- Email: [email protected]
Microglial reaction in Pick's disease
Neuroscienee Letters, 161 (1993) 89-92 © 1993 Elsevier Scientific Publishers Ireland Ltd. All rights reserved 0304-3940193/$ 06.00
89
NSL 09876
Microglial reaction in Pick's disease Werner Paulus a, Christian Bancher b and K u r t Jellinger b "Institute of Pathology, University of Wiirzburg, Wiirzburg ( FRG) and hLudwig Boltzmann Institute of Clinical Neurobiology, Lainz Hospital, Vienna (Austria) (Received 29 April 1993; Revised version received 15 July 1993; Accepted 16 July 1993)
Key words: Microglia; Pick's disease; Alzheimer's disease; Gliosis; Immunohistochemistry; Hippocampus; Neocortex N umber and morphology of microglial cells (MC) were compared in 6 cases each of Pick's disease (PD), Alzheimer's disease (AD) and controls using immunohistochemistry with the monoclonal antibody Ki-M 1P. The severely involved neocortex of both PD and AD, and in particular the white matter subjacent to spongy PD lesions showed a marked increase of MC density, whereas non-affected PD areas and AD white matter showed no M C changes. The PD hippocampus, particularly the dentate gyrus, showed reduction of MC density and processes. We conclude that (1) MC reaction represents a major element of PD histopathology, and (2) density, morphology and distribution of MC are different in AD and PD.
Microglial cells (MC) are increased and activated in various neurodegenerative disorders such as Parkinson's and Alzheimer's (AD) diseases [4, 7]. Possible pathogenetic roles for MC in these disorders include presentation of antigens, secretion of cytokines and proteases, release of both neurotoxic and neurotrophic factors, generation of free radicals, and phagocytosis [2, 10]. In addition, the participation of MC in synthesis, processing and phagocytosis of fl-amyloid protein as well as in the formation of senile plaques is under intense investigation [3, 9]. Pick's disease (PD) accounts for 0.4-2% of all cases of dementia in large autopsy series [6]. Pathologically, it is characterized by frontal or temporal lobar atrophy, severe neuronal loss with spongy loosening of the neuropil, intraneuronal argentophilic inclusions (Pick bodies) and ballooned neurons (Pick cells) in the cerebral cortex, as well as cortical and white matter astrogliosis. The functional and morphological features of MC in PD are unknown, and in both classical and recent texts on PD, MC have been either disregarded or thought not to play a special role [1, 5, 13]. On the other hand, the readiness of MC for reaction makes it unlikely that they are not involved in a lesion with massive histological abnormalities. We therefore compared the MC distribution in PD to that in AD and normal aged brains to gain insight into morphological features and possible roles for MC in PD. Correspondence: W. Paulus, Institute of Pathology, University of Wiirzburg, Josef-Schneider-Str. 2, D-97080 Wiirzburg, FRG. Fax: (49) (931) 201-3440.
We studied routinely processed, formalin-fixed and paraffin-embedded brain tissue from 6 cases of PD (65.4 + 8.0 years; duration of illness, 3 to 6 years), 6 cases of AD (79.7 + 9.3 years; duration of illness, 1 to 5 years) and 6 controls without neurological symptoms and without major neuropathological abnormalities (67.9 + 10.6 years). Brains were obtained 8 to 48 h after death. The clinical histories of the PD cases were compatible with this disorder, and all the typical pathological features were observed, including frontal and/or temporal lobar atrophy, Pick cells and numerous Pick bodies (except for one case aged 66 years lacking Pick bodies). Two brains showed considerable secondary degeneration of hemispheral white matter; none revealed Alzheimer lesions except for one that had neurofibrillary tangles in the spongy entorhinal cortex. The AD patients had been demented, and their brains met the histological AD criteria of both Khachaturian [8] and the Consortium to Establish a Registry for AD (CERAD) [11]. None of the AD brains revealed considerable white matter damage. The superior frontal gyrus and the hippocampal formation including the adjacent temporal cortex were immunohistochemically examined in each case. 5-/,tin-thick sections were immunostained using the mouse monoclonal antibody Ki-M 1P (diluted 1:1000), the peroxidaseanti peroxidase (PAP) technique and 3,3'-diaminobenzidine as substrate. Sections were counterstained with hematoxylin. Ki-M 1P is a specific and sensitive marker for monocytes, macrophages and microglial cells. It does not stain non-neoplastic astrocytes; it works well with
90
Fig. 1. Morphologicalanalysis of microglialcells in Pick's disease (a-c), Alzheimer'sdisease (d) and controls (e,f) in frontal cortex (a,d), frontal white matter (b,e) and dentate gyrus (c,f). Frontal cortex of Pick's disease (a) with spongy loosening and numerous ameboid microglial cells (asterisk: molecular layer), and of Alzheimer'sdisease (d) with small and ameboid microglial cells (arrow: senile plaque). Pick's disease white matter (b) with marked increase of microglia, particularly ameboid forms, and immunonegative astrocytes as compared to controls (e). Dentate gyrus of Pick's disease (c) with reduced number of microglia and predominance of cells with scanty cytoplasmas compared to controls (f). (Immunohistochemistry using Ki-M1P, hematoxylin counterstaining; a,d: x 160:b,c,e,f: x 320.)
routinely processed tissues; and its reactivity is not affected by the duration of the post-mortem interval [12]. MC were quantitated in four locations: fourth/fifth frontal neocortical layers, frontal white matter, CA1 sector of the hippocampus, and granular layer of the dentate gyrus. In the neocortex of the PD cases, areas without apparent pathological features (except for a few Pick cells) and pathological areas showing spongiosis and prominent neuronal loss were separately evaluated. Ramified microglia, ameboid microglia (cells with plump, ovale cytoplasm) and macrophages together were counted in three microscopic fields (0.25 mm 2 per field) using an ocular grid at a magnification of x 200, and the mean was calculated. In the dentate gyrus six fields of 0.125 mm 2 were counted. Areas showing highest density of positive cells were evaluated. Fields comprising senile plaques, which usually show high density of MC, were not counted in A D in order to enable better comparison between the neuropil of A D and that of PD, the latter
lacking senile plaques. Statistical significance was determined using Student's t-test. P < 0.01 was regarded as statistically significant. In the control brains, K i - M I P labeled ramified MC (Fig. le,f), perivascular cells, and a few ameboid MC and macrophages as described elsewhere [12]. In contrast, the markedly abnormal (spongy) cerebral cortex widely devoid of neurons in PD was largely populated by ameboid MC (Fig. la). Ramified MC were preferentially seen in the molecular layer and only occasionally in the deeper cortical layers. In the frontal white matter subjacent to spongy PD lesions, the ameboid type predominated also and only a few ramified elements were encountered (Fig. lb). The MC morphology in areas without apparent histological abnormalities was similar to that of controls. In the dentate gyrus, most Ki-M 1P-positive cells were characterized by small ovale nuclei and scanty perinuclear cytoplasm without ramified processes (Fig. lc). MC counts in PD revealed an increase in the spongy cortex
91
Frontal w h i t e matter
Frontal n e o c o r t e x
microglial cells per squmm
microglisl cells per sclumm
300
120 F
Pick's (spongy)
/
100I
Alzheimer's
~
250
D
200
8O
Pick's (not s p o n g y ) +
Controls 60
Controls
Pick's (not s p o n g y )
8
÷
* -~
0
150
Pick's (spongy)
Alzheimer's
o
B C] 1 O0
+ versus controls versus Alzhelmer's
n.s.
p , 0.001
p , 0.001
n.s.
p , 0.001
50
versus controls
n.s.
p ( o.ool
versus Alzheimer's
n.s.
p = 0.0Ol
microglial cells per squmm
microglial cells per sclumm Alzheimer's [3
14.0
180
Controls
o o
16o
Alzheimer's
[3
14o
120 100
Controls
120
Pick's
o
Pick's
D 0
80
0
60
Q
40
o
o
1O0
B
80
6
|
60
20
o n.s.
Hippocampus - d e n t a t e gyrus
Hippocampus - CA1 s e c t o r 160
o
40 versus controls versus Alzhelmer's
p c 0.005 p c 0.005
n.s.
20
versus controls versus Alzheirner's
p t 0.001 p ( 0.001
n.s.
0
0
Fig. 2. Quantitative analysis of density of microglial cells (ramified forms, ameboid forms and macrophages) in various brain regions.
(by 85.9%) and, most prominently, in the subjacent white matter (145%), but a decrease in the dentate gyrus (by 50.1%) and the CA1 sector (20.3%) as compared to controis (Fig. 2, Table I). The AD neocortex showed a mixture of ramified and ameboid forms; senile plaques mainly contained ameboid MC, and these cells predominated in areas with numerous senile plaques [2, 4], while the number of ramified forms was higher in the less affected areas (Fig. ld). Spongy loosening of the neuropil, a relatively rare finding in the present series of AD, was associated with a marked increase of ameboid MC. In the AD frontal white matter, MC with either fine, delicately ramified, or plump and frequently bipolar processes were the major elements. The hippocampus showed more ameboid MC than the neocortex. Both ameboid and ramified MC as well as a few smaltMC (similar to that seen in PD) were observed in the AD dentate gyrus. Compared to controls, MC density was increased in the frontal cortex by
70.8%, but not in white matter and hippocampus (Fig. 2, Table I). In conclusion, we found distinct microglial reactions TABLE I QUANTITATIVE EVALUATION OF M I C R O G L I A L CELL DENSITY Values expressed as number of microglial cells + S.D. per square millimeter. Controls
Pick's disease Spongy
Frontal
41.1 _+ 4.0
cortex Frontal white 105.3 -+ 25.5 matter CA1 sector 73.8 + 8.7 Dentate gyrus 104.2 + 40.0
Alzheimer's disease Not spongy
76.4 + 21.0 36.8 _+ 5.8
70.2 + 19.2
258.0 + 28.0 98.1 + 28.8
100.7 + 33.6
-
58.8 + 15.5 52.0 + 19.5
87.8 + 31.7 98.9 + 27.7
92
in A D and PD. While the abnormal neocortical areas in both diseases showed a similar increase of MC compared to controls, the subjacent white matter in PD, but not in AD, was characterized by a marked increase of MC. These data indicate that MC, in addition to astrocytes, constitute a prominent component of the white matter gliosis in PD. We did not detect MC differences in the white matter between controls and PD areas without apparent histological alterations, suggesting that the white matter gliosis in PD is related to secondary degeneration of myelinated axons. Our finding of reduced cell density of MC in the PD dentate gyrus and hippocampal CA1 sector compared to both control and A D brains was somewhat surprising, since MC are known to non-specifically increase in response to various stimuli. The MC reaction in PD was generally characterized by a marked increase of ameboid forms and small cells without processes, and by a decrease o f ramified MC. As we have counted nucleated MC as well as ramified MC without evident nucleus, the decreased MC counts in the hippocampus might be, at least in part, the consequence of a reduced number of anuclear processes encountered in two-dimensional sections. We do not know the reasons for the morphological and quantitative differences of MC between A D and PD. The lack of amyloid deposition in PD or the severity of the lesions might play a role. Spongy devastation of the neuropil is rarely present in A D unless in terminal stages, e.g. in the entorhinal region. In PD, the spongy areas may lead to retraction of MC processes and increase of ameboid forms. Whether the differences in number, distribution and morphology o f MC in A D and PD are due to different stages or types of tissue damage or to hitherto unknown disease-specific factors that might indicate distinct roles for MC in these two neurodegenerative disorders remains to be elucidated.
I Constantmidis, J., Richard. J. and Tissot, R., Pick's disease. Histological and clinical correlations, E ur. Neurol.. I I (1974) 208 217. 2 Dickson, D.W., Lee, S.C.. Mattiace. L.A.. Yen, S.H.C. and Brosnan, C., Microglia and cytokines in neurological disease, with special reference to AIDS and Alzheimer's disease, Gila, 7 (1993) 75 83. 3 Frackowiak, J., Wisniewski, ll.M., Wegiel, J., Merz, G.S., lqbal, K. and Wang, K.C., UItrastructure of the microglia that phagocytose amyloid and the microglia that produce beta-amyloid fibrils, Acta Neuropathol. (Bed.), 84 (1992) 225 233. 4 Grundke-lqbal, 1., Fleming, J., Tung. Y.C., Lassmann, H., lqbal. K. and Joshi, J.G., Ferritin is a component of the neuritic (senile) plaque in Alzheimer dementia, Acta Neuropathol. (Berl.), 81 (1990) 11)5 I 10. 5 Jakob, H., Zur pathologischen Anatomic der Pickschen Krankheit, Arch. Psychiat. Nervenkrankh., 202 (1961) 540 568. 6 Jellinger, K., Danielczyk, W., Fischer, R and Gabriel E., Clinicopathological analysis of dementia disorders in the elderly, ,I. Neurol. Sci., 95 (1990) 239 258. 7 Jellinger, K., Paulus. W., Grundke-lqbal, 1., Riederer, P. and Youdim, M.B.H., Brain iron and ferritin in Parkinson's and AIzheimer's diseases, J. Neural Transm., 2 (1990) 327 340. 8 Khachaturian, Z.S., Diagnosis of AIzheimer's disease. Arch. Neu1"o1., 42(1985) 1097 1105. 9 McGeer, EL., Akiyama, H., Kawamata, T., Yamada, T., Walker, D.G. and lshii, T., lmmunohistochemical localization o[ beta-amyloid precursor protein sequences in Alzheimer and normal brain tissue by light and electron microscopy, J. Neurosci. Res., 31 (1992) 428 442. 10 McGeer, EL., Kawamata, T., Walker, D.G., Akiyama, 1t., Tooyama, I. and McGeer, E.G., Microglia in degenerative neurological disease, Glia, 7 (1993) 84 92. 11 Mirra, S.S., Hart, M.N. and Terry, R.D., Making the diagnosis of Alzheimer's disease, Arch. Pathol. Lab. Med., 117 (1993) 132 144. 12 Paulus, W., Roggendorf, W. and Kirchner, T., Ki-M1P as a marker for microglia and brain macrophages in routinely processed human tissues, Acta Neuropathol. (Berl.), 84 (1992) 538 544. 13 Tomlinson, B.E., Ageing and the dementias. In J.H. Adams and L.W. Duchen {Eds.), Greenfield's Neuropathology, Edward Arnold, London, 1992, pp. 1284 1410.
89
NSL 09876
Microglial reaction in Pick's disease Werner Paulus a, Christian Bancher b and K u r t Jellinger b "Institute of Pathology, University of Wiirzburg, Wiirzburg ( FRG) and hLudwig Boltzmann Institute of Clinical Neurobiology, Lainz Hospital, Vienna (Austria) (Received 29 April 1993; Revised version received 15 July 1993; Accepted 16 July 1993)
Key words: Microglia; Pick's disease; Alzheimer's disease; Gliosis; Immunohistochemistry; Hippocampus; Neocortex N umber and morphology of microglial cells (MC) were compared in 6 cases each of Pick's disease (PD), Alzheimer's disease (AD) and controls using immunohistochemistry with the monoclonal antibody Ki-M 1P. The severely involved neocortex of both PD and AD, and in particular the white matter subjacent to spongy PD lesions showed a marked increase of MC density, whereas non-affected PD areas and AD white matter showed no M C changes. The PD hippocampus, particularly the dentate gyrus, showed reduction of MC density and processes. We conclude that (1) MC reaction represents a major element of PD histopathology, and (2) density, morphology and distribution of MC are different in AD and PD.
Microglial cells (MC) are increased and activated in various neurodegenerative disorders such as Parkinson's and Alzheimer's (AD) diseases [4, 7]. Possible pathogenetic roles for MC in these disorders include presentation of antigens, secretion of cytokines and proteases, release of both neurotoxic and neurotrophic factors, generation of free radicals, and phagocytosis [2, 10]. In addition, the participation of MC in synthesis, processing and phagocytosis of fl-amyloid protein as well as in the formation of senile plaques is under intense investigation [3, 9]. Pick's disease (PD) accounts for 0.4-2% of all cases of dementia in large autopsy series [6]. Pathologically, it is characterized by frontal or temporal lobar atrophy, severe neuronal loss with spongy loosening of the neuropil, intraneuronal argentophilic inclusions (Pick bodies) and ballooned neurons (Pick cells) in the cerebral cortex, as well as cortical and white matter astrogliosis. The functional and morphological features of MC in PD are unknown, and in both classical and recent texts on PD, MC have been either disregarded or thought not to play a special role [1, 5, 13]. On the other hand, the readiness of MC for reaction makes it unlikely that they are not involved in a lesion with massive histological abnormalities. We therefore compared the MC distribution in PD to that in AD and normal aged brains to gain insight into morphological features and possible roles for MC in PD. Correspondence: W. Paulus, Institute of Pathology, University of Wiirzburg, Josef-Schneider-Str. 2, D-97080 Wiirzburg, FRG. Fax: (49) (931) 201-3440.
We studied routinely processed, formalin-fixed and paraffin-embedded brain tissue from 6 cases of PD (65.4 + 8.0 years; duration of illness, 3 to 6 years), 6 cases of AD (79.7 + 9.3 years; duration of illness, 1 to 5 years) and 6 controls without neurological symptoms and without major neuropathological abnormalities (67.9 + 10.6 years). Brains were obtained 8 to 48 h after death. The clinical histories of the PD cases were compatible with this disorder, and all the typical pathological features were observed, including frontal and/or temporal lobar atrophy, Pick cells and numerous Pick bodies (except for one case aged 66 years lacking Pick bodies). Two brains showed considerable secondary degeneration of hemispheral white matter; none revealed Alzheimer lesions except for one that had neurofibrillary tangles in the spongy entorhinal cortex. The AD patients had been demented, and their brains met the histological AD criteria of both Khachaturian [8] and the Consortium to Establish a Registry for AD (CERAD) [11]. None of the AD brains revealed considerable white matter damage. The superior frontal gyrus and the hippocampal formation including the adjacent temporal cortex were immunohistochemically examined in each case. 5-/,tin-thick sections were immunostained using the mouse monoclonal antibody Ki-M 1P (diluted 1:1000), the peroxidaseanti peroxidase (PAP) technique and 3,3'-diaminobenzidine as substrate. Sections were counterstained with hematoxylin. Ki-M 1P is a specific and sensitive marker for monocytes, macrophages and microglial cells. It does not stain non-neoplastic astrocytes; it works well with
90
Fig. 1. Morphologicalanalysis of microglialcells in Pick's disease (a-c), Alzheimer'sdisease (d) and controls (e,f) in frontal cortex (a,d), frontal white matter (b,e) and dentate gyrus (c,f). Frontal cortex of Pick's disease (a) with spongy loosening and numerous ameboid microglial cells (asterisk: molecular layer), and of Alzheimer'sdisease (d) with small and ameboid microglial cells (arrow: senile plaque). Pick's disease white matter (b) with marked increase of microglia, particularly ameboid forms, and immunonegative astrocytes as compared to controls (e). Dentate gyrus of Pick's disease (c) with reduced number of microglia and predominance of cells with scanty cytoplasmas compared to controls (f). (Immunohistochemistry using Ki-M1P, hematoxylin counterstaining; a,d: x 160:b,c,e,f: x 320.)
routinely processed tissues; and its reactivity is not affected by the duration of the post-mortem interval [12]. MC were quantitated in four locations: fourth/fifth frontal neocortical layers, frontal white matter, CA1 sector of the hippocampus, and granular layer of the dentate gyrus. In the neocortex of the PD cases, areas without apparent pathological features (except for a few Pick cells) and pathological areas showing spongiosis and prominent neuronal loss were separately evaluated. Ramified microglia, ameboid microglia (cells with plump, ovale cytoplasm) and macrophages together were counted in three microscopic fields (0.25 mm 2 per field) using an ocular grid at a magnification of x 200, and the mean was calculated. In the dentate gyrus six fields of 0.125 mm 2 were counted. Areas showing highest density of positive cells were evaluated. Fields comprising senile plaques, which usually show high density of MC, were not counted in A D in order to enable better comparison between the neuropil of A D and that of PD, the latter
lacking senile plaques. Statistical significance was determined using Student's t-test. P < 0.01 was regarded as statistically significant. In the control brains, K i - M I P labeled ramified MC (Fig. le,f), perivascular cells, and a few ameboid MC and macrophages as described elsewhere [12]. In contrast, the markedly abnormal (spongy) cerebral cortex widely devoid of neurons in PD was largely populated by ameboid MC (Fig. la). Ramified MC were preferentially seen in the molecular layer and only occasionally in the deeper cortical layers. In the frontal white matter subjacent to spongy PD lesions, the ameboid type predominated also and only a few ramified elements were encountered (Fig. lb). The MC morphology in areas without apparent histological abnormalities was similar to that of controls. In the dentate gyrus, most Ki-M 1P-positive cells were characterized by small ovale nuclei and scanty perinuclear cytoplasm without ramified processes (Fig. lc). MC counts in PD revealed an increase in the spongy cortex
91
Frontal w h i t e matter
Frontal n e o c o r t e x
microglial cells per squmm
microglisl cells per sclumm
300
120 F
Pick's (spongy)
/
100I
Alzheimer's
~
250
D
200
8O
Pick's (not s p o n g y ) +
Controls 60
Controls
Pick's (not s p o n g y )
8
÷
* -~
0
150
Pick's (spongy)
Alzheimer's
o
B C] 1 O0
+ versus controls versus Alzhelmer's
n.s.
p , 0.001
p , 0.001
n.s.
p , 0.001
50
versus controls
n.s.
p ( o.ool
versus Alzheimer's
n.s.
p = 0.0Ol
microglial cells per squmm
microglial cells per sclumm Alzheimer's [3
14.0
180
Controls
o o
16o
Alzheimer's
[3
14o
120 100
Controls
120
Pick's
o
Pick's
D 0
80
0
60
Q
40
o
o
1O0
B
80
6
|
60
20
o n.s.
Hippocampus - d e n t a t e gyrus
Hippocampus - CA1 s e c t o r 160
o
40 versus controls versus Alzhelmer's
p c 0.005 p c 0.005
n.s.
20
versus controls versus Alzheirner's
p t 0.001 p ( 0.001
n.s.
0
0
Fig. 2. Quantitative analysis of density of microglial cells (ramified forms, ameboid forms and macrophages) in various brain regions.
(by 85.9%) and, most prominently, in the subjacent white matter (145%), but a decrease in the dentate gyrus (by 50.1%) and the CA1 sector (20.3%) as compared to controis (Fig. 2, Table I). The AD neocortex showed a mixture of ramified and ameboid forms; senile plaques mainly contained ameboid MC, and these cells predominated in areas with numerous senile plaques [2, 4], while the number of ramified forms was higher in the less affected areas (Fig. ld). Spongy loosening of the neuropil, a relatively rare finding in the present series of AD, was associated with a marked increase of ameboid MC. In the AD frontal white matter, MC with either fine, delicately ramified, or plump and frequently bipolar processes were the major elements. The hippocampus showed more ameboid MC than the neocortex. Both ameboid and ramified MC as well as a few smaltMC (similar to that seen in PD) were observed in the AD dentate gyrus. Compared to controls, MC density was increased in the frontal cortex by
70.8%, but not in white matter and hippocampus (Fig. 2, Table I). In conclusion, we found distinct microglial reactions TABLE I QUANTITATIVE EVALUATION OF M I C R O G L I A L CELL DENSITY Values expressed as number of microglial cells + S.D. per square millimeter. Controls
Pick's disease Spongy
Frontal
41.1 _+ 4.0
cortex Frontal white 105.3 -+ 25.5 matter CA1 sector 73.8 + 8.7 Dentate gyrus 104.2 + 40.0
Alzheimer's disease Not spongy
76.4 + 21.0 36.8 _+ 5.8
70.2 + 19.2
258.0 + 28.0 98.1 + 28.8
100.7 + 33.6
-
58.8 + 15.5 52.0 + 19.5
87.8 + 31.7 98.9 + 27.7
92
in A D and PD. While the abnormal neocortical areas in both diseases showed a similar increase of MC compared to controls, the subjacent white matter in PD, but not in AD, was characterized by a marked increase of MC. These data indicate that MC, in addition to astrocytes, constitute a prominent component of the white matter gliosis in PD. We did not detect MC differences in the white matter between controls and PD areas without apparent histological alterations, suggesting that the white matter gliosis in PD is related to secondary degeneration of myelinated axons. Our finding of reduced cell density of MC in the PD dentate gyrus and hippocampal CA1 sector compared to both control and A D brains was somewhat surprising, since MC are known to non-specifically increase in response to various stimuli. The MC reaction in PD was generally characterized by a marked increase of ameboid forms and small cells without processes, and by a decrease o f ramified MC. As we have counted nucleated MC as well as ramified MC without evident nucleus, the decreased MC counts in the hippocampus might be, at least in part, the consequence of a reduced number of anuclear processes encountered in two-dimensional sections. We do not know the reasons for the morphological and quantitative differences of MC between A D and PD. The lack of amyloid deposition in PD or the severity of the lesions might play a role. Spongy devastation of the neuropil is rarely present in A D unless in terminal stages, e.g. in the entorhinal region. In PD, the spongy areas may lead to retraction of MC processes and increase of ameboid forms. Whether the differences in number, distribution and morphology o f MC in A D and PD are due to different stages or types of tissue damage or to hitherto unknown disease-specific factors that might indicate distinct roles for MC in these two neurodegenerative disorders remains to be elucidated.
I Constantmidis, J., Richard. J. and Tissot, R., Pick's disease. Histological and clinical correlations, E ur. Neurol.. I I (1974) 208 217. 2 Dickson, D.W., Lee, S.C.. Mattiace. L.A.. Yen, S.H.C. and Brosnan, C., Microglia and cytokines in neurological disease, with special reference to AIDS and Alzheimer's disease, Gila, 7 (1993) 75 83. 3 Frackowiak, J., Wisniewski, ll.M., Wegiel, J., Merz, G.S., lqbal, K. and Wang, K.C., UItrastructure of the microglia that phagocytose amyloid and the microglia that produce beta-amyloid fibrils, Acta Neuropathol. (Bed.), 84 (1992) 225 233. 4 Grundke-lqbal, 1., Fleming, J., Tung. Y.C., Lassmann, H., lqbal. K. and Joshi, J.G., Ferritin is a component of the neuritic (senile) plaque in Alzheimer dementia, Acta Neuropathol. (Berl.), 81 (1990) 11)5 I 10. 5 Jakob, H., Zur pathologischen Anatomic der Pickschen Krankheit, Arch. Psychiat. Nervenkrankh., 202 (1961) 540 568. 6 Jellinger, K., Danielczyk, W., Fischer, R and Gabriel E., Clinicopathological analysis of dementia disorders in the elderly, ,I. Neurol. Sci., 95 (1990) 239 258. 7 Jellinger, K., Paulus. W., Grundke-lqbal, 1., Riederer, P. and Youdim, M.B.H., Brain iron and ferritin in Parkinson's and AIzheimer's diseases, J. Neural Transm., 2 (1990) 327 340. 8 Khachaturian, Z.S., Diagnosis of AIzheimer's disease. Arch. Neu1"o1., 42(1985) 1097 1105. 9 McGeer, EL., Akiyama, H., Kawamata, T., Yamada, T., Walker, D.G. and lshii, T., lmmunohistochemical localization o[ beta-amyloid precursor protein sequences in Alzheimer and normal brain tissue by light and electron microscopy, J. Neurosci. Res., 31 (1992) 428 442. 10 McGeer, EL., Kawamata, T., Walker, D.G., Akiyama, 1t., Tooyama, I. and McGeer, E.G., Microglia in degenerative neurological disease, Glia, 7 (1993) 84 92. 11 Mirra, S.S., Hart, M.N. and Terry, R.D., Making the diagnosis of Alzheimer's disease, Arch. Pathol. Lab. Med., 117 (1993) 132 144. 12 Paulus, W., Roggendorf, W. and Kirchner, T., Ki-M1P as a marker for microglia and brain macrophages in routinely processed human tissues, Acta Neuropathol. (Berl.), 84 (1992) 538 544. 13 Tomlinson, B.E., Ageing and the dementias. In J.H. Adams and L.W. Duchen {Eds.), Greenfield's Neuropathology, Edward Arnold, London, 1992, pp. 1284 1410.