Laser ablation for mesial temporal lobe epilepsy: Surgical and cognitive outcomes with and without mesial temporal sclerosis.

OBJECTIVES: Laser interstitial thermal therapy (LITT) is a minimally invasive surgical technique for focal epilepsy. A major appeal of LITT is that it may result in fewer cognitive deficits, especially when targeting dominant hemisphere mesial temporal lobe (MTL) epilepsy. To evaluate this, as well as to determine seizure outcomes following LITT, we evaluated the relationships between ablation volumes and surgical or cognitive outcomes in 43 consecutive patients undergoing LITT for MTL epilepsy. METHODS: All patients underwent unilateral LITT targeting mesial temporal structures. FreeSurfer software was used to derive cortical and subcortical segmentation of the brain (especially subregions of the MTL) using preoperative magnetic resonance imaging (MRI). Ablation volumes were outlined using a postablation T1-contrasted MRI. The percentages of the amygdala, hippocampus, and entorhinal cortex ablated were quantified objectively. The volumetric measures were regressed against changes in neuropsychological performance before and after surgery, RESULTS: A median of 73.7% of amygdala, 70.9% of hippocampus, and 28.3% of entorhinal cortex was ablated. Engel class I surgical outcome was obtained in 79.5% and 67.4% of the 43 patients at 6 and 20.3 months of follow-up, respectively. No significant differences in surgical outcomes were found across patient subgroups (hemispheric dominance, hippocampal sclerosis, or need for intracranial evaluation). Furthermore, no significant differences in volumes ablated were found between patients with Engel class IA vs Engel class II-IV outcomes. In patients undergoing LITT in the dominant hemisphere, a decline in verbal and narrative memory, but not in naming function was noted. SIGNIFICANCE: Seizure-free outcomes following LITT may be comparable in carefully selected patients with and without MTS, and these outcomes are comparable with outcomes following microsurgical resection. Failures may result from non-mesial components of the epileptogenic network that are not affected by LITT. Cognitive declines following MTL-LITT are modest, and principally affect memory processes.

The honeycomb maze provides a novel test to study hippocampal-dependent spatial navigation.

Here we describe the honeycomb maze, a behavioural paradigm for the study of spatial navigation in rats. The maze consists of 37 platforms that can be raised or lowered independently. Place navigation requires an animal to go to a goal platform from any of several start platforms via a series of sequential choices. For each, the animal is confined to a raised platform and allowed to choose between two of the six adjacent platforms, the correct one being the platform with the smallest angle to the goal-heading direction. Rats learn rapidly and their choices are influenced by three factors: the angle between the two choice platforms, the distance from the goal, and the angle between the correct platform and the direction of the goal. Rats with hippocampal damage are impaired in learning and their performance is affected by all three factors. The honeycomb maze represents a marked improvement over current spatial navigation tests, such as the Morris water maze, because it controls the choices of the animal at each point in the maze, provides the ability to assess knowledge of the goal direction from any location, enables the identification of factors influencing task performance and provides the possibility for concomitant single-cell recording.

Parahippocampal and Entorhinal Resection Extent Predicts Verbal Memory Decline in an Epilepsy Surgery Cohort.

The differential contribution of medial-temporal lobe regions to verbal declarative memory is debated within the neuroscience, neuropsychology, and cognitive psychology communities. We evaluate whether the extent of surgical resection within medial-temporal regions predicts longitudinal verbal learning and memory outcomes. This single-center retrospective observational study involved patients with refractory temporal lobe epilepsy undergoing unilateral anterior temporal lobe resection from 2007 to 2015. Thirty-two participants with Engel Class 1 and 2 outcomes were included (14 left, 18 right) and followed for a mean of 2.3 years after surgery (±1.5 years). Participants had baseline and postsurgical neuropsychological testing and high-resolution T1-weighted MRI scans. Postsurgical lesions were manually traced and coregistered to presurgical scans to precisely quantify resection extent of medial-temporal regions. Verbal learning and memory change scores were regressed on hippocampal, entorhinal, and parahippocampal resection volume after accounting for baseline performance. Overall, there were no significant differences in learning and memory change between patients who received left and right anterior temporal lobe resection. After controlling for baseline performance, the extent of left parahippocampal resection accounted for 27% (p = .021) of the variance in verbal short delay free recall. The extent of left entorhinal resection accounted for 37% (p = .004) of the variance in verbal short delay free recall. Our findings highlight the critical role that the left parahippocampal and entorhinal regions play in recall for verbal material.

Laser interstitial thermal therapy for medically intractable mesial temporal lobe epilepsy.

OBJECTIVE: To describe mesial temporal lobe ablated volumes, verbal memory, and surgical outcomes in patients with medically intractable mesial temporal lobe epilepsy (mTLE) treated with magnetic resonance imaging (MRI)-guided stereotactic laser interstitial thermal therapy (LiTT). METHODS: We prospectively tracked seizure outcome in 20 patients at Thomas Jefferson University Hospital with drug-resistant mTLE who underwent MRI-guided LiTT from December 2011 to December 2014. Surgical outcome was assessed at 6 months, 1 year, 2 years, and at the most recent visit. Volume-based analysis of ablated mesial temporal structures was conducted in 17 patients with mesial temporal sclerosis (MTS) and results were compared between the seizure-free and not seizure-free groups. RESULTS: Following LiTT, proportions of patients who were free of seizures impairing consciousness (including those with auras only) are as follows: 8 of 15 patients (53%, 95% confidence interval [CI] 30.1-75.2%) after 6 months, 4 of 11 patients (36.4%, 95% CI 14.9-64.8%) after 1 year, 3 of 5 patients (60%, 95% CI 22.9-88.4%) at 2-year follow-up. Median follow-up was 13.4 months after LiTT (range 1.3 months to 3.2 years). Seizure outcome after LiTT suggests an all or none response. Four patients had anterior temporal lobectomy (ATL) after LiTT; three are seizure-free. There were no differences in total ablated volume of the amygdalohippocampus complex or individual volumes of hippocampus, amygdala, entorhinal cortex, parahippocampal gyrus, and fusiform gyrus between seizure-free and non-seizure-free patients. Contextual verbal memory performance was preserved after LiTT, although decline in noncontextual memory task scores were noted. SIGNIFICANCE: We conclude that MRI-guided stereotactic LiTT is a safe alternative to ATL in patients with medically intractable mTLE. Individualized assessment is warranted to determine whether the reduced odds of seizure freedom are worth the reduction in risk, discomfort, and recovery time. Larger prospective studies are needed to confirm our preliminary findings, and to define optimal ablation volume and ideal structures for ablation.

Subregional Mesiotemporal Network Topology Is Altered in Temporal Lobe Epilepsy.

Temporal lobe epilepsy (TLE) is the most frequent drug-resistant epilepsy in adults and commonly associated with variable degrees of mesiotemporal atrophy on magnetic resonance imaging (MRI). Analyses of inter-regional connectivity have unveiled disruptions in large-scale cortico-cortical networks; little is known about the topological organization of the mesiotemporal lobe, the limbic subnetwork central to the disorder. We generated covariance networks based on high-resolution MRI surface-shape descriptors of the hippocampus, entorhinal cortex, and amygdala in 134 TLE patients and 45 age- and sex-matched controls. Graph-theoretical analysis revealed increased path length and clustering in patients, suggesting a shift toward a more regularized arrangement; findings were reproducible after split-half assessment and across 2 parcellation schemes. Analysis of inter-regional correlations and module participation showed increased within-structure covariance, but decreases between structures, particularly with regards to the hippocampus and amygdala. While higher clustering possibly reflects topological consequences of axonal sprouting, decreases in interstructure covariance may be a consequence of disconnection within limbic circuitry. Preoperative network parameters, specifically the segregation of the ipsilateral hippocampus, predicted long-term seizure freedom after surgery.

Lateral Transorbital Endoscopic Access to the Hippocampus, Amygdala, and Entorhinal Cortex: Initial Clinical Experience.

BACKGROUND/AIMS: Transorbital approaches traditionally have focused on skull base and cavernous sinus lesions medial to the globe. Lateral orbital approaches to the temporal lobe have not been widely explored despite several theoretical advantages compared to open craniotomy. Recently, we demonstrated the feasibility of the lateral transorbital technique in cadaveric specimens with endoscopic visualization. We describe our initial clinical experience with the endoscope-assisted lateral transorbital approach to lesions in the temporal lobe. METHODS: Two patients with mesial temporal lobe pathology presenting with seizures underwent surgery. The use of a transpalpebral or Stallard-Wright eyebrow incision enabled access to the intraorbital compartment, and a lateral orbital wall 'keyhole' opening permitted visualization of the anterior temporal pole. RESULTS: This approach afforded adequate access to the surgical target and surrounding structures and was well tolerated by the patients. To the best of our knowledge, this report constitutes the first case series describing the endoscope-assisted lateral transorbital approach to the temporal lobe. We discuss the limits of exposure, the nuances of opening and closing, and comparisons to open craniotomy. CONCLUSION: Further prospective investigation of this approach is warranted for comparison to traditional approaches to the mesial temporal lobe.

Behavioral effects of deep brain stimulation of different areas of the Papez circuit on memory- and anxiety-related functions.

Deep brain stimulation (DBS) has gained interest as a potential therapy for advanced treatment-resistant dementia. However, possible targets for DBS and the optimal stimulation parameters are not yet clear. Here, we compared the effects of DBS of the CA1 sub-region of the hippocampus, mammillothalamic tract, anterior thalamic nucleus, and entorhinal cortex in an experimental rat model of dementia. Rats with scopolamine-induced amnesia were assessed in the object location task with different DBS parameters. Moreover, anxiety-related side effects were evaluated in the elevated zero maze and open field. After sacrifice, we applied c-Fos immunohistochemistry to assess which memory-related regions were affected by DBS. When comparing all structures, DBS of the entorhinal cortex and CA1 sub-region was able to restore memory loss when a specific set of stimulation parameters was used. No anxiety-related side effects were found following DBS. The beneficial behavioral performance of CA1 DBS rats was accompanied with an activation of cells in the anterior cingulate gyrus. Therefore, we conclude that acute CA1 DBS restores memory loss possibly through improved attentional and cognitive processes in the limbic cortex.

Entorhinal denervation induces homeostatic synaptic scaling of excitatory postsynapses of dentate granule cells in mouse organotypic slice cultures.

Denervation-induced changes in excitatory synaptic strength were studied following entorhinal deafferentation of hippocampal granule cells in mature (≥ 3 weeks old) mouse organotypic entorhino-hippocampal slice cultures. Whole-cell patch-clamp recordings revealed an increase in excitatory synaptic strength in response to denervation during the first week after denervation. By the end of the second week synaptic strength had returned to baseline. Because these adaptations occurred in response to the loss of excitatory afferents, they appeared to be in line with a homeostatic adjustment of excitatory synaptic strength. To test whether denervation-induced changes in synaptic strength exploit similar mechanisms as homeostatic synaptic scaling following pharmacological activity blockade, we treated denervated cultures at 2 days post lesion for 2 days with tetrodotoxin. In these cultures, the effects of denervation and activity blockade were not additive, suggesting that similar mechanisms are involved. Finally, we investigated whether entorhinal denervation, which removes afferents from the distal dendrites of granule cells while leaving the associational afferents to the proximal dendrites of granule cells intact, results in a global or a local up-scaling of granule cell synapses. By using computational modeling and local electrical stimulations in Strontium (Sr(2+))-containing bath solution, we found evidence for a lamina-specific increase in excitatory synaptic strength in the denervated outer molecular layer at 3-4 days post lesion. Taken together, our data show that entorhinal denervation results in homeostatic functional changes of excitatory postsynapses of denervated dentate granule cells in vitro.

Stereotactic radiofrequency amygdalohippocampectomy: does reduction of entorhinal and perirhinal cortices influence good clinical seizure outcome?

PURPOSE: Stereotactic radiofrequency amygdalohippocampectomy (SAHE) has been modified recently in our center for the therapy of mesial temporal epilepsy (MTLE). It has promising clinical results comparable with microsurgical amygdalohippocampectomy despite smaller volume reduction of the hippocampus. We hypothesized that the extent of perirhinal and entorhinal cortex (PRC, EC) reduction could explain the clinical outcome. Therefore, we performed, retrospectively, volumetric analysis of PRC and EC and compared it with the seizure control. METHODS: Twenty-six consecutive patients with MTLE treated by SAHE were included. PRC and EC volumes were measured from magnetic resonance imaging (MRI) records obtained before and 1 year after SAHE. The clinical outcome was assessed each year after SAHE using Engel's classification. KEY FINDINGS: Twenty-six patients were analyzed. The volume of PRC decreased by 46 ± 17% (p < 10(-12) ); EC volume decreased by 56 ± 20% (p < 10(-10) ). Two years after the procedure, 73% of patients were classified as Engel's I, 19% as Engel's II; in 2 (8%) the treatment failed (were reoperated). Eighteen patients finished 3 years follow-up; 72% of them were classified as Engel's I, 17% as Engel's II, and in 2 (11%) above-mentioned patients the treatment failed. Thirteen patients finished 4 years of follow-up, 11 of them as Engel's I. There was no significant correlation of the clinical outcome to PRC and EC volume reductions. SIGNIFICANCE: The clinical effect of SAHE is not clearly explained by the volume reductions of PRC and EC (nor of the hippocampus and the amygdala). It promotes opinion that the extent of resection/destruction is not important for seizure outcomes.

A sense of direction in human entorhinal cortex.

Finding our way in spatial environments is an essential part of daily life. How do we come to possess this sense of direction? Extensive research points to the hippocampus and entorhinal cortex (EC) as key neural structures underlying spatial navigation. To better understand this system, we examined recordings of single-neuron activity from neurosurgical patients playing a virtual-navigation video game. In addition to place cells, which encode the current virtual location, we describe a unique cell type, EC path cells, the activity of which indicates whether the patient is taking a clockwise or counterclockwise path around the virtual square road. We find that many EC path cells exhibit this directional activity throughout the environment, in contrast to hippocampal neurons, which primarily encode information about specific locations. More broadly, these findings support the hypothesis that EC encodes general properties of the current context (e.g., location or direction) that are used by hippocampus to build unique representations reflecting combinations of these properties.

Directed fiber outgrowth from transplanted embryonic cortex-derived neurospheres in the adult mouse brain.

Neural transplantation has emerged as an attractive strategy for the replacement of neurons that have been lost in the central nervous system. Multipotent neural progenitor cells are potentially useful as donor cells to repopulate the degenerated regions. One important aspect of a transplantation strategy is whether transplanted cells are capable of fiber outgrowth with the aim of rebuilding axonal connections within the host brain. To address this issue, we expanded neuronal progenitor from the cortex of embryonic day 15 ubiquitously green fluorescent protein-expressing transgenic mice as neurospheres in vitro and grafted them into the entorhinal cortex of 8-week-old mice immediately after a perforant pathway lesion. After transplantation into a host brain with a lesion of the entorhino-hippocampal projection, the neurosphere-derived cells extended long fiber projections directed towards the dentate gyrus. Our results indicate that transplantation of neurosphere-derived cells might be a promising strategy to replace lost or damaged axonal projections.

Impaired verbal associative learning after resection of left perirhinal cortex.

Some patients considered for left temporal lobectomy for epilepsy present with normal verbal learning and no MRI evidence of hippocampal pathology. In order to preserve learning function, the surgical approach in these cases often aims at sparing the hippocampus. Parahippocampal structures, including the left perirhinal region, however, also appear to contribute to some forms of verbal learning. We studied aspects of verbal learning in four patients with left temporal lobe resections that preserved the hippocampus, but which included perirhinal/entorhinal cortices in two cases. Pre- and postoperative T1-weighted MRI scans were spatially normalized and residual mesial temporal structures identified. The two patients whose resection included perirhinal and entorhinal cortices exhibited a marked decrement in the ability to acquire arbitrarily related word pairs that persisted at 12-month follow-up. Word list learning showed an early postoperative impairment, but recovered to normal levels within 12 months. In two patients, resection encompassed anterolateral and inferior temporal neocortex but spared the perirhinal and entorhinal cortices, amygdala and hippocampus. No postoperative change in verbal learning was evident. We concluded that hippocampal-sparing left temporal lobe resections result in task-specific verbal learning deficits when perirhinal/entorhinal tissue is included in the resection.

Does resection of the medial temporal lobe improve the outcome of temporal lobe epilepsy surgery?

PURPOSE: Surgical removal of the hippocampus is the standard of care of patients with drug-resistant medial temporal lobe epilepsy (MTLE). The procedure carries a success rate of approximately 75%, but the reasons that some patients fail to achieve seizure control after surgery remain inexplicable. The question of whether the resection of medial temporal lobe structures in addition to the hippocampus would influence the surgical outcome in patients with MTLE was examined. METHODS: We conducted voxel-based statistical analyses of postoperative high-resolution MRI of MTLE patients who underwent anteromedial temporal resection. We applied a cost function transformation of the resection maps for each patient to a common set of spatial coordinates, and we analyzed the contribution of histologically distinct segments of the medial temporal lobe cortex to the surgical outcome. We also performed a voxel-wise mapping of surgical outcome to the temporal lobe. RESULTS: We observed that the extent of hippocampal removal was associated with better outcomes. However, when the resection of the hippocampus was combined with the resection of the medial temporal lobe, specifically the entorhinal cortex, a greater likelihood of higher seizure control after surgery was found. CONCLUSIONS: Based on this finding, it is possible that the efficiency of the surgical treatment of MTLE can be improved by adjusting the procedure to include the resection of the entorhinal cortex, in addition to the resection of the hippocampus.

Epilepsy.

The first Gamma Knife radiosurgery for mesial temporal lobe epilepsy was performed in Marseille in March 1993. Since then, around 130 patients have undergone epilepsy surgery using Gamma Knife at Marseille Timone University Hospital. The majority of epilepsy surgeries in our epilepsy surgery program in Marseille are performed conventionally because we still consider epilepsy radiosurgery as underevaluated. All epilepsy patients in Marseille are treated in the context of a successive prospective controlled trial, and we are convinced that few of the radiosurgical indications have been scrutinized and evaluated with more rigorous methodology. Some other centers (Madrid, San Diego, San Francisco) have now treated patients with comparable results.

Alterations of behavior and spatial learning after unilateral entorhinal ablation of rats.

The entorhinal cortex (EC) is the key input and output structure of the hippocampus. It plays a crucial role in sensory processing, memory and learning, as well as in mechanisms of epileptic seizures. Our previous studies on the 4-aminopyridin induced epilepsy model of rats showed that ablation of unilateral EC prompted weakening of limbic seizure manifestation, thus the possibility of therapeutical benefit of this kind of surgery can be risen. Open field, elevated plus-maze and Morris water-maze test were performed to analyze changes of the basal activity level, exploratory behavior, and spatial memory capacity, respectively, of adult Wistar rats having undergone left EC excision. Compared with the sham-operated control group, rats with lesions of the EC showed enhanced locomotor activity in the open-field test. The elevated plus-maze test revealed higher frequency of entries and more time spent in the open arms. Morris water-maze test suggested impairment of the spatial learning capacity following left lateral EC lesion. Therefore, our data showed that EC lesions induced hyperactivity, increased exploratory behavior, and impaired spatial learning. Entorhinal cortex ablation, as a potential method for controlling epileptic seizures has multiple effects on animals' behavior and spatial learning. To determine the cost-benefit ratio of a potential surgical intervention needs further experimental and human investigations.

Vascular endothelial growth factor and its receptor Flk-1 are expressed in the hippocampus following entorhinal deafferentation.

Vascular endothelial growth factor (VEGF) has been thought of as a mitogen that promotes proliferation of endothelial cells and as a neurotrophic factor that stimulates neurogenesis and axonal growth in both peripheral and central nervous systems. To investigate the potential involvement of VEGF in the lesion-induced reorganization in the brain, the expression changes of VEGF and its receptor Flk-1 were analyzed in the mouse hippocampus after transections of the entorhinal afferents. In situ hybridization and immunohistochemistry showed the time-dependent expression upregulation of VEGF mRNA and protein in the entorhinally denervated hippocampal stratum lacunosum-moleculare and dentate outer molecular layer, which initiated by 3 days postlesion, reached its maximum at 7-15 days postlesion, still persisted by 30 days postlesion for protein, and recovered to the normal levels at 30 days postlesion for mRNA and at 60 days postlesion for protein. Double labeling of VEGF and glial fibrillary acidic protein revealed that VEGF-expressing cells in the denervated areas were reactive astrocytes. Semi-quantitative RT-PCR analysis showed that VEGF receptor Flk-1 mRNA was also time-dependently upregulated in the deafferented hippocampus with its maximal elevation at 7-15 days postlesion while the Flt-1 mRNA levels remained unchanged at any time point we examined. Immunohistochemistry analysis also displayed the upregulation of Flk-1 protein in the denervated stratum lacunosum-moleculare and outer molecular layer with a time course similar to that of VEGF mRNA upregulation. Flk-1 receptors were found to be expressed not only by reactive astrocytes but also by neurites, which most likely belong to sprouting axons by 7 days postlesion and regrowing dendrites by 15-30 days postlesion. From these data we suggest that the spatiotemporal upregulation of VEGF and Flk-1 in the hippocampus is induced by entorhinal deafferentation and that VEGF may be involved in the structural reorganization in the deafferented hippocampus via directly or indirectly promoting neurite growth.

Effect of apolipoprotein E deficiency on reactive sprouting in the dentate gyrus of the hippocampus following entorhinal cortex lesion: role of the astroglial response.

This study investigated the effect of apolipoporotein E (apoE) deficiency on hippocampal reactive sprouting responses of the septohippocampal cholinergic (SHC) and commissural/associational fibers (C/A) following an electrolytic lesion of the entorhinal cortex (ECL), using apoE knockout (apoEKO) and age-matched control wild-type mice. Based on recent evidence suggesting that apoE plays a role in the modulation of glial inflammation, we also tested the hypothesis that the pattern of the astroglial response to ECL might be related to the defective reinnervation previously reported in apoEKO mice. Consistent with our hypothesis, we report a differential pattern of astroglial response that concurred with impairments in the sprouting of the SHC and corresponding synaptic replacement in apoEKO mice at 14 and 30 days post-lesion (DPL), a time range covering the onset of axonal/terminal sprouting to synaptogenesis. We also report a limited sprouting of the C/A fiber system in apoEKO relative to control mice at 30 DPL, a period of active dendritic remodeling. The results of the present study confirm and extend previous findings that apoEKO mice display impaired regenerative capacity in response to ECL and argue that in addition to the effect of apoE on lipid trafficking, apoE may also influence the astroglial response to damage, and that both of these effects account for the defective reinnervation observed in apoEKO mice.

Circulating monocytic cells infiltrate layers of anterograde axonal degeneration where they transform into microglia.

In this study, we demonstrate the infiltration of blood-derived monocytic cells and their morphologic transformation into microglia in zones of acute, anterograde (Wallerian) axonal degeneration induced by entorhinal cortex lesion (ECL). ECL was performed in mice which had received green fluorescent protein (GFP)-transduced bone marrow grafts allowing identification of blood-derived elements within the brain. While in the unlesioned hemisphere GFP+ cells were restricted to perivascular and leptomeningeal sites, many round fluorescent cells appeared in hippocampal zones of axonal degeneration at 24 h post lesion (hpl). Within 72 hpl, these GFP+ cells acquired ramified, microglia-like morphologies, which persisted for at least 7 days post ECL. Differentiation of GFP+ cells into glial fibrillary acidic protein (GFAP)+ astrocytes was never observed. To exclude that this recruitment is an artifact of irradiation or bone marrow transplantation, the fluorescent cell tracker 6-carboxylfluorescein diacetate (CFDA) was injected into spleens of normal mice 1 day before ECL. Again, fluorescent cells appeared at the lesion site and along the layers of axonal degeneration at 48 hpl and CFDA+/MAC-1+, cells exhibited amoeboid and ramified morphologies. Thus, blood-derived cells infiltrate not only the site of mechanical lesion, but also the layers of anterograde axonal degeneration, where they readily transform into microglia-like elements. A role for infiltrating leukocytes in facilitating or modulating postlesional plasticity, e.g., by phagocytosis of growth-inhibiting myelin should now be considered. Moreover, monocytic cells may serve as vehicles to transport therapeutic substances such as neurotrophic factors or caspase inhibitors to zones of axonal degeneration.

Regulated transcripts in the hippocampus following transections of the entorhinal afferents.

Based on the data from a cDNA microarray experiment which was carried out to screen the differential expressed genes in the rat hippocampus 10 days after removal of the entorhinal afferents, we confirmed the increase of expression of eight transcripts encoding protein osteonectin, thymosin-beta4, gelsolin, MHC I, MHC II, beta2-microglobulin, and interferon-gamma receptor using Northern blot. In situ hybridization revealed that the up-regulation of all these 8 transcripts localized specifically in the denervated target areas, the hippocampal stratum lacunosum-moleculare, and the dentate outer molecular layer. The results suggest that these molecules may have roles in the plasticity events in the hippocampus after entorhinal deafferentation.

Diffuse amyloid deposition, but not plaque number, is reduced in amyloid precursor protein/presenilin 1 double-transgenic mice by pathway lesions.

Alzheimer's disease (AD) is the most common form of dementia in the elderly, and the characteristic pathological hallmarks of the disease are neuritic plaques and neurofibrillary tangles. The sequence of events leading to the extracellular deposition of amyloidbeta (Abeta) peptides in plaques or in diffuse deposits is not clear. Here we investigate the relation between disrupted axonal transport of amyloid precursor protein (APP) and/or Abeta and the deposition of Abeta in the deafferented terminal fields in APP/presenilin 1 double-transgenic AD-model mice. In the first experiment we ablated entorhinal cortex neurons and examined the subsequent changes in amyloid deposition in the hippocampus 1 month later. We show that there is a substantial reduction in the amount of diffuse amyloid deposits in the denervated areas of the hippocampus. Further, to investigate the effects of long-term deafferentation, in a second experiment we cut the fimbria-fornix and analyzed the brains 11 months post-lesion. Diffuse amyloid deposits in the deafferented terminal fields of area CA1 and subiculum were dramatically reduced as assessed by image analysis of the Abeta load. Our findings indicate that neuronal ablations decrease diffuse amyloid deposits in the terminal fields of these neurons, and, further, that pathway lesions similarly decrease the amount of diffuse amyloid deposits in the terminal fields of the lesioned axons. Together, this suggests that the axonal transport of APP and/or Abeta and subsequent secretion of Abeta at terminals plays an important role in the deposition of Abeta protein in Alzheimer's disease, and, further, that diffuse deposits do not develop into plaques.py>