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The effects of age on serotonergic function have been hypothesized to underlie age-related changes in mood and behaviors such as sleep and eating. Of particular interest is the serotonin type-1A (5-HT1A) receptor, due to its putative role in mediating the therapeutic efficacy of antidepressant treatment. Using positron emission tomography (PET) and [11C--carbonyl] WAY100635, we assessed 5-HT1A receptor binding in 21 healthy subjects (10 men, 11 women) ranging in age from 21 to 80 years. Regional binding potential values were generated using a reference tissue model and corrected for partial volume effects. We observed an inverse relationship between age and binding of [11C--carbonyl] WAY100635 to the 5-HT1A receptor in men, but not women. This finding is in accord with observations reported in the postmortem literature. Gender-specific effects of age on central serotonergic function may relate to differences between men and women in behavior, mood, and susceptibility to neuropsychiatric disease across the adult lifespan.

Background: Lewy bodies (LB) are present in at least 20% to 30% of persons with Alzheimer disease (AD) and contribute to the risk of psychosis and to excess cognitive burden., Objective: To determine whether altered striatal dopamine receptor binding is associated with LB and psychosis in AD., Design: Postmortem case control., Setting: Alzheimer's Disease Research Center at the University of Pittsburgh (Pa)., Participants: Consecutive cases from the Alzheimer's Disease Research Center brain bank, neuroleptic free for at least 1 month prior to death, with neuropathologic diagnoses of AD with LB (AD + LB, n = 14), AD without LB (AD, n = 13), or normal brains (n = 8)., Main Outcome Measures: Dopamine D1, D2, and D3 receptor densities, and affinities as determined by selective saturation binding studies in striatal tissue., Results: Subjects with AD + LB, compared with those with AD, demonstrated increased D1 receptor density and decreased D2 and D3 receptor density. D3 receptor density was selectively increased, however, in AD subjects with a history of psychosis, independent of the presence or absence of LB. The effect of neuroleptic treatment on D3 binding was further examined in an additional group of subjects who had received neuroleptics near the time of death. Neuroleptic treatment reduced D3 affinity with no effect on D3 density., Conclusions: Alzheimer disease with LB is associated with selective alterations in dopamine receptor density, which may contribute to the distinct clinical profile of this group. The D3 receptor may be an important target of neuroleptic treatment of psychosis in AD.

This study was undertaken to investigate the role of two alpha2-macroglobulin (A2M) polymorphisms, an intronic 5-bp deletion and Ile1000Val, in the development of Alzheimer's disease (AD) and to evaluate the interaction between the apolipoprotein E (APOE) and A2M polymorphisms. The A2M polymorphisms were screened by using polymerase-chain-reaction-based assays in 555 white late-onset AD cases and 446 controls. The gentoype distributions of the 5-bp deletion and Ile1000Val polymorphisms were comparable between cases and controls (P = 0.158 and P = 0.148, respectively). Likewise, there was no significant difference in allele frequencies of each polymorphism among cases and controls (P = 0.361 and P = 0.062, respectively). The stratification of data by APOE*4 status also did not yield any significant association. In conclusion, we observed no association between either the intronic deletion polymorphism or the Ile1000Val polymorphism of A2M and AD in our case-control cohort.

Layer II of the entorhinal cortex contains the cells of origin for the perforant path, plays a critical role in memory processing, and consistently degenerates in end-stage Alzheimer's disease. The extent to which neuron loss in layer II of entorhinal cortex is related to mild cognitive impairment without dementia has not been extensively investigated. We analyzed 29 participants who came to autopsy from our ongoing longitudinal study of aging and dementia composed of religious clergy (Religious Orders Study). All individuals underwent detailed clinical evaluation within 12 months of death and were categorized as having no cognitive impairment (n = 8), mild cognitive impairment (n = 10), or mild or moderate Alzheimer's disease (n = 11). Sections through the entorhinal cortex were immunoreacted with an antibody directed against a neuron-specific nuclear protein (NeuN). Stereological counts of NeuN-immunoreactive stellate cells, their volume, and the volume of layer II entorhinal cortex were estimated. Cases exhibiting no cognitive impairment averaged 639,625 +/- 184,600 layer II stellate neurons in the right entorhinal cortex. Individuals with mild cognitive impairment (63.5%; p < 0.0003) and mild or moderate Alzheimer's disease (46.06%; p < 0.0017) displayed significant losses of layer II entorhinal cortex neurons relative to those with no cognitive impairment but not relative to each other (p > 0.33). There was also significant atrophy of layer II entorhinal cortex neurons in individuals with mild cognitive impairment (24.1%) and Alzheimer's disease (25.1%). The volume of layer II was also reduced in individuals with mild cognitive impairment (26.5%), with a further reduction in those with Alzheimer's disease (46.4%). The loss and atrophy of layer II entorhinal cortex neurons significantly correlated with performance on clinical tests of declarative memory. Atrophy of layer II entorhinal cortex and the neurons within this layer significantly correlated with performance on the Mini Mental Status Examination. These data indicate that atrophy and loss of layer II entorhinal cortex neurons occur in elderly subjects with mild cognitive impairment prior to the onset of dementia and suggests that these changes are not exacerbated in early Alzheimer's disease.

Researchers in Alzheimer's disease (AD) have made remarkable strides in the past 2 decades in characterizing the disorder, understanding its pathophysiology, and developing models for assessing treatment. With these successes and the promise of others to come, researchers and policy makers alike are keeping a nervous eye on the "demographic clock," which predicts that with the aging of the US population (and indeed the world), a massive increase in the number of AD cases and related dementias will emerge, flooding our medical care system and overwhelming our ability to care for these patients and their caregivers. This article explores some of the data underlying the explosion of AD and discusses the clinical disorder, its manifestations, and our advances in understanding the underlying pathobiology. Our growing knowledge of AD pathophysiology will lead us to the development of more effective medications to slow the progression or even prevent the emergence of this dreaded disorder.

To benefit Alzheimer's disease research, a central data co-ordinating centre (CDCC) is planned that will systematically collect data from 27 Alzheimer's disease centres (ADCs) located nationwide. This CDCC will combine, analyse and disseminate epidemiologic, demographic, clinical and neuropathological data to researchers from the ADCs and the broader scientific community. New and larger scale collaborative studies on Alzheimer's disease will be possible through this centre. Since 1 July 1997, an interim data co-ordinating centre (IDCC) has been serving as the agent of the ADCs to begin the data sharing process until a permanent CDCC is established. The data collected by the IDCC are limited to administrative information and to indexing of specimens and clinical material, with future plans for the transfer of the data collected to the CDCC once it is established., (Copyright 2000 John Wiley & Sons, Ltd.)

Background: The APOE*E4 allele of the gene for apolipoprotein E (APOE) has been reported as a risk factor for Alzheimer disease (AD) to varying degrees in different ethnic groups., Objective: To compare APOE*E4-AD epidemiological associations in India and the United States in a cross-national epidemiological study., Design: Case-control design within 2 cohort studies, using standardized cognitive screening and clinical evaluation to identify AD and other dementias and polymerase chain reaction to identify APOE genotyping., Participants: Rural community samples, aged 55 years or older (n=4450) in Ballabgarh, India, and 70 years or older (n=886) in the Monongahela Valley region of southwestern Pennsylvania., Main Outcome Measures: Criteria of the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association for probable and possible AD and Clinical Dementia Rating (CDR) scale for dementia staging., Results: Frequency of APOE*E4 was significantly lower (P<.001) in Ballabgarh vs the Monongahela Valley (0.07 vs 0.11). Frequency of probable or possible AD, with CDR of at least 1.0, in the Indian vs US samples, was as follows: aged 55 to 69 years, 0.1% (Indian sample only); aged 70 to 79 years, 0.7% vs 3.1%; aged 80 years or older, 4.0% vs 15.7%. Among those aged 70 years or older, adjusted odds ratios (95% confidence interval) for AD among carriers of APOE*E4 vs noncarriers were 3.4 (1.2-9.3) and 2.3 (1.3-4.0) in the Indian and US samples, respectively, and not significantly different between cohorts (P=. 20)., Conclusion: This first report of APOE*E4 and AD from the Indian subcontinent shows very low prevalence of AD in Ballabgarh, India, but association of APOE*E4 with AD at similar strength in Indian and US samples. Arch Neurol. 2000.

Alzheimer's disease (AD) is a complex disease involving several genetic and environmental components. Genetic studies have yet to identify all the genes involved in the pathogenesis of AD. Transforming growth factor-beta1 (TGF-beta1) is a candidate gene for AD. It is a multifunctional cytokine whose overexpression has been shown to promote the deposition of amyloid-beta peptide. The goal of this study was to investigate the association of three polymorphisms in TGF-beta1 with the risk of AD. Two of the polymorphisms are located in the 5' region at positions -800 (G-->A) and -509 (C-->T), and the third is in exon 5 at codon 263 (Thr-->Ile). We screened DNA samples from 428 sporadic, late-onset patients and 421 controls by PCR-based assays. There was no statistically significant difference in genotype or allele frequency distributions between cases and controls for the -800 or codon 263 polymorphisms (P=0.38 and P=0.60, respectively). The overall genotype distribution at the -509 site was significantly different between cases and controls. (P=0.017). The frequency of the -509/TT genotype was significantly higher in AD patients than controls (P=0.015). We further tested whether this polymorphism may alter the regulation of the TGF-beta1 gene using dual luciferase reporter assay. We subcloned the 5' flanking region, which contained the -509 C/T polymorphic sites, in front of the firefly luciferase reporter gene in pGL-3 basic vector and co-transfected with the pRL-CMV vector containing Renilla luciferase gene as a control for transfection efficiency in COS-1 cells. The activity of each promoter allele was directly measured by the ratio of firefly luciferase activity to Renilla luciferase activity. The -509 T allele was associated with marginally higher transcriptional activity of TGF-beta compared with the -509 C allele (P=0.051). These data suggest that the -509 polymorphism of TGF-beta1 may be modestly associated with the risk of AD. However, these data should be interpreted with caution as the differences associated with the -509 alleles in both the genetic association and the transfection studies were modest.

The Neuropsychiatric Inventory (NPI) is a validated clinical instrument for evaluating psychopathology in dementia. The authors developed a brief questionnaire form of the NPI (NPI-Q), intended for use in routine clinical practice, and cross-validated it with the NPI in 60 Alzheimer's patients. Test-retest reliability of the NPI-Q was acceptable. The prevalence of analogous symptoms reported on the NPI and NPI-Q differed on average by 5%; moderate or severe symptom ratings differed by less than 2%. The NPI-Q provides a brief, reliable, informant-based assessment of neuropsychiatric symptoms and associated caregiver distress that may be suitable for use in general clinical practice.

Objective: To determine whether there are abnormalities in the in vivo status of the serotonin type 2A (5-HT2A) receptor in late-life depression and Alzheimer's disease, the authors used positron emission tomography (PET) to assess patients with these two conditions and healthy subjects., Method: PET was performed by using [18F]altanserin to evaluate 5-HT2A receptor binding in 11 elderly patients with depression (four men, seven women; mean age = 65.0 years, SD = 5.5); nine Alzheimer's disease patients, including three with concurrent depression (two men, seven women; mean age = 69.7 years, SD = 5.0); and 10 age-matched healthy subjects (four men, six women; mean age = 69.8 years, SD = 5.0). Partial-volume correction of regional specific binding estimates was performed by using a method based on magnetic resonance imaging., Results: No significant abnormalities in [18F]altanserin binding (binding potential) were observed in the patients with late-life depression, and no effect of depression on binding potential was present within the Alzheimer's disease group. However, the patients with Alzheimer's disease had significantly lower binding than the normal subjects in several brain regions, including the anterior cingulate, prefrontal cortex, and sensorimotor cortex., Conclusions: These results suggest that the 5-HT2A receptor is differentially affected in late-life depression and Alzheimer's disease, a finding that has implications for the etiological basis of mood and cognitive features of neuropsychiatric disorders of late life.

Objective: To examine whether the use of psychiatric medication and the presence of abnormal behaviors affects the progression of Alzheimer disease., Design: Cross-sectional with longitudinal follow-up and the likelihood of arriving at 4 end points: (1) Mini-Mental State Examination score of 9 or lower; (2) Blessed Dementia Rating Scale score of 15 or higher for activities of daily living; (3) nursing home admission; and (4) death, evaluated using a proportional hazard model with 9 variables: psychosis, insomnia, wandering, aggression, psychomotor agitation, depression, and use of antidepressants, antipsychotic agents, or sedatives/hypnotics., Setting: Multidisciplinary dementia research clinic., Patients: We examined baseline and follow-up behavioral symptoms and the use of psychiatric medication in 179 mildly to moderately impaired patients with probable Alzheimer disease participating in a longitudinal study of dementia. Patients were observed from 2.4 to 172 months (mean duration +/- SD, 49.5+/-27.4 months)., Results: Nine patients (5%) were taking sedatives/ hypnotics; 16 (9%), antipsychotic agents; and 22 (12%), antidepressants at study entry. Patients taking antipsychotic agents had lower Mini-Mental State Examination scores and higher Blessed Dementia Rating Scale scores for activities of daily living than patients not taking any medication. Using proportional hazard analysis with time-dependent covariates for individual psychiatric symptoms and medications, we found that the development of psychosis was associated with functional decline (time to Blessed Dementia Rating Scale score of > or =15), institutionalization, aggression, and agitation with functional decline after adjusting for age at study entry, education, Mini-Mental State Examination scores, and Blessed Dementia Rating Scale scores. Use of antipsychotic medication was associated with functional decline, and sedatives/hypnotics with death. Neither the presence of psychiatric symptoms nor use of medication was associated with rate of cognitive decline (time to Mini-Mental State Examination score of < or =9)., Conclusions: These findings indicate that the use of antipsychotic agents and sedatives can affect the natural course of Alzheimer disease. Psychosis, agitation, and aggression are important predictors of outcome, even when the effects of medication to treat them is taken into account.

Nitric oxide (NO) derived from the inducible isoform of NO synthase (iNOS) is an inflammatory product implicated both in secondary damage and in recovery from brain injury. To address the role of iNOS in experimental traumatic brain injury (TBI), we used 2 paradigms in 2 species. In a model of controlled cortical impact (CCI) with secondary hypoxemia, rats were treated with vehicle or with 1 of 2 iNOS inhibitors (aminoguanidine and L-N-iminoethyl-lysine), administered by Alzet pump for 5 days and 1. 5 days after injury, respectively. In a model of CCI, knockout mice lacking the iNOS gene (iNOS(-/-)) were compared with wild-type (iNOS(+/+)) mice. Functional outcome (motor and cognitive) during the first 20 days after injury, and histopathology at 21 days, were assessed in both studies. Treatment of rats with either of the iNOS inhibitors after TBI significantly exacerbated deficits in cognitive performance, as assessed by Morris water maze (MWM) and increased neuron loss in vulnerable regions (CA3 and CA1) of hippocampus. Uninjured iNOS(+/+) and iNOS(-/-) mice performed equally well in both motor and cognitive tasks. However, after TBI, iNOS(-/-) mice showed markedly worse performance in the MWM task than iNOS(+/+) mice. A beneficial role for iNOS in TBI is supported.

Experimental traumatic brain injury (TBI) produces cholinergic neurotransmission deficits that may contribute to chronic spatial memory deficits. Cholinergic neurotransmission deficits may result from presynaptic alterations in the storage and release of acetylcholine (ACh) or from changes in the receptors for ACh. The vesicular ACh transporter (VAChT) mediates accumulation of ACh into secretory vesicles, and the M2 muscarinic receptor subtype can modulate cholinergic neurotransmission via a presynaptic inhibitory feedback mechanism. We examined the effects of controlled cortical impact (CCI) injury on hippocampal VAChT and M2 muscarinic receptor subtype protein and medial septal mRNA levels at 4 weeks following injury. Rats were anesthetized and surgically prepared for CCI injury (4 m/sec, 2.5 to 2.9 mm in depth) and sham surgery. Animals were sacrificed, and coronal sections (35 microm thick) were cut through the dorsal hippocampus for VAChT and M2 immunohistochemistry. Semiquantitative measurements of VAChT and M2 protein in hippocampal homogenates from injured and sham rats were assessed with Western blot analysis. Changes in VAChT and M2 mRNA levels were evaluated by reverse transcriptase polymerase chain reaction (RT-PCR). At 4 weeks after injury, both immunohistochemical and Western blot methods demonstrated an increase in hippocampal VAChT protein. An increase in VAChT mRNA was also observed. Immunohistochemistry demonstrated a loss of M2; however, there was no significant change in M2 mRNA levels in comparison with sham controls. These changes may represent a compensatory response of cholinergic neurons to increase the efficiency of ACh neurotransmission chronically after TBI through differential transcriptional regulation.

Controlled cortical impact (CCI) produces blood-brain barrier (BBB) permeability and an acute inflammatory response in injured brain, associated with upregulation of cell adhesion molecules and accumulation of neutrophils. Nevertheless, the role of acute inflammation in the pathogenesis of BBB permeability after traumatic brain injury (TBI) is undefined. The purpose of this study was to examine the time course of acute inflammation and BBB permeability after CCI in rats and to determine the effect of neutrophil depletion on BBB permeability early after CCI. In the first protocol, four groups of rats (n = 4-7/group) were subjected to CCI. Expression of endothelial (E)-selectin on cerebrovascular endothelium, accumulation of neutrophils, and BBB permeability were measured in brain at 1, 4, 8, and 24 hours after injury by immunohistochemistry or spectrophotometric quantification of Evans blue. E-selectin upregulation and neutrophil accumulation in injured brain occurred at later times than maximal BBB permeability. In a second protocol, rats made neutropenic with a murine monoclonal IgM antibody (RP-3) specific for rat neutrophils were subjected to CCI, given Evans blue at 3.5 hours, and sacrificed at 4 hours after injury. Neutrophil depletion did not affect BBB permeability at 4 hours after CCI. We conclude that events other than those mediated by neutrophils initiate BBB permeability early after CCI.

Background: The temporal relationship between the appearance of depressive symptoms and the clinical onset of dementia and Alzheimer disease was evaluated in a community sample., Methods: An original sample of 1366 subjects aged 65 years or older, selected randomly from a rural Pennsylvania community, was cognitively screened at study entry and every 2 years thereafter. A subset of 954 survivors of this cohort without dementia was screened for depressive symptoms at the second and subsequent data-collection waves. A "depression cluster" was identified by the presence of 5 or more depressive symptoms, including depressed mood, at the time of screening. Cognitively impaired subjects and a sample of unimpaired controls underwent standardized clinical evaluation to determine the presence of incident dementia (by DSM-III-R criteria) and probable or possible Alzheimer disease (by criteria of the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association) and to estimate the clinical onset of dementia symptoms., Results: A highly increased probability of the depression cluster developing existed among subjects following the onset of dementia (15.4% [6/39]) and Alzheimer disease (17.6% [6/34]) compared with subjects without dementia (3.2% [23/712]). The odds ratios, after adjustment for age, sex, education level, and self reported memory loss, for the development of depression were 6.5 (95% confidence interval, 2.2-19.1) in subjects with Alzheimer disease and 5.2 (95% confidence interval, 1.8-15.2) in subjects with overall dementia. Depressive symptoms did not confer a significantly increased relative risk of dementia (1.27; 95% confidence interval, 0.55-2.93) or Alzheimer disease (1.28; 95% confidence interval, 0.51-3.20)., Conclusion: Depressive symptoms appeared to be early manifestations, rather than predictors, of Alzheimer disease in this community sample.

Alzheimer's disease (AD) is a complex disease with the possible involvement of several genes. Genetic studies on sporadic late-onset AD have determined APOE*4 to be the major risk factor. Members of the synuclein gene family are potential candidates for the risk of AD. The persyn gene (gamma-synuclein) has recently been characterized and a common polymorphism (Glu110Val) has been identified. In this study we investigated the association of this polymorphism with sporadic late-onset AD patients. We screened DNA samples of 313 late-onset cases and 352 controls. No significant association was observed between the missense mutation and AD. When the data were stratified by APOE*4 carriers and non-APOE*4 carriers, no difference was seen for the Glu110Val polymorphism. There was also no difference in genotype or allele frequency when stratified by the ACT*A allele. Although our data show no effect of this persyn polymorphism in AD, characterization of additional polymorphisms in this gene may provide more conclusive answers.

Persistent cognitive deficits are one of the most important sequelae of head injury in humans. In an effort to model some of the structural and neuropharmacological changes that occur in chronic postinjury brains, we examined the longitudinal effects of moderate vertical controlled cortical impact (CCI) on place learning and memory using the Morris water maze (MWM) test, morphology, and vesicular acetylcholine (ACh) transporter (VAChT) and muscarinic receptor subtype 2 (M2) immunohistochemistry. Vertical CCI (left parietal cortex, 4 m/sec, 2.5 mm; n = 10) or craniotomy (sham) was produced in male Sprague-Dawley rats (n = 10). Place learning was tested at 2 weeks, 4 weeks, 3 months, 6 months, and 12 months postinjury with the escape platform in a different maze quadrant for each time point. At each interval, rats received 5 days of water maze acquisition (latency to find hidden platform), a probe trial to measure place memory, and 2 days of visible platform trials to control for nonspecific deficits. At 3 weeks, half the animals were sacrificed for histology. At these injury parameters, CCI produced no significant differences in place learning between injured and sham rats at 2 weeks, 4 weeks, or 6 months after injury. However, at 3 and 12 months, the injured rats took significantly longer to find the hidden platform than the sham rats. Probe trial performance differed only at 12 months postinjury between injured (25.73+/-2.1%, standard error of the mean) and sham rats (44.09+/-7.0%, p < 0.05). The maze deficits at 1 year were not due to a worsening of performance, but may have resulted from a reduced ability of injured rats to benefit from previous water maze experience. Hemispheric loss of 30.4+/-5.5 mm3 was seen at 3 weeks after injury (versus respective sham). However, hemispheric loss almost doubled by 1 year after injury (51.5+/-8.5 mm3, p < 0.05 versus all other groups). Progressive tissue loss was also reflected by a three- to fourfold increase in ipsilateral ventricular volume between 3 weeks and 1 year after injury. At 1 year after injury, immunostaining for VAChT was dramatically increased in all sectors of the hippocampus and cortex after injury. Muscarinic receptor subtype 2 (M2) immunoreactivity was dramatically decreased in the ipsilateral hippocampus. This suggests a compensatory response of cholinergic neurons to increase the efficiency of ACh neurotransmission. Moderate CCI in rats produces subtle MWM performance deficits accompanied by persistent alteration in M2 and VAChT immunohistochemistry and progressive tissue atrophy. The inability of injured rats to benefit from repeated exposures to the MWM may represent a deficit in procedural memory that is independent of changes in hippocampal cholinergic systems.

Nerve growth factor beta subunit (beta-NGF) transgene delivery and expression by herpes simplex virus type 1 (HSV-1) vectors was examined in a cell culture model of neuroprotection from hydrogen peroxide toxicity. Replication-competent (tk- K mutant background) and replication-defective (ICP4(-);tk- S mutant background) vectors were engineered to contain the murine beta-NGF cDNA under transcriptional control of either the human cytomegalovirus immediate-early gene promoter (HCMV IEp) (e.g., KHN and SHN) or the latency-active promoter 2 (LAP2) (e.g., KLN and SLN) within the viral thymidine kinase (tk) locus. Infection of rat B103 and mouse N2A neuronal cell lines, 9L rat glioma cells, and Vero cells with the KHN or SHN vectors resulted in the production of beta-NGF-specific transcripts and beta-NGF protein reaching a maximum at 3 days postinfection (p.i.). NGF protein was released into the culture media in amounts ranging from 10.83 to 352.86 ng/ml, with the highest levels being achieved in B103 cells, and was capable of inducing neurite sprouting of PC-12 cells. The same vectors produced high levels of NGF in primary dorsal root ganglion (DRG) cultures at 3 days. In contrast to HCMV IEp-mediated expression, the LAP2-NGF vectors showed robust expression in primary DRG neurons at 14 days. The neuroprotective effect of vector produced NGF was assessed by its ability to inhibit hydrogen peroxide-induced neuron toxicity in primary DRG cultures. Consistent with the kinetics of vector-mediated NGF expression, HCMV-NGF vectors were effective in abrogating the toxic effects of peroxide at 3 but not 14 days p.i. whereas LAP2-NGF vector transduction inhibited apoptosis in DRG neurons at 14 days p.i. but was ineffective at 3 days p.i. Similar kinetics of NGF expression were observed with the KHN and KLN vectors in latently infected mouse trigeminal ganglia, where high levels of beta-NGF protein expression were detected at 4 wks p.i. only from the LAP2; HCMV-NGF-driven expression peaked at 3 days but could not be detected during HSV latency at 4 weeks. Together, these results indicate that (i) NGF vector-infected cells produce and secrete mature, biologically active beta-NGF; (ii) vector-synthesized NGF was capable of blocking peroxide-induced apoptosis in primary DRG cultures; and (iii) the HCMV-IEp functioned to produce high levels of NGF for several days; but (iv) only the native LAP2 was capable of long-term expression of a therapeutic gene product in latently infected neurons in vivo.

The serotonin (5-HT) neurotransmitter system, which has a widespread distribution in the central nervous system, has been implicated in regulating mood and many human behaviors. There is evidence from postmortem human studies and limited information from prior in vivo studies to support a decline in 5-HT2A receptor density with aging. We examined nine elderly (ages 61-76) and nine young (ages 18-29) healthy individuals with positron emission tomography (PET) and [18F]altanserin, a ligand with high affinity for the 5-HT2A binding site. The PET data were corrected for differences in brain tissue volume between the young and elderly subjects using a magnetic resonance (MR) imaging-based partial volume correction method. Highly significant and widespread cortical reductions in 5-HT2A specific binding were demonstrated in the elderly group relative to young controls. Regional losses averaged 61% before and 57% following correction for effects of cerebral atrophy. This finding, which is consistent with prior postmortem and in vivo studies, has both etiological and potential therapeutic implications for behavioral changes commonly observed in the elderly, including geriatric depression., (Copyright 1998 Published by Elsevier Science B.V.)

Objective: To examine if selected polymorphisms in the dopamine receptor genes DRD1, DRD2, DRD3, and DRD4 are associated with the presence of psychosis or aggressive behavior in patients with Alzheimer disease (AD)., Design: A cohort of patients with AD were longitudinally evaluated for behavioral symptoms and classified with regard to the presence of psychotic symptoms and physical aggression., Setting: Alzheimer's Disease Research Center., Patients: Two hundred seventy-five elderly outpatients diagnosed as having probable AD., Results: Among white patients, psychosis and aggression were both significantly more frequent in DRD1 B2/B2 homozygotes (P < .02), while psychosis was significantly more frequent in DRD3 1/1 or 2/2 homozygotes (P < .05). The joint risk for psychosis due to the DRD1 and DRD3 polymorphisms exceeded the risks due to either locus alone, suggesting an interaction. Neither the DRD2 S311C polymorphism nor the presence of long alleles for the DRD4 exon III repeat sequence was associated with psychosis or aggression., Conclusions: Genetic variation in DRD1 and DRD3 genes may act to modify the course of AD, predisposing to the development of psychotic or aggressive symptoms. Confirmation in other samples of patients with AD is required.

Leukocyte-endothelial adhesion molecules, critical to the development of acute inflammation, are expressed in brain as part of the acute inflammatory response to traumatic brain injury (TBI). We measured the concentrations of the adhesion molecules P-selectin, ICAM-1, E-selectin, L-selectin, and VCAM-1 in ventricular cerebrospinal fluid (CSF) from children with severe TBI (Glasgow coma score < 8) and compared these findings with those from children with bacterial meningitis. P-selectin, an adhesion molecule associated with ischemia/reperfusion, was increased in children with TBI versus meningitis and control. Univariate and multivariate regression analyses demonstrated associations between CSF P-selectin and child abuse and age of < 4 years, and a significant, independent association between CSF intercellular adhesion molecule-1 (ICAM-1) and child abuse. These results are consistent with a specific acute inflammatory component to TBI in children. Future studies of secondary injury mechanisms and therapy after TBI should assess on the roles of P-selectin and ICAM-1 in injury and repair processes in brain after TBI.

We have investigated the association of two candidate genes on chromosome 14, presenilin 1 (PS1) and alpha1-antichymotrypsin (ACT), with the risk of sporadic Alzheimer's disease (AD) by using 427 AD cases and 250 controls. The frequency of the ACT*A allele was significantly higher in cases than controls (0.550 vs 0.466). The stratification of the ACT data by PS1 genotypes showed that the risk associated with the ACT*A allele was confined to PS1*1 carriers only. The two-site haplotype data for PS1 and ACT showed that the A1 haplotype, carrying the ACT*A and PS1*1 alleles, was more frequent in cases than controls (0.310 vs 0.251), whereas the frequency of the T2 haplotype, carrying the ACT*T and PS1*2 alleles, was lower in cases than controls (0.177 vs 0.237). These data indicate a possible synergistic effect of these two loci on the risk of AD.

Type 2 5'-deiodinase (5'-D2), which converts thyroxine to the more active thyroid hormone 3,5,3'-triiodothyronine (T3), is believed to be an important source of intracellular T3 in the brain. The activity of this enzyme is increased in hypothyroidism and decreased in hyperthyroidism, and as such, it serves an important role to protect the brain from wide fluctuations in T3 during changes in thyroidal state. Although it has been hypothesized that T3 may facilitate neuronal regeneration after CNS injury, the 5'-D2 response to brain injury is unknown. To assess the 5'-D2 mRNA response to injury, we performed in situ hybridization following traumatic brain injury. In unlesioned animals, 5'-D2 mRNA was undetectable. At 3 days posttrauma, 5'-D2 mRNA was detected in ipsilateral cortex near the contusion. A significant further increase of 5'-D2 mRNA was noted 7 days posttrauma in both hippocampus and cortex. Similar response was also observed on the contralateral side. Colocalization of 5'-D2 mRNA with glial fibrillary acidic protein indicates that reactive astrocytes were the major cellular source for the trauma-induced 5'-D2 expression. These data demonstrate, for the first time, a trauma-induced, astrocytic up-regulation of 5'-D2 mRNA, suggesting a potential role for T3 action in adult brain's response to injury and recovery.

A variety of factors and processes have been implicated in the development and progression of the pathology of Alzheimer's Disease (AD), including amyloid fragment deposition, reactive gliosis, alpha-1-antichymotrypsin (ACT), and apolipoprotein E (APOE). Carriers of the APOE 4 allele have been shown to have an enhanced risk of developing AD, and the ACT signal peptide A/A genotype may modify the APOEepsilon4 risk. The protein products of these genes have been shown to enhance conversion of diffuse beta amyloid (Abeta) fibrils, which are found in diffuse plaques, to the fibrillar form found in neuritic plaques. In affected regions of AD brain, ACT and APOE colocalize with Abeta deposits and reactive microglia and astrocytes. We examined the regional distribution of ACT, APOE, and reactive glia in temporal cortex, where neuritic plaques are abundant, and cerebellum (in areas where diffuse plaques but not neuritic plaques accumulate) to examine the relationship of these markers to the deposition of Abeta. In temporal cortex, ACT and APOE staining was localized to plaque-like profiles, reactive astrocytes, and blood vessels; human leukocyte antigen-DR (HLA-DR) and glial fibrillary acidic protein (GFAP) staining revealed focal clusters of reactive microglia and astrocytes. In cerebellum, ACT and APOE immunoreactivity was never localized to plaque-like profiles but was weakly localized to unreactive astrocytes; weak HLA-DR and GFAP immunoreactivity was present on quiescent microglia throughout the cerebellum. The lack of fibrillar amyloid deposits in cerebellum, despite the presence of well-characterized markers thought to mediate the production of Abeta, suggests that this brain region may be lacking certain factors necessary for fibril formation or that the cerebellum responds differently to stimuli that successfully mediate inflammation in affected cortex.

Experimental traumatic brain injury (TBI) produces cholinergic neurotransmission deficits that may contribute to chronic spatial memory deficits. Cholinergic neurotransmission deficits may be due to presynaptic alterations in the storage and release of acetylcholine (ACh) or from changes in the receptors for ACh. The vesicular ACh transporter (VAChT) mediates accumulation of ACh into secretory vesicles, and M2 receptors can modulate cholinergic neurotransmission via a presynaptic inhibitory feedback mechanism. We examined the effects of controlled cortical impact (CCI) injury on hippocampal VAChT and M2 muscarinic subtype receptor protein levels at four time points: 1 day, 1 week, 2 weeks, and 4 weeks following injury. Rats were anesthetized and surgically prepared for controlled cortical impact injury (4 m/s, 2.5- to 2.9-mm depth) and sham surgery. Animals were sacrificed and coronal sections (35 micro(m) thick) were cut through the dorsal hippocampus for VAChT and M2 immunohistochemistry. Semiquantitative measurements of VAChT and M2 protein in hippocampal homogenates from injured and sham rats were assessed using Western blot analysis. Immunohistochemistry showed no obvious changes in VAChT and M2 immunoreactivity at 1 day and 1 week postinjury. At 2 and 4 weeks postinjury, an increase in hippocampal VAChT protein and a corresponding loss of hippocampal M2 protein was observed compared to sham controls. Consistent with these results, Western blot analyses at 4 weeks postinjury demonstrated a 40-50% increase in VAChT and a 25-30% decrease in M2. These changes may represent a compensatory response of cholinergic neurons to increase the efficiency of ACh neurotransmission chronically after TBI, by upregulating the storage capacity and subsequent release of ACh and downregulating presynaptic inhibitory receptors., (Copyright 1998 Academic Press.)

Serotonin (5-HT) neuron and neurotransmitter loss in normal aging and neuropsychiatric diseases of late life may contribute to behavioral changes commonly observed in the elderly population. Extensive evidence implicates a deficit in serotonergic neurotransmission in the development of major depression. It has been further suggested that the age-related changes in 5-HT neurons may predispose the elderly to develop depression. There is also increasing evidence that a combination of disturbances in cholinergic and serotonergic function may play a role in cognitive impairment in Alzheimer's disease (AD), with serotonergic dysfunction potentially responsible for a significant portion of the behavioral aspects of the disease. This implication of the 5-HT system in aging and age-related cognitive and mood disorders rests in large part on post mortem studies and animal models, which are limited in their capacity to predict dynamic human biochemical-behavior relationships or to accurately model the living human brain. Initial applications of functional brain imaging with positron emission tomography (PET) in the in vivo study of the brain in aging depression, and dementia focused on characterizing alterations in physiological measurements of cerebral metabolism and perfusion. However, recent advances in PET radiochemistry, instrumentation, and image processing have paved the way for noninvasive means to test specific hypotheses regarding the direct involvement of 5-HT neurons in the behavioral features of aging and to define and monitor therapeutic regimens for neuropsychiatric conditions of late life. Coupling of clinical trials in well-characterized subject populations with PET imaging using ligands specific for 5-HT receptor subtypes and transporter proteins promises to increase our understanding of the role of the 5-HT system in affective and cognitive aspects of treatment response. Longitudinal studies in aging, late-life depression, and AD are also needed to evaluate the complex interplay between neurodegenerative processes and serotonergic neurotransmission.

We tested the hypothesis that quinolinic acid, a tryptophan-derived N-methyl-D-aspartate agonist produced by macrophages and microglia, would be increased in CSF after severe traumatic brain injury (TBI) in humans, and that this increase would be associated with outcome. We also sought to determine whether therapeutic hypothermia reduced CSF quinolinic acid after injury. Samples of CSF (n = 230) were collected from ventricular catheters in 39 patients (16 to 73 years old) during the first week after TBI, (Glasgow Coma Scale [GCS] < 8). As part of an ongoing study, patients were randomized within 6 hours after injury to either hypothermia (32 degrees C) or normothermia (37 degrees C) treatments for 24 hours. Otherwise, patients received standard neurointensive care. Quinolinic acid was measured by mass spectrometry. Univariate and multivariate analyses were used to compare CSF quinolinic acid concentrations with age, gender, GCS, time after injury, mortality, and treatment (hypothermia versus normothermia). Quinolinic acid concentration in CSF increased maximally to 463 +/- 128 nmol/L (mean +/- SEM) at 72 to 83 hours after TBI. Normal values for quinolinic acid concentration in CSF are less than 50 nmol/L. Quinolinic acid concentration was increased 5- to 50-fold in many patients. There was a powerful association between time after TBI and increased quinolinic acid (P < 0.00001), and quinolinic acid was higher in patients who died than in survivors (P = 0.003). Age, gender, GCS, and treatment (32 degrees C versus 37 degrees C) did not correlate with CSF quinolinic acid. These data reveal a large increase in quinolinic acid concentration in CSF after TBI in humans and raise the possibility that this macrophage-derived excitotoxin may contribute to secondary damage.

Unlabelled: Minimizing secondary injury after severe traumatic brain injury (TBI) is the primary goal of cerebral resuscitation. For more than two decades, hyperventilation has been one of the most often used strategies in the management of TBI. Laboratory and clinical studies, however, have verified a post-TBI state of reduced cerebral perfusion that may increase the brain's vulnerability to secondary injury. In addition, it has been suggested in a clinical study that hyperventilation may worsen outcome after TBI., Object: Using the controlled cortical impact model in rats, the authors tested the hypothesis that aggressive hyperventilation applied immediately after TBI would worsen functional outcome, expand the contusion, and promote neuronal death in selectively vulnerable hippocampal neurons., Methods: Twenty-six intubated, mechanically ventilated, isoflurane-anesthetized male Sprague-Dawley rats were subjected to controlled cortical impact (4 m/second, 2.5-mm depth of deformation) and randomized after 10 minutes to either hyperventilation (PaCO2 = 20.3 +/- 0.7 mm Hg) or normal ventilation groups (PaCO2 = 34.9 +/- 0.3 mm Hg) containing 13 rats apiece and were treated for 5 hours. Beam balance and Morris water maze (MWM) performance latencies were measured in eight rats from each group on Days 1 to 5 and 7 to 11, respectively, after controlled cortical impact. The rats were killed at 14 days postinjury, and serial coronal sections of their brains were studied for contusion volume and hippocampal neuron counting (CA1, CA3) by an observer who was blinded to their treatment group. Mortality rates were similar in both groups (two of 13 in the normal ventilation compared with three of 13 in the hyperventilation group, not significant [NS]). There were no differences between the groups in mean arterial blood pressure, brain temperature, and serum glucose concentration. There were no differences between groups in performance latencies for both beam balance and MWM or contusion volume (27.8 +/- 5.1 mm3 compared with 27.8 +/- 3.3 mm3, NS) in the normal ventilation compared with the hyperventilation groups, respectively. In brain sections cut from the center of the contusion, hippocampal neuronal survival in the CA1 region was similar in both groups; however, hyperventilation reduced the number of surviving hippocampal CA3 neurons (29.7 cells/hpf, range 24.2-31.7 in the normal ventilation group compared with 19.9 cells/hpf, range 17-23.7 in the hyperventilation group [25th-75th percentiles]; *p < 0.05, Mann-Whitney rank-sum test)., Conclusions: Aggressive hyperventilation early after TBI augments CA3 hippocampal neuronal death; however, it did not impair functional outcome or expand the contusion. These data indicate that CA3 hippocampal neurons are selectively vulnerable to the effects of hyperventilation after TBI. Further studies delineating the mechanisms underlying these effects are needed, because the injudicious application of hyperventilation early after TBI may contribute to secondary neuronal injury.

Few reports exist of cognitive impairment and associated factors in developing countries. An age-stratified random sample of 388 men and women, 55 years and older, was drawn from a community-based population in the rural area of Ballabgarh in northern India. We classified as "cognitively impaired" those subjects who had scores below the 10th percentile of the population on a general mental status test (the Hindi Mental State Exam, HMSE) and, separately, on a memory test (Delayed Recall of a 10-Item Word List, DRWL). Three hundred seventy-six subjects also underwent a standardized neurologic history and examination. Neurologic factors associated with cognitive impairment, after adjusting for age, gender, and literacy, were history of impaired consciousness and findings of gait disturbance, diminished deep tendon reflexes, and the presence of at least one primitive reflex. We speculate that there may be unique risk factors in developing countries such as nutritional deficiencies leading to focal deficits and cognitive impairment.

Objectives: To develop an adjunct scale to the Neuropsychiatric Inventory (NPI) for assessing the impact of neuropsychiatric symptoms in Alzheimer's disease (AD) patients on caregiver distress., Design: Cross-sectional descriptive and correlational study., Setting: University out-patient memory disorders clinics., Participants: Eighty-five AD subjects and their caregivers (54 spouses, 31 children)., Measurements: The NPI and NPI Caregiver Distress Scale (NPI-D) were used to assess neuropsychiatric symptoms in AD patients and related caregiver distress, respectively. Criterion validity of the NPI-D was examined (N = 69) by comparison with an abridged version of the Relatives' Stress Scale (RSS'), a general measure of caregiver stress, using item clusters that had previously been correlated to behavioral disturbances in demented patients. Test-retest (n = 20) and inter-rater reliability (n = 16) of the NPI-D were also assessed., Results: Test-retest and interrater reliability of the NPI-D were both adequate. Overall, caregiver NPI-D distress ratings were correlated significantly with the RSS' (r = .60, P < .001). RSS' ratings correlated strongly with NPI scores (r = .64, P < .001), even after controlling for degree of cognitive impairment based on the Mini-Mental State Exam (MMSE) score (r = .61). MMSE scores showed a moderate correlation to RSS' ratings (-.30, P = .02), but this association was markedly attenuated when controlling for the degree of neuropsychiatric disturbance based on the NPI score (r = -. 14). NPI-D ratings for 9 of 10 NPI symptom domains correlated most strongly with either NPI symptom severity or total (frequency x severity) scores. Agitation, dysphoria, irritability, delusions, and apathy were the symptoms most often reported to be severely distressing to caregivers., Conclusions: The NPI-D provides a reliable and valid measure of subjective caregiver distress in relation to neuropsychiatric symptoms measured by the NPI. Neuropsychiatric alterations are more strongly associated than cognitive symptoms to caregiver distress. The NPI-D may be useful in both clinical and research settings for assessing the contribution to caregiver distress of neuropsychiatric symptoms in AD patients.

Previous studies from our group have demonstrated an upregulation in nerve growth factor (NGF) RNA and protein in the cortex 24 h following traumatic brain injury (TBI) in a rat model. This increase in NGF is suppressed if rats are subjected to 4 h of whole-body hypothermia following TBI. In the present study we used in situ hybridization to extend our initial RNA gel-blot (Northern) hybridization findings by demonstrating that NGF RNA is increased in the cortex following TBI and that hypothermia diminishes this response. Further, by combining in situ hybridization with immunocytochemistry for glial fibrillary acidic protein we demonstrate that astrocytes are the major cellular source for the upregulation in NGF and that this upregulation can be observed in the hippocampus as early as 3 h posttrauma. The predominantly astrocytic origin suggests that the NGF upregulation is not related primarily to cholinotrophic activities. We hypothesize that its function is to stimulate upregulation of antioxidant enzymes, as part of an injury-induced cascade, and that supplementation of NGF or antioxidants may be warranted in hypothermic therapies for head injury.

We examined the distribution of the apolipoprotein E (APOE) polymorphism in two Caucasian populations of Alzheimer's disease (AD) patients referred to dementia clinics; one in Gerona, Spain (66 AD patients, 49 controls), and the other in Pittsburgh, Pa., USA (209 AD patients, 58 controls). The presence of the APOE*4 allele was a significant risk for developing AD in both cohorts: Gerona (odds ratio = 2.34, CI: 1.03-5.55) and Pittsburgh (odds ratio = 3.64, CI: 1.78-7.69). The proportion of AD with the APOE*4 allele was greater in the Pittsburgh cohort than in the Gerona cohort (p = 0.02). However, no statistical difference was noted between the two populations in nondemented controls (p = 0.41). These data emphasize the importance of geographical and ethnic variations in the study of APOE genotypes.

We have previously reported that epidermal growth factor receptor (EGFR) was expressed on vascular endothelial cells from postmortem specimens of demented but not cognitively normal subjects. In the present study, we examined skin biopsies from 35 living patients who were either normal or had a clinical diagnosis of probable Alzheimer's disease. In this living cohort, there was no correlation between the presence of vascular EGFR expression and clinically determined cognitive status. While a variety of factors may be responsible for these findings, endothelial EGFR expression cannot be used to confirm a premortem clinical diagnosis of dementia.

Objective: A consensus conference on the diagnosis and treatment of Alzheimer disease (AD) and related disorders was organized by the American Association for Geriatric Psychiatry, the Alzheimer's Association, and the American Geriatrics Society on January 4 and 5, 1997. The target audience was primary care physicians, and the following questions were addressed: (1) How prevalent is AD and what are its risk factors? What is its impact on society? (2) What are the different forms of dementia and how can they be recognized? (3) What constitutes safe and effective treatment for AD? What are the indications and contraindications for specific treatments? (4) What management strategies are available to the primary care practitioner? (5) What are the available medical specialty and community resources? (6) What are the important policy issues and how can policymakers improve access to care for dementia patients? (7) What are the most promising questions for future research?, Participants: Consensus panel members and expert presenters were drawn from psychiatry, neurology, geriatrics, primary care, psychology, nursing, social work, occupational therapy, epidemiology, and public health and policy., Evidence: The expert presenters summarized data from the world scientific literature on the questions posed to the panel., Consensus Process: The panelists listened to the experts' presentations, reviewed their background papers, and then provided responses to the questions based on these materials. The panel chairs prepared the initial drafts of the consensus statement, and these drafts were read by all panelists and edited until consensus was reached., Conclusions: Alzheimer disease is the most common disorder causing cognitive decline in old age and exacts a substantial cost on society. Although the diagnosis of AD is often missed or delayed, it is primarily one of inclusion, not exclusion, and usually can be made using standardized clinical criteria. Most cases can be diagnosed and managed in primary care settings, yet some patients with atypical presentations, severe impairment, or complex comorbidity benefit from specialist referral. Alzheimer disease is progressive and irreversible, but pharmacologic therapies for cognitive impairment and nonpharmacologic and pharmacologic treatments for the behavioral problems associated with dementia can enhance quality of life. Psychotherapeutic intervention with family members is often indicated, as nearly half of all caregivers become depressed. Health care delivery to these patients is fragmented and inadequate, and changes in disease management models are adding stresses to the system. New approaches are needed to ensure patients' access to essential resources, and future research should aim to improve diagnostic and therapeutic effectiveness.

The Fetal ALZ-50 Reactive Clone 1 (FAC1) gene is expressed at high levels during brain development and is re-expressed in some neurodegenerative diseases. It is hypothesized that FAC1 functions during neuronal differentiation and may play an active role in neuritic re-organization following brain injury. We have previously employed the entorhinal cortex lesion model to examine reactive synaptogenesis and plasticity in the hippocampal dentate molecular layer following denervating lesion. We now report re-expression of FAC1 in the molecular layer (ML) of the dentate gyrus following entorhinal cortex (ERC) lesion. Denervated hippocampi (2,6,15, and 30 days post ERC lesion) were stained with anti-FAC1 antibody and processed for both light and electron microscopy. FAC1 was rapidly re-expressed (by 2 days) following ERC lesion, paralleling our previous observations with embryonic neural cell adhesion molecule (eN-CAM). Like eN-CAM, FAC1 expression was restricted to the denervated outer ML (OML) at 2 days post lesion. Analysis of later time points revealed an elimination of FAC1 immunostaining at the inner ML (IML)/(OML) interface as IML sprouts into the denervated zone. Image analysis confirmed the diminution of FAC1 staining in the OML as the IML sprouted into the denervated zone and revealed that FAC1 expression paralleled the temporal and spatial expression of eN-CAM following ERC lesion. Ultrastructural analysis of FAC1 staining at 6 and 30 days post lesion revealed immunoreactive profiles with the morphological characteristics of dendrites and cytoplasmic staining of granule cell perikarya. Dendritic staining was localized to the denervated OML and was not associated with any other neuropil profiles within this zone; IML staining was rare and restricted to large apical dendrites proximal to granule cell perikarya. These findings suggest that re-expression of FAC1 in the denervated OML is a rapid response to brain injury and may be important in synaptic plasticity and sprouting.

The objective of our study was to examine the relationship between the presence of the apolipoprotein E (apo E) epsilon 4 allele, psychiatric symptoms, and extrapyramidal signs (EPS) in probable Alzheimer's disease (AD). The apo E epsilon 4 allele modifies the risk and age at onset of AD. However, it still needs to be determined whether it is a marker for specific clinical subgroups. The frequency of clinical signs and symptoms was examined in 194 AD patients with the apo E epsilon 3/3 (N = 79), epsilon 3/4 (N = 96), and epsilon 4/4 (N = 19) genotypes participating in a longitudinal study of dementia. Each patient was assessed with semistructured psychiatric and neurologic examinations. Patients with the epsilon 4/4 genotype had an earlier age at onset of dementia (p = 0.03). However, no individual psychiatric symptom or neurologic sign was associated with the presence of the apo E epsilon 4 allele, including major depression (odds ratio [OR], 1.14; CI, 0.50 to 2.45; p = 0.78), psychosis (e.g., delusions and hallucinations) (OR, 0.66, CI, 0.35 to 1.25; p = 0.20), and EPS (in neuroleptic-free patients) (OR, 0.82, CI, 0.45 to 1.49; p = 0.52), after controlling by age at onset, duration of the symptoms, education, and severity of dementia. The presence of the apo E epsilon 4 allele has limited utility in the characterization of neurologic and psychiatric subgroups in probable AD patients. The apo E epsilon 4/4 genotype appears to be related to age at onset of AD, consistent with previous findings.

We measured CBF and CO2 reactivity after traumatic brain injury (TBI) produced by controlled cortical impact (CCI) using magnetic resonance imaging (MRI) and spin-labeled carotid artery water protons as an endogenous tracer. Fourteen Sprague-Dawley rats divided into TBI (CCI; 4.02 +/- 0.14 m/s velocity; 2.5 mm deformation), sham, and control groups were studied 24 hours after TBI or surgery. Perfusion maps were generated during normocarbia (Paco2 30 to 40 mm Hg) and hypocarbia (PaCO2 15 to 25 mm Hg). During normocarbia, CBF was reduced within a cortical region of interest (ROI, injured versus contralateral) after TBI (200 +/- 82 versus 296 +/- 65 mL.100 g-1.min-1, P < 0.05). Within a contusion-enriched ROI, CBF was reduced after TBI (142 +/- 73 versus 280 +/- 64 mL.100 g-1.min-1, P < 0.05). Cerebral blood flow in the sham group was modestly reduced (212 +/- 112 versus 262 +/- 118 mL.100 g-1.min-1, P < 0.05). Also, TBI widened the distribution of CBF in injured and contralateral cortex. Hypocarbia reduced cortical CBF in control (48%), sham (45%), and TBI rats (48%) versus normocarbia, P < 0.05. In the contusion-enriched ROI, only controls showed a significant reduction in CBF, suggesting blunted CO2 reactivity in the sham and TBI group. CO2 reactivity was reduced in the sham (13%) and TBI (30%) groups within the cortical ROI (versus contralateral cortex). These values were increased twofold within the contusion-enriched ROI but were not statistically significant. After TBI, hypocarbia narrowed the CBF distribution in the injured cortex. We conclude that perfusion MRI using arterial spin-labeling is feasible for the serial, noninvasive measurement of CBF and CO2 reactivity in rats.

The effect of varying brain temperature on neutrophil accumulation in brain and the expression of E-selectin and intercellular adhesion molecule-1 (ICAM-1) on cerebrovascular endothelium after controlled cortical impact (CCI) was studied in rats. Sprague Dawley rats were anesthetized and subjected to CCI to the left parietal cortex. Ten minutes after CCI, brain temperature was modulated and maintained at 32 degrees C, 37 degrees C, or 39 degrees C (n = 8 per group) for 4 h. Rats were then decapitated and immunohistochemistry on brain sections was performed using monoclonal antibodies (MoAb) that recognize neutrophils (RP-3), ICAM-1 (TM-8, Athena Neurosciences), or MoAb that react with E-selectin (La-Roche). Each of these markers was quantified in 100 x fields. Neutrophil accumulation was also quantified with myeloperoxidase (MPO) assay. Absolute neutrophil count (ANC) was measured in blood samples before and 1 h and 4 h after CCI. Neutrophil accumulation in injured brain was decreased in rats maintained at 32 degrees C vs 39 degrees C (4-fold difference as assessed by immunohistochemistry, p < 0.05; 8-fold difference as assessed by MPO assay, p < 0.05). Peripheral blood ANC was not affected by temperature. E-selectin was induced on cerebrovascular endothelium after CCI (p < 0.05), but was only decreased modestly at 32 degrees C versus 39 degrees C (p = 0.11). ICAM-1 was not upregulated on cerebrovascular endothelium at this early time following CCI. Neutrophil accumulation is directly dependent on brain temperature during the initial 4 h after CCI. This appears to be mediated by mechanisms other than effects of temperature on E-selectin or ICAM-1 expression or systemic ANC.

The inflammatory response following mechanical brain injury is characterized by an increase in the cytokine interleukin-1 beta (IL-1 beta) followed by a large elevation in the neurotrophin, nerve growth factor (NGF). The substantial upregulation in NGF observed in our previous studies suggests that it may have functions in addition to that of a target-derived neuronal support mechanism. We hypothesize that NGF is a mediator of oxidative homeostasis, by inducing the production of oxygen-free radical scavengers in brain tissue following injury. We tested this hypothesis by measuring the activity of the antioxidant enzymes, glutathione peroxidase (GSH-Px), and catalase in cortical brain tissue following experimentally induced cortical contusion. We observed a twofold increase in GSH-Px and a threefold increase in catalase activities in a time course which reflected the temporal increase in NGF observed following the same cortical contusion model. These findings support the hypothesis and illuminate an important reparative role for NGF following trauma.

Cytokines may play an important role in the pathophysiology of traumatic brain injury (TBI) in children. Interleukin-6 (IL-6) is a proinflammatory cyotkine that plays a role in regenerative processes within the central nervous system (CNS), whereas interleukin-10 (IL-10) is an antiinflammatory cytokine. Both have been measured in serum and cerebrospinal fluid (CSF) as an index of the degree of inflammation in diseases, including sepsis and meningitis. We hypothesized that both IL-6 and IL-10 would be increased in the CSF of children after severe TBI. Fifteen children who sustained severe TBI (Glascow Coma Score [GCS] < or = 7) were studied. Standard neurointensive care was provided. Ventricular CSF collected the first 3 days after TBI was analyzed for IL-6 and IL-10 concentrations by ELISA. Controls were 20 children who were evaluated for meningitis with diagnostic lumbar puncture subsequently found to have no CSF pleocytosis and negative cultures. IL-6 was increased in children after TBI versus controls on all days studied (day 1, 3158.2 +/- 621.8 pg/ml; day 2, 1111.6 +/- 337.0 pg/ml; day 3, 826.7 +/- 193.5 pg/ml vs. 20.6 +/- 5.8 pg/ml, p < 0.0001, Mann-Whitney Rank Sum). IL-10 was increased in children after TBI vs controls on all days studied (day 1, 47.2 +/- 12.9 pg/ml; day 2, 21.0 +/- 6.7 pg/ml; day 3, 15.5 +/- 5.9 pg/ml vs. 8.9 +/- 7.5 pg/ml, p < 0.01). Increased IL-10 concentrations were independently associated with age < 4 years and mortality (p = 0.004 and 0.04, respectively, multivariate linear model). This study demonstrates that IL-6 is increased after TBI in children to levels similar to those reported in adults and is the first to show that IL-10 is increased in CSF of humans after TBI. These data suggest that there may be an age-dependent production of IL-10 after TBI in children.

Hypoxemia has detrimental effects after traumatic brain injury (TBI) in both experimental models and humans. The purpose of this study was to determine the effect of mild or moderate hypoxemia on early histologic and motor functional outcome after controlled cortical impact (CCI) in rats. Anesthetized rats underwent CCI and were randomized to receive mild (FiO2 = 13%, n = 6), moderate (FiO2 = 11%, n = 9), or no (FiO2 = 33%, n = 6) hypoxemia for 30 min after trauma. Sham-operated rats without hypoxemia (n = 7) were used as controls. Motor function (beam balance latency) was assessed on days 0-5. Rats were killed 7 days after injury and their brains removed for assessment of survival of hippocampal neurons and contusion volume. Terminal deoxynucleotidyl transferase-mediated biotin-dUTP nick end labeling (TUNEL) was performed on brain sections from rats killed at 6, 24, and 72 h after CCI and moderate hypoxemia to assess DNA fragmentation in situ. Mild and moderate hypoxemia augmented motor function deficits after CCI in a dose-dependent manner. Moderate hypoxemia after CCI reduced 7-day survival of CA3 neurons but not CA1 neurons vs. sham (55 [46-86] vs. 99 [95-130], p < 0.05, and 79 [63-86] vs. 101 [81-123], NS, respectively; % uninjured hemisphere, median [range]). The addition of mild or moderate hypoxemia did not increase contusion volume. TUNEL-positive neurons were seen in ipsilateral cortex and dentate gyrus at 6, 24, and 72 h after trauma, and in ipsilateral CA3 hippocampal neurons and thalamus at 24 and 72 h. Moderate hypoxemia augments CA3 neuronal death and early motor functional deficits after CCI. The pattern of DNA fragmentation in selectively vulnerable neurons suggests that apoptosis may play a role in the delayed neuronal death seen after TBI.

The authors examined the relationship between psychiatric symptoms and the presence of of MR deep white matter lesions (DWMLs) in 28 probable Alzheimer's disease (AD) patients with mild to moderate dementia. The difference in frequency of psychiatric symptoms between patients with and without DWMLs was not statistically significant. However, MR global scores of severity correlated with the presence of ideational disturbances (such as low self-esteem and suicidal ideation). Analysis of specific cerebral regions indicated that the highest correlation occurred in the frontal white matter. Thus, DWMLs are correlated with specific symptoms of depression in AD. Whether DWMLs are etiologically related to these symptoms remains to be determined.

Background: Traumatic brain injury initiates several metabolic processes that can exacerbate the injury. There is evidence that hypothermia may limit some of these deleterious metabolic responses., Methods: In a randomized, controlled trial, we compared the effects of moderate hypothermia and normothermia in 82 patients with severe closed head injuries (a score of 3 to 7 on the Glasgow Coma Scale). The patients assigned to hypothermia were cooled to 33 degrees C a mean of 10 hours after injury, kept at 32 degrees to 33 degrees C for 24 hours, and then rewarmed. A specialist in physical medicine and rehabilitation who was unaware of the treatment assignments evaluated the patients 3, 6, and 12 months later with the use of the Glasgow Outcome Scale., Results: The demographic characteristics and causes and severity of injury were similar in the hypothermia and normothermia groups. At 12 months, 62 percent of the patients in the hypothermia group and 38 percent of those in the normothermia group had good outcomes (moderate, mild, or no disabilities). The adjusted risk ratio for a bad outcome in the hypothermia group was 0.5 (95 percent confidence interval, 0.2 to 1.2). Hypothermia did not improve the outcomes in the patients with coma scores of 3 or 4 on admission. Among the patients with scores of 5 to 7, hypothermia was associated with significantly improved outcomes at 3 and 6 months (adjusted risk ratio for a bad outcome, 0.2; 95 percent confidence interval, 0.1 to 0.9 at both intervals), although not at 12 months (risk ratio, 0.3; 95 percent confidence interval, 0.1 to 1.0)., Conclusions: Treatment with moderate hypothermia for 24 hours in patients with severe traumatic brain injury and coma scores of 5 to 7 on admission hastened neurologic recovery and may have improved the outcome.

Inflammation may play an important role in the evolution of damage after traumatic brain injury (TBI). IL-6 and IL-10 are markers of inflammation that are pro- and anti-inflammatory in nature, respectively. They have been used as an index of the degree of inflammation in diseases including sepsis and meningitis. We hypothesized that both IL-6 and IL-10 would be increased in the cerebrospinal fluid (CSF) of children after TBI. We measured ventricular CSF concentrations of these metabolites (ELISA) each of the first 3 days after TBI in 15 children. CSF IL-6 was increased on day 1 (p < 0.05 vs days 2 or 3). CSF IL-10 was similarly increased on day 1 (p < 0.05). CSF IL-6 after TBI is similar to serum IL-6 levels previously reported in children with septic shock. In contrast, the CSF IL-10 response was markedly attenuated following TBI compared to sepsis. These data suggest a unique balance between pro- and anti-inflammatory cytokines in brain after TBI.

A common polymorphism in the alpha 1-antichymotrypsin (ACT) gene has been found co modify the APOE*4-associated risk of Alzheimer's disease due to an apparent interaction between the two loci. This study was undertaken to determine the gender- and age-related distributions of these two polymorphisms in two large population-based samples of Caucasians (n = 803) and Nigerian Blacks (n = 730). Significantly higher frequencies of the ACT*A (78.6% vs. 48.4%; P < 0.001) and APOE*4 (25.6% vs. 15.6%; P < 0.001) alleles were observed in Nigerian Blacks than in Caucasians. In Caucasian women but not in men, the frequency of the APOE*4 allele was significantly lower in the ACT/AA genotype as compared to the ACT/AT and ACT/TT genotypes, while a reverse trend was seen for the APOE*3 allele frequency among the ACT genotypes. The distribution of the ACT*A allele between the APOE*4 carriers and non-APOE*4 carriers was also different in Caucasian women but not in men. A similar gender-specific nonrandom association between the two polymorphisms was observed in Black women but this was not as strong as observed in Caucasian women. When the two samples were stratified by age group, an association or trend of association was observed in all age groups in women only. These data indicate the existence of a nonrandom association between the APOE and ACT loci in women which may have an important implication for the higher prevalence of Alzheimer's disease in women.

The identification of apolipoprotein E (APOE) as a genetic risk factor modifying the chances of developing Alzheimer's disease (AD) has opened the possibility that other susceptibility genes exist that either independently modify the risk of developing AD or alter the risk imparted by APOE. We have identified alpha-1-antichymotrypsin (ACT) as a potential risk gene, by virtue of the interactive effect of either of its two alleles (A and T) on the risk of AD associated with the APOE epsilon 4 allele. In a large population of AD (n = 308) and control (n = 579) cohorts, we found the expected elevation in the APOE epsilon 4 allele frequency in the AD cases compared to controls, with threefold and sevenfold increases in the risk of AD for APOE epsilon 4/X and APOE epsilon 4/epsilon 4, respectively. Of the three ACT genotypes, the ACT A/T genotype did not affect the risk of AD beyond that which is conferred by the APOE epsilon 4 allele. However, the ACT A/A genotype greatly increased the risk associated with APOE epsilon 4 homozygosity. On the other hand, the ACT T/T genotype suppressed the gene dosage effect of the APOE epsilon 4 allele; the risk of AD in APOE epsilon 4/epsilon 4, ACT T/T cases was the same as that of APOE epsilon 4/X. A variety of potential mechanisms for interactions of ACT and APOE are discussed.