Cognitive Impairment after Lacunar Stroke and the Risk of Recurrent Stroke and Death.

INTRODUCTION: Patients with poststroke cognitive impairment appear to be at higher risk of recurrent stroke and death. However, whether cognitive impairment after lacunar stroke is associated with recurrent stroke and death remains unclear. We assessed whether global or domain-specific cognitive impairment after lacunar stroke is associated with recurrent stroke and death. METHODS: We considered patients from the Secondary Prevention of Small Subcortical Strokes (SPS3) trial with a baseline cognitive exam administered in English by certified SPS3 personnel, 14-180 days after qualifying lacunar stroke. We considered a baseline score of ≤86 on the Cognitive Assessment Screening Instrument to indicate global cognitive impairment, <10 on the Clock Drawing on Command test to indicate executive function impairment, and domain-specific summary scores in the lowest quartile to indicate memory and nonmemory impairment. We used Cox proportional hazards models to estimate the association between poststroke cognitive impairment and subsequent risk of recurrent stroke and death. RESULTS: The study included 1,528 participants with a median enrollment time of 62 days after qualifying stroke. During a mean follow-up of 3.9 years, 11.4% of participants had recurrent stroke and 8.2% died. In the fully adjusted models, memory impairment was independently associated with an increased risk of recurrent stroke (hazard ratio, 1.48; 95% confidence interval [95% CI]: 1.04-2.09) and death (hazard ratio, 1.87; 95% CI: 1.25-2.79). Global impairment (hazard ratio, 1.66; 95% CI: 1.06-2.59) and nonmemory impairment (hazard ratio, 1.74; 95% CI: 1.14-2.67) were associated with an increased risk of death. DISCUSSION/CONCLUSION: After lacunar stroke, memory impairment was an independent predictor of recurrent stroke and death, while global and nonmemory impairment were associated with death. Cognitive screening in lacunar stroke may help identify populations at higher risk of recurrent stroke and death.

Impaired verbal memory is a significant predictor of early cerebral-cardiovascular death, an 18-year follow-up of a national cohort.

BACKGROUND: The mortality pattern of individuals with impaired verbal memory (IVM) has not yet been well described. We sought to describe the risk of all-causes, as well as specific causes of death associated with IVM. METHOD: We used the data of 4151 nationally representative adults ≥60 years old who participated in the third National Health and Nutrition Examination Survey, 1988-1994, and completed one non-contextual (i.e., word list memory) and one contextual delayed-recall tests (i.e., short story recall). The participants were passively followed up through 31 December 2006. We determined the hazard ratio of death from all-causes and specific cause through Cox proportional hazard regression. RESULTS: Severe and moderate IVM were present in 268 (6.5%) and 495 (11.9%) participants at baseline survey, and 2550 deaths occurred by the end of 18-year follow-up (median = 12 years). The medians of survival time adjusted for all-causes death were 6.17 (95% CI: 5.50, 6.92), 9.50 (8.92, 10.25), and 13.17 (12.75, 13.58) years, respectively for the individuals with severe, moderate, and no IVM. Severe IVM was significantly associated with death from cardio-cerebral vascular diseases [hazard ratio = 1.70, 95% CI = (1.36-2.12)], stroke [2.60 (1.69-3.99)], and Alzheimer's disease [3.50 (1.40-8.76)]. The shortened survival time of the participants with IVM was mainly driven by the deaths of cerebral-cardiovascular diseases, which accounted for almost half of all deaths. CONCLUSION: The predictability of memory scores to early cerebral-cardiovascular deaths demonstrated that central challenge among individuals with cognitive impairment was cardiovascular diseases management.

Morris water maze function and histologic characterization of two age-at-injury experimental models of controlled cortical impact in the immature rat.

PURPOSE: Controlled cortical impact (CCI) is commonly used in adult animals to study focal traumatic brain injury (TBI). Our study aims to further study injury mechanisms in children and variable models of pathology in the developing brain. METHODS: Develop a focal injury model of experimental TBI in the immature, postnatal days (PND) 7 and 17 rats that underwent a CCI at varying depths of deflection, 1.5-2.5 mm compared with sham and then tested using the Morris water maze (MWM) beginning on post-injury day (PID) 11. Histopathologic analysis was performed at PID 1 and 28. RESULTS: In PND 7, the 1.75- and 2.0-mm deflections (diameter (d) = 3 mm; velocity = 4 m/s; and duration = 500 ms) resulted in significant MWM deficits while the 1.5-mm injury did not produce MWM deficits vs. sham controls. In PND 17, all injury levels resulted in significant MWM deficits vs. sham controls with a graded response; the 1.5-mm deflection (d = 6 mm; velocity = 4 m/s; and duration = 500 ms) produced significantly less deficits as compared WITH the 2.0- and 2.5-mm injuries. Histologically, a graded injury response was also seen in both ages at injury with cortical and more severe injuries, hippocampal damage. Cortical contusion volume increased in most injury severities from PID 1 to 28 in both ages at injury while hippocampal volumes subsequently decreased. CONCLUSIONS: CCI in PND 7 and 17 rat results in significant MWM deficits and cortical histopathology providing two different and unique experimental models of TBI in immature rats that may be useful in further investigations into the mechanisms and treatments of pediatric TBI.

Subjective memory complaints in primary care patients and death from all causes: a four-year follow-up.

OBJECTIVE: To investigate the prognostic value of subjective memory complaints for all-cause mortality in order to determine whether elderly persons with subjective memory complaints may be regarded as a group of vulnerable patients who need close follow-up. DESIGN: Prospective cohort study. Setting. Primary care units in the central district of Copenhagen, Denmark. SUBJECTS: 758 community-dwellers aged 65 years and older consulting their general practitioner in October and November 2002. MAIN OUTCOME MEASURES: Information on subjective memory complaints, socio-demographics, and health-related quality of life were collected at the enrolment primary care consultation. Dates of death from all causes occurring during the four-year follow-up were retrieved from the national databases. Cox proportional hazard regression models on time to death (censored after four years) were used to examine the influence of subjective memory complaints on all-cause mortality. RESULTS: 88 patients died during the four-year follow-up. The association between subjective memory complaints and mortality had a statistically not significant hazard ratio (HR) of 0.91, adjusting for known confounders. Statistically significant predictors for mortality were Age (HR = 1.43 for 75-84 years and HR = 3.39 for 85 + years), Sex (HR = 0.51 for women), Mobility (HR = 2.39 for some problems), Self-care (HR = 2.34 for some problems) and Comorbidity (HR = 2.06, 3.19 and 5.89 for a Charlson comorbidity index of 1, 2, or ≥ 3 respectively). CONCLUSION: In an elderly population presenting for primary care the presence of subjective memory complaints was not significantly associated with an increase in all-cause mortality.

Evaluation of destructive effects of exposure to cisplatin during developmental stage: no profound evidence for sex differences in impaired motor and memory performance.

We have elucidated the alteration in hippocampal and cerebellum function following chronic cisplatin treatment in male and female rats. Hippocampus and cerebellum related behavioral dysfunction in cisplatin-treated [intraperitoneally, 5 mg/(kg/week) for 5 weeks from 23-day-old] rats were analyzed using explorative, motor function, learning, and memory tasks (grasping, rotarod, open field, and Morris water maze tests). Exposure to cisplatin impaired the motor coordination in male and female rats. Exposure to cisplatin was reflected by a decrease in grasping time compared to vehicle-treated controls (saline) only in male rat while there were not any differences in female rats. When the rearing frequency, total distance moved and velocity of their recorded in open fieldtest, both males and females were dramatically affected by exposure to cisplatin. Compared to the saline, male and female rats trained 5 weeks after cisplatin injection showed significant memory deficits in the Morris water maze test. However, hippocampal and cerebellum functions of male and female rats were profoundly affected by exposure to cisplatin while no sex differences in the most variable were evident.

Memory impairment in a simple recall task increases mortality at 10 years in non-demented elderly.

OBJECTIVE: To evaluate whether memory impairment detected in the three-word delayed recall task of the Mini-Mental State Examination (MMSE) increases the risk of mortality. METHODS: The NEDICES (Neurological Diseases in Central Spain) cohort study, is a population census-based study, aimed at detecting age-associated neurological diseases in people aged 65 and over, living in one rural and two urban communities in central Spain. Participants with dementia or without MMSE evaluation at baseline were excluded. Mortality was evaluated 10.67 years after enrollment. Cox's proportional hazards regression models were used to evaluate the hazard of death according to performance in the three-word delayed recall task included in the MMSE (score 0-3), adjusting for potential covariates (sex, age, level of education, and comorbidity). Survival was estimated using Kaplan-Meier method. RESULTS: The final study population comprised 3778 non-demented elderly subjects. After adjusting for confounding covariates, mortality was 52% greater in persons with the lowest memory score (0) vs. persons with the highest score (3). Hazard ratios (HR) showed a tendency to an increase in mortality from the highest to the lowest memory score, which was statistically significant for the groups with none (HR=1.52; CI=1.27-1.80) or one (HR=1.24; CI=1.04-1.48) word recall. Older age, male sex, and comorbidity were also associated with mortality, but level of education was not. CONCLUSIONS: Memory impairment in the three-word delayed free recall, a very simple task used by physicians worldwide, increases the risk of mortality at 10 years in non-demented elderly.

MRI biomarkers of vascular damage and atrophy predicting mortality in a memory clinic population.

BACKGROUND AND PURPOSE: MRI biomarkers play an important role in the diagnostic work-up of dementia, but their prognostic value is less well-understood. We investigated if simple MRI rating scales predict mortality in a memory clinic population. METHODS: We included 1138 consecutive patients attending our memory clinic. Diagnostic categories were: subjective complaints (n=220), mild cognitive impairment (n=160), Alzheimer disease (n=357), vascular dementia (n=46), other dementia (n=136), and other diagnosis (n=219). Baseline MRIs were assessed using visual rating scales for medial temporal lobe atrophy (range, 0-4), global cortical atrophy (range, 0-3), and white matter hyperintensities (range, 0-3). Number of microbleeds and presence of infarcts were recorded. Cox-regression models were used to calculate the risk of mortality. RESULTS: Mean follow-up duration was 2.6 (+/-1.9) years. In unadjusted models, all MRI markers except infarcts predicted mortality. After adjustment for age, sex, and diagnosis, white matter hyperintensities, and microbleeds predicted mortality (white matter hyperintensities: hazard ratio [HR], 1.2; 95% CI, 1.0-1.4; microbleeds: HR, 1.02 95% CI, 1.00-1.03; categorized: HR, 1.5; 95% CI, 1.1-2.0). The predictive effect of global cortical atrophy was restricted to younger subjects (HR, 1.7; 95% CI, 1.2-2.6). An interaction between microbleeds and global cortical atrophy indicated that mortality was especially high in patients with both microbleeds and global cortical atrophy. CONCLUSIONS: Simple MRI biomarkers, in addition to their diagnostic use, have a prognostic value with respect to mortality in a memory clinic population. Microbleeds were the strongest predictor of mortality.

Impairment of short-term memory and Korsakoff syndrome are common in AIDS patients with cytomegalovirus encephalitis.

BACKGROUND AND PURPOSE: The diagnosis of cytomegalovirus encephalitis (CMV-E) in AIDS patients is challenging as other illnesses may obscure the symptoms. Here, we characterize the clinical symptoms of CMV-E and link them to post-mortem findings. Patients and methods In 254 homosexual men with AIDS, followed from HIV diagnosis to death before the antiretroviral combination therapy era, CMV-E was suspected in 93 cases. All were CMV-positive in blood. Neurological examination, including cognitive testing was performed in 34 of them within 6 months before death. CMV-E was diagnosed by CMV-PCR in cerebrospinal fluid (n = 24) or by post-mortem (n = 24). RESULTS: The majority complained of forgetfulness (91%), balance difficulties (85%) and impotence (85%). Impaired short-term memory was present in 29 patients. It was extreme in 17, justifying the diagnosis of Korsakoff's syndrome. This was often associated with infectious CMV in blood (P = 0.01). Brainstem symptoms were found in 19 patients. Post-mortem examination often revealed ventriculoencephalitis. CMV was found primarily around the ventricles and in other structures, described in Korsakoff's syndrome. CONCLUSION: The location of CMV in the brain corresponded well to the clinical findings, demonstrating the close relationship between the neurological symptoms and the neuroanatomical lesions.

Prominent Non-Memory Deficits in Alzheimer's Disease Are Associated with Faster Disease Progression.

BACKGROUND: Alzheimer's disease (AD) is a heterogeneous disorder. OBJECTIVE: To investigate whether cognitive AD subtypes are associated with different rates of disease progression. METHODS: We included 1,066 probable AD patients from the Amsterdam Dementia Cohort (n = 290), Alzheimer's Disease Neuroimaging Initiative (n = 268), Dementia Competence Network (n = 226), and University of California, San Francisco (n = 282) with available follow-up data. Patients were previously clustered into two subtypes based on their neuropsychological test results: one with most prominent memory impairment (n = 663) and one with most prominent non-memory impairment (n = 403). We examined associations between cognitive subtype and disease progression, as measured with repeated Mini-Mental State Examination (MMSE) and Clinical Dementia Rating scale sum of boxes (CDR sob), using linear mixed models. Furthermore, we investigated mortality risk associated with subtypes using Cox proportional hazard analyses. RESULTS: Patients were 71±9 years old; 541 (51%) were female. At baseline, pooled non-memory patients had worse MMSE scores (23.1±0.1) and slightly worse CDR sob (4.4±0.1) than memory patients (MMSE 24.0±0.1; p < 0.001; CDR sob 4.1±0.1; p < 0.001). During follow-up, pooled non-memory patients showed steeper annual decline in MMSE (-2.8±0.1) and steeper annual increase in CDR sob (1.8±0.1) than memory patients (MMSE - 1.9±0.1; pinteraction<0.001; CDR sob 1.3±0.1; pinteraction<0.001). Furthermore, the non-memory subtype was associated with an increased risk of mortality compared with the memory subtype at trend level (HR = 1.36, CI = 1.00-1.85, p = 0.05). CONCLUSIONS: AD patients with most prominently non-memory impairment show faster disease progression and higher risk of mortality than patients with most prominently memory impairment.

Vasodilators and nootropics as predictors of dementia and mortality in the PAQUID cohort.

OBJECTIVES: To assess the effects of treatment for memory impairment and the Ginkgo biloba extract (EGb 761) on dementia, mortality, and survival without dementia. DESIGN: Prospective community-based cohort study. SETTING: France. PARTICIPANTS: Three thousand five hundred thirty-four subjects aged 65 and older. MEASUREMENTS: Information on drug consumption was obtained by interview and visual assessment of patients' medicine chests. Active screening of dementia was performed every 2 years over a 13-year period. The independent effects of treatment for memory impairment and the Ginkgo biloba extract on the risks of dementia and death were estimated using Cox proportional hazards models, adjusted for potentially confounding factors (including comorbidities). RESULTS: The initial consumption of Ginkgo biloba did not modify the risk of dementia (relative risk (RR)=1.16, 95% confidence interval (CI)=0.84-1.60), whereas the consumption of other treatments for memory impairment was associated with a higher risk of dementia (RR=1.35, 95% CI=1.11-1.63). Subjects who took Ginkgo biloba had a significantly lower risk of mortality in the long term (RR=0.76, 95% CI=0.62-0.93), even after adjustment for potentially confounding factors. The initial consumption of treatment for memory impairment other than Ginkgo biloba did not modify the risk of mortality. CONCLUSION: These results suggest that treatment with EGb 761 may increase the probability of survival in the elderly population. These findings need to be corroborated and further assessed using randomized, controlled trials.

Mild cognitive impairments predict dementia in nondemented elderly patients with memory loss.

BACKGROUND: Some elderly individuals exhibit significant memory deficits but do not have dementia because their general intellect is preserved and they have no impairments in everyday activities. These symptoms are often a precursor to Alzheimer disease (AD), but sometimes dementia does not occur, even after many years of observation. There is currently no reliable way to distinguish between these 2 possible outcomes in an individual patient. We hypothesized that clear impairments in at least 1 cognitive domain in addition to memory would help identify those who will progress to AD. OBJECTIVE: To determine whether nondemented patients with impairments in memory and other domains are more likely than those with memory impairment alone to develop AD. DESIGN AND METHODS: In a retrospective study, we evaluated 48 nondemented, nondepressed patients with clinical and psychometric evidence of memory impairment who were followed up for 2 or more years. Age-adjusted normative criteria were used to identify whether additional impairments were present in language, attention, motor visuospatial function, and verbal fluency at this initial evaluation. The presence or absence of dementia after 2 years and at the most recent neurological evaluation was compared in subjects with normal scores in all 4 of these cognitive areas apart from memory (M-) and those with impairment in 1 or more of these areas (M+). Outcomes were adjusted for age, intelligence at initial evaluation, and years of education. RESULTS: Of the 48 nondemented patients with memory loss, 17 met M- criteria, leaving 31 in the M+ group. Deficits in block design were the most frequent abnormality other than memory loss. At the 2-year follow-up, 1 M- subject (6%) had progressed to AD, whereas 15 (48%) of the M+ group had progressed to AD (P =.003). At the most recent follow-up (mean +/- SD, 4.0 +/- 2.0 years), 4 (24%) of the M- patients progressed to AD compared with 24 (77%) of the M+ patients (P<.001). CONCLUSIONS: Among nondemented elderly patients, memory loss alone rarely progresses to dementia in the subsequent 2 years. However, the risk of dementia is significantly increased among patients with clear cognitive impairments beyond memory loss. Further study is needed to determine whether patients with impairments limited to memory loss have a distinctive clinical course or pathophysiology.

Preservation of memory with conformal avoidance of the hippocampal neural stem-cell compartment during whole-brain radiotherapy for brain metastases (RTOG 0933): a phase II multi-institutional trial.

PURPOSE: Hippocampal neural stem-cell injury during whole-brain radiotherapy (WBRT) may play a role in memory decline. Intensity-modulated radiotherapy can be used to avoid conformally the hippocampal neural stem-cell compartment during WBRT (HA-WBRT). RTOG 0933 was a single-arm phase II study of HA-WBRT for brain metastases with prespecified comparison with a historical control of patients treated with WBRT without hippocampal avoidance. PATIENTS AND METHODS: Eligible adult patients with brain metastases received HA-WBRT to 30 Gy in 10 fractions. Standardized cognitive function and quality-of-life (QOL) assessments were performed at baseline and 2, 4, and 6 months. The primary end point was the Hopkins Verbal Learning Test-Revised Delayed Recall (HVLT-R DR) at 4 months. The historical control demonstrated a 30% mean relative decline in HVLT-R DR from baseline to 4 months. To detect a mean relative decline ≤ 15% in HVLT-R DR after HA-WBRT, 51 analyzable patients were required to ensure 80% statistical power with α = 0.05. RESULTS: Of 113 patients accrued from March 2011 through November 2012, 42 patients were analyzable at 4 months. Mean relative decline in HVLT-R DR from baseline to 4 months was 7.0% (95% CI, -4.7% to 18.7%), significantly lower in comparison with the historical control (P < .001). No decline in QOL scores was observed. Two grade 3 toxicities and no grade 4 to 5 toxicities were reported. Median survival was 6.8 months. CONCLUSION: Conformal avoidance of the hippocampus during WBRT is associated with preservation of memory and QOL as compared with historical series.

Survival rate in patients affected by dementia followed by memory clinics (UVA) in Italy.

People affected by dementia experienced decreased life expectancy with a 2-4 times higher risk of death at a given age compared to non-demented people. Dementia represents a major cost to health care and society in the Western world and, particularly in Italy, is projected to become a high-resource demanding chronic disease. The present study aimed to estimate the average survival rate of a group of community dwelling elderly affected by dementia in Italy, and to assess the predictive variables associated with survival length. This retrospective study collected the data of patients (n = 290) who died from 2008 to 2012. The data were extracted from a cohort of over 2,000 patients from three outpatient Dementia Clinics of Genoa (Italy). Demographic data and other clinical parameters listed in the patients' clinical records were collected. The mean survival rate after dementia diagnosis was 3.3 ± 0.1 years, lower compared to the age-matched healthy population. The survival rate of these patients showed a significant correlation with age (n = 290; r = -0.16: p < 0.006), with the cognitive status (n = 285; r = 0.16: p < 0.007), with education (n = 204; r = 0.23: p < 0.001), with comorbidity (n = 138; r = -0.41: p < 0.0001), with depressive mood (n = 74; r = 0.44: p < 0.0001), and with the functional status (ADL: n = 242, r = 0.29: p < 0.0001; IADL: n = 243; r = 0.25: p < 0.0001). Multivariate regression revealed age, gender, and functional status as the main determinants informing patient survival. The study provides interesting and reliable data on the pivotal value of early dementia diagnosis in predicting longer survival and addresses comprehensive geriatric assessment, which encompasses most of the predictive variables provided by the study, as a remarkable tool in estimating life expectancy of patients with dementia.

Prediction of cognitive dysfunction after resuscitation from out-of-hospital cardiac arrest using serum neuron-specific enolase and protein S-100.

BACKGROUND: More than 50% of patients initially resuscitated from out-of-hospital cardiac arrest die in hospital. OBJECTIVE: To investigate the prognostic value of serum protein S-100 and neuron-specific enolase (NSE) concentrations for predicting (a) memory impairment at discharge; (b) in-hospital death, after resuscitation from out-of-hospital cardiac arrest. METHODS: In a prospective study of 143 consecutive survivors of out-of-hospital cardiac arrest, serum samples were obtained within 12, 24-48 and 72-96 hours after the event. S-100 and NSE concentrations were measured. Pre-discharge cognitive assessment of patients (n = 49) was obtained by the Rivermead Behavioural Memory Test (RBMT). The relationship between biochemical brain marker concentrations and RBMT scores, and between marker concentrations and the risk of in-hospital death was examined. RESULTS: A moderate negative relationship was found between S-100 concentration and memory test score, at all time points. The relationship between NSE and memory test scores was weaker. An S-100 concentration >0.29 microg/l at time B predicted moderate to severe memory impairment with absolute specificity (42.8% sensitivity). S-100 remained an independent predictor of memory function after adjustment for clinical variables and cardiac arrest timing indices. NSE and S-100 concentrations were greater in patients who died than in those who survived, at all time points. Both NSE and S-100 remained predictors of in-hospital death after adjustment for clinical variables and cardiac arrest timing indices. The threshold concentrations yielding 100% specificity for in-hospital death were S-100: 1.20 microg/l (sensitivity 44.8%); NSE 71.0 microg/l (sensitivity 14.0%). CONCLUSIONS: Estimation of serum S-100 concentration after out-of-hospital cardiac arrest can be used to identify patients at risk of significant cognitive impairment at discharge. Serum S-100 and NSE concentrations measured 24-48 hours after cardiac arrest provide useful additional information.

Decline in cognitive and functional skills increases mortality risk in nondemented elderly.

OBJECTIVE: To investigate the relation between rate of decline in cognitive and functional/physical abilities and risk of death in nondemented elderly. METHODS: Data were included from individuals participating in a prospective study of aging and dementia in Medicare recipients, 65 years and older, residing in northern Manhattan. The authors included 878 members of the cohort who had measures of memory, cognitive, language, or functional scores over three study intervals, excluding all participants who were demented or had more than one problem in activity of daily living (ADL) skills at baseline. Participants were classified as showing no decline, slow, medium, or rapid rate of decline, based on the slope of change in cognitive and functional/physical factors. The authors used survival methods to examine the relation of rate of decline in cognitive and functional performance to subsequent mortality in younger and older nondemented elderly and across three ethnic groups, adjusting for potential confounders. RESULTS: Nondemented elderly with preserved ADL skills who showed rapid rates of decline on measures of visuospatial reasoning/cognitive, language, ADL, and instrumental ADL functions were approximately twice as likely to die as nondemented elderly who showed no decline or slower rates of decline, while rate of decline in memory or in measures of extremity mobility was not related to risk of death. The association of the rate of decline to risk of death was stronger in relatively young (< or =75 years) than in older participants. CONCLUSIONS: Rate of decline in cognitive and functional skills predicts mortality in nondemented elderly.

Increased mortality and spatial memory deficits in TNF-alpha-deficient mice in ceftriaxone-treated experimental pneumococcal meningitis.

Tumor necrosis factor-alpha (TNF-alpha) is critically involved in inflammation and may participate in hippocampal injury in bacterial meningitis. In a mouse model of ceftriaxone-treated pneumococcal meningitis, spatial memory and motor performance of TNF-alpha-deficient (n = 57) and control mice (n = 55) were investigated. After infection, therapy was initiated with ceftriaxone (100 mg/kg twice daily for 5 days). Sixty-three percent TNF-alpha-deficient mice and 40% control animals died within 6 days (Fisher's exact test: P = 0.02). TNF-alpha-deficient mice surviving pneumococcal meningitis took substantially longer to reach the hidden platform than controls, and the distance of swim tracks was longer (P = 0.02). The swim speed in both groups was similar (P = 0.59). The proliferation of dentate granule cells was lower in TNF-alpha-deficient than in wild-type mice (P = 0.03). In pneumococcal meningitis, TNF-alpha deficiency caused increased mortality and stronger deficits in spatial memory possibly due to impaired neurogenesis.