between the midbrain and putamen is altered in patients with impairments in the dopamine system. This study examines whether individual differences in midbrain-striatal connectivity are proportional to the integrity of the dopamine system in patients with nigrostriatal dopamine loss (Parkinson's disease and dementia with Lewy bodies). We assessed functional connectivity of the putamen during resting state fMRI and dopamine transporter (DAT) availability in the striatum using 11C-Altropane PET in twenty patients. In line with the hypothesis that functional connectivity between the midbrain and the putamen reflects the integrity of the dopaminergic neurotransmitter system, putamen-midbrain functional connectivity was significantly correlated with striatal DAT availability even after stringent control for effects of head motion. DAT availability did not relate to functional connectivity between the caudate and thalamus/prefrontal areas. As such, resting state functional connectivity in the midbrain-striatal pathway may provide a useful indicator of underlying pathology in patients with nigrostriatal dopamine loss.

Application of the National Institute on Aging (NIA)-Reagan Institute criteria for the neuropathological diagnosis of Alzheimer disease.

The Khachaturian criteria and the Consortium to Establish a Registry for Alzheimer Disease (CERAD) criteria for the neuropathological assessment of Alzheimer disease (AD) emphasize senile or neuritic plaques, age, and clinical history. A new scheme stressing topographic staging of neurofibrillary changes in addition to neuritic plaques has been proposed by the National Institute on Aging (NIA)-Reagan Institute Consensus Conference. This scheme assigns cases to high, intermediate, or low likelihood categories that the dementia is due to AD. We applied this method to 84 brains from subjects with clinical and neuropathological diagnoses of AD (n = 33), non-AD dementing illnesses (n = 34), including dementia with Lewy bodies (DLB) and progressive supranuclear palsy (PSP), and no neurological disease (n = 17). We also used Khachaturian and CERAD criteria. Neurofibrillary tangle and neuropil thread densities were assessed on 6-micrometer-thick modified Bielschowsky-stained paraffin sections from entorhinal-perirhinal cortex, CA1 of hippocampus, and neocortex including inferior temporal, visual association, and primary visual cortices. Each case was assigned a Braak and Braak stage. Using the NIA-Reagan criteria, we found excellent agreement between clinical history of AD dementia and brains assigned to the high likelihood category that dementia was due to AD. Among brains diagnosed neuropathologically with other degenerative diseases, NIA-Reagan criteria were more conservative than previous criteria, and these cases were likely to be categorized as intermediate or low likelihood that dementia was due to AD. All brains from nondemented subjects were assigned to the low (81%) or intermediate (19%) categories. In summary, we found good correlation between the NIA-Reagan criteria and clinical dementia, and there was generally good agreement between these criteria and existing neuropathological methods, Khachaturian and CERAD, in diagnosing AD. In studying several other neurodegenerative diseases, such as DLB, which shows neuropathological and clinical overlap with AD, the staging of neurofibrillary changes offered potential diagnostic refinement.

Piracetam combined with lecithin in the treatment of Alzheimer's disease.

Nootropics, a new class of drugs believed to activate mental functions, have been proposed as a treatment for clinical disorders in which cognition is impaired. We therefore administered the nootropic drug piracetam, alone and in combination with phosphatidylcholine (PC), to 18 patients with Alzheimer's disease (AD), and measured the effects of treatment on a broad range of cognitive functions. Piracetam was administered according to three double-blind crossover protocols and a replication study that differed in piracetam dose (2.4 to 9.9 g/day) and whether PC (18 g/day) was administered concurrently. The drug was well tolerated, and there were not toxic side effects. Plasma choline levels rose significantly during piracetam and PC administration; monoamine metabolites in cerebrospinal fluid were unaffected by treatment. Piracetam, either alone or in combination with PC, did not significantly affect cognition in the AD group as a whole, nor did it improve test performance in any single patient.

Incomplete achromatopsia in Alzheimer's disease.

We report that patients with Alzheimer's disease (AD) have a selective deficit in blue hue discrimination, as assessed with three clinical measures of color vision. The Farnsworth D-15 Test, the Lanthony New Color Test, and the City University Color Vision Test were administered to 32 patients with AD (ranging in dementia severity from mild to severe) and 32 age-matched normal control subjects (NCS). Of the AD patients, 11 who were representative of the larger group for age, education level, and dementia severity received a complete neuro-ophthalmological examination that ruled out obvious disorders of the anterior visual structures. AD patients made significantly more tritan (blue) errors than NCS on all three color vision tests but did not make more protan (red) or deutan (green) errors on two of the three tests. The results support the conclusion that there is a deficit in color discrimination in AD that is specific to blue hues, and oppose the hypothesis that AD does not deleteriously affect the color-opponent visual channel. In the absence of obvious damage to anterior visual structures, the likely substrates for the observed deficit are peristriate and inferotemporal visual cortices, which are subject to significant neuropathology in AD.

Broad-band visual capacities are not selectively impaired in Alzheimer's disease.

Histological examination of the optic nerves of Alzheimer's disease (AD) patients has revealed a selective degeneration of large axon ganglion cells. This morphological abnormality raises the possibility of a selective impairment of broad-band channel visual function. To test this hypothesis, we administered visual psychophysical tests associated with either the color-opponent or the broad-band retinocortical channel to 14 AD patients and 29 elderly control subjects (ECS). In previous studies in monkeys, these tests had been sensitive to the effects of either parvocellular or magnocellular LGN lesions. In the present study, the color-opponent channel was assessed by tests of texture and color discrimination; the broad-band channel was assessed by tests of flicker and motion detection. Logistic regression analysis indicated that all tests collectively discriminated diagnostic groups at a borderline level of significance (p = 0.09). ANOVA also indicated a trend towards overall depressed function for AD patients on some capacities tested. Analyses comparing the prevalence of deficits in the AD and ECS groups showed that a significantly greater number of AD patients than ECS had deficits on texture discrimination, blue-violet discrimination, and 4.72 degrees/s motion detection. No individual subject demonstrated a selective impairment of broad-band channel function. The visual deficits in AD did not resemble those caused by lesions of magnocellular LGN in monkeys, indicating that the visual impairment in AD is not a functional reflection of damage limited to the broad-band channel.(ABSTRACT TRUNCATED AT 250 WORDS)

Choline and lecithin in the treatment of tardive dyskinesia: preliminary results from a pilot study.

Tardive dyskinesia is thought to reflect increased dopaminergic activity of the central nervous system. To compensate for this by increasing CNS cholinergic tone, the authors administered oral choline and its natural dietary source, lecithin, to 5 men with mild to severe tardive dyskinesia in a nonblind trial. Both choline and lecithin increased serum choline levels and improved abnormal movements in all patients. Lecithin had fewer adverse effects.

The effects of dietary neurotransmitter precursors on human behavior.

The neurotransmitter precursors tryptophan and tyrosine are present in a variety of foods. In order to document possible effects of tryptophan and tyrosine on human behavior, single oral doses of these substances and matched placebos were administered to 20 men in a double-blind, crossover study. Various tests of mood state and performance were then administered. Tryptophan increased subjective fatigue and decreased self-ratings of vigor and alertness, but did not impair performance on any of the tests. Tyrosine produced no effects in our young population compared with placebo, but did decrease reaction time relative to tryptophan. It may be concluded that tryptophan has significant sedative-like properties, but unlike other sedatives may not impair performance.

Biomarkers of Alzheimer disease.

A definitive diagnosis of Alzheimer disease (AD) depends on finding widespread neurofibrillary tangles and plentiful neuritic plaques in the brain of an individual with a clinical diagnosis of progressive dementia. Using contemporary diagnostic criteria, the antemortem diagnosis of probable AD in centers specialized for AD is confirmed 80% to 90% of the time. There is the suspicion, but no firm data, that diagnostic accuracy is much lower outside of practices dedicated to patients with dementia. Furthermore, the diagnostic workup is expensive. In most settings, the evaluation generally includes a careful medical history and physical examination; neurologic examination (and psychiatric consultation as indicated); laboratory blood studies to exclude underlying metabolic and medical illnesses that masquerade as AD; a mental status assessment and formal cognitive tests; and a computed tomographic scan or magnetic resonance imaging of the brain. Because these procedures are time-consuming and costly, there is a need to identify biological tests that can circumvent aspects of this workup and point the physician to the correct diagnosis. It would be highly desirable to measure a substance or substances in blood or urine samples or cerebrospinal fluid (CSF) that would lead to a positive diagnosis of AD without the need for specialized dementia clinics and the expense and time of standard diagnostic evaluations. In response to this need, the Reagan Research Institute of the Alzheimer's Association and the National Institute on Aging convened a working group in 1997 to examine the status of various antemortem markers for AD. The consensus statement of this group, entitled "Molecular and Biochemical Markers of AD," was published in 1998. The consensus statement first defined the characteristics of an ideal biomarker, and then outlined the steps required for a proposed biomarker to achieve acceptance by the medical community. Finally, the statement reviewed the current state of all proposed biological markers. The workshop participants observed that none of the current biomarkers had yet achieved universal acceptance and concluded none fully met the consensus criteria for an ideal marker. Nonetheless, several tests were identified as good markers for familial AD, and several other tests showed promise as a diagnostic aid for sporadic AD. The purpose of this review is to put these recommendations into a practical context. What does the consensus statement tell the practicing clinician? How do the opinions in the consensus statement affect clinical practice in diagnosing and treating patients with dementia?

Cognitive test performance in detecting, staging, and tracking Alzheimer's disease.

OBJECTIVES: To identify the specific cognitive deficits that characterize Alzheimer's disease (AD) and determine which cognitive tests, or combination of tests, are best for detecting AD (ie, distinguishing patients with AD from normal control subjects), staging AD (ie, distinguishing different severities of dementia), and tracking disease progression. SUBJECTS: Patients with AD (n = 123) and normal control subjects (n = 60) of comparable age, education, and gender distribution. SETTING: Outpatient care. MEASURES: Ten cognitive tests of memory, language, visuospatial abilities, and reasoning; the Information, Memory and Concentration subtest of the Blessed Dementia Scale, and the total score on an activities of daily living questionnaire. DESIGN: Patients with AD were tested every 6 to 24 months over a span of up to 5.5 years. RESULTS: Patients with AD were significantly inferior to normal control subjects on all cognitive tests. The scores of patients with AD worsened over time. Delayed recall of stories and figures showed sharp deterioration to an early floor, consistent with the finding that these tests discriminated patients with mild AD from normal control subjects well but were poor for staging. Confrontation naming, semantic fluency, and immediate recognition of geometric figures showed steady linear decline across time for patients with AD, consistent with these tests being found best for staging dementia severity. CONCLUSIONS: We postulate that the pathologic bases of impairment in delayed recall are atrophy of cholinergic ventral forebrain neurons and partial deafferentation of the hippocampus, both of which occur early in the course of AD. Worsening language and visuospatial abilities likely reflect progressive loss of neocortical neurons and their connections.

CSF monoamine metabolite levels in Alzheimer's and Parkinson's disease.

Levels of the monoamine metabolites homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), and 3-methoxy-4-hydroxyphenylglycol (MHPG) were measured in lumbar CSF from 32 patients with a clinical diagnosis of Alzheimer's disease (AD) and from 21 patients with Parkinson's disease (PD). The baseline CSF metabolite values did not differ significantly between the two groups of patients, although HVA levels were lowest in patients with PD and in the more severely demented patients with AD. Levels of all three metabolites increased significantly in both patient groups during probenecid administration, but HVA levels were significantly higher in patients with AD than in patients with PD. Within the AD group, those with the most severe dementia had the greatest rise in MHPG levels. Alterations in monoamine metabolite levels in the CSF detected during probenecid administration aid in the differential diagnosis of neurodegenerative diseases such as AD.

Association of decreased paternal age and late-onset Alzheimer's disease. An example of genetic imprinting?

Several studies have identified advanced maternal age as a risk factor for Alzheimer's disease. This study evaluated maternal and paternal age at birth of 237 patients with Alzheimer's disease, each of whom was matched to five control subjects based on sex, year of birth, survival age, and location of residence. It was found that decreased paternal age substantially increased the susceptibility to the common form of Alzheimer's disease that occurs after the age of 67 years, whereas advanced maternal age had a negligible effect on risk of Alzheimer's disease. The higher incidence of late-onset Alzheimer's disease among persons born to younger fathers is consistent with a genetic imprinting mechanism involving DNA methylation. The proposed model postulates a role for environmental agents in the pathogenesis of Alzheimer's disease and accounts for families that show an aggregation of cases but no apparent pattern of inheritance.

Pupil dilation to tropicamide is not specific for Alzheimer disease.

BACKGROUND: The extent of pupil dilation after instillation of a dilute tropicamide solution was proposed as a noninvasive neurobiological diagnostic test for Alzheimer disease (AD). Pupils in patients with AD dilated 23% vs only 5% in control subjects. OBJECTIVE: To determine whether pupil dilation in response to tropicamide distinguishes patients with AD from control subjects without dementia. METHODS: There were 50 patients with AD and 51 control subjects; no participant had primarily ocular pathological conditions or took drugs that affected cholinergic tone. All participants received 1 drop of 0.01% tropicamide in 1 eye and 1 drop of 0.9% saline solution in the other eye in random order. Pupil measurements were obtained using a pupil and corneal reflection tracking system (RK-426 PC system, ISCAN Inc, Burlington, Mass) that illuminated the eye with a low-level infrared source and measured pupil diameters, fixation, and light level every 16.7 milliseconds during each 30-second-measurement. Pupil measurements were obtained from each eye at baseline and 5, 10, 15, and 30 minutes after drop instillation. RESULTS: The increase in pupil size after tropicamide instillation was equal between patients with AD and control subjects. The mean (+/- SD) pupil diameter increased from 4.5 +/- 1.1 to 5.5 +/- 1.1 mm after 30 minutes in patients with AD and from 4.7 +/- 0.9 to 5.8 +/- 0.9 mm in control subjects. Anisocoria and the mean rate of dilation did not differ between patients with AD and control subjects. Eye color and corneal moisture did not affect these results. The extent of pupil dilation in patients with AD was not related to clinical estimates of dementia severity. CONCLUSION: Pupil dilation in response to instillation of 0.01% tropicamide is not useful as an antemortem diagnostic test for AD.

Differences between Pick disease and Alzheimer disease in clinical appearance and rate of cognitive decline.

OBJECTIVES: To define the cognitive characteristics of Pick disease (PcD), and to determine which features distinguish PcD from Alzheimer disease (AD), in a cross-sectional and longitudinal study. METHODS: The participants were 44 patients with PcD (10 pathologically verified), 121 patients with AD (14 pathologically verified), and 60 normal control subjects. We obtained information regarding the initial symptom of dementia from each patient's caregiver, estimated global dementia severity by the Blessed Dementia Scale and the Activities of Daily Living Scale, and assessed specific cognitive domains by administering 10 tests of memory, language, visuospatial, and reasoning abilities and selective attention. RESULTS: Among initial symptoms reported by caregivers, personality change and language impairment were significantly more common in PcD than AD; deficits in memory were common in both groups but more prevalent in AD (P<.001). At initial cognitive testing, the scores of patients with PcD were inferior to those of normal controls on all tests, except on a measure of visuospatial function; the scores of patients with AD were inferior to those of controls on all tests. Patients with PcD were superior to patients with AD on measures of explicit memory (P<.001) and visuospatial function (P = .001) but had greater impairments on the Activities of Daily Living Scale (P<.05). During the course of illness, patients with PcD declined significantly faster than those with AD on language tests and on global measures of dementia severity (P<.05), whereas measures of explicit memory and visuospatial and reasoning abilities worsened equally in both patient groups. CONCLUSIONS: There is a characteristic cognitive profile and course of dementia in PcD. Nonetheless, cognitive test performance does not clearly distinguish PcD from AD.

Spatial vision in Alzheimer's disease. General findings and a case report.

Visual contrast sensitivity to sinusoidal gratings of five spatial frequencies was measured in 15 patients with Alzheimer's disease and in eight control subjects. Contrast sensitivity thresholds were elevated at all frequencies in 14 patients compared with control subjects. The 15th patient was unique: she had an impairment in object and face recognition so severe that she could not recognize her husband visually. Her sensitivity to low and intermediate frequencies was markedly reduced in relation to that of other patients, whereas her sensitivity to the highest frequency tested equaled theirs. These observations emphasize the importance of low spatial frequency information for visual object and face recognition.

Comparison of magnetic resonance and roentgen ray computed tomography in dementia.

To compare the merits of magnetic resonance imaging (MRI) and roentgen ray computed tomography (CT) in assessing patients with dementia, we examined pairs of MR and CT brain images obtained from 26 patients with Alzheimer's disease (AD), eight patients with vascular or mixed dementia, and two patients with Parkinson's disease plus dementia. Magnetic resonance and CT images were independently rated on a qualitative scale of 0 (normal) to 3 (severely abnormal) in 39 separate brain regions. Ratios of anterolateral and third ventricular linear spans to linear skull spans were measured. Abnormalities in subcortical white matter and in hippocampus, enlargement of basal and sylvian cisterns, and ventriculomegaly were more evident on MR than CT scans, but qualitative ratings in all other brain regions were similar. Linear ventricular span ratios based on MR images did not differ significantly from those measured on CT. White matter abnormalities on MR were high signal foci on T2-weighted images whose pathologic substrate was uncertain; in a single case studied pathologically, no abnormalities were detected in brain regions that contained high signal foci. Dementia severity correlated with periventricular white matter abnormalities on both MR and CT images.

Single photon emission computed tomography in Alzheimer's disease. Abnormal iofetamine I 123 uptake reflects dementia severity.

To determine whether abnormalities in regional cerebral functional activity estimated by iofetamine hydrochloride I 123 and single photon emission computed tomography can be detected in mild or moderate as well as severe cases of Alzheimer's disease (AD), we performed iofetamine I 123-single photon emission computed tomography in 37 patients with probable AD (nine patients with mild, 18 patients with moderate, and ten patients with severe dementia) and nine age-matched control subjects. Iofetamine I 123 uptake was measured in right and left frontal, temporal, parietal, and occipital cortices. Mean (right and left) iofetamine I 123 activity was lowest in the parietal region of patients with AD and was significantly reduced in the other three regions compared with control subjects. Only in the parietal region was lower relative iofetamine I 123 activity associated with an impaired level of patient function and with cognitive deficit.

Rate of progression of Alzheimer's disease is associated with genetic risk.

OBJECTIVE: To determine whether differences in genetic origin affect the clinical course of Alzheimer's disease (AD). The limited number of cases of AD linked to a known genetic abnormality is a major obstacle in determining whether the disorder is expressed differently in patients with familial AD and those with sporadic AD. DESIGN: Cross-sectional study. SETTING: Memory Disorders Unit of the Alzheimer's Disease Research Center at Massachusetts General Hospital, Boston. PARTICIPANTS: A total of 186 patients who had a clinical diagnosis of probable AD, family history information available for all first-degree relatives, and three or more outpatient visits were identified from a consecutive case series. MAIN OUTCOME MEASURES: Rate of decline on the Blessed Dementia Scale and the Activities of Daily Living Scale. RESULTS: We calculated the probability that an individual patient has a major genetic locus for AD (MGAD) using an algorithm that incorporates information from a genetic model and the individual's family. We measured cognitive and functional changes by the average annual rate of increase (slope) in scores for the Blessed Dementia Scale and Activities of Daily Living Scale, respectively. Multivariate analysis adjusted for age at onset, duration of illness at entry into the study, and education level indicated that scores on the Activities of Daily Living Scale worsened significantly faster in men with MGAD than in men with non-MGAD. No differences in Activities of Daily Living Scale slopes were observed among women with MGAD and non-MGAD. The slopes for Blessed Dementia Scale scores were similar in men and women regardless of the MGAD probability. CONCLUSIONS: Genetic factors may account for heterogeneity in rates of functional decline in AD. This study also illustrates the practical application of a probabilistic method that characterizes the genetic status of AD in an individual patient.

Retinocalcarine function in Alzheimer's disease. A clinical and electrophysiological study.

Impaired visual function in Alzheimer's disease (AD) could result from either precortical or cortical lesions, or both. In a parallel psychophysical study of visual function in AD, we found that contrast sensitivity function, color vision, stereoacuity, and backward masking were impaired relative to the performance of age-matched control subjects, whereas performance on a critical flicker fusion test was normal. The intent of the present study was to determine whether abnormalities of the retinocalcarine pathway contribute to visual dysfunction. We performed neuro-ophthalmological examinations on 38 patients with AD; from this group, 25 received additional psychophysical testing and 13 underwent electrophysiological testing. Clinical neuro-ophthalmological examinations, full-field electroretinograms, focal electroretinograms, and pattern visual evoked potentials were normal in all patients tested. There was no evidence of retinocalcarine abnormality specific to AD. We conclude that the visual impairment experienced by some patients with AD primarily results from involvement of the visual association cortices rather than from precortical damage, at least before the end stage of the disease.