Pathways and Patterns of Cell Loss in Verified Alzheimer’s Disease: A Factor and Cluster Analysis of Clinico-Pathological Subgroups

Behavioural Neurology, Jul 2018

Thirty-seven patients with neuropathologically verified Alzheimer's disease (AD) have been studied prospectively. A principal components analysis of neuron numbers in cortical and subcortical areas revealed two variables: Variable I with high loadings for the hippocampo-parahippocampo-parietal neuron counts and Variable II with high loadings for coeruleo-frontal cell numbers. Both may reflect functional neuroanatomical connections which may act as pathways of neurodegeneration in AD. A cluster analysis based on these neuron numbers yielded three groups of patients: Cluster A with low hippocampo-parahippocampo-parietal cell counts, Cluster B with well-preserved neuron numbers, and Cluster C with low coeruleo-frontal neuron numbers. Differences in clinical features between these patient groups indicated the potential clinical relevance of these clusters.

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Pathways and Patterns of Cell Loss in Verified Alzheimer’s Disease: A Factor and Cluster Analysis of Clinico-Pathological Subgroups

Pathways and patterns of cell loss in verified A l z h e i m e r ' s disease: a factor and cluster analysis of clinico-pathological subgroups H. Forstl 0 1 R. Levy 0 1 A. Burns 0 1 P. Luthert 0 1 N. Cairns 0 1 0 Mannheim , Germany 1 1Section of Old Age Psychiatry, 2Department of Neuropathology and 3MRC Alzheimer's Disease Brain Bank, Institute of Psychiatry , London , UK Thirty-seven patients with neuropathologicaUy verified Alzheimer's disease (AD) have been studied prospectively. A principal components analysis of neuron numbers in cortical and subcortical areas revealed two variables: Variable I with high loadings for the hippocampo-parahippocampo-parietal neuron counts and Variable n with high loadings for coeruleo-frontal cell numbers. Both may reflect functional neuroanatomical connections which may act as pathways of neurodegeneration in AD. A cluster analysis based on these neuron numbers yielded three groups of patients: Cluster A with low hippocampoparahippocampo-parietal cell counts, Cluster B with well-preserved neuron numbers, and Cluster C with low coeruleo-frontal neuron numbers. Differences in clinical features between these patient groups indicated the potential clinical relevance of these clusters. Alzheimer's disease; neurodegeneration; sub-groups; neuropathology INTRODUCTION Alzheimer's disease (AD) manifests a large variety of clinical symptoms and signs, course characteristics and neuroradiological or neuropathological changes (Burns et ai., 1990a) . Several attempts have been made to characterize clinical "subtypes" of AD and to corroborate these distinctions by post-mortem evidence of different types of underlying pathology (Berrios, 1985; Jorm, 1985; Bondareff et ai., 1987) . Because of the paucity of clinico-pathological studies, it is still unclear whether the clinical heterogeneity of AD is related to different patterns of neuro­ degeneration which may develop along different func­ tional pathways (Pearson et ai., 1985; Hertz, 1989) . Clinical or neuropathological evidence for different subtypes of AD should be validated by external cri­ teria (Jorm, 1985; Mohr et ai., 1990) . We have there­ fore examined both neuropathological and clinical variables in patients with verified AD. The following questions were addressed using principal components and cluster analysis: (1) Can the variation of neuron counts in different brain areas be explained by principal components related to functional neuroanatomical pathways? (2) Can different patterns of neuronal loss be detected which distinguish different clusters of patients? (3) Are these potential subtypes of AD associated with other characteristic clinical features? METHODS Demographic characteristics of the patient sample, details about the prospective clinical examination and the neuropathological work-up have been pub­ lished in previous papers (Bums et ai., 1990a; Forstl et al., 1992a) . The clinical diagnosis of AD according to NINCDS-ADRDA criteria (McKhan 1984 etal) was verified neuropathologically in 56 of the first 65 patients from a prospective longitudinal study who came to post-mortem examination (Forstl et ai., 1992a) . The clinical examination was last adminis­ tered within 12 months before death. It included the Clinical Dementia Rating (CDR; Berg, 1984) , the Cambridge Cognitive Examination (CAMCOG; Roth et ai., 1986) , the Geriatric Mental State Schedule (GMSS; Copeland et ai., 1976; Gurland et ai., 1976) and a standardized neurological examination (Bums et ai., 1990b). The following tissue blocks were taken from the brains, fixed in 10% formol saline and embedded in paraffin wax: frontal lobe (including Area 32), parietal lobe (Area 7), mediotemporal lobe (para­ hippocampal gyrus, hippocampus), mesencephalon (substantia nigra) and pons (including the largest diameter of the locus coeruleus and the dorsal raphe nucleus; Forst! et al., 1992a) . Fourteen p.m sections were stained according to Kluver Barrera and impreg­ nated with silver according to Glees and Marsland. Our earlier analyses had shown significant associ­ ations between the clinical features and neuronal change, therefore we decided to study neurons, and not plaques and tangles. Large neurons were defined as Nissl-positive, nucleolated cells with a maximum diameter of more than 20 p.m in cortex (layer III), hippocampus (pyramidal cell layer of the CAl field), substantia nigra and locus coeruleus, and of more than 25 p.m in the dorsal raphe nucleus. All counts reported in this paper were carried out visually with an ocular grid at x 400 magnification. Numbers are given as counts per mm2 for the cortical and hippo­ campal areas and as counts per nucleus per horizontal section for the brainstem nuclei. The examiner was blind to the clinical findings. A complete set ofartefact­ free slides and stains was available from 37 cases. Variables accounting for the variance of cell num­ bers in different brain areas of the patients with verified AD were extracted with principal compo­ nents analysis (Everitt and Dunn, 1983) . The neuron counts were standardized using a z-transformation and the components were transformed orthogonally (Varimax rotation). Ward's method of cluster analy­ sis was employed to differentiate the patterns of cell loss in the patient sample (Ward, 1963; Everitt, 1989) . The differences of neuron numbers between the clus­ ters were examined with a one-way analysis of vari­ ance and Scheffe's test for multiple comparisons (Maxwell and Delaney, 1990) . The data analysis was carried out with SPSS/PC + (Norusis, 1988). RESULTS A complete set of clinical and neuropathological data was available from 37 of 56 patients with neuropatho­ logically verified AD. Principal components analysis based on the neuron counts in the frontal lobe (Area 32), parietal lobe (Area 7), the parahippocampal gyrus, the hippocampal CAl field, the substantia nigra, locus coeruleus and dorsal raphe nucleus yielded two variables with Eigenvalues higher than 1 which accounted for 52% of the observed variance (Table I). Variable I accounted for 29% of the ob­ served variance and showed high loadings for the cell counts in the hippocampus, parahippocampal gyrus and parietal lobe, indicating that the neuron numbers in these areas tended to vary together. Variable II had high loadings for the neuron numbers in the locus coeruleus and frontal lobe (Area 32). The dendrogram of a cluster analysis based on these two variables is shown in Fig. 1. In a three cluster solution, 11 patients formed Group A 500 200 100 • • tt-~ I i o f':.. l!\ ~ L * _ I Locus coeruleus 1.000 [""""-::::-:::-::----.....i.....*=l=i*-l--~--i*-l----:__-r--*--'1-__.__i-*_l_, i*l Area 7 Gyrus parahlppocampalls I CA1 I Area 32 which was characterized by low hippocampo­ parahippocampo-parietal neuron numbers (Fig. 2). Twelve patients formed Group B with well-preserved cortical and subcortical neuron numbers, but mildly decreased counts in the dorsal raphe nucleus. Group C consisted of 14 patients with predominant coeruleo­ frontal cell loss. Solutions with larger cluster numbers will not be presented because of the small sample sizes. The patients belonging to Cluster C had the earliest onset, the longest duration of illness, the highest rate of "frontal" release signs and the greatest density of intraneuronal neurofibrillary tangles (Table II). De­ pressive disturbances were least frequent in the group with the highest neuron counts in the locus coeruleus (Cluster A). Most delusions and hallucinations were observed in Cluster B. There were no significant differences between the groups regarding the clinical stage of dementia during the last year of life or performance on the last cognitive test administered. DISCUSSION The results can be summarized as follows: (1) Principal components analysis revealed two vari­ ables underlying more than 50% of the observed variance of neuron numbers: a "hippocampoparahippocampo-parietal" component and a "coeruleo-frontal" component. (2) Three patterns of neuronal change emerged from a cluster analysis: hippocampo-parahlppocampo­ parietal cell loss (Cluster A), well-preserved neuron numbers (Cluster B), and coeruleo-frontal cell loss (Cluster C). (3) The patient groups defined by these patterns tended to show different psychopathological, neur­ ological and neuropathological features. It has been shown that neurodegeneration in AD may extend along interconnected areas of the brain (Pearson et al., 1985; Fewster et al., 1991) . The ana­ tomical connection between the hippocampus, para­ hippocampus and parietal lobe is well established (Duvernoy, 1988; Cavada and Goldman-Rakic, 1989) . In most cases of AD, changes in the hippocam­ pus are severe and may precede less severe changes in other brain areas (Fewster et al., 1991; Forstl et al., 1993) . A recent computed tomography and single photon emission tomography study demonstrated a close morphological and functional association be­ tween changes in the mediotemporal and parietal lobe occurring in the course of AD (Jobst et al., 1992) . Connections of similar functional importance may exist between the locus coeruleus and frontal lobe areas. Parallel changes of neuron numbers in the locus coeruleus and Area 32 may relate to neocor­ tical noradrenergic projections which are most intense to the frontal lobe (Nagai et al., 1981; Pearson et al., 1990) . Dopamine-p-hydroxylase, the noradrenaline synthesizing enzyme, is decreased in AD and this decrease is most severe in the frontal lobe (Adolfsson et al., 1979; Cross et al., 1981) . The noradrenaline concentration in the frontal lobe is significantly correl­ ated with the neuron numbers in the locus coeruleus (Ichimaya et al., 1986) . It has been hypothesized that neurodegeneration in AD may start in the aminergic brainstem nuclei (Hertz, 1989) . A previous report indicated that this may be the case in patients with prominent affective disturbance early in the course of AD (Forstl et al., 1992a) . Regarding our first ques­ tion, we hypothesize that the statistical relationship between neuron numbers in various areas of the brain may reflect anatomical connections shown in previous work and that these connections represent potential pathways ofneurodegeneration in AD. Alzheimer (1911) felt that the extent of neurofibril­ lary deposition may characterize subtypes of AD. It has been shown that patients with higher neurofibril­ lary tangle density have more severe clinical deficits and neuropathological changes (Terry et al., 1987) . This is in line with our findings in Cluster C, where patients had the highest intraneuronal tangle counts and the longest duration of illness. Our data indicate an association with "frontal" release signs and affec­ tive disturbance, the latter relating to neuron loss in the locus coeruleus (Forstl et al., 1992a, b) . Bondareff (1982, 1987) distinguished mild senile AD1 from presenile AD2 with high genetic loading, rapid deterioration and severe neuropathological changes, typically a marked cell loss in the locus coeruleus. The patients in Cluster C did have the earliest onset and longest duration of illness, a posi­ tive family history in three cases and the worst cog­ nitive performance, but none of these differences was statistically significant (p > 0.10). Berrios (1985) thought that a syndrome of "presbyophrenia" with predominant mnestic disturbance, confabulation and elated mood was related to neuronal loss in the locus coeruleus. This view cannot be supported by our data. They are in agreement with neuroimaging stud­ ies which described a subgroup of patients with clinic­ ally diagnosed AD and frontal hypometabolism (e.g. Haxby et al., 1988) . A recent investigation suggested a relationship between decreased frontal glucose metabolism or neuropsychological "frontal" lobe function and a faster progression of illness (Mann et al., 1992) . Conversely, "parietal" lobe changes - sensory aphasia, visual agnosia, apraxia or even decreased radiodensity - have been related to rapid cognitive decline and increased mortality (McDonald, 1969; Naguib and Levy, 1982) . These findings have not been replicated unequivocally (Gilleard et al., 1987; O'Carroll et al., 1991) and cannot be verified by our results. The patients in Cluster A with low hippocampo-parahippocampo-parietal neuron num­ bers had the shortest duration of illness, but this effect was not significant (p > 0.10). The patient sample in our study was strongly biased towards senile dementia with a late onset of illness (Burns et al., 1990a) . The majority of the patients who came to post-mortem examination had reached a severe clinical stage of dementia according to CDR (Berg, 1984). Thus, neither large variations of demographic variables nor of cognitive test profiles were to be expected. These variables had contributed to the characterization of subtypes in earlier studies (Chen et al., 1991; Chiu et al., 1985; Mayeux et al., 1985; Nyth et al., 1991) . Psychopathological, neuro­ logical and histopathological features however showed differences between Clusters A, Band C and these differences were in agreement with our previous analyses (Forstl et al., 1992a, b) . It is still a matter of debate whether the clinical or neuropathological heterogeneity of manifestations can be subdivided into meaningful "subtypes" of AD (Jorm, 1985; Chui, 1987; Mohr et al., 1990) . The term "subtype" is open to different interpretations and the varying emphasis placed by previous authors may have contributed to the divergent and sometimes incompatible attempts at subclassification. Cluster analysis tends to yield results even if the data under investigation lack a clear structure (Everitt, 1989) . This may represent an additional source of conflicting results between cross-sectional studies based on differ­ ent types of clinical information. In order to avoid a delineation of spurious or artefactual clusters we felt that the evidence for neuropathological subtypes should be strengthened by corresponding evidence of clinical differences between these clusters. Our results suggest that subtypes of AD may be based on different patterns of neurodegeneration. It is unlikely that these subtypes are related to the admixture of other degenerative brain changes which had been allowed for by careful clinical and neuro­ pathological examination. Patients with predominant coeruleo-frontal changes may benefit from different therapeutic strategies than those with predominant hippocampo-parahippocampo-parietal neurodegen­ eration. This and the stability of potential course characteristics will need further prospective investiga­ tion before the existence of subtypes of AD can be legitimately claimed (Jorm, 1985) . Acknowledgements We acknowledge the statistical advice of Professor B. Everitt and Dr G. Dunn. This work was supported by grants from the Medical Research Council, by the German Research Foundation, by a Parke Davis Research Fellow­ ship and by an H. & L. Schilling professorship to H.F. 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H. Förstl, R. Levy, A. Burns, P. Luthert, N. Cairns. Pathways and Patterns of Cell Loss in Verified Alzheimer’s Disease: A Factor and Cluster Analysis of Clinico-Pathological Subgroups, Behavioural Neurology, DOI: 10.3233/BEN-1994-73-411