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Background: Despite an alarming rise in the global prevalence of dementia, the available modalities for improving cognition and mental wellbeing of dementia patients remain limited. Environmental enrichment is an experimental paradigm that has shown promising anti-depressive and memory-enhancing effects in pre-clinical studies. However, its clinical utility has remained limited due to the lack of effective implementation strategies. Objective: The primary objective of this study was to evaluate the usability (tolerability and interactivity) of a long-term virtual reality (VR)- based environmental enrichment training program in older adults with mild cognitive impairment (MCI) and mild dementia. A secondary objective was to assess the effect of VR-based environmental enrichment on stabilization of cognitive functioning and improvement of mental wellbeing in older adults with MCI and mild dementia. Methods: A total of seven participants (four patients with MCI and three with mild dementia) received biweekly VR-based environmental enrichment over a course of 6 months. The tolerability and interactivity of the participants in the VR training was serially assessed via virtual reality sickness questionnaire (VRSQ) and recording of input-error ratio. Cognitive functioning was assessed through Montreal cognitive assessment (MoCA) before and after the study. Mental wellbeing was assessed through Warwick-Edinburgh Mental Well Being Scale (WEMWBS). Results: VR-based environmental enrichment was well-tolerated by the patients with significant decrease in VRSQ scores (p &lt, 0.01) and input-error ratio (p &lt, 0.001) overtime. VR training was also effective in stabilization of MoCA scores over the course of therapy (non-significant difference in the MoCA scores before and after the therapy) and was associated with a trend (p &lt, 0.1) towards improvement in WEMWBS scores between the first and the last assessments. Qualitative observations by the care-givers further corroborated a noticeable improvement in mental wellbeing of patients. Conclusions: This pilot study shows that VR can be a feasible, tolerable, and potentially effective tool in long-term support of older adults with MCI and mild dementia.

The goal of this retrospective cohort study was to determine whether stressors related to military service, determined by a diagnosis of chronic post-traumatic stress disorder (cPTSD) or receiving a Purple Heart (PH), are associated with an increased risk of vascular risk factors and disease, which are of great concern for veterans, who constitute a significant portion of the aging US population. The Veterans Integrated Service Network (VISN) 16 administrative database was searched for individuals 65 years or older between October 1, 1997 to September 30, 1999 who either received a PH but did not have cPTSD (PH+/cPTSD−; n = 1499), had cPTSD without a PH (PH−/cPTSD+; n = 3593), had neither (PH−/cPTSD−; n = 5010), or had both (PH+/cPTSD+; n = 153). In comparison to the control group (PH−/cPTSD−), the PH+/cPTSD− group had increased odds ratios for incidence and prevalence of diabetes mellitus, hypertension, and hyperlipidemia. The PH−/cPTSD+ group had increased odds ratios for prevalence of diabetes mellitus and for the incidence and prevalence of hyperlipidemia. The PH−/cPTSD+ and PH+/cPTSD− groups were associated with ischemic heart disease and cerebrovascular disease, but not independently of the other risk factors. The PH+/cPTSD+ group was associated only with an increase in the incidence and prevalence of hyperlipidemia, though this group’s much smaller sample size may limit the reliability of this finding. We conclude that certain physical and psychological stressors related to military service are associated with a greater incidence of several vascular risk factors in veterans aged 65 years or older, which in turn are associated with greater rates of ischemic heart disease and cerebrovascular disease.

International audience; Aging is characterized by progressive memory decline that can lead to dementia when associated with neurodegeneration. Here, we show in mice that aging-related memory decline involves defective biogenesis of microRNAs (miRNAs), in particular miR-183/96/182 cluster, resulting from increased protein phosphatase 1 (PP1) and altered receptor SMAD (R-SMAD) signaling. Correction of the defect by miR-183/96/182 overexpression in hippocampus or by environmental enrichment that normalizes PP1 activity restores memory in aged animals. Regulation of miR-183/96/182 biogenesis is shown to involve the neurodegeneration-related RNA-binding proteins TDP-43 and FUS. Similar alterations in miR-183/96/182, PP1, and R-SMADs are observed in the brains of patients with amyotrophic lateral sclerosis (ALS) or frontotemporal lobar degeneration (FTLD), two neurodegenerative diseases with pathological aggregation of TDP-43. Overall, these results identify new mechanistic links between miR-183/96/182, PP1, TDP-43, and FUS in age-related memory deficits and their reversal.

Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are two fatal neurodegenerative disorders with considerable clinical, pathological and genetic overlap. Both disorders are characterized by the accumulation of pathological protein aggregates that contain a number of proteins, most notably TAR DNA binding protein 43 kDa (TDP-43). Surprisingly, recent clinical studies suggest that dyslipidemia, high body mass index, and type 2 diabetes mellitus are associated with better clinical outcomes in ALS. Moreover, ALS and FTLD patients have a significantly lower incidence of cardiovascular disease, supporting the idea that an unfavorable metabolic profile may be beneficial in ALS and FTLD. The two most widely studied ALS/FTLD models, super-oxide dismutase 1 (SOD1) and TAR DNA binding protein of 43 kDA (TDP-43), reveal metabolic dysfunction and a positive effect of metabolic strategies on disease onset and/or progression. In addition, molecular studies reveal a role for ALS/FTLD-associated proteins in the regulation of cellular and whole-body metabolism. Here, we systematically evaluate these observations and discuss how changes in cellular glucose/lipid metabolism may result in abnormal protein aggregations in ALS and FTLD, which may have important implications for new treatment strategies for ALS/FTLD and possibly other neurodegenerative conditions., Molecular Neurodegeneration, 13

Compared with other major dementias, very little is known about the medical and environmental risk factors associated with frontotemporal dementia (FTD). In this study, we evaluated medical and environmental disorders associated with FTD in a veteran population.The medical records of 845 consecutive veterans who were evaluated for cognitive and/or behavioral complaints at a cognitive disorders clinic in an academic medical center between March 1, 2003, and June 30, 2008, were reviewed and 554 patients received a diagnosis of dementia. Medical disorders and environmental risk factors in 63 patients with behavioral variant of FTD were compared with 491 patients with non-FTD dementias.The prevalence of traumatic brain injury (TBI) was significantly greater in patients with FTD versus those with non-FTD dementias (12.7% vs 3.5%; P.05). The FTD group also had a lower prevalence of heart disease (19.0% vs 36.7%; P.05) and cerebrovascular diseases (12.7% vs 26.1%; P.05), although the prevalence of vascular risk factors was comparable between FTD and non-FTD dementia groups: hypertension (65.1% vs 68.2%), diabetes (31.7% vs 26.9%), hyperlipidemia (42.9% vs 48.9%), and tobacco use (7.9% vs 8.8%; P.05 for all). In multivariate analysis, the risk for FTD was increased in patients with TBI (OR, 4.4; 95% CI, 1.6-11.8). The risk for FTD was marginally decreased in patients with heart disease (OR, 0.4; 95% CI, 0.3-0.96).In a clinical sample of veterans, risk of FTD was increased in patients with TBI and marginally decreased in patients with heart disease. Prospective studies are needed to confirm these associations temporally and to identify their underlying mechanisms.

In some neuro-developmental disorders, the combined effect of intellectual disability and atypicalities of social cognition may put individuals at increased vulnerability in their social environment. The neuro-developmental disorders Williams syndrome, characterised by 'hypersociability', and autism spectrum disorders, characterised by 'social withdrawal', are at two extremes of atypical social functioning in humans. In this article, we use Williams syndrome and autism spectrum disorders as exemplars to demonstrate how atypicalities of social cognition may contribute to social vulnerability in these populations. The lives of individuals with both these disorders are marred by an increased risk of social isolation, bullying, unsteady relationships, employment difficulties and abuse. While different behavioural interventions have been tried to improve social functioning in these populations, there has been great variability in their success. Finally, we discuss different issues regarding social independence of these individuals; including employment, safety and decision making.

Background: The presence of the apolipoprotein E (ApoE) 4 genotype is associated with an earlier age of onset for Alzheimer’s disease (AD) and several other neurodegenerative disorders. The objective of this study was to investigate the effect of ApoE genotypes on the clinical course of amyotrophic lateral sclerosis (ALS). Methods: Eight hundred and fifty-two consecutive patients with sporadic ALS evaluated at a tertiary care center were investigated for the effect of ApoE genotype on age of onset, rate of motor disease progression, cognitive functioning, and survival in ALS. Results: The frequencies of individual ApoE genotypes did not differ between patients with ALS and ALS-free Caucasian populations. Patients with different ApoE genotypes did not differ in the age of onset for ALS (years) (ApoE2 = 57.8 ± 13.7, ApoE3 = 57.3 ± 13.7, ApoE4 = 57.7 ± 13.2; P = 0.97), the rate of disease progression (Appel ALS score/month) (ApoE2 = 2.91 ± 2.66, ApoE3 = 2.67 ± 2.66, ApoE4 = 2.61 ± 2.47; P = 0.89), cognitive status (% cognitively impaired) (ApoE2 = 31.7, ApoE3 = 26.8, ApoE4 = 34.3, P = 0.28), or survival in years (ApoE2 = 3.79 ± 3.70, ApoE3 = 3.17 ± 2.27, ApoE4 = 3.05 ± 1.75; P = 0.85). Conclusions: Our results suggest that ApoE genotype does not modify clinical course of sporadic ALS, in stark contrast to the influence of ApoE genotype on the disease course of AD and other neurodegenerative disorders.

Our objective was to test the hypothesis that changes in body mass index (BMI) are associated with changes in the clinical course of ALS. We examined the relationships between BMI at first clinical visit and changes in BMI up to a two-year follow-up, and multiple clinical variables related to ALS: age of onset, rate of progression of motor symptoms, and survival. Baseline BMI was classified according to the World Health Organization (WHO) criteria. Changes in BMI were classified as a loss of >1 unit, no change, or a gain of >1 unit. Our results showed that baseline BMI was not associated with age of onset, rate of progression or survival. In contrast, a loss of BMI >1 over two years was associated with significantly shorter survival and a faster rate of progression. In a multiple regression model, these results were independent of gender, site of onset, history of diabetes mellitus and apolipoprotein (ApoE) genotype. In summary, a change in BMI after ALS diagnosis was significantly associated with rate of progression and survival. This raises the possibility that early changes in BMI may identify patients likely to have a more malignant course of the disease. However, further research is needed to clarify the relationship between BMI and ALS.

Background:The etiology of complex regional pain syndrome (CRPS) is unknown. Different environmental and genetic factors have been postulated to contribute to CRPS.Methods:We reviewed the clinical data from a cohort of 69 patients with CRPS. Four families were identified with two or more members affected with CRPS yielding a total of nine patients. Six more patients reported the presence of pain symptoms in their family members, however; this could not be clinically confirmed.Results:The case histories of the nine individuals with ‘familial’ CRPS suggested a younger age at onset and more frequent history of migraine versus the non-familial patients. A pattern of inheritance could not be ascertained.Conclusion:This data supports the hypothesis that CRPS can be familial and hence may have a genetic basis in some families. Larger studies will be needed to ascertain clearer patterns of inheritance and to determine whether the clinical features of ‘familial’ CRPS are the same as the sporadic form.

Background Several metabolic derangements associated with diabetes mellitus type 2 (DM) have been associated with a better outcome in amyotrophic lateral sclerosis (ALS), including hyperlipidemia and obesity. Here, we tested the hypothesis that DM would have a positive effect on the motor and cognitive findings of ALS. Methods: We compared data from ALS patients with pre-morbid DM (ALS-DM; n = 175) versus without DM (ALS; n = 2196) with regard to the age of onset, rate of motor progression, survival, and neuropsychological test performance. Results: The age of onset was later for women, Caucasians and patients with bulbar-onset ALS. However, we also found that after adjusting for gender, ethnicity and site of onset, DM was associated with a 4-year later onset of ALS (ALS = 56.3, ALS-DM = 60.3, P

Several studies have demonstrated impaired cognition in amyotrophic lateral sclerosis (ALS) patients, but it has been difficult to identify risk factors for this impairment. An association between cognitive changes and bulbar site of onset or dysarthria has been suggested, but the findings are variable. We tested for both associations in a large cohort of ALS patients. At the time of diagnosis of sporadic ALS, all patients (n=355) in this prospective study underwent comprehensive neuropsychological testing. In addition, a subset of 175 patients underwent a detailed assessment of dysarthria, which was quantified using the Appel ALS Score (AALSS). ALS patients with bulbar site of onset performed significantly worse than limb onset patients on a few timed ((VSAT-time, p

Background: Cognitive impairment secondary to frontal lobe atrophy exists in 40–60% of Amyotrophic Lateral Sclerosis (ALS) cases. We aimed to determine the prevalence of frontal-lobe mediated behavioral impairment in (ALS) and to ascertain its relationship to cognitive impairment. Methods: Two-hundred and twenty five patients diagnosed with sporadic ALS were evaluated for behavioral dysfunction using the Frontal Systems Behavior Scale (FrSBe), a validated measure used to examine frontal-lobe mediated behaviors, specifically apathy, executive dysfunction and disinhibition; a total behavior score is also provided. Additionally, a subset of patients also underwent a comprehensive neuropsychological evaluation. Results: Changes in the total FrSBe scores were observed in 24.4% of the patients and 39.6% of the patients had impairment in at least one behavioral domain with symptoms of Apathy being the most common (31.1%). Cognitively impaired ALS patients had worse total (P = 0.05) and apathy scores (P

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with limited therapeutic options. Clinical trials of several drugs shown to be effective in the superoxide dismutase (SOD1) model of ALS have shown no or negative effects when tested in humans. Here we discuss the role of pioglitazone, a peroxisome proliferator-activated receptor-γ agonist, which failed to show efficacy in a recently published phase II clinical trial of ALS patients. The antioxidant and anti-inflammatory properties of pioglitazone make it an attractive therapeutic candidate for neurodegenerative disorders. However, its antidiabetic and antidyslipidemic effects might be detrimental, as emerging evidence suggests that some features of the metabolic syndrome may be protective in ALS. A number of clinical studies show that dyslipidemia, high body mass index, and possibly diabetes mellitus type 2 are associated with better clinical outcomes in ALS. This is further corroborated by studies on transgenic animal models and immortalized neuronal cell lines. Finally, the intricate interplay between glucose/lipid metabolism and susceptibility to oxidative damage in neurons warrants a judicious approach in further trials of antidiabetic drugs in ALS.

The authors and others have recently demonstrated that veterans with chronic combat-related PTSD (CR-PTSD) have a twofold increased risk of dementia. To understand this increased incidence, they performed a systematic review of the literature on neuroanatomical differences between veterans with chronic CR-PTSD and control subjects (22 included studies). The hippocampus was most commonly and consistently reported to differ between groups, thereby suggesting the hypothesis that PTSD is associated with smaller hippocampi, which increases the risk for dementia. However, an alternate hypothesis is that smaller hippocampal volumes are a preexisting risk factor for PTSD and dementia. Studies are clearly needed to differentiate between these important possibilities.

Radionuclide cisternography (RC) is an underutilized but sensitive modality used to differentiate between normal pressure and non-communicating hydrocephalus and can also detect cerebrospinal fluid (CSF) leakage. We present a case of intracranial tuberculous with severe headache and hydrocephalus. RC was performed with Tc-99m labeled DTPA showing communicating hydrocephalus with characteristics Christmas tree sign and early appearance of renal activity due to spinal CSF leak into systemic circulation. This patient responded well to ventriculo-peritoneal shunt (VP shunt).

Schizophrenia (SZP) has been historically referred to as “dementia praecox” because of the recognition that its onset is associated with deficits in memory, attention and visuospatial orientation. We wondered whether there is evidence for additional cognitive decline late in the course of chronic SZP. This review examined the evidence (1) for cognitive decline late in the course of chronic SZP, (2) for how often the late cognitive decline occurs, and (3) whether the cognitive decline in late-life SZP is related to pathophysiology of SZP versus the superimposition of another type of dementia. A PUBMED search was performed combining the MESH terms schizophrenia and dementia, cognitive decline, cognitive impairment and cognitive deficits. A manual search of article bibliographies was also performed. We included longitudinal clinical studies employing standard tests of cognition. Cross-sectional studies and those that did not test cognition through standard cognitive tests were excluded. The initial search produced 3898 studies. Employing selection criteria yielded twenty-three studies. Our data extraction tool included the number of patients in the study, whether a control group was present, the age of patients at baseline and follow-up, the study setting (inpatients versus outpatients), the cognitive tests employed, study duration, and results. Only three longitudinal studies tested for dementia using Diagnostic and statistical manual of mental disorder (DSM) or International classification of disease (ICD) criteria and compared them to controls: two studies demonstrated an increase in the prevalence of dementia and one did not. Twenty longitudinal studies tested for one or more cognitive domains without employing standard criteria for dementia: twelve studies demonstrated a heterogeneous pattern of cognitive decline and eight did not. Studies generally did not control for known risk factors for cognitive impairment such as education, vascular risk factors, apolipoprotein (ApoE) genotype and family history. The evidence for late cognitive decline in SZP is mixed, but, slightly more studies suggest that it occurs. If it occurs, it is unclear whether it is related to SZP or other risks for cognitive impairment. Hence, prospective, longitudinal, controlled studies are needed to confirm that there is progressive cognitive decline in chronic SZP which occurs independent of other risk factors for cognitive impairment.

Accumulation of the DNA/RNA binding protein fused in sarcoma as cytoplasmic inclusions in neurons and glial cells is the pathological hallmark of all patients with amyotrophic lateral sclerosis with mutations in FUS as well as in several subtypes of frontotemporal lobar degeneration, which are not associated with FUS mutations. The mechanisms leading to inclusion formation and fused in sarcoma-associated neurodegeneration are only poorly understood. Because fused in sarcoma belongs to a family of proteins known as FET, which also includes Ewing's sarcoma and TATA-binding protein-associated factor 15, we investigated the potential involvement of these other FET protein family members in the pathogenesis of fused in sarcoma proteinopathies. Immunohistochemical analysis of FET proteins revealed a striking difference among the various conditions, with pathology in amyotrophic lateral sclerosis with FUS mutations being labelled exclusively for fused in sarcoma, whereas fused in sarcoma-positive inclusions in subtypes of frontotemporal lobar degeneration also consistently immunostained for TATA-binding protein-associated factor 15 and variably for Ewing's sarcoma. Immunoblot analysis of proteins extracted from post-mortem tissue of frontotemporal lobar degeneration with fused in sarcoma pathology demonstrated a relative shift of all FET proteins towards insoluble protein fractions, while genetic analysis of the TATA-binding protein-associated factor 15 and Ewing's sarcoma gene did not identify any pathogenic variants. Cell culture experiments replicated the findings of amyotrophic lateral sclerosis with FUS mutations by confirming the absence of TATA-binding protein-associated factor 15 and Ewing's sarcoma alterations upon expression of mutant fused in sarcoma. In contrast, all endogenous FET proteins were recruited into cytoplasmic stress granules upon general inhibition of Transportin-mediated nuclear import, mimicking the findings in frontotemporal lobar degeneration with fused in sarcoma pathology. These results allow a separation of fused in sarcoma proteinopathies caused by FUS mutations from those without a known genetic cause based on neuropathological features. More importantly, our data imply different pathological processes underlying inclusion formation and cell death between both conditions; the pathogenesis in amyotrophic lateral sclerosis with FUS mutations appears to be more restricted to dysfunction of fused in sarcoma, while a more global and complex dysregulation of all FET proteins is involved in the subtypes of frontotemporal lobar degeneration with fused in sarcoma pathology. © 2011 The Author.

Amyotrophic lateral sclerosis (ALS) has been associated with changes in frontal and temporal lobe-mediated cognitive and behavioral functions. Verbal fluency, a sensitive measure to these changes, was utilized to investigate phonemic and semantic abilities in 49 ALS patients and 25 healthy controls (HCs). A subset of the ALS patients was classified as ALS-intact, ALS with mild cognitive impairments (ALS-mild), and ALS with fronto-temporal dementia (ALS-FTD) based on a comprehensive neuropsychological evaluation. Clustering and switching, the underlying component processes of verbal fluency, were analyzed using Troyer's (Troyer, Moscovitch, & Winocur, 1997) and Abwender's (Abwender, Swan, Bowerman, & Connolly, 2001) scoring systems. ALS patients exhibited decreased fluency versus HCs. For phonemic fluency, the intact ALS sample generated fewer clusters and more switches than the ALS-mild and ALS-FTD patients using both scoring systems. This suggests temporal involvement in ALS patients, with increasing frontal lobe involvement in patients with greater cognitive dysfunction. For semantic fluency, similar results were obtained with a greater emphasis on declines in clustering or increased temporal lobe dysfunction. These results suggest that verbal fluency measures identify frontal and temporal lobe involvement in the cognitive decline associated with ALS, particularly when the component processes are evaluated. The clinical utility of these scoring systems with ALS patients is also discussed.

Frontotemporal lobar degeneration with TAR-DNA-binding protein inclusions (FTLD-TDP) is the most common pathological subtype of frontotemporal dementia (FTD). Mutations leading to a loss of function in the progranulin gene (PGRN) are the most common known cause of FTLD-TDP. In agreement with the proposed loss of function disease mechanism, several groups have reported decreased plasma levels of PGRN in patients carrying PGRN mutations compared to individuals without PGRN mutations. We propose that traumatic brain injury (TBI), an environmental factor, may also increase the risk of FTD by altering PGRN metabolism. TBI may lead to an increase in the central nervous system levels of microglial elastases, which proteolyze PGRN into proinflammatory products called granulins causing a reduction in PGRN levels. Hence, inhibiting microglial activation may have an important implication for the prevention of FTD in patients with TBI.

We read with great interest the paper of Riby et al. regarding atypical, unfamiliar face processing in Williams syndrome (WS; Riby, Doherty-Sneddon, & Bruce, 2008a). It offers considerable insight into the mechanism of facial perception in humans and a further elaboration of the hypersociability observed in patients with Williams syndrome. We would like to suggest that the neurologic mechanisms underlying the hypersociability in WS may be attributable to an impaired recognition of facial expressions of threat, a feature that localises to the amygdala.

Stribl et al. (1) observed 10% reduction in body weight and an altered lipid profile in a TDP-43 knock-in mouse model. These observations complement the emerging hypothesis that metabolic abnormalities are characteristic of TDP-43 proteinopathies, notably amyotrophic lateral sclerosis (ALS) (2). However, there are a number of inconsistencies in their observations and the data from ALS patients. Furthermore, we have some reservations about the interpretation of some of the data. In the Summary and under “Discussion,” Stribl et al. (1) mention that TDP-43 heterozygous mutants have an increase of glucose in the blood. However, Fig. 7 shows no difference in the level of blood glucose in either fasted or ad libitum fed mutant mice when compared with controls (1). Additionally, since pre-morbid diabetes mellitus delays the onset of ALS by 4 years (2), an increase in glucose is expected to be beneficial rather than detrimental in ALS models, an effect that has also been shown in TDP-43 Caenorhabditis elegans models (3). Further, Stribl et al. (1) demonstrate that the morphology and function of mitochondria are impaired in TDP-43 mutant mice. Hence, hypoglycemia rather than hyperglycemia is expected, because under mitochondrial impairment, the rate of glucose consumption through glycolysis is increased. Indeed, hypoglycemia is a feature of many mitochondrial disorders (4). One of the most probable reasons for increased blood glucose in TDP-43 knock-in mice is increased resistance to insulin, a feature of hypermetabolism observed in some ALS patients (5). To address this possibility, analyses of glucose and insulin tolerance would be essential.

Alteplase (tPA) remains the only approved treatment for stroke that has a beneficial functional outcome if used within 3 h of an ischemic event. The results of the recently published European Cooperative Stroke Study III trial (1) and the Safe Implementation of Thrombolysis in Stroke-International Stroke Register (2) study suggest that the time window during which alteplase could be safely administered in stroke patients may extend up to 4 5 h. In these studies and previous tPA trials, the focus of outcome measures has been on physical disability and dependence in basic activities of daily living assessed via the NIH stroke scale, modified Rankin, Barthel, and Glasgow outcome scales (1, 2). An evaluation of the instrumental and cognitive outcomes, however, has been overlooked. It would seem to be important to assess cognitive outcomes since almost onefourth of stroke patients develop poststroke dementia within 3 months of the event (3). Thus far, the cognitive and instrumental outcomes have only been studied by Nys and colleagues, who showed that tPA administration within 3 h of stroke did not have a beneficial cognitive outcome. They suggested that either the reduction in the volume of the ischemic region by tPA is not sufficient to have an effect on cognitive outcomes or that the focal cognitive improvement by tPA is countered by a global cognitive decline that could potentially result from tPA treatment (4). It has been suggested that tPA could be deleterious to neurons through a number of mechanisms involving excitotoxicity, activation of microglia, and degradation of extracellular matrix components (5). N-methyl-D-aspartate (NMDA) receptor-mediated excitotoxicity is a key pathway leading to neuronal cell death during ischemic stroke. Glutamate is the main trigger of NMDA-mediated excitotoxicity and its parenchymal levels increase with the duration of the ischemic insult (6). tPA has been shown to potentiate NMDA-mediated excitotoxicity by increasing the calcium influx and production of nitric oxide. Mouse models deficient in tPAwere shown to be resistant to the NMDA-mediated excitotoxic neuronal death, whereas exogenous administration of tPA reinstated excitotoxicity in these animals (5). A delayed administration of tPA in patients with ischemic stroke, given the greater concentration and geographic localization of glutamate with the passage of time might as well provide a greater substrate for the tPA potentiating of excitotoxicity. Perhaps, it would seem appropriate to assess the patients treated with alteplase in the ongoing International Stroke Trial III and any subsequent trials for more comprehensive clinical outcome including cognition and instrumental functioning. That might be the best way we assure ourselves that the thrombolytic benefits of tPA continue to outweigh the risk of neurotoxicity associated with it, even outside the conventional 3-h time window.