Selective Vulnerability of Neocortical Association Areasin Alzheimer’s DiseasePANTELEIMON GIANNAKOPOULOS,1* PATRICK R. HOF,2–4 AND CONSTANTIN BOURAS1,2

1Department of Psychiatry, HUG Belle-Idee, University of Geneva School of Medicine, 1225 Geneva, Switzerland2Neurobiology of Aging Laboratories and Fishberg Research Center for Neurobiology, Mount Sinai School of Medicine,New York, New York 100293Department of Geriatrics and Adult Development, Mount Sinai School of Medicine, New York, New York 100294Department of Ophthalmology, Mount Sinai School of Medicine, New York, New York 10029

KEY WORDS corticocortical disconnection; neurofibrillary tangles; senile plaques

ABSTRACT This article reviews the possible relationships between the localization of cellularpathologic changes in Alzheimer’s disease (AD), and the distribution of neuronal components of theneocortical circuitry that are affected by these alterations. In particular, evidence from the study oflarge autopsy series supporting the role of the inferior temporal cortex as a key area in theprogression of the dementing process is presented. The notion of selective vulnerability in AD at thelevel of affected neocortical association areas, layers, and specific cell populations is discussed toprovide insight into the molecular background of the development of neurofibrillary tangles withinthe cerebral cortex. Moreover, recent data on pathological correlates of apraxia in AD are examinedin the light of the hypothesis of global corticocortical disconnection in this disorder. Microsc. Res.Tech. 43:16–23, 1998. r 1998 Wiley-Liss, Inc.

INTRODUCTIONAlzheimer’s disease (AD) is the most common form of

dementia in old age. Based on clinical and epidemio-logic studies, at least 11% of the population older than65, and up to 50% of individuals over age 85, may have‘‘probable AD’’ (Evans et al., 1992; Moss and Albert,1988). Several studies of the distribution of AD patho-logic changes indicate that dementia affects predomi-nantly the cerebral cortex; that subpopulation of neu-rons characterized by particular regional and laminardistributions, as well as distinct connectivity patterns,appears to be highly vulnerable, whereas other neuro-nal subgroups display an increased resistance to thedegenerative process (Hof and Morrison, 1990, 1996;Hof et al., 1990a; Morrison, 1993). Neuropathologically,AD is characterized by the presence in the cerebralcortex of two classical lesions, neurofibrillary tangles(NFT) and senile plaques (SP) (reviewed in Hof andMorrison, 1990, 1996; Hof et al., 1990a; Morrison,1993). In addition, severe neuronal and synapse lossthat mainly involves the hippocampal formation andassociation neocortical areas is also consistently ob-served in the brain of AD patients and has been shownto be a strong correlate of cognitive decline in dementedpeople (reviewed in Gomez-Isla et al., 1996; Morrisonand Hof, 1997; Terry et al., 1981). Synapse loss has beenencountered in the neocortex of nondemented elderlyindividuals, demonstrating the existence of an age-dependent mechanism for the loss of synapses in theneocortex (Terry et al., 1981). NFT represent the accu-mulation of abnormal components of the neuronalcytoskeleton that aggregate into paired helical fila-ments, whereas classic SP are composed of dystrophicneurites and glial elements, and have an amyloid core(reviewed in Brion, 1990; Hof and Morrison, 1996;Morisson, 1993; Vickers et al., 1992). These changes are

also present in normal brain aging, but they are far lesssevere than in AD, and occur in restricted regions of thecerebral cortex (Ball, 1977; Mountjoy et al., 1983; Terryet al., 1981; Tomlinson et al., 1968; Ulrich, 1985). Innondemented elderly individuals, the hippocampal for-mation consistently displays a moderate to severedegree of pathologic changes, whereas the neocorticalareas remain mostly unaffected by NFT formation(Arriagada et al., 1992a,b; Bouras et al., 1993; Gianna-kopoulos et al., 1994; Hof et al., 1992; Price et al., 1991).When a very mild cognitive impairment is present,NFT and SP densities are comparable to those seen indementia in mesial temporal lobe structures (Ar-riagada et al., 1992a,b; Bouras et al., 1993; Crystal etal., 1988; Hof et al., 1992; Morris et al., 1991; Price etal., 1991), with a relative sparing by NFT of otherneocortical regions (Arriagada et al., 1992b; Bierer etal., 1995; Bouras et al., 1993, 1994; Hof et al., 1992;Morris et al., 1991; Price et al., 1991). These casesexhibit preferential distribution of NFT in the entorhi-nal cortex, whereas lower NFT densities are observedin the CA1 field and temporal neocortex (Arriagada etal., 1992b; Bierer et al., 1995; Bouras et al., 1993, 1994;Hof et al., 1992; Morris et al., 1991; Price et al., 1991).

Interestingly, Braak and Braak (1991) demonstratedthat the transition zone between the allo- and neocortexwas systematically involved at early stages of AD, andthey proposed a neuropathologic staging of dementia

Contract grant sponsor: NIH; Contract grant number: AG05138; Contractgrant sponsor: Brookdale Foundation; Contract grant sponsor: Swiss NationalScience Foundation; Contract grant numbers: 3200–039767.93/1, 31–45960.95,31–52997.97, 1994.

*Correspondence to: Dr. Panteleimon Giannakopoulos, Department of Psychia-try, HUG Belle-Idee, University of Geneva School of Medicine, 2 chemin du PetitBel-Air, CH-1225 Chene-Bourg, Geneva, Switzerland. E-mail: giannako@ cmu.u-nige.ch

Received 23 March 1998; Accepted in revised form 6 June 1998

MICROSCOPY RESEARCH AND TECHNIQUE 43:16–23 (1998)

r 1998 WILEY-LISS, INC.

based on progressive alterations in the hippocampalcortex. These differences in regional lesion density anddistribution are useful in distinguishing elderly nonde-mented cases from AD patients, whose neocorticalareas are dramatically affected (Arriagada et al.,1992a,b; Bouras et al., 1993; Crystal et al., 1988;Giannakopoulos et al., 1994; Hof and Morrison, 1990;Hof et al., 1990a, 1992; Lewis et al., 1987; Morris et al.,1991; Pearson et al., 1985; Price et al., 1991; Rogers andMorrison, 1985). We provide here a critical review ofcurrent concepts on neocortical vulnerability in brainaging and AD, with particular reference to correlationsbetween the disruption of specific neocortical pathwaysand the development of neuropsychological deficitsin AD.

DIFFERENTIAL VULNERABILITY OFNEOCORTICAL AREAS IN NORMAL BRAIN

AGING AND AD: THE ROLE OF THEINFERIOR TEMPORAL CORTEX

A frequent development of NFT in mesial and inferiortemporal structures, contrasting with the relative pres-ervation of other neocortical areas, is observed incognitively intact individuals and patients with age-associated memory impairment (AAMI), suggestingthat the damage to these areas may be associated withmemory impairment but is not always sufficient tocause the massive cognitive deterioration observed inAD. In particular, several analyses have shown thatAAMI is related to a pattern of lesion distribution in thehippocampal formation that is compatible with a neuro-pathological diagnosis of AD, yet the degree of neocorti-cal damage differs dramatically from that of AD pa-tients, since there are relatively few NFT outside of thehippocampal formation (Fig. 1; Arnold et al., 1991;

Braak and Braak, 1991; Giannakopoulos et al., 1994;Hof et al., 1990a; Lewis et al., 1987; Pearson et al.,1985; Price et al., 1991; Rogers and Morrison, 1985).

The onset of AD correlates with NFT density in theinferior temporal cortex (Brodmann area 20), suggest-ing that the massive involvement of this area is animportant step in the clinical development of dementia(Bierer et al., 1995; Bouras et al., 1993, 1994; Hof et al.,1992). A small percentage of patients with AAMI andcognitively intact cases also display substantial NFTformation in area 20, and it has been postulated that aprogression in NFT density within adjacent corticalcomponents of the medial and inferior aspects of thetemporal cortex may be a neuropathological hallmarkof incipient dementia (Bouras et al., 1993; Hof et al.,1992; Hubbard et al., 1990). In their neuropathologicalstudy of 70 nonselected cases in a general hospital,Hubbard et al. (1990) showed that widespread forma-tion of NFT in the hippocampus and in area 20 withoutimplication of other neocortical areas is not associatedwith overt clinical signs of dementia. Similarly, in aquantitative neuropathological evaluation of 61 ran-domly selected nondemented elderly patients, we re-ported the presence of eight intellectually normal caseswith much higher NFT densities in the hippocampalformation and area 20, and proposed that the existenceof many NFT in these regions could precede the develop-ment of clinical signs of dementia (Bouras et al., 1993).It is thus likely that the visual association area 20 inthese cases might be an interface between substantiallyaffected and relatively unaffected areas, such as thesuperior frontal and occipital cortex. This indicates thatthis area may be a reliable landmark for examiningclinicopathologic correlations in brain aging. In thiscontext, it is worth noting that in experimental models

Fig. 1. Neurofibrillary tangles (a–c) and senile plaques in layersV–VI of area 20 (d–f) in a nondemented 78-year-old patient (a, d), a79-year-old patient with AAMI (b, e), and an 80-year-old patient withAD (c, f). Note the substantial NFT formation in this area in the AD

case. Note also that the AAMI and AD cases show comparable SPdensities. Samples were stained with antibodies against the microtu-bule-associated tau protein (a–c) and the amyloid Ab protein (d–f).Scale bars: a–c, 100 µm; d–f, 200 µm.

17NEOCORTICAL PATHOLOGY IN ALZHEIMER’S DISEASE

of memory impairment, macaque monkeys with lesionsconfined to the hippocampus and amygdala display asparing of their learning skills, whereas lesions of theperirhinal and parahippocampal fields produced severememory disturbances, stressing the fact that thesecortical fields are key elements of the memory system(Squire and Zola-Morgan, 1991; Suzuki et al., 1993;Zola-Morgan and Squire, 1984; Zola-Morgan et al.,1989).

In contrast to NFT, several well-conducted neuro-pathological studies demonstrated that SP develop-ment in the neocortex is not necessarily associated withovert dementia symptomatology (Arriagada et al.,1992a; Bouras et al., 1994; Giannakopoulos et al.,1994). For example, Katzman et al. (1988) reported on aseries of nondemented cases with SP densities in theneocortical regions comparable to those observed insome demented patients, but with no NFT in the frontalor parietal cortex. Crystal et al. (1988) studied prospec-tively a small series of nondemented patients present-ing with NFT only in the hippocampus and with SPdensities in the neocortex similar to those in patientsaffected by AD. More recently, similar observationswere reported in several quantitative immunocyto-chemical analyses of nondemented and very mildlydemented cases (Hof et al., 1992; Dickson et al., 1991;Morris et al., 1991; Price et al., 1991). Additionalclinicopathologic studies also demonstrated that neocor-tical SP were unrelated to the number of NFT innondemented cases and degree of dementia in AD cases(Berg et al., 1993; Bouras et al., 1994). Altogether, thesedata suggest that widespread neocortical amyloid depo-sition is not incompatible with relatively preservedhigher cortical functions, but that extensive NFT devel-opment in neocortex is clearly linked to significantcognitive decline.

NEURON DEATH IN NORMAL BRAINAGING AND AD

Early reports indicated that most neocortical areasand certain hippocampal subdivisions lose 25–50% oftheir neurons with age (reviewed in Morrison and Hof,1997). More recently, a careful review of these studiesled to the conclusion that the data could be biased byspecies and strain differences, tissue processing, andsampling design. In the last few years, the applicationof stereological procedures for estimating neuron num-bers, and not neuron densities, has revealed thatage-related neuronal loss is not significantly involvedin normal brain aging, at least with respect to thehippocampus and neocortex. For instance, a report byGomez-Isla et al.(1996), who estimated total neuronnumbers in the entorhinal cortex of patients youngerthan 95 years, showed a decrease of 60% in the numberof neurons in layer II of the entorhinal cortex inpatients with a Clinical Demetia Rating Scale score of0.5, and of 90% in severe AD cases. Although West et al.(1994) demonstrated a substantial loss of neurons inthe hilus and subiculum in normal brain aging, correla-tions between age and neuron numbers in the CA1 fieldand subiculum and a severe decrease in neuron num-bers in the dentate gyrus and subiculum have beenfound only in AD. Moreover, there is only a 10%decrease in the total neocortical neuron number inhumans across the age spectrum. All these studies, as

well as data from rodents and nonhuman primates,indicate that neuron death is not likely to be the causeof the well-known memory deficits associated with age(reviewed in Morrison and Hof, 1997). Alternatively, ithas been proposed that subtle molecular changes inintact circuits crucial for memory processes are suffi-cient to cause these deficits. In this respect, Gazzaley etal.(1996) reported an age-related decrease in N-methyl-D-aspartate receptor subunit 1 immunofluorescenceintensity within the distal dendrites of the dentategyrus granule cells, which receive the perforant path-way input, in the absence of severe synaptic pathology.These authors proposed that such alterations in thedistribution of key molecules may precede structuraldegeneration of the hippocampal formation in patientswith AAMI (reviewed in Morrison and Hof, 1997).

In contrast to normal aging, very mild AD is charac-terized by a significant degree of neuron loss in the CA1field of the hippocampus and layer II of the entorhinalcortex, whereas neocortical areas display preservedneuron densities. Among the pyramidal neurons of thehippocampal formation, cell death appears closely re-lated to the presence of NFT, many of which arevisualized in the neuropil when the neuronal nucleusand cytoplasm disappear. Later in the course of thedisease, most association neocortical areas are affected,and the degree of neuron loss parallels NFT densities inthese regions. However, NFT numbers alone cannotaccount for the total loss of neurons in these areas,suggesting that both NFT-related and NFT-unrelatedneuronal loss may take place, in particular in very oldpatients with AD (reviewed in Morrison and Hof, 1997;Giannakopoulos et al., 1996).

DISCONNECTION OF SPECIFICCORTICOCORTICAL PATHWAYS: A MAINCHARACTERISTIC OF AD PATHOLOGY

Several studies have revealed correlations betweenNFT and SP patterns of distribution within the neocor-tex and cells of origin of long corticocortical projections(De Lacoste and White, 1993; Duyckaerts et al., 1986;Esiri et al., 1986; Hof and Morrison, 1990a; Hof et al.,1990; Lewis et al., 1987; Morrison, 1993; Morrison etal., 1987; Pearson et al., 1985; Rogers and Morrison,1985; Senut et al., 1996). NFT are mainly observedwithin layers III and V, whereas primary sensory andmotor regions have lower NFT counts than associationareas (Arnold et al., 1991; Hof and Morrison, 1990; Hofet al., 1990; Lewis et al., 1987; Pearson et al., 1985). Forexample, the secondary visual cortex (Brodmann area18) displays NFT densities 20-fold higher compared tothe primary visual cortex (Brodmann area 17), andhigh-order visual association areas in the inferior tem-poral cortex are characterized by a further doubling ofNFT counts (Lewis et al., 1987). Also, there are markeddifferences in the laminar distribution of NFT betweendifferent neocortical areas. In areas 17 and 18, most ofthe NFT are in layer III, whereas there is a shift towardlayer V in area 20. SP have a more widespread distribu-tion than NFT between cortical areas, and tend to bemore numerous in the neocortex, where they predomi-nate in the superficial layers, than in the hippocampalformation (Lewis et al., 1987; Morrison, 1993; Morrisonet al., 1987; Pearson et al., 1985; Rogers and Morrison,1985). Recent studies have shown that AD involves

18 P. GIANNAKOPOULOS ET AL.

preferentially long association pathways in the neocor-tex, and it has been proposed that the distribution ofNFT and SP is a reflection of the degeneration ofcertain corticocortical connections (Hof and Morrison,1990; Hof et al., 1990; Lewis et al., 1987; Morrison,1993; Pearson et al., 1985; Rogers and Morrison, 1985).Consequently, AD symptomatology may be due to thedamage of a defined set of projections, eventuallyevolving to a syndrome of cortical disconnection (Hof etal., 1990a; Hof and Morrison, 1990; Lewis et al., 1987;Pearson et al., 1985; Rogers and Morrison, 1985). Thispossibility is further confirmed by the laminar distribu-tion of NFT and SP in areas participating in hierarchi-cally organized distributed systems, such as the visualand auditory cortical pathways, which reflects theorigin and termination of corticocortical projections asdefined in connectivity studies in nonhuman primates(Arnold et al., 1991; Esiri et al., 1986; Hof and Morri-son, 1990; Lewis et al., 1987; Morrison, 1993; Morrisonet al., 1987; Nimchinsky et al., 1986; Pearson et al.,1985; Rogers and Morrison, 1985; Senut et al., 1996).

Additional indications that AD lesion formation maylead to the disconnection of specific corticocortical path-ways come from the study of AD cases with posteriorcortical atrophy. Most of these cases present withatypical neuro-ophthalmological presentation whichprecedes the classical memory impairment and cogni-tive deficits of AD (Benson et al., 1988). In particular,these patients exhibit, to varying degrees, complexneurological symptoms including alexia, anomia,agraphia, and transcortical sensory aphasia, as well asBalint’s and Gerstmann’s syndromes (Damasio, 1985),with a preservation of memory until late in the courseof their illness. The cortical atrophy, as demonstratedby computer-assisted tomography and magnetic reso-nance imaging, is mainly present in the parieto-occipital areas, suggesting that in the early stages ofdementia there is a predominant involvement of pari-etal and occipital association cortex including areas 18and 19 (Benson et al., 1988; Berthier et al., 1991; Hof etal., 1989, 1993; Jacquet et al., 1990; Levine et al., 1993).This was confirmed by functional imaging studiesshowing large metabolic deficits in these areas and arelative preservation of inferior temporal, frontal, andlimbic structures in AD cases with visual deficits (Men-tis et al., 1996; Pietrini et al., 1996). Neuropathologi-cally, all these cases show posterior cortical atrophy andhave higher NFT and SP densities in the occipitalcortex than is usually observed in AD, whereas inBrodmann areas 9, 46, and 45 of the prefrontal cortex,NFT counts are always lower than generally seen inAD. In addition, the visual association cortex of theinferior parietal lobe (Brodmann area 7b), and theposterior cingulate cortex (Brodmann area 23), showmore NFT and SP in cases with posterior corticalatrophy. Cases of posterior cortical atrophy presentingwith early prosopoagnosia and aperceptive visual agno-sia exhibit a comparable involvement of the occipitalcortex, but differ from AD cases with Balint’s syndromein that there is a preferential distribution of NFT andSP in Brodmann area 20.

The functional implications of atypical lesion localiza-tion may reflect the distribution of corticocortical connec-tions between the different visual areas. For instance,the consistent involvement of posterior cingulate cortex

in AD cases with posterior cortical atrophy is relevant,since this cortical area is a key component of thevisuomotor system (Olson and Musil, 1992; Olson et al.,1993). In primates, there are direct projections from theoccipital cortex to area 23, and between area 7 and area23 (Baleydier and Mauguiere, 1987; Vogt and Pandya,1987; Vogt et al., 1979), and each of these cortical areasmay be involved in different aspects of visual process-ing (see below). Functional imaging studies demon-strated severe metabolic reductions in area 23 thatwere closely related to reductions in area 7 in AD cases,indicating the presence of a functional network whichincludes parietal, cingulate, and occipital regions(Minoshima et al., 1997). Thus, in contrast to typicalAD cases which are characterized by severe damage ofvisual association cortices of the inferior temporal lobeas described above, AD cases with posterior corticalatrophy display a selective disruption of cortical cir-cuits linking the occipital, parietal, and cingulate re-gions (Minoshima et al., 1997).

CLINICAL CORRELATES OF THE DAMAGEOF NEOCORTICAL PATHWAYS IN AD: THE

PARADIGM OF APRAXIAHow is the damage to specific corticocortical path-

ways related to AD symptomatology? Although clinico-pathological studies of large retrospective series havecontributed to differentiate the hierarchical patterns ofNFT and SP distribution between elderly dementedand nondemented individuals, determining whetherthe disruption of neocortical circuits causes specificcognitive deficits in AD remains a hard task. Apraxia isa good candidate for this type of study since investiga-tions of focal pathology have suggested that this condi-tion is associated with both structural and functionalabnormalities in restricted neocortical areas (Forstl etal., 1993; Nielson et al., 1996). Apraxia usally appearsin late stages of AD (Della Salla et al., 1986), althoughcases with early constructional and ideomotor praxisdisability have been described (Nielson et al., 1996;Rapcsak et al., 1995). We recently performed a prospec-tive study of 23 AD cases, including detailed examina-tion of ideomotor, dressing and constructional praxicperformance, and quantitative assessment of NFT andSP in several neocortical areas (Giannakopoulos et al.,1998). SP densities did not correlate with any type ofapraxia. Conversely, our data reveal a significant corre-lation between ideomotor and dressing apraxias andNFT densities in the anterior cingulate cortex (Brod-mann area 24), yet mild NFT formation was present inthis area in all AD cases. It is well-documented that theanterior cingulate cortex participates in the acquisitionand performance of spatial memory tasks in experimen-tals animals, implying that this area plays a key role inselection and recruitment of processing centers appro-priate for complex task execution. Furthermore, theanterior cingulate cortex possesses a motor area somato-topically connected to the primary motor cortex and isinvolved in the integration of somatic and visceralactivities (reviewed in Giannakopoulos et al., 1995).These observations suggest that even mild NFT forma-tion in the anterior cingulate cortex may participate inthe development of dressing apraxia by disturbingboth programming and execution of complex motorbehaviors.

19NEOCORTICAL PATHOLOGY IN ALZHEIMER’S DISEASE

Most importantly, constructional apraxia in AD maybe a clinical indicator of NFT formation in areas 7, 19,and 23 (Fig. 2; Nielson et al., 1996). Although thefunction of these areas is still a matter of debate,several lines of evidence suggest that they participatein visuospatial processing (Nobre et al., 1997; Rolandand Gulyas, 1995; Sutherland et al., 1988; Vogt et al.,1990). Several studies of the monkey visual systemhave demonstrated the presence of a striatal-parietalpathway that subserves visuospatial tasks and motionanalysis (De Yoe and Van Essen, 1988; Livingstone andHubel, 1988; Mishkin et al., 1983; Zeki and Schipp,1988). Recently, positron emission tomography activa-tion studies have reported the involvement of thesuperior parietal and occipital cortex in visual learningand recognition of complex visual geometric patterns aswell as in visuospatial attention processes (Nobre et al.,1997; Roland and Gulyas, 1995). Moreover, area 23 is

strongly connected with areas 7 and 19. These datastrongly suggest that constructional praxic perfor-mance in AD may depend on the integrity of posteriorcortical networks mediating visuospatial cognition. In-terestingly, in contrast to atypical AD cases with poste-rior cortical atrophy, constructional apraxia in typicalAD is associated with only mild NFT formation in areas7, 19, and 23. This strengthens the hypothesis that thepattern of neocortical involvement by NFT may play akey role in the final AD symptomatology. In fact, typicalAD with constructional apraxia may be characterizedby mild NFT formation in areas 7, 19, and 23 andsubstantial damage of anterior neocortical areas,whereas AD with more complex visuospatial difficul-ties, such as Balint’s syndrome, may show a preferen-tial involvement of posterior parietal and occipitalareas and relative preservation of the prefrontal andtemporal neocortex.

Fig. 2. Representative examples of neurofibrillary tangles (a, b)and senile plaques (c, d) in area 7 from an 85-year-old AD patient withconstructional apraxia (a, c) and from an 82-year-old AD patientwithout constructional apraxia (b, d). Note the presence of higher NFTdensities in area 7 in the AD patient with constructional apraxia. In

contrast, SP densities did not correlate with the presence of thisdeficit. Samples were stained with antibodies against the microtubule-associated tau protein (a, b) and Ab protein (c, d). Scale bar: a, b, 75µm; c, d, 150 µm.

20 P. GIANNAKOPOULOS ET AL.

CONCLUSIONSSelective vulnerability in the neocortex is a key

notion for the comprehension of clinicopathologicalcorrelations in AD. This vulnerability is evident at thelevel of affected neocortical association areas, layers,and specific cell populations. In recent years, detailedquantitative studies of large autopsy series have re-vealed that the final clinical symptomatology of AD maycorrespond to several distinct patterns of lesion distri-bution, depending on morphologic and neurochemicalcharacteristics specific to susceptible neuronal subpopu-lations. Depending on the cortical region, NFT are thefirst lesions to appear, and the rate of occurrence oflesions may be a determinant for the severity of clinicalsymptoms. Thus, the early pathologic alterations re-stricted to the hippocampal formation are stronglycorrelated with the development of AAMI (Arriagada etal., 1992a,b; Bouras et al., 1993, 1994; Hof et al., 1992),while involvement of the neocortex is a necessarycondition for the development of dementia (Bouras etal., 1994; Giannakopoulos et al., 1994; Hof et al., 1992).Elderly individuals may maintain cognitive functionscompatible with intact daily living abilities even in thepresence of significant damage to hippocampal circuits,and may rely more on neocortical circuits than on thehippocampal formation for memories essential for thoseactivities. This connectionist view of AD pathologicchanges distribution is further supported by the corre-lation between the presence of specific cognitive defi-cits, such as the different types of apraxia, and thedamage of specific corticocortical pathways.

Besides these morphological considerations, a com-plete analysis of selective vulnerability in the neocortexmust include the neuroanatomical and anatomical fea-tures that are most clearly linked to differential cellularvulnerability in AD. At this level, it is worth noting thatpyramidal neurons prone to developing cytoskeletalpathology have been shown to be enriched in neurofila-ment protein, a cytoskeletal protein which has beenimplicated in NFT formation (Trojanowski et al., 1993;Vickers et al., 1992, 1994). The localization of neurofila-ment protein-containing cells corresponds to that ofcorticocortically projecting cells, as demonstrated intransport studies in monkey cortex (Campbell andMorrison, 1989; Hof and Morrison, 1996; Hof et al.,1996; Nimchinsky et al., 1996), and their laminardistribution in human cortex is very similar to that ofNFT. Furthermore, the regions containing high NFTdensities in an AD brain suffer a severe loss of neurofila-ment protein-containing neurons (Hof and Morrison,1990; Hof et al., 1990a; Morrison et al., 1987; Vickers etal., 1992). It should be noted that in addition toneurofilament protein and other components of thecytoskeleton, many proteins have been found in associa-tion with neuronal degeneration in AD (Hof and Morri-son, 1996). In particular, abnormalities in many cyto-skeletal proteins as well as pathologic neuronal featureshave been reported in AD, using neuronal markers suchas microtubule-associated proteins, brain spectrin, andcalcium-calmodulin-dependent protein kinase II. Thus,age-related factors involving modifications of cytoskel-etal elements and resulting in the formation of abnor-mal proteins may be a fundamental step in the develop-ment of NFT. In contrast to pyramidal neurons, the

interneurons containing the calcium-binding proteinsparvalbumin, calbindin, and calretinin are generallyresistant to the degenerative process, even in severe ADcases with high densities of NFT and SP (Hof andMorrison, 1991; Hof et al., 1991, 1993). Parvalbuminand calretinin-immunoreactive neurons are resistantto degeneration, and show a well-preserved morphologyand staining pattern (Hof and Morrison, 1991; Hof etal., 1991), but dystrophic calretinin-immunoreactivefibers and dendrites have been reported in AD (Brionand Resibois, 1994). Most calbindin-containing interneu-rons in layers II and III are strongly resistant todegeneration in AD, while a smaller population ofcalbindin-immunoreactive cells in layer V is affectedonly in AD cases with high NFT densities (Hof et al.,1993). This differential vulnerability could reflect sepa-rate patterns of connectivity and specific interactionswith their target cells of the calbindin-positive interneu-rons located in layers II and III, and those located inlayer V. In addition, interneurons can be further subdi-vided according to colocalization of certain neuropep-tides (reviewed in Hof and Morrison, 1996). Thus,somatostatin is observed in calbindin-positive resistantneurons, although a subgroup of somatostatin-immuno-reactive neurons that do not contain calbindin is likelyto be vulnerable in AD. Similarly, somatostatin iscolocalized with neuropeptide Y and NADPH-diapho-rase in neurons that appear to be mostly resistant inAD (Gaspar et al., 1989). Substance P is found invulnerable neurons in the deep layers of the cerebralcortex, and corticotropin-releasing factor is colocalizedwith parvalbumin in resistant chandelier neurons (re-viewed in Hof and Morrison, 1996). Interestingly, asubpopulation of layer III pyramidal neurons thatcontain the calcium-binding protein calbindin has beenshown to be highly sensitive to degeneration in ADcases (Hof et al., 1991). Some of these of calbindin-positive pyramidal neurons have been shown to colocal-ize neurofilament protein (Hayes and Lewis, 1992).These observations show that the mechanisms whichdetermine increased cellular vulnerability in the neocor-tex in AD are more complex than originally thought, inthat they depend on both biochemical and connectivitycharacteristics of neuronal subpopulations. A betterunderstanding of these characteristics will be crucial todeveloping therapeutic strategies aiming at the protec-tion of those brain cell subpopulations that are particu-larly prone to degeneration in AD.

ACKNOWLEDGMENTSWe thank Drs. A. Delacourte and N.K. Robakis for

their generous gift of antibodies; Drs. P.G. Vallet, E.Kovari, F.R. Herrmann, G. Gold, L. Buee, V. Buee-Scherrer, E.A. Nimchinsky, and J.H. Morrison for par-ticipation in these studies and helpful discussion; andM. Surini and P.Y. Vallon for expert technical assis-tance. This work was supported by grants from the NIH(AG05138), the Brookdale Foundation (to P.R.H.), andthe Swiss National Science Foundation (grants 3200–039767.93/1, 31–45960.95, and 31–52997.97 to P.G. andC.B., and fellowship grant 1994 to P.G.).

21NEOCORTICAL PATHOLOGY IN ALZHEIMER’S DISEASE

REFERENCESArnold, S.E., Hyman, B.T., Flory, J., Damasio, A.R., and Van Hoesen,

G.W. (1991) The topographical and neuroanatomical distribution ofneurofibrillary tangles and neuritic plaques in the cerebral cortex ofpatients with Alzheimer’s disease. Cereb. Cortex, 1:103–116.

Arriagada, P.V., Growdon, J.H., Hedley-White, E.T., and Hyman, B.T.(1992a) Neurofibrillary tangles but not senile plaques parallelduration and severity of Alzheimer’s disease. Neurology, 42:631–639.

Arriagada, P.V., Marzloff, K., and Hyman, B.T. (1992b) Distribution ofAlzheimer-type pathologic changes in nondemented elderly individu-als matches the pattern in Alzheimer’s disease. Neurology, 42:1681–1688.

Baleydier, C., and Mauguiere, F. (1987) Network organization of theconnectivity between parietal area 7, posterior cingulate cortex andmedial pulvinar nucleus: A double fluorescent tracer study inmonkey. Exp. Brain Res., 66:385–393.

Ball, M.J. (1977) Neuronal loss, neurofibrillary tangles and granulo-vacuolar degeneration in the hippocampus with ageing and demen-tia. Acta Neuropathol. (Berl.), 37:111–118.

Benson, D.F., Davis, R.J., and Snyder, B.D. (1988) Posterior corticalatrophy. Arch. Neurol., 45:789–793.

Berg, L., McKeel, D.W., Miller, P., Baty, J., and Morris, J.C. (1993)Neuropathological indexes of Alzheimer’s disease in demented andND persons aged 80 years and older. Arch. Neurol., 50:349–358.

Berthier, M.L., Leiguarda, R., Starkstein, S.E., Sevlever, G., andTaratuto, A.L. (1991) Alzheimer’s disease in a patient with posteriorcortical atrophy. J. Neurol. Neurosurg. Psychiatry, 54:1110–1111.

Bierer, L.M., Hof, P.R., Purohit, D.P., Carlin, L., Schmeidler, J., Davis,K.L., and Perl, D.P. (1995) Neocortical neurofibrillary tangles corre-late with dementia severity in Alzheimer’s disease. Arch. Neurol.,52:81–88.

Bouras, C., Hof, P.R., and Morrison, J.H. (1993) Neurofibrillary tangledensities in the hippocampal formation in a non-demented popula-tion define subgroups of patients with differential early pathologicchanges. Neurosci. Lett., 153:131–135.

Bouras, C., Hof, P.R., Giannakopoulos, P., Michel, J.P., and Morrison,J.H. (1994) Regional distribution of neurofibrillary tangles andsenile plaques in the cerebral cortex of elderly patients: A quantita-tive evaluation of a one-year autopsy population from a geriatrichospital. Cereb. Cortex, 4:138–150.

Braak, H., and Braak, E. (1991) Neuropathological staging of Alzhei-mer-related changes. Acta Neuropathol. (Berl.), 82:239–259.

Brion, J.P. (1990) Molecular pathology of Alzheimer amyloid andneurofibrillary tangles. Semin. Neurosci., 2:89–100.

Brion, J.P., and Resibois, A. (1994) A subset of calretinin-positiveneurons are abnormal in Alzheimer’s disease. Acta Neuropathol.(Berl.), 88:33–43.

Campbell, M.J., and Morrison, J.H. (1989) A monoclonal antibody toneurofilament protein (SMI-32) labels a subpopulation of pyramidalneurons in the human and monkey neocortex. J. Comp. Neurol.,282:191–205.

Crystal, H., Dickson, D., Fuld, P., Masur, D., Scott, R., Mehler, M.,Masdeu, J., Kawas, C., Aronson, M., and Wolfson, L. (1988) Clinico-pathologic studies in dementia: Nondemented subjects with patho-logically confirmed Alzheimer’s disease. Neurology, 38:1682–1687.

Damasio, A.R. (1985) Disorders of complex visual processing: Agno-sias, achromatopsias, Balint’s syndrome and related difficulties oforientation and construction. In: Principles of Behavioral Neurol-ogy, Contemporary Neurology Series, Volume 26. M.M. Mesulam,ed. F.A. Davis, Philadelphia, pp. 259–288.

De Lacoste, M.C., and White, C.L., III (1993) The role of corticalconnectivity in Alzheimer’s disease pathogenesis: A review andmodel system. Neurobiol. Aging, 14:1–16.

Della Sala, S., Lucchelli, F., and Spinnler, H. (1987) Ideomotor apraxiain patients with dementia of Alzheimer type. J. Neurol., 234:91–93.

DeYoe, E.A., and Van Essen, D.C. (1988) Concurrent processingstreams in monkey visual cortex. Trends Neurosci., 11:219–226.

Dickson, D.W., Crystal, H.A., Mattiace, L.A., Masur, D.M., Blau, A.D.,Davies, P., Yen, S.H., and Aronson, M.K. (1991) Identification ofnormal and pathological aging in prospectively studied nonde-mented elderly humans. Neurobiol. Aging, 13:179–189.

Duyckaerts, C., Hauw, J.-J., Bastenaire, F., Piette, F., Poulain, C.,Rainsard, V., Javoy-Agid, F., and Berthaux, P. (1986) Laminardistribution of neocortical senile plaques in senile dementia of theAlzheimer type. Acta Neuropathol. (Berl.), 70:249–256.

Esiri, M.M., Pearson, R.C.A., and Powell, T.P.S. (1986) The cortex ofthe primary auditory area in Alzheimer’s disease. Brain Res.,366:385–387.

Evans, D.A., Scherr, P.A., Cook, N.A., Albert, M.S., Funkenstein, H.H.,Beckett, L.A., Hebert, L.E., Wetle, T.T., Branch, L.G., Chown, M.J.,Hennekens, C.H., and Taylor, J.O. (1992) The impact of Alzheimer’sdisease in the United States population. In: The Oldest-Old. R.M.Suzman, D.P. Willis, and K.G. Manton, eds. Oxford UniversityPress, New York, pp. 283–299.

Forstl, H., Burns, A., Levy, R., and Cairs, N. (1993) Neuropathologicalbasis of drawing disability (constructional apraxia) in Alzheimer’sdisease. Psychol. Med., 23:623–629.

Gaspar, P., Duyckaerts, C., Febvret, A., Benoit, R., Beck, B., andBerger, B. (1989) Subpopulations of somatostatin 28-immunoreac-tive neurons display differential vulnerability in senile dementia ofthe Alzheimer type. Brain Res., 490:1–13.

Gazzaley, A.H., Siegel, S.J., Kordower, J.H., Mufson, E.J., and Morri-son, J.H. (1996) Circuit-specific alterations of N-methyl-D-aspartatereceptor subunit 1 in the dentate gyrus of aged monkeys. Proc. Natl.Acad. Sci. USA, 93:3121–3125.

Giannakopoulos, P., Hof, P.R., Mottier, S., Michel, J.-P., and Bouras, C.(1994) Neuropathologic changes in the neocortex of 1258 cases froma geriatric hospital: Retrospective clinicopathologic evaluation of aten year autopsy population. Acta Neuropathol. (Berl.), 87:456–468.

Giannakopoulos, P., Hof, P.R., Giannakopoulos, A.-S., Hermann, F.,Michel, J.-P., and Bouras, C. (1995) Regional distribution of neurofi-brillary tangles and senile plaques in the cerebral cortex of very oldpatients. Arch. Neurol., 52:1150–1159.

Giannakopoulos, P., Hof, P.R., Kovari, E., Vallet, P.G., and Bouras, C.(1996) Distinct patterns of neuronal loss and Alzheimer’s diseaselesion distribution in elderly individuals older than 90 years. J.Neuropathol. Exp. Neurol., 55:1210–1120.

Giannakopoulos, P., Duc, M., Gold, G., Hof, P.R., Michel, J.-P., andBouras, C. (1998) Pathological correlates of apraxia in Alzheimer’sdisease. Arch. Neurol., 55:689–695.

Gomez-Isla, T., Price, J.L., McKeel, D.W., Jr., Morris, J.C., Growdon,J.H., and Hyman, B.T. (1996) Profound loss of layer II entorhinalcortex neurons occurs in very mild Alzheimer’s disease. J. Neurosci.,16:4491–4500.

Hayes, T.L., and Lewis, D.A. (1992) Nonphosphorylated neurofilamentprotein and calbindin immunoreactivity in layer III pyramidalneurons of human neocortex. Cereb. Cortex, 2:56–67.

Hof, P.R., and Morrison, J.H. (1990) Quantitative analysis of avulnerable subset of pyramidal neurons in Alzheimer’s disease: II.Primary and secondary visual cortex. J. Comp. Neurol., 301:55–64.

Hof, P.R., and Morrison, J.H. (1991) Neocortical neuronal subpopula-tions labeled by a monoclonal antibody to calbindin exhibit differen-tial vulnerability in Alzheimer’s disease. Exp. Neurol., 111:293–301.

Hof, P.R., and Morrison, J.H. (1996) Hippocampal and neocorticalinvolvement in normal brain aging and dementia: Morphologic andneurochemical profile of the vulnerable circuits. J. Am. Geriatr. Soc.,44:857–864.

Hof, P.R., Bouras, C., Constantinidis, J., and Morrison, J.H. (1989)Balint’s syndrome in Alzheimer’s disease: Specific disruption of theoccipito-parietal visual pathway. Brain Res., 493:368–375.

Hof, P.R., Cox, K., and Morrison, J.H. (1990a) Quantitative analysis ofa vulnerable subset of pyramidal neurons in Alzheimer’s disease: I.Superior frontal and inferior temporal cortex. J. Comp. Neurol.,301:44–54.

Hof, P.R., Bouras, C., Constantinidis, J., and Morrison, J.H. (1990b)Selective disconnection of specific visual association pathways incases of Alzheimer’s disease presenting with Balint’s syndrome. J.Neuropathol. Exp. Neurol., 49:168–184.

Hof, P.R., Cox, K., Young, W.G., Celio, M.R., Rogers, J., and Morrison,J.H. (1991) Parvalbumin-immunoreactive neurons in the neocortexare resistant to degeneration in Alzheimer’s disease. J. Neuro-pathol. Exp. Neurol., 50:451–462.

Hof, P.R., Bierer, L.M., Perl, D.P., Delacourte, A., Buee, L., Bouras, C.,and Morrison, J.H. (1992) Evidence for early vulnerability of themedial and inferior aspects of the temporal lobe in an 82-year-oldpatient with preclinical signs of dementia—Regional and laminardistribution of neurofibrillary tangles and senile plaques. Arch.Neurol., 49:946–953.

Hof, P.R., Archin, N., Osmand, A.P., Dougherty, G.H., Wells, C.,Bouras, C., and Morrison, J.H. (1993a) Posterior cortical atrophy inAlzheimer’s disease: Analysis of a new case and re-evaluation of anhistorical report. Acta Neuropathol. (Berl.), 86:215–223.

Hof, P.R., Nimchinsky, E.A., Celio, M.R., Bouras, C., and Morrison,J.H. (1993b) Calretinin-immunoreactive neocortical interneuronsare unaffected in Alzheimer’s disease. Neurosci. Lett., 152:145–149.

Hubbard, B.M., Fenton, G.W., and Anderson, J.M. (1990) A quantita-tive histological study of early clinical and preclinical Alzheimer’sdisease. Neuropathol. Appl. Neurobiol., 16:111–121.

22 P. GIANNAKOPOULOS ET AL.

Jacquet, M.F., Boucquey, D., Theaux, R., Smidts, M., Callewaert, A.,Brucher, J.M., and Kevers, L. (1990) L’atrophie corticale pos-terieure: Variante anatomo-clinique de la maladie d’Alzheimer. ActaNeurol. Belg., 90:265–273.

Katzman, R., Terry, R., DeTeresa, R., Brown, T., Davies, P., Fuld, P.,Renbing, X., and Peck, A. (1988) Clinical, pathological, and neuro-chemical changes in dementia: A subgroup with preserved mentalstatus and numerous neocortical plaques. Ann. Neurol., 23:138–144.

Levine, D.N., Lee, J.M., and Fisher, C.M. (1993) The visual variant ofAlzheimer’s disease: A clinicopathologic case study. Neurology,43:305–313.

Lewis, D.A., Campbell, M.J., Terry, R.D., and Morrison, J.H. (1987)Laminar and regional distribution of neurofibrillary tangles andneuritic plaques in Alzheimer’s disease: A quantitative study ofvisual and auditory cortices. J. Neurosci., 7:1799–1808.

Livingstone, M., and Hubel, D. (1988) Segregation of form, color,movement, and depth: Anatomy, physiology, and perception. Sci-ence, 240:740–749.

Mentis, M.J., Horwitz, B., Grady, C.L., Alexander, G.E., VanMeter,J.W., Maisog, J.-M., Pietrini, P., Schapiro, M.B., and Rapoport, S.I.(1996) Visual cortical dysfunction in Alzheimer’s disease evaluatedwith a temporally graded ‘‘stress test’’ during PET. Am. J. Psychia-try, 153:32–40.

Minoshima, S., Giordani, B., Berent, S., Frey, K.A., Foster, N.L., andKuhl, D.E. (1997) Metabolic reduction in the posterior cingulatecortex in very early Alzheimer’s disease. Ann. Neurol., 42:85–94.

Mishkin, M., Ungerleider, L.G., and Macko, K.A. (1983) Object visionand spatial vision: Two cortical pathways. Trends Neurosci., 6:414–417.

Morris, J.C., McKeel, J.D.W., Storandt, M., Rubin, E.H., Price, J.L.,Grant, E.A., Ball, M.J., and Berg, L. (1991) Very mild Alzheimer’sdisease: Informant-based clinical, psychometric, and pathologicdistinction from normal aging. Neurology, 41:469–478.

Morrison, J.H. (1993) Differential vulnerability, connectivity, and celltypology. Neurobiol. Aging, 14:51–54.

Morrison, J.H., and Hof, P.R. (1997) Life and death of neurons in theaging brain. Science, 278:412–419.

Morrison, J.H., Lewis, D.A., Campbell, M.J., Huntley, G.W., Benson,D.L., and Bouras, C. (1987) A monoclonal antibody to non-phosphorylated neurofilament protein marks the vulnerable corti-cal neurons in Alzheimer’s disease. Brain Res., 416:331–336.

Moss, M.B., and Albert, M.S. (1988) Alzheimer’s disease and otherdementing disorders. In: Geriatric Neuropsychology. M.S. Albertand M.B. Moss, eds. Guilford Press, New York, pp. 145–178.

Mountjoy, C.Q., Roth, M., Evans, N.J.R., and Evans, H.M. (1983)Cortical neuronal counts in normal elderly controls and dementedpatients. Neurobiol. Aging, 4:1–11.

Nielson, K.A., Cummings, B.J., and Cotman, C.W. (1996) Construc-tional apraxia in Alzheimer’s disease correlates with neuritic neuro-pathology in occipital cortex. Brain Res., 741:284–293.

Nimchinsky, E.A., Hof, P.R., Young, W.G., and Morrison, J.H. (1996)Neurochemical, morphologic and laminar characterization of corti-cal projection neurons in the cingulate motor areas of the macaquemonkey. J. Comp. Neurol., 374:136–160.

Nobre, A.C., Sebestyen, G.N., Gitelman, D.R., Mesulam, M.M., Frack-owiak, R.S., and Frith, C.D. (1997) Functional localization of thesystem for visuospatial attention using positron emission tomogra-phy. Brain, 120:515–533.

Olson, C.R., and Musil, S.Y. (1992) Topographic organization ofcortical and subcortical projections to posterior cingulate cortex inthe cat: Evidence for somatic, ocular, and complex subregions. J.Comp. Neurol., 324:237–260.

Olson, C.R., Musil, S.Y., and Goldberg, M. (1993) Posterior cingulatecortex and visuospatial cognition: Properties of single neurons in thebehaving monkey. In: The Neurobiology of Cingulate Cortex andLimbic Thalamus. B.A. Vogt and M. Gabriel, eds. Birkhauser,Boston, pp. 336–380.

Pearson, R.C.A., Esiri, M.M., Hiorns, R.W., Wilcock, G.K., and Powell,T.P.S. (1985) Anatomical correlates of the distribution of the patho-logical changes in the neocortex in Alzheimer disease. Proc. Natl.Acad. Sci. USA, 82:4531–4534.

Pietrini, P., Furey, M.L., Graff-Radford, N., Freo, U., Alexander, G.E.,Grady, C.L., Dani, A., Mentis, M.J., and Schapiro, M.B. (1996)Preferential metabolic involvement of visual cortical areas in asubtype ofAlzheimer’s disease: Clinical implications.Am. J. Psychia-try, 153:1261–1268.

Price, J.L., Davis, P.B., Morris, J.C., and White, D.L. (1991) Thedistribution of tangles, plaques and related immunohistochemicalmarkers in healthy aging and Alzheimer’s disease. Neurobiol.Aging, 12:295–312.

Rapcsak, S.Z., Ochipa, C., Anderson, K.C., and Poizner, H. (1995)Progressive ideomotor apraxia: Evidence for a selective impairmentof the action production system. Brain Cogn., 27:213–236.

Rogers, J., and Morrison, J.H. (1985) Quantitative morphology andregional and laminar distributions of senile plaques in Alzheimer’sdisease. J. Neurosci., 5:2801–2808.

Roland, P.E., and Gulyas, B. (1995) Visual memory, visual imagery,and visual recognition of large field patterns by the human brain:Functional anatomy by positron emmission tomography. Cereb.Cortex, 5:79–93.

Senut, M.C., Roudier, M., Davous, P., Fallet-Bianco, C., and Lamour, Y.(1996) Senile dementia of the Alzheimer type: Is there a correlationbetween entorhinal cortex and dentate gyrus? Acta Neuropathol.(Berl.), 82:306–315.

Squire, L.R., and Zola-Morgan, S. (1991) The medial temporal lobememory system. Science, 253:1380–1386.

Sutherland, R.J., Whishaw, I.Q., and Kolb, B. (1988) Contributions ofcingulate cortex to two forms of spatial learning and memory. J.Neurosci., 8:1863–1872.

Suzuki, W.A., Zola-Morgan, S., Squire, L.R., and Amaral, D.G. (1993)Lesions of the perirhinal and parahippocampal cortices in themonkey produce long-lasting impairment in the visual and tactilemodalities. J. Neurosci., 13:2430–2451.

Terry, R.D., Peck, A., DeTeresa, R., Schechter, R., and Horoupian, D.S.(1981) Some morphometric aspects of the brain in senile dementia ofthe Alzheimer’s type. Ann. Neurol., 10:184–192.

Tomlinson, B.E., Blessed, G., and Roth, M. (1968) Observations on thebrains of ND old people. J. Neurol. Sci., 7:331–356.

Trojanowski, J.Q., Schmidt, M.L., Shin, R.W., Bramblett, G.T., Rao, D.,and Lee, V.M.Y. (1993) Altered tau and neurofilament proteins inneurodegenerative diseases: Diagnostic implications for Alzhei-mer’s disease and Lewy body dementias. Brain Pathol., 3:45–54.

Ulrich, J. (1985) Alzheimer changes in non-demented patients youn-ger than sixty-five: Possible early stages of Alzheimer’s disease andsenile dementia of Alzheimer type. Ann. Neurol., 17:273–277.

Vickers, J.C., Delacourte, A., and Morrison, J.H. (1992) Progressivetransformation of the cytoskeleton associated with normal agingand Alzheimer’s disease. Brain Res., 594:273–278.

Vickers, J.C., Riederer, B.M., Marugg, R.A., Buee-Scherrer, V., Buee,L., Delacourte, A., and Morrison, J.H. (1994) Alterations in neurofila-ment protein immunoreactivity in human hippocampal neurons relatedto normal aging and Alzheimer’s disease. Neuroscience, 62:1–13.

Vogt, B.A., and Pandya, D.N. (1987) Cingulate cortex of rhesusmonkey: II. Cortical afferents. J. Comp. Neurol., 262:271–289.

Vogt, B.A., Rosene, D.L., and Pandya, D.N. (1979) Thalamic andcortial afferents differentiate anterior from posterior cingulatecortex in the monkey. Science, 204:205–207.

Vogt, B.A., Van Hoesen, G.W., and Vogt, L.J. (1990) Laminar distribu-tion of neuron degeneration in posterior cingulate cortex in Alzhei-mer’s disease. Acta Neuropathol. (Berl.), 80:581–589.

West, M.J., Coleman, P.D., Flood, D.G., and Troncoso, J.C. (1994)Differences in the pattern of hippocampal neuronal loss in normalageing and Alzheimer’s disease. Lancet, 344:769–772.

Zeki, S., and Schipp, S. (1988) The functional logic of cortical connec-tions. Nature, 335:311–317.

Zola-Morgan, S., and Squire, L.R. (1984) Preserved learning inmonkeys with medial temporal lesions: Sparing of motor andcognitive skills. J. Neurosci., 4:1072–1085.

Zola-Morgan, S., Squire, L.R., Amaral, D.G., and Suzuki, W.A. (1989)Lesions of perirhinal and parahippocampal cortex that spare theamygdala and hippocampal formation produce severe memoryimpairment. J. Neurosci., 9:4355–4370.

23NEOCORTICAL PATHOLOGY IN ALZHEIMER’S DISEASE