HIPPOCAMPUS, VOL. 1, NO. 1, PAGES 1-8, JANUARY 1991
COMMENTARY
Entorhinal Cortex Pathology in Alzheimer’s Disease Gary W. Van Hoesen,*? Bradley T. Hyman,S and Antonio R. Damasio,? Departments of “Anatomy and ?Neurology, University of Iowa, Iowa City, IA 52242 U.S.A. a n d $Neurology Service, Massachusetts General Hospital, Harvard Medical School, Boston, MA 021 14 U . S . A .
ABSTRACT The anatomical distribution of pathological changes in Alzheimer’s disease, although highly selective for only certain brain areas, can be widespread at the endstage of the illness and can affect many neural systems. Propriety for onset among these is a question of importance for clues to the etiology of the disease, but one that is formidable without an experimental animal model. The entorhinal cortex (Brodmann’s area 28) of the ventromedial temporal lobe is an invariant focus of pathology in all cases of Alzheimer’s disease with selective changes that alter some layers more than others. The authors’ findings reveal that i t is the most heavily damaged cortex i n Alzheimer’s disease. Neuroanatomical studies in higher mammals reveal that the entorhinal cortex gives rise to axons that interconnect the hippocampal formation bidirectionally with the rest of the cortex. Their destruction in Alzheimer’s disease could play a prominent role in the memory deficits that herald the onset of Alzheimer’s disease and that characterize it throughout its courfe. Key words: Alzheimer’s disease, entorhinal cortex, cortical pathology, hippocampal formation
Clinical observations in humans, although infrequent, have played a major part in shaping thinking about the functional role of the entorhinal cortex and hippocampal formation and, especially, their participation in certain forms of memory (Scoville and Milner, 1957; Damasio, 1984; Zola-Morgan et al., 1986; Squire, 1987). Recently, animal experimentation, particularly in nonhuman primates (Mishkin, 1982; Squire and Zola-Morgan, 1983; Zola-Morgan and Squire, 1985), has further buttressed these conceptions (Squire and Zola-Morgan, 1988), as have experimental neuroanatomical results in higher mammals (Van Hoesen, 1982). Alzheimer’s disease, a common disorder characterized by memory impairments (Katzman and Terry, 1983), provides an additional rich source of clinical material and, importantly, an instance where naturally occurring pathology dissects neural systems in vivo with a degree of precision not often seen with vascular, viral, or surgical damage to the hippocampal formation and entorhinal cortex. These structures are prime targets of the dissection in Alzheimer’s disease, and the highly selective pathology observed provides rare insight in humans about the cellular basis of some forms of memory (Hyman et al.. 1984;
Pearson et al., 1985; Lewis et al.. 1987). This commentary focuses on the entorhinal cortex because it forms a central element of hippocampal and cortical interconnectivity and because changes in this cortex are both extensive and an invariant feature of the pathological picture in Alzheimer’s disease. In fact, our observations point clearly to the conclusion that it is the most heavily damaged of all cortical areas in Alzheimer’s disease.
ENTORHINAL TOPOGRAPHY Brodmann’s area 28, the entorhinal cortex, is an atypical part of the cortical mantle that forms the major part of the parahippocampal area in nonprimates (Room and Groenewegen, 1986) and the anterior portion of the parahippocampal gyrus in primates (Van Hoesen and Pandya, 1975a, Amaral et al., 1987). Entorhinal structure departs noticeably from other cortices and, in terms of cytoarchitecture, has no close counterpart (Fig. I). In fact, developmentally it appears to be a hybrid whose deeper layers seem related to the phylogenetically older and less elaborate allocortex of the hippocampal formation, and whose superficial layers seem related more closely to the phylogenetically newer and more elaborate isocortex (Rakic and Nowakowski, 1981; Nowakowski and Rakic, 1981). Several features of its architecture immediately
Correspondence and reprint requests to Gary W. Van Hoesen, Department of Anatomy, University of Iowa, Iowa City, IA 52242 U.S.A.
1
2
HZPPOCAMPUS VOL. I, NO. 1, JANUARY 1991 extent there is a conspicuous cell-free lamina dissecans occupied by the dendrites of neurons in adjacent lamina and by axons. Cajal termed the lamina dissecans layer IV, whereas his student Lorente de NO considered it a special, deeper subdivision of layer 111. Layer IV in Lorente de No’s assessment was formed by large modified pyramidal neurons deep to the lamina dissecans. Neither is entirely satisfactory, since they both imply analogies to the isocortex, whose genesis is somewhat different and not entirely comparable. Last, as recently highlighted by Amaral and Insausti (1990) in reviewing Klingler’s (1948) astute and classic observations, the entorhinal cortex actually can be visualized from the external surface of the brain because of the wart-like elevations discernible with wetting and differential lighting of the brain surface. Klingler viewed these as reminiscent of the epidermal tumor of viral origin in dermatological disease and termed them verrucae (Fig. 2 ) .
ENTORHINAL NEURAL SYSTEMS The entorhinal cortex is related intimately to its temporal lobe neighbor, the hippocampal formation, and projects massively to it via a cortical association neural system known as the perforant pathway (Van Hoesen and Pandya. 1975b: Witter and Groenewegen, 1984: Witter et al., 1989). The latter’s origin is largely from the superficial layers of the entorhinal cortex, including the large multipolar neurons of layer 11 (Steward and Scoville, 1976). Perforant pathway volleys exert a potent excitatory influence on the neurons of the hippocampal formation (Andersen et al., 1966a, 1966b), providing their major cortical input. Ascertaining the input to the entorhinal cortex has been a topic of substantial neuroanatomical interest during the last two decades, since such knowledge would illuminate the cortical neural influences that govern hippocampal activity (Van Hoesen et al., 1975). Additionally, it might shed light on the role played by the hippocampal formation in certain forms of memory, which would seem to necessitate that this structure be apprised of ongoing cortical sensory activity (Van Hoesen and Pandya. 1975a). Suffice it t o say, there is now abundant Fig. 1 . (A-C) Three Nissl-stained cross-sections through the experimental evidence in higher mammals (Van Hoesen and ventromedial part of the temporal lobe of the normal human Pandya. 1975a; Van Hoesen et al., 1975: Beckstead. 1978: brain at the level of the anterior, middle, and posterior parts Deacon et al., 1983; Room and Groenewegen. 1986: Insausti of the uncus that demonstrate the mediolateral extent of en- et al., 1987) to support the fact that the entorhinal cortex and, torhinal cortex. Note the proximity of this cortex to the sub- particularly, the cells of origin for the perforant pathway, reicular cortices (PASUB, parasubiculum; PRSUB, presubi- ceive extensive cortical input, and that much of this is derived culum; and SUB. subiculum): and hippocampus (HP). Also, note the prominent islands of neurons that form layer I1 of from sensory and multimodal cortices. In addition. its layer this cortex. AMG, amygdala: DG. dentate gyrus: HF, hip- IV receives a particularly heavy hippocampal output (Shipley and Sorensen, 1975; Rosene and Van Hoesen, 1977: Sorensen pocampal fissure: LV, inferior horn of the lateral ventricle. and Shipley, 1979), and these neurons project widely back t o association and limbic cortices (Kosel et al., 1982; Sorensen, 1985: Swanson and Kohler, 1986: Witter and Groenewegen, set it apart. First, layer I1 of the entorhinal cortex is formed 1986). Thus, in a morphological sense, the entorhinal cortex not by smaller neurons, a cardinal feature of isocortex, but appears to be a pivotal two-way station with a dual role, conby large multipolar neurons whose dendritic arborizations veying cortical input to the hippocampal formation on the one create a star-like o r stellate appearance in Golgi preparations. hand, but also conveying hippocampal output back t o wideAdditionally, in many species, and particularly humans, these spread areas of the cortex on the other hand. In functional neurons are clumped together in what would appear to be terms, the hippocampal formation appears to play a role in islands when cut in cross-section. Second, the entorhinal cor- assessing the relevance or significance of newly processed tex lacks an inner granular layer. Instead, for much of its sensory stimuli, then exerts an equally significant role in de-
ENTORHINAL CORTEX AND ALZHEIMER’S DISEASE / Van Hoesen, et a [ .
3
Fig. 2. Klingler’s (1948) illustration of the ventromedial temporal lobe in humans. Note the location of the entorhinal cortex (14) and its relationship to the uncus of the hippocampal formation (4).Note also that Klingler illustrated the wart-like irregular surface of the entorhinal cortex as seen in the fresh brain that marks the location of the cell islands seen characteristically in layer I1 of the entorhinal cortex.
termining whether they be registered in other parts of the cortex. The neuroanatomy of the entorhinal cortex and hippocampal formation, as garnered during the past two decades, is very much in keeping with this general, o r working, conceptualization.
ENTORHINAL CORTEX IN ALZHEIMER’S DISEASE In terms of gross morphology, the entorhinal cortex is atrophied markedly in a high percentage of cases of Alzheimer’s disease (Fig. 3). This is conspicuous and is often more intense than atrophy in other gyri. Discoloration and a pitted, shrunken appearance are not unusual features for the anterior part of the parahippocampal gyrus where the entorhinal cortex is located. These pits may be a correlate of the massive loss of
neurons from the superficial cell layers. After the entorhinal cortex is sectioned and stained with pathological stains, such as the fluorochrome thioflavin S o r Congo red, a highly characteristic pattern of disease markers is observed (Figs. 4 and 5 ) , namely, the presence of neurofibrillary tangles investing only certain cellular laminae of the entorhinal cortex, and particularly layers I1 and IV (Hyman et al., 1984, 1986). It will be recalled that layer I1 forms a major component of the perforant pathway, conveying cortical input to the hippocampal formation, and that layer IV receives a large hippocampal output and projects widely back to the cortex. We have examined the laminar involvement of the cell layers of the entorhinal cortex in 22 cases of Alzheimer’s disease using thioflavin S. The percentage of cases that contained greater than 50 neurofibrillary tanglesi2.0 mm2 microscopic field in
4
HIPPOCAMPUS VOL. 1, NO. 1, JANUARY 1991
Fig. 3 . Entorhinal pathology is often conspicuous in the fixed brain simply by gross inspection of the anterior part of the parahippocampal gyrus. Note the atrophic, shrunken, and pitted appearance of’ the entorhinal cortex (EC) in 5 cases of Alzheimer’s disease (AD 1-5). These brains were from patients with a duration of illness of 6 to 13 years and an age range of 59-84 years. The normal brain was from an individual 73 years of age at death. Patients AD 1-5 all had a clinical history and pathological changes consistent with the diagnosis of Alzheimer’s disease, whereas the normal did not. CS, collateral sulcus; TP, temporal pole; OLF TR, olfactory tract.
the entorhinal cortex was 100% for layer 11, 45% for layer 111, 86% for layer IV, and 14% for layers V and VI (Hyman and Van Hoesen, 1990). Also, we have recently conducted an extensive semiquantitative analysis of all cortical areas according to Brodmann’s map in both hemispheres of 1 1 confirmed Alzheimer’s disease victims, counting both neuritic plaques and neurofibrillary tangles. In all 22 hemispheres, the entorhinal cortex had both the greatest number of neurofibrillary tangles and by far the
least variance from case to case for all of Brodmann’s areas. Curiously, it had one of the lowest densities of neuritic plaques (Arnold et al., 1990). As alluded to above, two major types of pathology occur in the entorhinal cortex. The first and most dominant is the neurofibrillary tangle, present largely in layer 11, the superficial parts of layer 111, and layer IV. Those in layer I1 are particularly notable since they appear to be of the “extraneuronal or tombstone” variety. This is predicated on the
ENTORHINAL CORTEX AND ALZHEIMER’S DISEASE / Van Hoesen, et al.
5
Fig. 4. (A,B) Photomicrographs of thioflavin S-stained cross-sections through the entorhinal cortex in Alzheimer’s disease to reveal neurofibrillary tangles and neuritic plaques. Note the distribution of neurofibrillary tangles in the islands of neurons in layer 11 and in layer IV. Variability in the distribution of neuritic plaques (white arrowheads) is a common feature, with some located in the middle parts of layer 111, as in A, and others in the deep and superficial extremes of this layer, as in B.
fact that in cell stains such as methylene blue, cresyl violet, thionin, etc., no stainable cytoplasm can be detected and, in essence, the layer is not visible under the microscope. With Congo red, thioflavin S, and certain silver stains, the neurons seemingly reappear, but, of course, this appearance is due to the insoluble tangles that persist and faithfully mark the location of once viable neurons, which, at death, lack cytoplasm, ribosomes, and rough endoplasmic reticulum. Neuritic plaques are present in the entorhinal cortex in most Alzheimer’s disease cases, although their density is low. Typically they are confined largely to layer 111 but may have a variable location within this layer (Fig. 4). Thus, the entorhinal cortex projection to the hippocampal formation, the perforant pathway, is destroyed in Alzheimer’s disease, and its cells of origin, in layer 11, are invested by neurofibrillary tangles. As we have shown in other reports, neuritic plaques and neuroplasticity-induced sprouting occupy the perforant pathway’s terminal zone (Geddes et al., 1985; Hyman et al., 1987a). There is a depletion of glutamate (Hyman et al., 1987b), the putative perforant pathway transmitter, in the terminal zone. Moreover, Alz-50 immunoreactivity appears in a pattern consistent with the perforant path-
way terminal zone demonstrated in experimental studies in higher primates (Hyrnan et al., 1988).
HIPPOCAMPAL PATHOLOGY IN ALZHEl MER’S DISEASE Entorhinal cortex pathology cannot be viewed in isolation, even though this cortex is the most frequently targeted part of the cortical mantle in Alzheimer’s disease. Pathological changes in the nearby, and closely related, hippocampal formation have been noted for years and are very much a part of the picture (Hirano and Zimmerman, 1962; Corsellis, 1970; Hooper and Vogel, 1976; Ball, 1978; Brun and Englund, 1981). However, these are quite selective and involve largely the subicular and CAI parts of the hippocampal formation. The CA2, CA3, and CA4 zones are typically devoid of neurofibrillary tangles, even in endstage Alzheimer’s disease, and the granule cells are infrequently altered. Neuritic plaques are distributed more widely but d o tend to be concentrated in the molecular layer of the subiculum and CA1 zones and in the molecular layer of the dentate gyrus. The presubicular part of the hippocampal formation contains few neuritic plaques and neurofibrillary tangles in Alzheimer’s
6
HIPPOCAMPUS VOL. 1, NO. 1, JANUARY 1991
Fig. 5. Computer-assisted reconstruction of thioflavin S patterns of layer I1 pathology in Alzheimer’s disease as seen in the middle parts of entorhinal cortex in 6 serial sections cut horizontal to the pial surface. The white patches denote a complementary hue cancellation and indicate pathology throughout the depth of the layer I1 islands. Note that bridges of neurons appear to interconnect the islands at various levels. The disruption of this matrix in Alzheimer’s disease effectively destroys the part of the entorhinal cortex that links it to the dentate gyrus of the hippocampal formation, severely compromising input from the cerebral cortex. The letters in the axial orientation guide denote anterior, posterior, medial, and lateral directions.
disease, but the adjacent parasubiculum is typically devastated, resembling very closely the adjacent entorhinal cortex in terms of laminar involvement.
DISCONNECTION OF THE HIPPOCAMPAL FORMATION IN ALZHEIMER’S DISEASE Given our knowledge of hippocampal neuroanatomy in several higher mammals, one has to conclude that the hippocampal formation is likely both deafferented and deefferented from the cortex in Alzheimer’s disease. However, there are many additional complications. For example, several of the sources of cortical and subcortical input to the entorhinal cortex are themselves targeted selectively for pathology in Alzheimer’s disease. These include the temporal polar, superior temporal, perirhinal, and posterior parahippocampal corti-
ces, where thioflavin S-staining reveals neurofibrillary tangles in layers 111 and V (Van Hoesen and Damasio, 1987). The same can be said for key nuclei in the amygdala that contribute afferents to the entorhinal cortex and in other subcortical structures, such as the midline thalamus, locus coeruleus, raphe complex, and nucleus basalis of Meynert. Additionally, while layer IV of the entorhinal cortex must be viewed as a major disseminator of hippocampal output, the major hippocampal sources for the input to layer IV, namely the subicular cortex and CAI zone, are themselves major targets for pathology in Alzheimer’s disease. Therefore, the interconnections between many parts of the cortex, including those with the association cortices and key subcortical areas, are disrupted at multiple levels. This alone may be a unique and devastating pathological correlate of Alzheimer’s dis-
ENTORHINAL CORTEX AND ALZHEIMER’S DISEASE / Van Hoesen, et al.
ease, since it eliminates nearly all potential redundancy, a situation that may not be the case in other types of less devastating neurological diseases. Among the areas and neural systems affected, it is difficult to assign a proprietary locus for the early or initial changes in Alzheimer’s disease. However, in our collection, which now has more than 220 cases, the entorhinal and perirhinal cortices consistently contain pathology. Pathology in other brain areas can be extensive in many of these, but it varies and is not as invariant as those of Brodmann’s area 28.
CONCLUDING REMARKS The alterations in entorhinal cortex alone would not seem to account for all of the memory impairment typically seen at endstage after a significant duration of Alzheimer’s disease. All forms of memory, with the exception of those related to skill and motor memory (Eslinger and Damasio, 1986), are typically damaged in endstage Alzheimer’s patients such as these. However, the early memory changes in Alzheimer’s disease, characterized by confusion and an inability to recall new and changing daily episodes, undoubtedly relate to the pathological changes that target the entorhinal cortex and its associated neural systems. Thus these changes can be viewed as a structural basis for the early memory impairment in Alzheimer’s disease. There are no clues at the moment to understanding the selective vulnerability of entorhinal and hippocampal neurons in Alzheimer’s disease, but the problem is focused clearly for future neuroscientific research. A set of neural systems that interconnect the hippocampal formation and the remainder of the cortex are major targets of pathology in Alzheimer’s disease, and the weight of clinical evidence in humans and experimental studies in nonhumans links them to fundamental mechanisms relating to memory. It is provocative to entertain the fact that the precision of the pathology, which literally dissects the cortex, relates in a fundamental manner to the precision of the anatomical interconnectivity between the various neurons that compose these systems (Pearson et al., 1985; Saper et al., 1987). However, whether this might involve the neuronal transport of a pathogen, an abnormal genome, the breakdown of a system-specific trophic agent, or the neuron-to-neuron propagation of a toxic metabolite awaits a scientific foothold. For the moment, we are left with the fact that a heavy functional demand during wakefulness and, probably, sleep, is placed on these neural systems in the course of a lifetime. This overload may increase their vulnerability and trigger the downward spiral in the quality of life that characterizes Alzheimer’s disease.
ACKNOWLEDGMENTS The authors extend special thanks to P. Reimann for photographic assistance, L. Spence for brain and tissue procurement, and M. M. Thebert for charting assistance. Supported by grants NS 14944, PO NS 19632, AG 08487, and a grant from the Mathers Foundation.
References Amaral, D. G., and R. Insausti (1990) The human hippocampal formation. In The Human Nervous System, G. Paxinos, ed., in press, Academic Press, New York.
7
Amaral, D. G., R. Insausti, and W. M. Cowan (1987) The entorhinal cortex of the monkey. I . Cytoarchitectonic organization. J . Comp. Neurol. 264:326-355. Andersen, P., B. Holmqvist, and P. E. Voorhoeve (1966a) Entorhinal activation of dentate granule cells. Acta Physiol. Scand. 66:448460. Andersen, P., B. Holmqvist, and P. E. Voorhoeve (1966b) Excitatory synapses on hippocampal apical dendrites activated by entorhinal stimulation. Acta Physiol. Scand. 66:461-472. Arnold, S . E., J. E. Flory, B. T. Hyman, A. R. Damasio, a n d G . W. Van Hoesen (1990) Distribution of neurofibrillary tangles and neuritic plaques in the cerebral cortex in Alzheimer’s disease. SOC. Neurosci. Abstr. 16:460. Ball, M. J . (1978) Histopathology of cellular changes in Alzheimer’s disease. In Senile Demenriu: A B i o m e d i d Approach, K. Nandy, ed.. pp. 89-104, Elsevier, New York. Beckstead, R. M. (1978) Afferent connections of the entorhinal area in the rat as demonstrated by retrograde cell-labeling with horseradish peroxidase. Brain Res. 152:249-264. Brun, A., and E. Englund (1981) Regional pattern of degeneration in Alzheimer’s disease: Neuronal loss and histopathological grading. Histopathology 5549-564. Corsellis, J . A. N. (1970)The limbic areas in Alzheimer’s disease and in other conditions associated with dementia. In Alzheimer’s Diseuse und Related Conditions, G. E. W. Wolstenhome and M. O’Connor, eds., pp. 37-45, J . A. Churchill, London. Damasio, A. R. (1984) The anatomic basis of memory disorders. Semin. Neurol. 4:223-225. Deacon, T. W., H. Eichenbaum, P. Rosenberg. and K. W. Eckmann (1983) Afferent connections of the perirhinal cortex in the rat. J . Comp. Neurol. 220:168-190. Eslinger, P. J . , and A. R. Damasio (1986) Preserved motor learning in Alzheimer’s disease. J . Neurosci. 6:3006-3009. Geddes, J . W., D. T . Monaghan, C. W. Cotman, 1. T. Loh, R. C. Kim, and H. C. Chui (1985) Plasticity of hippocampal circuitry in Alzheimer’s disease. Science 230:1170-1181. Hirano, A,, and H . M. Zimmerman (1962) Alzheimer’s neurofibrillary changes. Arch. Neurol. 7:227-242. Hooper, M. W., and F. S. Vogel (1976) The limbic system in Alzheimer’s disease. Am. J . Pathol. 85:l-13. Hyman, 9 . T.. L. J . Kromer, and G. W. Van Hoesen (1987a) Reinnervation of the hippocampal perforant pathway zone in Alzheimer’s disease. Ann. Neurol. 21:259-267. Hyman, B. T., L . J . Kromer, and G. W. Van Hoesen (1988) A direct demonstration of the perforant pathway terminal zone in Alzheimer’s disease using the monoclonal antibody Alz-50. Brain Res. 450:392-397. Hyman, B. T.. and G. W. Van Hoesen (1990) Hierarchical vulnerability of the entorhinal cortex and the hippocampal formation to Alzheimer neuropathological changes: A semiquantitative study. Neurology 40(Suppl. 1):403. Hyman, B. T., G. W. Van Hoesen, and A. R. Damasio (1987b) Alzheimer’s disease: Glutamate depletion in perforant pathway terminals. Ann. Neurol. 22:37-40. Hyman, B. T., G. W. Van Hoesen, A. R. Damasio, and C. L. Barnes (1984) Alzheimer’s disease: Cell-specific pathology isolates the hippocampal formation. Science 225:1168-1170. Hyman, B. T., G . W. Van Hoesen, L . J. Kromer, and A. R. Damasio (1986) Perforant pathway changes and the memory impairment of Alzheimer’s disease. Ann. Neurol. 20:472-481. Insausti, R., D. G. Amaral, and W. M. Cowan (1987) The entorhinal cortex of the monkey. 11. Cortical afferents. J . Comp. Neurol. 264~356-395. Katzman, R., and R. D. Terry (1983) The Neuro/ogy o f d g i n g , F. A. Davis, Philadelphia.
8
HZPPOCAMPUS VOL. I, NO. I, JANUARY 1991
Klingler, J , (1948) Die mnkr-oskopische Antrtomir d r r Anirnonsformation, Denkschriften der Schweizerischen Naturforschenden Gesellschaft, Band LXVIII. Abh. l , Gebriider Fretz Ag., Zurich. Kosel, K . C., G . W. Van Hoesen, and D. L . Rosene (1982) Nonhippocampal cortical projections from the entorhinal cortex in the rat and rhesus monkey. Brain Res. 244:201-213. Lewis, D. A,, M. J . Campbell, R. D. Terry. and J . H. Morrison (1987) Laminar and regional distributions of neurofibrillary tangles and neuritic plaques in Alzheimer’s disease: A quantitative study of visual and auditory cortices. J . Neurosci. 7: 1799-1808. Mishkin, M. (1982) A memory system in the monkey. Philos. Trans. R. Soc. Lond. 298:85-95. Nowakowski. R . S., and P. Rakic (1981) The site oforigin and route and rate of migration of neurons to the hippocampal region of the rhesus monkey. J . Comp. Neurol. 196: 129-154. Pearson, R. C. A,. M. M. Esiri. R. W. Hiorns. G. K. Wilcock. and T. P. S. Powell (1985) Anatomical correlates of the distribution of pathological changes in the neocortex in Alrheimer‘s disease. Proc. Natl. Acad. Sci. USA 82:4531-4534. Rakic. P., and R . S. Nowakowski (1981) The time of origin of neurons in the hippocampal region of the rhesus monkey. .I.Conip. Neurol. l96:Y- 128. Room, P., and H. J. Groenewegen (1986) Connections of the parahippocampal cortex in the cat. I . Cortical afferents. J . Comp. Neurol. 251:415-450. Rosene. D. L.. and G . W. Van Hoesen (1977) Hippocampal efferents reach widespread areas of cerebral cortex and amygdala in the rhesus monkey. Science 198:315-317. Saper, C. B.. B. H. Wainer. and D. C. German (1987) Axonal and transneuronal transport in the transmission of neurological disease: Potential role in system degenerations. including Alrheimer’s disease. Neuroscience 23:389-398. Scoville. W. B., and B. Milner (1957) Loss of recent memory after bilateral hippocampal lesions. J . Neurol. Neurosurg. Psychiatry 20: 11-21. Shipley, M. T., and K . W. Sorensen (1975) Some afferent and intrinsic connections in the guinea pig hippocampal region and a new pathway from subiculum feeding back to parahippocampal cortex. Exp. Brain Res. suppl. 1:188-190. Sorensen, K . E. (1985) Projections o f t h e entorhinal area to the striaturn, nucleus accumbens, and cerebral cortex in the guinea pig. J . Comp. Neurol. 238:308-322. Sbrensen, K. E., and M. T. Shipley (1979) Projections from the subiculum to the deep layers of the ipsilateral presubicular and entorhinal cortices in the guinea pig. J. Comp. Neurol. 188:313-334. Squire, L. R. (1987) Mernory cind Bruin, Oxford University Press, New York.
Squire. L. R.. and S. Zola-Morgan (1983) The neurology of memory: The case for correspondence between the findings for human and nonhuman primate. In Thc Plly.sio/o,qic~u/Bctsis of’Meniory. J . A. Deutsch. e d . , pp. 199-268. Academic Press, New York. Squire, L. R.. and S. Zola-Morgan (1988) Memory: Brain systems and behavior. Trends Neurosci. I I : 170-175. Steward, O . , and S. A . Scoville (1976) Cells of origin of entorhinal cortical afferents to the hippocampus and fascia dentata of the rat. J . Comp. Neurol. 169:347-370. Swanson. I,. W.. and C. K(ihlcr( 1986) Anatomical evidence lor direct prqjections from the entorhinal area to the entire cortical mantle in the rat. J . Neurosci. 6:3010-3023. Van Hoesen, G. W. (1982) The primate parahippocampal gyrus: New insights regarding its cortical connections. Trends Neurosci. 5:345350. Van Hoesen, G. W.. and A . R. Damasio (1987) Neural correlates of cognitive impairment in Alrheimer’s disease. In Higho. Frrnc~tioris of f / i r Ncrvorrs Sy.\rc.tn ( T / w HundhooA of’ Plix,sioh,vy). F. Plum. ed., pp. 871-898, American Physiological Society. Bethesda. MD. Van Hoesen. G . W., and L). N . Pandya (197%) Some connections of the entorhinal (area 28) and perirhinal (area 3 5 ) cortices 0 1 the rhe>us monkey. I . Temporal lobe afferents. Brain Rea. 95: 1-24 Van Hoesen, G. W., and D. N . Pandya (1975b) Some connections of the entorhinal (area 28) and perirhinal (area 3.5) cortices of the rhesus monkey. 111. Efferent connections. Brain Reb. 95:3959. Van Hoesen. G . W.. D. N . Pandya. and N. Butters (1975) Some connections of the entorhinal (area 28) and perirhinal (area 3 5 ) cortices of the rhesus monkey. I I . Frontal lobe afferents. Brain Res. 95:25-38. Witter. M. P.. and H. J . Groenewegen (1984) Laminar origin and septotemporal distribution of entorhinal and perirhinal projections to the hippocampus in the cat. J . Comp. Neurol. 224:371-385. Witter. M. P.. and H. J . Groenewegen (1986) Connections of the parahippocampal cortex in the cat. I l l . Cortical and thalamic efferents. J. Comp. Neurol. 252:1-31. Witter. M. P . , G . W. Van Hoesen. and D. G . Amaral (1989) Topographical organization of the entorhinal projection to the dentate gyrus of the monkey. J . Neurosci. 9:216-228. Zola-Morgan, S., and L. R. Squire (1985) Medial temporal lesions in monkeys impair memory in il variety of tasks sensitive to amnesia. Behav. Neurosci. 99:22-34. Zola-Morgan, S.. L . R . Squire. and D. G . Amaral (1986) Human amnesia and the medial temporal region: Memory impairment following a bilateral lesion limited to the CAI field of the hippocampus. J . Neurosci. 6:2950-2967.
COMMENTARY
Entorhinal Cortex Pathology in Alzheimer’s Disease Gary W. Van Hoesen,*? Bradley T. Hyman,S and Antonio R. Damasio,? Departments of “Anatomy and ?Neurology, University of Iowa, Iowa City, IA 52242 U.S.A. a n d $Neurology Service, Massachusetts General Hospital, Harvard Medical School, Boston, MA 021 14 U . S . A .
ABSTRACT The anatomical distribution of pathological changes in Alzheimer’s disease, although highly selective for only certain brain areas, can be widespread at the endstage of the illness and can affect many neural systems. Propriety for onset among these is a question of importance for clues to the etiology of the disease, but one that is formidable without an experimental animal model. The entorhinal cortex (Brodmann’s area 28) of the ventromedial temporal lobe is an invariant focus of pathology in all cases of Alzheimer’s disease with selective changes that alter some layers more than others. The authors’ findings reveal that i t is the most heavily damaged cortex i n Alzheimer’s disease. Neuroanatomical studies in higher mammals reveal that the entorhinal cortex gives rise to axons that interconnect the hippocampal formation bidirectionally with the rest of the cortex. Their destruction in Alzheimer’s disease could play a prominent role in the memory deficits that herald the onset of Alzheimer’s disease and that characterize it throughout its courfe. Key words: Alzheimer’s disease, entorhinal cortex, cortical pathology, hippocampal formation
Clinical observations in humans, although infrequent, have played a major part in shaping thinking about the functional role of the entorhinal cortex and hippocampal formation and, especially, their participation in certain forms of memory (Scoville and Milner, 1957; Damasio, 1984; Zola-Morgan et al., 1986; Squire, 1987). Recently, animal experimentation, particularly in nonhuman primates (Mishkin, 1982; Squire and Zola-Morgan, 1983; Zola-Morgan and Squire, 1985), has further buttressed these conceptions (Squire and Zola-Morgan, 1988), as have experimental neuroanatomical results in higher mammals (Van Hoesen, 1982). Alzheimer’s disease, a common disorder characterized by memory impairments (Katzman and Terry, 1983), provides an additional rich source of clinical material and, importantly, an instance where naturally occurring pathology dissects neural systems in vivo with a degree of precision not often seen with vascular, viral, or surgical damage to the hippocampal formation and entorhinal cortex. These structures are prime targets of the dissection in Alzheimer’s disease, and the highly selective pathology observed provides rare insight in humans about the cellular basis of some forms of memory (Hyman et al.. 1984;
Pearson et al., 1985; Lewis et al.. 1987). This commentary focuses on the entorhinal cortex because it forms a central element of hippocampal and cortical interconnectivity and because changes in this cortex are both extensive and an invariant feature of the pathological picture in Alzheimer’s disease. In fact, our observations point clearly to the conclusion that it is the most heavily damaged of all cortical areas in Alzheimer’s disease.
ENTORHINAL TOPOGRAPHY Brodmann’s area 28, the entorhinal cortex, is an atypical part of the cortical mantle that forms the major part of the parahippocampal area in nonprimates (Room and Groenewegen, 1986) and the anterior portion of the parahippocampal gyrus in primates (Van Hoesen and Pandya, 1975a, Amaral et al., 1987). Entorhinal structure departs noticeably from other cortices and, in terms of cytoarchitecture, has no close counterpart (Fig. I). In fact, developmentally it appears to be a hybrid whose deeper layers seem related to the phylogenetically older and less elaborate allocortex of the hippocampal formation, and whose superficial layers seem related more closely to the phylogenetically newer and more elaborate isocortex (Rakic and Nowakowski, 1981; Nowakowski and Rakic, 1981). Several features of its architecture immediately
Correspondence and reprint requests to Gary W. Van Hoesen, Department of Anatomy, University of Iowa, Iowa City, IA 52242 U.S.A.
1
2
HZPPOCAMPUS VOL. I, NO. 1, JANUARY 1991 extent there is a conspicuous cell-free lamina dissecans occupied by the dendrites of neurons in adjacent lamina and by axons. Cajal termed the lamina dissecans layer IV, whereas his student Lorente de NO considered it a special, deeper subdivision of layer 111. Layer IV in Lorente de No’s assessment was formed by large modified pyramidal neurons deep to the lamina dissecans. Neither is entirely satisfactory, since they both imply analogies to the isocortex, whose genesis is somewhat different and not entirely comparable. Last, as recently highlighted by Amaral and Insausti (1990) in reviewing Klingler’s (1948) astute and classic observations, the entorhinal cortex actually can be visualized from the external surface of the brain because of the wart-like elevations discernible with wetting and differential lighting of the brain surface. Klingler viewed these as reminiscent of the epidermal tumor of viral origin in dermatological disease and termed them verrucae (Fig. 2 ) .
ENTORHINAL NEURAL SYSTEMS The entorhinal cortex is related intimately to its temporal lobe neighbor, the hippocampal formation, and projects massively to it via a cortical association neural system known as the perforant pathway (Van Hoesen and Pandya. 1975b: Witter and Groenewegen, 1984: Witter et al., 1989). The latter’s origin is largely from the superficial layers of the entorhinal cortex, including the large multipolar neurons of layer 11 (Steward and Scoville, 1976). Perforant pathway volleys exert a potent excitatory influence on the neurons of the hippocampal formation (Andersen et al., 1966a, 1966b), providing their major cortical input. Ascertaining the input to the entorhinal cortex has been a topic of substantial neuroanatomical interest during the last two decades, since such knowledge would illuminate the cortical neural influences that govern hippocampal activity (Van Hoesen et al., 1975). Additionally, it might shed light on the role played by the hippocampal formation in certain forms of memory, which would seem to necessitate that this structure be apprised of ongoing cortical sensory activity (Van Hoesen and Pandya. 1975a). Suffice it t o say, there is now abundant Fig. 1 . (A-C) Three Nissl-stained cross-sections through the experimental evidence in higher mammals (Van Hoesen and ventromedial part of the temporal lobe of the normal human Pandya. 1975a; Van Hoesen et al., 1975: Beckstead. 1978: brain at the level of the anterior, middle, and posterior parts Deacon et al., 1983; Room and Groenewegen. 1986: Insausti of the uncus that demonstrate the mediolateral extent of en- et al., 1987) to support the fact that the entorhinal cortex and, torhinal cortex. Note the proximity of this cortex to the sub- particularly, the cells of origin for the perforant pathway, reicular cortices (PASUB, parasubiculum; PRSUB, presubi- ceive extensive cortical input, and that much of this is derived culum; and SUB. subiculum): and hippocampus (HP). Also, note the prominent islands of neurons that form layer I1 of from sensory and multimodal cortices. In addition. its layer this cortex. AMG, amygdala: DG. dentate gyrus: HF, hip- IV receives a particularly heavy hippocampal output (Shipley and Sorensen, 1975; Rosene and Van Hoesen, 1977: Sorensen pocampal fissure: LV, inferior horn of the lateral ventricle. and Shipley, 1979), and these neurons project widely back t o association and limbic cortices (Kosel et al., 1982; Sorensen, 1985: Swanson and Kohler, 1986: Witter and Groenewegen, set it apart. First, layer I1 of the entorhinal cortex is formed 1986). Thus, in a morphological sense, the entorhinal cortex not by smaller neurons, a cardinal feature of isocortex, but appears to be a pivotal two-way station with a dual role, conby large multipolar neurons whose dendritic arborizations veying cortical input to the hippocampal formation on the one create a star-like o r stellate appearance in Golgi preparations. hand, but also conveying hippocampal output back t o wideAdditionally, in many species, and particularly humans, these spread areas of the cortex on the other hand. In functional neurons are clumped together in what would appear to be terms, the hippocampal formation appears to play a role in islands when cut in cross-section. Second, the entorhinal cor- assessing the relevance or significance of newly processed tex lacks an inner granular layer. Instead, for much of its sensory stimuli, then exerts an equally significant role in de-
ENTORHINAL CORTEX AND ALZHEIMER’S DISEASE / Van Hoesen, et a [ .
3
Fig. 2. Klingler’s (1948) illustration of the ventromedial temporal lobe in humans. Note the location of the entorhinal cortex (14) and its relationship to the uncus of the hippocampal formation (4).Note also that Klingler illustrated the wart-like irregular surface of the entorhinal cortex as seen in the fresh brain that marks the location of the cell islands seen characteristically in layer I1 of the entorhinal cortex.
termining whether they be registered in other parts of the cortex. The neuroanatomy of the entorhinal cortex and hippocampal formation, as garnered during the past two decades, is very much in keeping with this general, o r working, conceptualization.
ENTORHINAL CORTEX IN ALZHEIMER’S DISEASE In terms of gross morphology, the entorhinal cortex is atrophied markedly in a high percentage of cases of Alzheimer’s disease (Fig. 3). This is conspicuous and is often more intense than atrophy in other gyri. Discoloration and a pitted, shrunken appearance are not unusual features for the anterior part of the parahippocampal gyrus where the entorhinal cortex is located. These pits may be a correlate of the massive loss of
neurons from the superficial cell layers. After the entorhinal cortex is sectioned and stained with pathological stains, such as the fluorochrome thioflavin S o r Congo red, a highly characteristic pattern of disease markers is observed (Figs. 4 and 5 ) , namely, the presence of neurofibrillary tangles investing only certain cellular laminae of the entorhinal cortex, and particularly layers I1 and IV (Hyman et al., 1984, 1986). It will be recalled that layer I1 forms a major component of the perforant pathway, conveying cortical input to the hippocampal formation, and that layer IV receives a large hippocampal output and projects widely back to the cortex. We have examined the laminar involvement of the cell layers of the entorhinal cortex in 22 cases of Alzheimer’s disease using thioflavin S. The percentage of cases that contained greater than 50 neurofibrillary tanglesi2.0 mm2 microscopic field in
4
HIPPOCAMPUS VOL. 1, NO. 1, JANUARY 1991
Fig. 3 . Entorhinal pathology is often conspicuous in the fixed brain simply by gross inspection of the anterior part of the parahippocampal gyrus. Note the atrophic, shrunken, and pitted appearance of’ the entorhinal cortex (EC) in 5 cases of Alzheimer’s disease (AD 1-5). These brains were from patients with a duration of illness of 6 to 13 years and an age range of 59-84 years. The normal brain was from an individual 73 years of age at death. Patients AD 1-5 all had a clinical history and pathological changes consistent with the diagnosis of Alzheimer’s disease, whereas the normal did not. CS, collateral sulcus; TP, temporal pole; OLF TR, olfactory tract.
the entorhinal cortex was 100% for layer 11, 45% for layer 111, 86% for layer IV, and 14% for layers V and VI (Hyman and Van Hoesen, 1990). Also, we have recently conducted an extensive semiquantitative analysis of all cortical areas according to Brodmann’s map in both hemispheres of 1 1 confirmed Alzheimer’s disease victims, counting both neuritic plaques and neurofibrillary tangles. In all 22 hemispheres, the entorhinal cortex had both the greatest number of neurofibrillary tangles and by far the
least variance from case to case for all of Brodmann’s areas. Curiously, it had one of the lowest densities of neuritic plaques (Arnold et al., 1990). As alluded to above, two major types of pathology occur in the entorhinal cortex. The first and most dominant is the neurofibrillary tangle, present largely in layer 11, the superficial parts of layer 111, and layer IV. Those in layer I1 are particularly notable since they appear to be of the “extraneuronal or tombstone” variety. This is predicated on the
ENTORHINAL CORTEX AND ALZHEIMER’S DISEASE / Van Hoesen, et al.
5
Fig. 4. (A,B) Photomicrographs of thioflavin S-stained cross-sections through the entorhinal cortex in Alzheimer’s disease to reveal neurofibrillary tangles and neuritic plaques. Note the distribution of neurofibrillary tangles in the islands of neurons in layer 11 and in layer IV. Variability in the distribution of neuritic plaques (white arrowheads) is a common feature, with some located in the middle parts of layer 111, as in A, and others in the deep and superficial extremes of this layer, as in B.
fact that in cell stains such as methylene blue, cresyl violet, thionin, etc., no stainable cytoplasm can be detected and, in essence, the layer is not visible under the microscope. With Congo red, thioflavin S, and certain silver stains, the neurons seemingly reappear, but, of course, this appearance is due to the insoluble tangles that persist and faithfully mark the location of once viable neurons, which, at death, lack cytoplasm, ribosomes, and rough endoplasmic reticulum. Neuritic plaques are present in the entorhinal cortex in most Alzheimer’s disease cases, although their density is low. Typically they are confined largely to layer 111 but may have a variable location within this layer (Fig. 4). Thus, the entorhinal cortex projection to the hippocampal formation, the perforant pathway, is destroyed in Alzheimer’s disease, and its cells of origin, in layer 11, are invested by neurofibrillary tangles. As we have shown in other reports, neuritic plaques and neuroplasticity-induced sprouting occupy the perforant pathway’s terminal zone (Geddes et al., 1985; Hyman et al., 1987a). There is a depletion of glutamate (Hyman et al., 1987b), the putative perforant pathway transmitter, in the terminal zone. Moreover, Alz-50 immunoreactivity appears in a pattern consistent with the perforant path-
way terminal zone demonstrated in experimental studies in higher primates (Hyrnan et al., 1988).
HIPPOCAMPAL PATHOLOGY IN ALZHEl MER’S DISEASE Entorhinal cortex pathology cannot be viewed in isolation, even though this cortex is the most frequently targeted part of the cortical mantle in Alzheimer’s disease. Pathological changes in the nearby, and closely related, hippocampal formation have been noted for years and are very much a part of the picture (Hirano and Zimmerman, 1962; Corsellis, 1970; Hooper and Vogel, 1976; Ball, 1978; Brun and Englund, 1981). However, these are quite selective and involve largely the subicular and CAI parts of the hippocampal formation. The CA2, CA3, and CA4 zones are typically devoid of neurofibrillary tangles, even in endstage Alzheimer’s disease, and the granule cells are infrequently altered. Neuritic plaques are distributed more widely but d o tend to be concentrated in the molecular layer of the subiculum and CA1 zones and in the molecular layer of the dentate gyrus. The presubicular part of the hippocampal formation contains few neuritic plaques and neurofibrillary tangles in Alzheimer’s
6
HIPPOCAMPUS VOL. 1, NO. 1, JANUARY 1991
Fig. 5. Computer-assisted reconstruction of thioflavin S patterns of layer I1 pathology in Alzheimer’s disease as seen in the middle parts of entorhinal cortex in 6 serial sections cut horizontal to the pial surface. The white patches denote a complementary hue cancellation and indicate pathology throughout the depth of the layer I1 islands. Note that bridges of neurons appear to interconnect the islands at various levels. The disruption of this matrix in Alzheimer’s disease effectively destroys the part of the entorhinal cortex that links it to the dentate gyrus of the hippocampal formation, severely compromising input from the cerebral cortex. The letters in the axial orientation guide denote anterior, posterior, medial, and lateral directions.
disease, but the adjacent parasubiculum is typically devastated, resembling very closely the adjacent entorhinal cortex in terms of laminar involvement.
DISCONNECTION OF THE HIPPOCAMPAL FORMATION IN ALZHEIMER’S DISEASE Given our knowledge of hippocampal neuroanatomy in several higher mammals, one has to conclude that the hippocampal formation is likely both deafferented and deefferented from the cortex in Alzheimer’s disease. However, there are many additional complications. For example, several of the sources of cortical and subcortical input to the entorhinal cortex are themselves targeted selectively for pathology in Alzheimer’s disease. These include the temporal polar, superior temporal, perirhinal, and posterior parahippocampal corti-
ces, where thioflavin S-staining reveals neurofibrillary tangles in layers 111 and V (Van Hoesen and Damasio, 1987). The same can be said for key nuclei in the amygdala that contribute afferents to the entorhinal cortex and in other subcortical structures, such as the midline thalamus, locus coeruleus, raphe complex, and nucleus basalis of Meynert. Additionally, while layer IV of the entorhinal cortex must be viewed as a major disseminator of hippocampal output, the major hippocampal sources for the input to layer IV, namely the subicular cortex and CAI zone, are themselves major targets for pathology in Alzheimer’s disease. Therefore, the interconnections between many parts of the cortex, including those with the association cortices and key subcortical areas, are disrupted at multiple levels. This alone may be a unique and devastating pathological correlate of Alzheimer’s dis-
ENTORHINAL CORTEX AND ALZHEIMER’S DISEASE / Van Hoesen, et al.
ease, since it eliminates nearly all potential redundancy, a situation that may not be the case in other types of less devastating neurological diseases. Among the areas and neural systems affected, it is difficult to assign a proprietary locus for the early or initial changes in Alzheimer’s disease. However, in our collection, which now has more than 220 cases, the entorhinal and perirhinal cortices consistently contain pathology. Pathology in other brain areas can be extensive in many of these, but it varies and is not as invariant as those of Brodmann’s area 28.
CONCLUDING REMARKS The alterations in entorhinal cortex alone would not seem to account for all of the memory impairment typically seen at endstage after a significant duration of Alzheimer’s disease. All forms of memory, with the exception of those related to skill and motor memory (Eslinger and Damasio, 1986), are typically damaged in endstage Alzheimer’s patients such as these. However, the early memory changes in Alzheimer’s disease, characterized by confusion and an inability to recall new and changing daily episodes, undoubtedly relate to the pathological changes that target the entorhinal cortex and its associated neural systems. Thus these changes can be viewed as a structural basis for the early memory impairment in Alzheimer’s disease. There are no clues at the moment to understanding the selective vulnerability of entorhinal and hippocampal neurons in Alzheimer’s disease, but the problem is focused clearly for future neuroscientific research. A set of neural systems that interconnect the hippocampal formation and the remainder of the cortex are major targets of pathology in Alzheimer’s disease, and the weight of clinical evidence in humans and experimental studies in nonhumans links them to fundamental mechanisms relating to memory. It is provocative to entertain the fact that the precision of the pathology, which literally dissects the cortex, relates in a fundamental manner to the precision of the anatomical interconnectivity between the various neurons that compose these systems (Pearson et al., 1985; Saper et al., 1987). However, whether this might involve the neuronal transport of a pathogen, an abnormal genome, the breakdown of a system-specific trophic agent, or the neuron-to-neuron propagation of a toxic metabolite awaits a scientific foothold. For the moment, we are left with the fact that a heavy functional demand during wakefulness and, probably, sleep, is placed on these neural systems in the course of a lifetime. This overload may increase their vulnerability and trigger the downward spiral in the quality of life that characterizes Alzheimer’s disease.
ACKNOWLEDGMENTS The authors extend special thanks to P. Reimann for photographic assistance, L. Spence for brain and tissue procurement, and M. M. Thebert for charting assistance. Supported by grants NS 14944, PO NS 19632, AG 08487, and a grant from the Mathers Foundation.
References Amaral, D. G., and R. Insausti (1990) The human hippocampal formation. In The Human Nervous System, G. Paxinos, ed., in press, Academic Press, New York.
7
Amaral, D. G., R. Insausti, and W. M. Cowan (1987) The entorhinal cortex of the monkey. I . Cytoarchitectonic organization. J . Comp. Neurol. 264:326-355. Andersen, P., B. Holmqvist, and P. E. Voorhoeve (1966a) Entorhinal activation of dentate granule cells. Acta Physiol. Scand. 66:448460. Andersen, P., B. Holmqvist, and P. E. Voorhoeve (1966b) Excitatory synapses on hippocampal apical dendrites activated by entorhinal stimulation. Acta Physiol. Scand. 66:461-472. Arnold, S . E., J. E. Flory, B. T. Hyman, A. R. Damasio, a n d G . W. Van Hoesen (1990) Distribution of neurofibrillary tangles and neuritic plaques in the cerebral cortex in Alzheimer’s disease. SOC. Neurosci. Abstr. 16:460. Ball, M. J . (1978) Histopathology of cellular changes in Alzheimer’s disease. In Senile Demenriu: A B i o m e d i d Approach, K. Nandy, ed.. pp. 89-104, Elsevier, New York. Beckstead, R. M. (1978) Afferent connections of the entorhinal area in the rat as demonstrated by retrograde cell-labeling with horseradish peroxidase. Brain Res. 152:249-264. Brun, A., and E. Englund (1981) Regional pattern of degeneration in Alzheimer’s disease: Neuronal loss and histopathological grading. Histopathology 5549-564. Corsellis, J . A. N. (1970)The limbic areas in Alzheimer’s disease and in other conditions associated with dementia. In Alzheimer’s Diseuse und Related Conditions, G. E. W. Wolstenhome and M. O’Connor, eds., pp. 37-45, J . A. Churchill, London. Damasio, A. R. (1984) The anatomic basis of memory disorders. Semin. Neurol. 4:223-225. Deacon, T. W., H. Eichenbaum, P. Rosenberg. and K. W. Eckmann (1983) Afferent connections of the perirhinal cortex in the rat. J . Comp. Neurol. 220:168-190. Eslinger, P. J . , and A. R. Damasio (1986) Preserved motor learning in Alzheimer’s disease. J . Neurosci. 6:3006-3009. Geddes, J . W., D. T . Monaghan, C. W. Cotman, 1. T. Loh, R. C. Kim, and H. C. Chui (1985) Plasticity of hippocampal circuitry in Alzheimer’s disease. Science 230:1170-1181. Hirano, A,, and H . M. Zimmerman (1962) Alzheimer’s neurofibrillary changes. Arch. Neurol. 7:227-242. Hooper, M. W., and F. S. Vogel (1976) The limbic system in Alzheimer’s disease. Am. J . Pathol. 85:l-13. Hyman, 9 . T.. L. J . Kromer, and G. W. Van Hoesen (1987a) Reinnervation of the hippocampal perforant pathway zone in Alzheimer’s disease. Ann. Neurol. 21:259-267. Hyman, B. T., L . J . Kromer, and G. W. Van Hoesen (1988) A direct demonstration of the perforant pathway terminal zone in Alzheimer’s disease using the monoclonal antibody Alz-50. Brain Res. 450:392-397. Hyman, B. T.. and G. W. Van Hoesen (1990) Hierarchical vulnerability of the entorhinal cortex and the hippocampal formation to Alzheimer neuropathological changes: A semiquantitative study. Neurology 40(Suppl. 1):403. Hyman, B. T., G. W. Van Hoesen, and A. R. Damasio (1987b) Alzheimer’s disease: Glutamate depletion in perforant pathway terminals. Ann. Neurol. 22:37-40. Hyman, B. T., G. W. Van Hoesen, A. R. Damasio, and C. L. Barnes (1984) Alzheimer’s disease: Cell-specific pathology isolates the hippocampal formation. Science 225:1168-1170. Hyman, B. T., G . W. Van Hoesen, L . J. Kromer, and A. R. Damasio (1986) Perforant pathway changes and the memory impairment of Alzheimer’s disease. Ann. Neurol. 20:472-481. Insausti, R., D. G. Amaral, and W. M. Cowan (1987) The entorhinal cortex of the monkey. 11. Cortical afferents. J . Comp. Neurol. 264~356-395. Katzman, R., and R. D. Terry (1983) The Neuro/ogy o f d g i n g , F. A. Davis, Philadelphia.
8
HZPPOCAMPUS VOL. I, NO. I, JANUARY 1991
Klingler, J , (1948) Die mnkr-oskopische Antrtomir d r r Anirnonsformation, Denkschriften der Schweizerischen Naturforschenden Gesellschaft, Band LXVIII. Abh. l , Gebriider Fretz Ag., Zurich. Kosel, K . C., G . W. Van Hoesen, and D. L . Rosene (1982) Nonhippocampal cortical projections from the entorhinal cortex in the rat and rhesus monkey. Brain Res. 244:201-213. Lewis, D. A,, M. J . Campbell, R. D. Terry. and J . H. Morrison (1987) Laminar and regional distributions of neurofibrillary tangles and neuritic plaques in Alzheimer’s disease: A quantitative study of visual and auditory cortices. J . Neurosci. 7: 1799-1808. Mishkin, M. (1982) A memory system in the monkey. Philos. Trans. R. Soc. Lond. 298:85-95. Nowakowski. R . S., and P. Rakic (1981) The site oforigin and route and rate of migration of neurons to the hippocampal region of the rhesus monkey. J . Comp. Neurol. 196: 129-154. Pearson, R. C. A,. M. M. Esiri. R. W. Hiorns. G. K. Wilcock. and T. P. S. Powell (1985) Anatomical correlates of the distribution of pathological changes in the neocortex in Alrheimer‘s disease. Proc. Natl. Acad. Sci. USA 82:4531-4534. Rakic. P., and R . S. Nowakowski (1981) The time of origin of neurons in the hippocampal region of the rhesus monkey. .I.Conip. Neurol. l96:Y- 128. Room, P., and H. J. Groenewegen (1986) Connections of the parahippocampal cortex in the cat. I . Cortical afferents. J . Comp. Neurol. 251:415-450. Rosene. D. L.. and G . W. Van Hoesen (1977) Hippocampal efferents reach widespread areas of cerebral cortex and amygdala in the rhesus monkey. Science 198:315-317. Saper, C. B.. B. H. Wainer. and D. C. German (1987) Axonal and transneuronal transport in the transmission of neurological disease: Potential role in system degenerations. including Alrheimer’s disease. Neuroscience 23:389-398. Scoville. W. B., and B. Milner (1957) Loss of recent memory after bilateral hippocampal lesions. J . Neurol. Neurosurg. Psychiatry 20: 11-21. Shipley, M. T., and K . W. Sorensen (1975) Some afferent and intrinsic connections in the guinea pig hippocampal region and a new pathway from subiculum feeding back to parahippocampal cortex. Exp. Brain Res. suppl. 1:188-190. Sorensen, K . E. (1985) Projections o f t h e entorhinal area to the striaturn, nucleus accumbens, and cerebral cortex in the guinea pig. J . Comp. Neurol. 238:308-322. Sbrensen, K. E., and M. T. Shipley (1979) Projections from the subiculum to the deep layers of the ipsilateral presubicular and entorhinal cortices in the guinea pig. J. Comp. Neurol. 188:313-334. Squire, L. R. (1987) Mernory cind Bruin, Oxford University Press, New York.
Squire. L. R.. and S. Zola-Morgan (1983) The neurology of memory: The case for correspondence between the findings for human and nonhuman primate. In Thc Plly.sio/o,qic~u/Bctsis of’Meniory. J . A. Deutsch. e d . , pp. 199-268. Academic Press, New York. Squire, L. R.. and S. Zola-Morgan (1988) Memory: Brain systems and behavior. Trends Neurosci. I I : 170-175. Steward, O . , and S. A . Scoville (1976) Cells of origin of entorhinal cortical afferents to the hippocampus and fascia dentata of the rat. J . Comp. Neurol. 169:347-370. Swanson. I,. W.. and C. K(ihlcr( 1986) Anatomical evidence lor direct prqjections from the entorhinal area to the entire cortical mantle in the rat. J . Neurosci. 6:3010-3023. Van Hoesen, G. W. (1982) The primate parahippocampal gyrus: New insights regarding its cortical connections. Trends Neurosci. 5:345350. Van Hoesen, G. W.. and A . R. Damasio (1987) Neural correlates of cognitive impairment in Alrheimer’s disease. In Higho. Frrnc~tioris of f / i r Ncrvorrs Sy.\rc.tn ( T / w HundhooA of’ Plix,sioh,vy). F. Plum. ed., pp. 871-898, American Physiological Society. Bethesda. MD. Van Hoesen. G . W., and L). N . Pandya (197%) Some connections of the entorhinal (area 28) and perirhinal (area 3 5 ) cortices 0 1 the rhe>us monkey. I . Temporal lobe afferents. Brain Rea. 95: 1-24 Van Hoesen, G. W., and D. N . Pandya (1975b) Some connections of the entorhinal (area 28) and perirhinal (area 3.5) cortices of the rhesus monkey. 111. Efferent connections. Brain Reb. 95:3959. Van Hoesen. G . W.. D. N . Pandya. and N. Butters (1975) Some connections of the entorhinal (area 28) and perirhinal (area 3 5 ) cortices of the rhesus monkey. I I . Frontal lobe afferents. Brain Res. 95:25-38. Witter. M. P.. and H. J . Groenewegen (1984) Laminar origin and septotemporal distribution of entorhinal and perirhinal projections to the hippocampus in the cat. J . Comp. Neurol. 224:371-385. Witter. M. P.. and H. J . Groenewegen (1986) Connections of the parahippocampal cortex in the cat. I l l . Cortical and thalamic efferents. J. Comp. Neurol. 252:1-31. Witter. M. P . , G . W. Van Hoesen. and D. G . Amaral (1989) Topographical organization of the entorhinal projection to the dentate gyrus of the monkey. J . Neurosci. 9:216-228. Zola-Morgan, S., and L. R. Squire (1985) Medial temporal lesions in monkeys impair memory in il variety of tasks sensitive to amnesia. Behav. Neurosci. 99:22-34. Zola-Morgan, S.. L . R . Squire. and D. G . Amaral (1986) Human amnesia and the medial temporal region: Memory impairment following a bilateral lesion limited to the CAI field of the hippocampus. J . Neurosci. 6:2950-2967.
