Hippocampus in Alzheimer's disease: a 3-year follow-up MRI study.

BACKGROUND: Due to the progressive nature of Alzheimer's disease (AD), it has been proposed that serial imaging studies tracking the course of progression might improve the diagnostic accuracy of AD. METHODS: Longitudinal changes in hippocampal volumes were evaluated using magnetic resonance imaging (MRI) over a period of 3 years in 27 AD patients and 8 control subjects. RESULTS: A statistically nonsignificant trend towards accelerated volume loss in the AD group compared to control subjects was observed. During the study period, the average shrinkage of the hippocampal volume ranged from -2.2% to -5.8% in control subjects, and from -2.3% to -15.6% in AD patients. CONCLUSIONS: The observed changes at an individual level were small, and within the accuracy range of the measurements. Therefore, serial MRI of the hippocampus did not offer any advantage over a single MRI to support the diagnosis of AD in this study sample.

Predictors of seizure outcome in newly diagnosed partial epilepsy: memory performance as a prognostic factor.

The epilepsy patients whose seizures will prove to be refractory should be identified as early as possible, and thus the need for new prognostic factors of intractable epilepsy is evident. The aim of the study was to investigate predictors of seizure outcome in a multivariate analysis. Neurological, electroencephalography (EEG) and neuropsychological variables were analyzed as potential predictors of epilepsy. Eighty-nine newly diagnosed adult patients with partial epilepsy were, after a prospective 2-year follow-up period, categorized into one of the two groups: patients with satisfactorily controlled epilepsy, and patients with refractory epilepsy. Six variables predicted 2-year seizure outcome: presence of spike focus in EEG, partial complex or mixed seizure type, remote symptomatic etiology, moderately impaired memory performance in immediate recall and in delayed recognition of the word list, and age at the time of diagnosis. The correct seizure outcome could be predicted with the model in 94% of newly diagnosed epilepsy patients. The presence of verbal memory impairment at the time of the diagnosis of partial epilepsy is a significant predictor of seizure outcome and, together with clinical and EEG variables, it predicts seizure outcome in the majority of the patients. Memory performance as a prognostic factor is of most value in patients with risk of refractory epilepsy and when used in a multidisciplinary setting.

Long-term treatment with vigabatrin - 10 years of clinical experience.

This report describes the long-term follow-up of 56 patients with refractory partial epilepsy who, within 3 months of vigabatrin add-on therapy (3 g/day), showed a reduction in monthly seizure frequency of more than 50%. The short-term (6 months) and long-term (5 years) effects of vigabatrin on seizure frequency in this patient cohort have been published separately. The reduction in seizure frequency appeared to be long-lasting in the patients followed-up (n = 36) and, importantly, a significant number of the patients (n = 7) became seizure-free, especially during long-term treatment. Thus, the efficacy of vigabatrin appears to be progressive, at least in patients who show an early response to treatment. These results are consistent with experimental findings that suggest that vigabatrin may have anti-epileptogenic and neuroprotective effects.

Major decrease in the volume of the entorhinal cortex in patients with Alzheimer's disease carrying the apolipoprotein E epsilon4 allele.

OBJECTIVE: Recent evidence indicates that the apolipoprotein E (ApoE) epsilon4 allele is a risk factor for developing Alzheimer's disease. It has also been proposed that it is associated with increased counts of amyloid plaques and neurofibrillary tangles that in turn are neuropathological hallmarks initially appearing in the medial temporal lobe structures in Alzheimer's disease. In this study, the effect of the ApoE epsilon4 allele on the volume of the entorhinal cortex was evaluated in vivo. METHODS: The volume of the entorhinal cortex was measured on MR images using a recently designed histology based protocol in 16 patients with Alzheimer's disease with ApoE epsilon4 (mean age 70.4 (SD 9.9)), 11 patients with Alzheimer's disease without ApoE epsilon4 (mean age 69.1 (SD7.1)), and in 31 healthy age and sex matched normal controls (72.2 (SD 3.9)). The patients met the NINCDS-ADRDA criteria for probable Alzheimer's disease and were in mild to moderate stages of the disease. MRI was performed with a 1.5 Tesla Magnetom and a 3D technique permitting the reconstruction of 2.0 mm thick contiguous slices perpendicular to the axis of the anterior-posterior commissure. RESULTS: The patients with Alzheimer's disease without the ApoE epsilon4 allele had atrophy in the entorhinal cortex, the volume was reduced by 27% compared with control subjects. However, the most prominent shrinkage (45%) in the entorhinal cortex was seen in patients with Alzheimer's disease with the ApoE epsilon4 allele (p=0.0001). The effect of epsilon4 on the entorhinal cortex volume was especially prominent in female patients with Alzheimer's disease compared to male patients with Alzheimer's disease (p=0.014). Additionally, patients with the ApoE epsilon4 allele had inferior performance in verbal and visual memory functions than those without the allele CONCLUSIONS: Volumetric MRI measurements disclose that ApoE epsilon4 is associated with the degree of atrophy in the entorhinal cortex in early Alzheimer's disease, this effect being especially prominent in female patients with Alzheimer's disease.

Efficacy of antiplatelet treatment in hypertensive patients with TIA or stroke.

We performed a subgroup analysis of the first European Stroke Prevention Study including 1,306 patients recruited in a single center, Kuopio, Finland, to investigate whether or not antiplatelet therapy is effective in the secondary prevention of stroke in hypertensive patients with transient ischemic attack (TIA) or stroke. The patients were treated with aspirin, 990 mg/day, plus dipyridamole, 225 mg/day, or placebo for 2 years. The patients with high systolic blood pressure (> or = 140 mm Hg; n = 1.105) or high diastolic blood pressure (> or = 85 mm Hg; n = 1,120) at entry, were classified into subgroups by blood pressure level. The effect of treatment was statistically significant in all subgroups with high systolic (end-point reduction, 55.2-68.2%) and diastolic blood pressure (end-point reduction, 47.3-82.1%). Risk reduction was, however, greatest in patients with the highest diastolic blood pressure. One possible explanation is that platelets are more activated in these patients, and this can be effectively prevented by antiplatelet therapy. Further studies are needed to confirm this hypothesis.

MRI of the hippocampus in Alzheimer's disease: sensitivity, specificity, and analysis of the incorrectly classified subjects.

In this study, magnetic resonance imaging (MRI) of the hippocampus for the diagnosis of early Alzheimer's disease (AD) is evaluated. We measured hippocampal volumes and the area of the medial hippocampus with a 1.5 T MR imager in 160 subjects: 55 patients with probable AD according to the NINCDS-ADRDA criteria, 43 subjects fulfilling the NIMH criteria of age-associated memory impairment (AAMI), 42 cognitively normal elderly controls, and 20 controls younger than 50 years. Three methods for normalization were compared. The hippocampi were atrophied in the AD patients, but not in the AAMI subjects or the elderly controls. There was no significant correlation between hippocampal volumes and age in the nondemented subjects. The discrimination based on volumetry resulted in an overall correct classification of 92% of AD patients vs. nondemented elderly subjects, whereas discrimination based on hippocampal area was less accurate, producing a correct classification in 80% of the subjects. We conclude that the hippocampus as assessed by MRI volumetry is atrophied early in AD, and spared by aging or AAMI. A brief critical review of previous studies is in concordance with the presented data: all the previous studies that have used volumetry, have similarly ended up with a good classification, whereas simpler or subjective measurements, subject to various sources of bias, have produced most variable results.

Association between features of the insulin resistance syndrome and Alzheimer's disease independently of apolipoprotein E4 phenotype: cross sectional population based study.

OBJECTIVE: To determine the association between features of the insulin resistance syndrome and Alzheimer's disease. DESIGN: Cross sectional population based study. SUBJECTS: 980 people aged 69 to 78 (349 men, 631 women). SETTING: Population of Kuopio, eastern Finland. MAIN OUTCOME MEASURES: Presence of features of the insulin resistance syndrome and diagnosis of Alzheimer's disease by detailed neurological and neuropsychological evaluation. RESULTS: 46 (4.7%) subjects were classified as having probable or possible Alzheimer's disease. In univariate analyses, apolipoprotein E4 phenotype (odds ratio; 95% confidence interval 3.24: 1.77 to 5.92), age (1.16; 1.05 to 1.29), low level of education (0.82; 0.72 to 0.93), low total cholesterol concentration (0.77; 0.59 to 1.00), high systolic blood pressure (1.01; 1.00 to 1.03), high fasting and 2 hour plasma glucose concentrations (1.11; 1.01 to 1.23 and 1.08; 1.03 to 1.13, respectively), high fasting and 2 hour insulin concentrations (1.05; 1.02 to 1.08 and 1.003; 1.00 to 1.01, respectively), and abnormal glucose tolerance (1.86; 1.23 to 2.80) were significantly associated with Alzheimer's disease. In multivariate analysis including apolipoprotein E4 phenotype, age, education, systolic blood pressure, total cholesterol concentration, fasting glucose concentration, and insulin concentration, apolipoprotein E4 phenotype, age, education, total cholesterol, and insulin were significantly associated with Alzheimer's disease. In 532 non-diabetic subjects without the e4 allele hyperinsulinaemia was associated with an increased risk for Alzheimer's disease (prevalence of disease 7.5% v 1.4% in normoinsulinaemic subjects, P = 0.0004). In contrast, in the 228 with the e4 allele hyperinsulinaemia had no effect on the risk of disease (7.0% v 7.1%, respectively). CONCLUSION: Features of the insulin resistance syndrome are associated with Alzheimer's disease independently of apolipoprotein E4 phenotype.

Characterization of target cells for aberrant mossy fiber collaterals in the dentate gyrus of epileptic rat.

Previous studies have demonstrated formation of recurrent excitatory circuits between sprouted mossy fibers and granule cell dendrites in the inner molecular layer of the dentate gyrus (9, 28, 30). In addition, there is evidence that inhibitory nonprincipal cells also receive an input from sprouted mossy fibers (39). This study was undertaken to further characterize possible target cells for sprouted mossy fibers, using immunofluorescent staining for different calcium-binding proteins in combination with Timm histochemical staining for mossy fibers. Rats were injected intraperitoneally with kainic acid in order to induce epileptic convulsions and mossy fiber sprouting. After 2 months survival, hippocampal sections were immunostained for parvalbumin, calbindin D28k, or calretinin followed by Timm-staining. Under a fluorescent microscope, zinc-positive mossy fibers in epileptic rats were found to surround parvalbumin-containing neurons in the granule cell layer and to follow their dendrites, which extended toward the molecular layer. In addition, dendrites of calbindin D28k-containing cells were covered by multiple mossy fiber terminals in the inner molecular layer. However, the calretinin-containing cell bodies in the granule cell layer did not receive any contacts from the sprouted fibers. Electron microscopic analysis revealed that typical Timm-positive mossy fiber terminals established several asymmetrical synapses with the soma and dendrites of nonpyramidal cells within the granule cell layer. These results provide direct evidence that, in addition to recurrent excitatory connections, inhibitory circuitries, especially those responsible for the perisomatic feedback inhibition, are formed as a result of mossy fiber sprouting in experimental epilepsy.

Dexmedetomidine reduces response tendency, but not accuracy of rats in attention and short-term memory tasks.

The present study investigated the role of alpha 2-adrenergic mechanisms in the performance of motor responses, attention and short-term memory in rats. A low dose (3.0 micrograms/kg, s.c.) of dexmedetomidine, an alpha 2-adrenoceptor agonist, reduced response tendency in an attentional task and a working memory task, but it did not affect the choice accuracy of rats. Atipamezole (300 micrograms/kg), an alpha 2-adrenoceptor antagonist, increased anticipatory responding. Although atipamezole did not affect the number of omissions, it reversed the effects of dexmedetomidine on that parameter. We also investigated the effects of dexmedetomidine in rats with partial destruction of noradrenergic nerves induced by the neurotoxin DSP-4 (N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride). On its own, DSP-4 treatment did not affect choice accuracy or behavioural activity of rats in the attentional task. The effects of dexmedetomidine (0.3-3.0 micrograms/kg) on anticipatory responses did not differ between controls and DSP-4 group. Furthermore, the effect on omissions was not consistently diminished in DSP-4 treated rats. These results suggest that the activation of postsynaptic alpha 2-adrenoreceptors may be responsible for dexmedetomidine-induced reduction of response tendency while attention and short-term memory are not markedly affected.

Decline of frontal lobe functions in subjects with age-associated memory impairment.

OBJECTIVE: To assess frontal lobe functions of subjects with age-associated memory impairment (AAMI) and to examine whether performance on neuropsychological tests is correlated with the volume of the frontal lobes in magnetic resonance imaging. DESIGN: Cross-sectional two-group comparison. SETTING: The Memory Research Clinic of Kuopio University and the Magnetic Resonance Imaging Center of Kuopio University Hospital. PARTICIPANTS: Ninety subjects (mean age, 70.5 years), 43 with AAMI diagnosed according to National Institute of Mental Health criteria and 47 age-matched healthy controls. MEASUREMENTS: Four neuropsychological tests were used to assess frontal lobe function: Verbal Fluency Test (VFT), Modified Wisconsin Card Sorting Test (WCST), Trail Making Test (TMT), and Stroop Test (ST). A 1.5-T magnetic resonance imager was used for volume measurements. RESULTS: The AAMI subjects scored significantly worse on the WCST, ST, and TMT compared with controls (ANCOVA, adjusted for age and education, p < 0.05). The frontal lobe volumes did not differ between AAMI subjects and controls. CONCLUSIONS: AAMI subjects appear to be impaired not only in tests assessing memory but also in tests of executive functions. This finding agrees with previous reports suggesting a central role for frontal dysfunction in memory loss of elderly people.

Protocols to demonstrate slowing of Alzheimer disease progression. Position paper from the International Working Group on Harmonization of Dementia Drug Guidelines. The Disease Progression Sub-Group.

Two suggested clinical trial designs for assessing progression of Alzheimer disease are the randomized withdrawal design and the randomized start design. The most promising of these, the randomized start design, has the potential to demonstrate a delay in progression, but there remain problematic design, ethical, and statistical issues to be solved before the protocol can be used in a clinical trial. The development of biological markers of the disease process using neuroimaging or other measures also may provide a robust method of measuring disease progression and demonstrating the biological effect of a drug on the disease process.

The calretinin-containing mossy cells survive excitotoxic insult in the gerbil dentate gyrus. Comparison of excitotoxicity-induced neuropathological changes in the gerbil and rat.

Our preliminary results showed that mossy fibres do not undergo sprouting after global ischaemia in gerbils, although the pattern of hippocampal cell damage resembled that seen in ischaemic and epileptic rats, where mossy fibre sprouting is known to occur. In order to investigate whether the observed differences in the appearance of mossy fibre sprouting are related to the animal model or species used, this study was undertaken to compare the neuropathological changes induced in gerbils by systemic injection of kainate or by occlusion of carotid arteries with the changes induced in rats by injection of kainate. The pattern of pyramidal cell damage was very similar in each group. Mossy fibre sprouting was present in epileptic rats but not in ischaemic or epileptic gerbils. The number of somatostatin-immunoreactive neurons was decreased in the hilus of epileptic rats and ischaemic gerbils, but not in epileptic gerbils. The analysis of calretinin immunoreactivity in the dentate gyrus revealed differences between the rat and gerbil. The most striking difference between these species was that mossy cells contained calretinin in gerbils but not in rats. Cell counting showed that the calretinin-containing mossy cells had survived both in epileptic and ischaemic gerbils. Therefore, since the mossy cells are known to be highly susceptible to excitotoxic insult in rats and degeneration of these cells is thought to be a key element in the induction of mossy fibre sprouting, we propose that the absence of mossy fibre sprouting in gerbils is related to the survival of the mossy cells.

Long-term cognitive and EEG effects of tiagabine in drug-resistant partial epilepsy.

A new anti-epileptic drug, tiagabine, is a potent inhibitor of GABA uptake into neurons and glia. Tiagabine has shown promising efficacy and safety profiles as add-on treatment for partial seizures. We evaluated the long-term effects of tiagabine on cognition and EEG in 37 patients with partial epilepsy. The study protocol consisted of a randomized, double-blind, placebo-controlled, parallel-group add-on study and an open-label extension study. During the 3 month double-blind phase at low doses (30 mg/day) tiagabine treatment did not cause any cognitive or EEG changes as compared with placebo. Tiagabine treatment did not cause deterioration in cognitive performance or produce any rhythmic slow-wave activity or other constant, new abnormalities on EEG during longer follow-up with successful treatment on higher doses after 6-12 months (mean 65.7 mg/day, range 30-80 mg/day) and after 18-24 months (mean dose 67.6 mg/day, range 24-80 mg/day). The daily dosages in the long-term follow-up of the present study are higher than in the previous reports.

MR T2 relaxometry in Alzheimer's disease and age-associated memory impairment.

A prolonged MR T2 relaxation time was proposed to mark the presence and severity of Alzheimer's disease (AD). We studied the value of T2 relaxometry in diagnosing early AD. T2 was measured from 54 patients with AD, 25 subjects with age-associated memory impairment (AAMI), 18 elderly and 16 young controls. The AD patients had longer T2 in the right hippocampal head (104 +/- 11 ms) and tail (98 +/- 10 ms) than age-matched controls (95 +/- 5 and 92 +/- 9 ms, respectively). This prolongation was not related to age. In the AD group, the T2 of the left hippocampal head also correlated with the clinical severity. The T2 of the amygdala did not differ across the groups. Increased T2 in the temporal and parietal white matter and the thalamus related to increasing age rather than to the diagnostic category. The AAMI subjects had T2 comparable with those of age-matched controls. Despite the prolongation of T2 in the AD group the possible diagnostic value was compromized by a substantial overlap between the study groups. We, thus, conclude that the T2 relaxometry is not a reliable method for diagnosing early AD.

Apolipoprotein E, memory and Alzheimer's disease.

Apolipoprotein E (ApoE) epsilon 4 is a well-documented risk factor for Alzheimer's disease (AD). Patients with AD show neuronal damage, particularly in the medial temporal lobe structures involved in memory processing. ApoE has been implicated in nerve regeneration following injury, and synaptogenesis in the hippocampus of experimental animals. Recent studies have shown an increased accumulation of beta A4 amyloid and an increased deficit in ACh-containing neurons in the brains of AD patients that are homozygous for ApoE epsilon 4 compared with those lacking epsilon 4. Furthermore, AD patients with two ApoE epsilon 4 alleles have more-severe loss in hippocampal volume in magnetic resonance imaging (MRI) scans, and more impairment in tests assessing delayed memory, than AD patients without the epsilon 4 allele, in spite of similar global severity of dementia. Minor changes in hippocampal MRI volumetry can also be detected in nondemented elderly, particularly in those with an epsilon 4/4 genotype. Data from a population-based study revealed that elderly subjects carrying the epsilon 4 allele had worse learning ability than those with the epsilon 2/2 or epsilon 2/3 phenotypes, whereas these groups did not differ in other cognitive domains. These data suggest that ApoE epsilon 4 might influence the magnitude of medial temporal lobe atrophy and memory impairment in AD and also in nondemented elderly.

SPECT and MRI analysis in Alzheimer's disease: relation to apolipoprotein E epsilon 4 allele.

OBJECTIVES: The epsilon 4 allele of apolipoprotein E (ApoE) is a risk factor for late onset Alzheimer's disease. ApoE is present in senile plaques, neurofibrillary tangles, and cerebrovascular amyloid, and it is implicated in synaptogenesis. The effect of ApoE polymorphism on the volumes of hippocampus, amygdala, and frontal lobe was studied. The hypothesis was that the patients with Alzheimer's disease carrying the epsilon 4 allele have more pronounced atrophy. The relation of ApoE and cerebral blood flow on cortical areas was also assessed. METHODS: Fifty eight patients with Alzheimer's disease at the early stage of the disease and 34 control subjects were studied. Patients with Alzheimer's disease were divided into subgroups according to the number of the epsilon 4 alleles. Volumes were measured by MRI and regional cerebral blood flow ratios referred to the cerebellum were examined by 99mTc-HMPAO SPECT. ApoE genotypes were determined by digestion of ApoE polymerase chain reaction products with the restriction enzyme Hha1. RESULTS: patients with Alzheimer's disease had smaller volumes of hippocampi and amygdala compared with control subjects, and the patients with Alzheimer's disease homozygous for the epsilon 4 allele had the most prominent volume loss in the medial temporal lobe structures. The frontal lobe volumes did not differ significantly. All patients with Alzheimer's disease had bilateral temporoparietal hypoperfusion and the subgroups with one or no epsilon 4 alleles also had frontal hypoperfusion compared with control subjects. The occipital perfusion ratios tended to decrease with increasing number of epsilon 4 alleles. CONCLUSIONS: Patients with Alzheimer's disease homozygous for the epsilon 4 allele seem to have severe damage in the medial temporal lobe structures early in the disease process and differ from the patients with Alzheimer's disease with one or no epsilon 4 alleles.

Prevalence of ageing-associated cognitive decline in an elderly population.

Different diagnostic definitions have been proposed for use in the characterization of mild cognitive disorders associated with ageing. Previously, we reported a high (38.4%) prevalence of age-associated memory impairment (AAMI) using the National Institute of Mental Health criteria in an elderly population. Recently, a work group of the International Psychogeriatric Association proposed criteria for 'ageing-associated cognitive decline' (AACD). The objective of this study was to evaluate the prevalence of AACD in an elderly population. We examined 403 randomly selected subjects (68-78 years of age) with tests of memory, cognitive processing, attention, verbal and visuoconstructive functions and with a structured questionnaire for health status and subjective complaints of cognitive decline. In all, 26.6% of the subjects (24.4% of women, 30. 1% or men) fulfilled the AACD criteria. The prevalence was slightly related to age and education. The rate was lowest in the oldest age of 75 - 78 years (20.5%) and highest in the age of 71 -74 years (30%). Subjects with less than 4 years of education had the lowest (14.3%) and subjects with more than 6 years of education had the highest rate (29.4%) for AACD. However, the differences between these subgroups were not statistically significant. These results suggest that the prevalence of AACD is lower than that of AAMI. As AAMI tends to identify a very heterogeneous subject group, the AACD diagnosis, which takes into account age and education specific norms in its inclusion criteria, might prove superior to AAMI in differentiating a meaningful subgroup from an elderly population both for research purposes and in clinical settings.

Clinical and neuropsychological characteristics in familial and sporadic Alzheimer's disease: relation to apolipoprotein E polymorphism.

Alzheimer's disease (AD) is a heterogeneous entity presenting as sporadic and familial disease. In familial AD, there is evidence for genetic linkage to a yet undefined gene on chromosome 14 in early-onset pedigrees and on chromosome 19 in late-onset pedigrees. In a few early-onset kindreds, there were mutations in the amyloid precursor gene on chromosome 21. There is an increased frequency of apolipoprotein E (ApoE) epsilon4 allele in patients with late-onset AD. We studied the clinical presentation and profile of cognitive deficits in 58 AD patients at the early stage of the disease. We divided the AD patients into subgroups of sporadic late-onset (SLO) (> or = 65 years), familial late-onset (FLO) (> or = 65 years), sporadic early-onset (SEO) (<65 years), and familial early-onset (FEO) (<65 years) patients and into three subgroups according to their ApoE genotype zero epsilon4, one epsilon4, and two epsilon4 alleles. The AD subgroups did not differ in the global clinical severity of dementia or the duration of the disease. SLO, FLO, SEO, and FEO subgroups did not differ in clinical characteristics such as occurrence of rigidity, hypokinesia, tremor, myoclonus, hallucinations, delusions, or epileptic seizures nor in the profile of deficits on tests assessing memory, language, visuospatial, executive, and praxic functions. The epsilon4++ allele frequency was 0.43 for all AD patients and did not differ across subgroups divided according to the familial aggregation and age of onset. Patients with two epsilon4 alleles had earlier age at onset of dementia than those with no epsilon4 allele (63 +/- 9 versus 68 +/- 9 years), but otherwise the clinical symptoms and signs were not related to the ApoE genotype. However, the AD patients with two epsilon 4 alleles had lowest scores on memory tests and differed significantly from those with one or zero epsilon4 allele in the delayed list learning (p<0.05) and from those with zero epsilon4 allele in the immediate and delayed story recall. In contrast, verbal functions were better preserved in two epsilon4 patients than in those with other ApoE genotypes. This study failed to confirm the earlier reports of severe aphasia, agnosia, and apraxia in familial AD patients, but the clinical phenotype was similar irrespective to the familial aggregation. However, AD patients with two epsilon4 alleles are characterized by more severe memory loss and earlier age of onset than those without the epsilon4 allele.

The systemic administration of tacrine or selegiline facilitate spatial learning in aged fisher 344 rats.

When compared to young Fisher 344 rats, aged Fisher 344 rats were impaired in their acquisition of the water maze task as indicated by longer escape latencies and distances to find a hidden platform. In a free swim trial which was performed after the training period, young rats had a better spatial bias, since they spent more time swimming in the previous training quadrant. Tacrine 3 mg/kg, an anticholinesterase, and selegiline 0.25 mg/kg, a MAO-B inhibitor, partially reversed the acquisition deficit in aged rats when administered on their own, and drug-treated aged rats swam more in the previous training quadrant than vehicle-treated aged rats during the free swim trial. Aged rats also swam slower than young rats. Tacrine, but not selegiline, increased swimming speed in aged rats. Taken as a whole, these data support the proposal that tacrine may be effective at alleviating age-related learning impairment and confirm the role of cholinergic dysfunction in the spatial learning deficit in aged rats.