Amygdala pathology in Parkinson's disease

The amygdala undergoes severe pathological changes during the course of Parkinson's disease (PD). Lewy bodies and Lewy neurites are distributed in a specific manner throughout the nuclear complex. The lesional pattern displays only minor interindividual variation. The most prominent changes occur in the accessory cortical and central nuclei. The cortical, accessory basal and granular nuclei show less severe alterations, while the basal and lateral nuclei, as well as the intercalated cell masses, generally remain uninvolved. The amygdala receives a broad range of afferents, allowing integration of exteroceptive information with interoceptive data. It generates major projections to the isocortex (the prefrontal cortex in particular), limbic system (hippocampus and entorhinal region) and centers regulating endocrine and autonomic functions. The specific lesional pattern seen in PD destroys part of the nuclear gray matter and its connections and, thus, may likely contribute to the development of behavioral changes and autonomic dysfunction.     

Development of α-synuclein immunoreactive astrocytes in the forebrain parallels stages of intraneuronal pathology in sporadic Parkinson’s disease

Astrocytic α-synuclein-immunoreactive inclusions have recently been noted to develop in sporadic Parkinson’s disease (PD). Here, the presence of immunoreactive astrocytes is reported in 14 autopsy cases with clinically diagnosed PD and a neuropathological stage of 4 or higher. The labeled astrocytes occur preferentially in prosencephalic regions (amygdala, thalamus, septum, striatum, claustrum, and cerebral cortex). They appear first in layers V–VI of the temporal mesocortex, then in the striatum and in thalamic nuclei that project to the cortex. The topographical distribution pattern of these astrocytes closely parallels that of the cortical intraneuronal Lewy neurites and Lewy bodies, which, from their foothold in the mesocortex, gradually encroach upon neocortical association areas and even the primary fields. Thus, labeling of astrocytes appears to accompany the formation of neuronal inclusion bodies. Relatively small immunoreactive cortical pyramidal neurons in layers V–VI probably project to nearby destinations, such as the striatum and thalamus. Inasmuch as the projection neurons of both the striatum and the dorsal thalamus do not develop Lewy bodies, it is suggested that the most likely cause of the astrocytic reaction may be a slightly altered α-synuclein molecule that escapes from terminal axons of affected cortico-striatal or cortico-thalamic neurons and is taken up by astrocytes. Other aggregated proteins known to co-occur with PD-associated intraneuronal lesions, e.g., Aβ protein or neurofibrillary changes of the Alzheimer type, do not appear to influence the development of the α-synuclein immunoreactive astrocytes.     

An autopsied case of Down syndrome with Alzheimer pathology and α-synuclein immunoreactivity

An autopsied case of a 49-year-old man with Down syndrome is described. The patient developed mental deterioration and parkinsonism at the age of 44 years. The brain revealed Alzheimer's disease (AD) pathology in addition to anomalies and lesions of premature senility. In the substantia nigra, many neurofibrillary tangles (NFT) and some Lewy bodies (LB) were found, suggesting that a limited degree of Parkinson's disease (PD) pathology may combine with AD pathology to develop parkinsonism. However, spongiform change and ubiquitin-positive spheroids in the central nucleus of the amygdala, which are peculiar to dementia with Lewy bodies (DLB), were observed, suggesting that the substantia nigra lesion is similar to that of DLB rather than that of PD. In addition, α-synuclein-positive neurons in the limbic areas, predominantly in the amygdala, were found. Their incidence and distribution did not fulfill the criteria of DLB. These neurons did not show the typical features of cortical type LB, and were mostly accompanied by tau-positive NFT. These findings suggest that the presence of α-synuclein-positive neurons does not always indicate the presence of LB, and that the present case should not be regarded as the complication of DLB in Down syndrome.     

α-Synuclein-positive structures in cases with sporadic Alzheimer’s disease: morphology and its relationship to tau aggregation

Alzheimer’s disease (AD) and Parkinson’s disease share common clinical and pathological features. In this study, we examined the relationship between AD pathology and α-synuclein aggregation. The frequency and distribution of α-synuclein-positive structures were systematically investigated in 27 cases with sporadic AD by α-synuclein immuno-histochemistry. Thirteen (48.2%) of 27 cases had various α-synuclein-positive structures as well as Lewy bodies. The frequency and density of senile plaques and neurofibrillary tangles were not significantly different between cases with α-synuclein structures and those without. α-Synuclein-positive structures were found most frequently in the amygdala. The α-synuclein-positive inclusions that are different from Lewy bodies were observed at the highest rate in the hippocampus. The discovery of α-synuclein as the constituent of Lewy bodies facilitated the detection of Lewy-related structures even in AD cases with widespread and numerous neurofibrillary tangles. α-Synuclein-positive inclusions except for Lewy bodies are exposed, and the distribution of them indicates that Lewy body formation may be influenced by the degree of tau aggregation. This study also supports the suggestion that cases with AD pathology can be classified into two groups according to the existence or absence of α-synuclein aggregation.     

Lewy body-related α-synucleinopathy in the aged human brain

To clarify the significance of Lewy body (LB)-related alpha-synucleinopathy in aging and various neurodegenerative disorders, its incidence and topographic pattern were examined in 260 brains of elderly patients, including 116 autopsy-proven cases of Alzheimer disease (AD), 71 cases of clinically and autopsy-proven Parkinson disease (PD), 38 of dementia with Lewy bodies (DLB), 8 patients with progressive supranuclear palsy (PSP), one with senile tremor, and 26 age-matched controls without neuropsychiatric disorders. Using immunohistochemistry, alpha-synuclein (AS) positive lesions were assessed semiquantitatively. For technical reasons, the olfactory system was not systematically studied. All PD-brains showed AS-positive lesions in medullary, pontine and mesencephalic nuclei, with involvement of the nucleus basalis (90.1%), limbic cortex (58.9%), cingulate cortex (46%), amygdala, CA 2/3 hippocampal region (36.2%), neocortex (28.8%), and striatum (11%). 88% of clinical PD cases corresponded to LB pathology stages 4-6, 12% to stage 3 according to Braak et al. (2003). 84% of DLB brains were PD stage 5 or 6 and 17% stage 4, without significant differences between DLB with and without neuritic AD pathology, suggesting morphologic similarities betwee these disorders. 6/8 PSP and senile tremor cases, 49.1% of AD and 69% of aged controls were negative. AS-positive lesions in AD showed decreasing incidence from midbrain (24-28%), limbic cortex and amygdala (17-18%), nucleus basalis and medullary nuclei (13-17%), cingulate cortex (12%), CA 2/3 region (8%) to neocortex (2%), without gender differences or relationship to the severity of AD pathology (mean Braak stage 5.1). AD cases with AS positive lesions, particularly those with AS pathology in the amygdala, were older at death than negative ones (86.6 vs 83.3 yrs), but this difference was not statistically significant. 15 AD cases (seven of them with mild PD symptoms) and 3 aged controls without parkinsonian signs but LB pathology stages 3 (n=5) and 4 (n=13) were considered "incidental LB disease". 16 AD brains without parkinsonian symptoms had AS positive lesions in various areas without medullary involvement, suggesting deviation from the proposed stereotypic expansion pattern. Located AS-pathology in the midbrain and limbic cortex was seen in 31% of asymptomatic aged controls. These data 1. largely confirm Braak's staging of LB-pathology in PD; 2. suggest morphologic and pathogenic relations between PD (brainstem type) and DLB with and without coexistent AD pathology; 3. the occurrence of LB-related alpha-synucleinopathy in about 50% of AD brains and about 30% of aged controls. However, the basic mechanisms of LB-related AS-pathology and their pathogenic and clinical relevance in aged brain and neurodegenerative disorders await further elucidation.     

Progression and staging of Lewy pathology in brains from patients with dementia with Lewy bodies

Using alpha-synuclein-immunohistochemistry, 27 brains of dementia with Lewy bodies (DLB) were investigated to identify the progression of Lewy pathology including Lewy bodies (LB) and LB-related neurites in the cerebrum. The numbers of alpha-synuclein-positive LB and LB-related neurites were semiquantitatively evaluated in the amygdala, hippocampus, entorhinal cortex, transentorhinal cortex, insular cortex, middle temporal cortex and superior frontal cortex. The results indicated that Lewy pathology within the neuron progresses first in the axonal terminal, subsequently in the cell body and finally in the dendrite, that Lewy pathology in the cerebral cortex progresses first in layers V-VI, subsequently in layer III and finally in layer II, and that Lewy pathology in the cerebrum progresses first in the amygdala, subsequently in the limbic cortex and finally in the neocortex. In addition, Lewy pathology was graded from stage I to stage IV based on the progression of Lewy pathology. The 27 brains examined were classified into 3 brains showing stage I, 11 showing stage II, 7 showing stage III and 6 showing stage IV. Comparing these stages with the pathological subtypes of DLB brains, brains of the subtype showing severe Alzheimer pathology corresponded to brains showing an advanced stage, suggesting that Alzheimer pathology exacerbates Lewy pathology.     

Non‐uniformity in the regional pattern of Lewy pathology in brains of dementia with Lewy bodies

We examined the regional pattern of Lewy pathology in brains of dementia with Lewy bodies (DLB) to clarify whether Lewy pathology uniformly progresses or not. Thirty‐five autopsied DLB cases were examined using α‐synuclein‐immunohistochemistry, and the regional degree of Lewy pathology in the brainstem, diencephalon and cerebral cortex was quantitatively evaluated. Consequently, we found that the regional pattern of Lewy pathology differed according to the pathological subtype, and was divided into three types: type 1 showed a brainstem‐predominant pattern, type 2 was almost equal for the brainstem and cerebral cortex, and type 3 showed a cerebral cortex‐predominant pattern. The limbic type/pure and common forms were mainly composed of type 1, whereas the neocortical type/common and Alzheimer's disease (AD) forms were mainly composed of type 3. These findings suggest the possibility that Lewy pathology of the limbic type/pure and common forms mainly progresses from the brainstem to the cerebrum, whereas that of the neocortical type/common and AD forms mainly progresses from the cerebrum to the brainstem. Cases with type 1 Lewy pathology mainly developed parkinsonism, whereas those with type 3 Lewy pathology mainly developed dementia. This corresponded to most of the limbic type/pure and common forms which developed parkinsonism, whereas most of the neocortical type/common and AD forms developed dementia. Type 1 cases may thus be clinically diagnosed as having Parkinson's disease (PD) with dementia. These findings suggest that PD has clinico‐pathological continuity with DLB, and that the regional pattern of Lewy pathology is not uniform.     

Convergence of Lewy bodies and neurofibrillary tangles in amygdala neurons of Alzheimer’s disease and Lewy body disorders

Amygdalae of patients with Alzheimer’s disease (AD), Parkinson’s disease, Down’s syndrome, diffuse Lewy body disease or a combination of these diseases were probed with antibodies to neurofilament proteins as well as with Lewy body (LB)- and paired helical filament-specific antibodies. The results indicate that the amygdala is severely affected by the accumulation of both neurofibrillary tangles (NFTs) and LBs in most cases of the diseases mentioned above, and that amygdala LBs have a similar epitope composition to that of LBs in the brain stem and cerebral cortex. While large numbers of both LBs and NFTs were seen in different neurons within the amygdala, these two lesions frequently occurred together in the same neurons of the amygdala. These findings are in contrast to other sites that accumulate LBs and NFTs, but rarely both lesions in the same neuron. Thus, amygdala neurons may be selectively vulnerable to developing both LBs and NFTs, and these inclusions may play a role in the massive degeneration of these neurons in AD and LB disorders of the elderly. Received: 6 September 1995 / Revised, accepted: 30 October 1995     

Lewy body and Alzheimer pathology in a family with the amyloid-β precursor protein APP717 gene mutation

Mutations in the amyloid precursor protein (APP) gene cause one form of early onset familial Alzheimer’s disease (AD). One such family has been studied genetically and neuropathologically and represents the basis of the present report. Four siblings with the APP717 Val to Ile mutation, aged 59, 65, 61 and 64 years, apolipoprotein E (APOE) genotyped 2,4 (first three) and 2,3 respectively, had severe AD, Braak stage VI with frequent neurofibrillary tangles in the primary visual cortex, Brodmann area 17. The first one also met McKeith criteria for the limbic stage of dementia with Lewy bodies but did not have substantia nigra Lewy bodies. The second two met McKeith criteria for the neocortical stage of dementia with Lewy bodies and both had substantia nigra Lewy bodies. The fourth had AD but no Lewy bodies. A cousin without the APP717 mutation who was APOE 3, 4, developed dementia at age 60 and died at age 75. She had severe cerebrovascular atherosclerosis, less severe AD, Braak stage V, with sparing of area 17. She also had Lewy bodies in the substantia nigra and in the cortex and met McKeith criteria for neocortical stage of dementia with Lewy bodies. Extrapyramidal features were present in all five. Lewy bodies have been described in 53% of reported autopsies on individuals with the APP717 Val to Ile mutation coincident with dementia and AD neuropathologic changes. These observations suggest an association between the chromosome 21 APP mutation and Lewy body formation, possibly mediated by other environmental or genetic factors. Received: 6 July 1999 / Revised, accepted: 19 October 1999     

Cortical Lewy bodies and Alzheimer-type changes in patients with Parkinson’s disease

We investigated the role of cortical Lewy bodies (LB) and Alzheimer-type changes in cognitive impairment in patients with idiopathic Parkinson’s disease (PD). We evaluated 44 cases for the extent of neuropathological lesions with a CERAD neuropathological assessment battery and the stage of dementia using Reisberg’s global deterioration scale (GDS). Substantia nigra, amygdala, hippocampus and cerebral cortex were examined for LB and Alzheimer-type changes. For detection of LB, the cortical areas were stained with polyclonal antibodies against ubiquitin and tau. We found at least one cortical LB in 93% of cases. Furthermore, 43% of the cases had histological findings of definite Alzheimer’s disease (AD). The association between cognitive impairment and the number of cortical LB and Alzheimer-type changes in the amygdala, hippocampus and six selected gyri from cerebral cortex were analyzed using stepwise linear regression. In this analysis the total number of cortical LB, and the amount of neurofibrillary tangles in the temporal cortex remained statistically significant. When the cases with neuropathological changes consistent with a diagnosis of AD were excluded, the correlation between the total number of cortical LB and cognitive impairment was more obvious. A stepwise linear regression analysis in these cases found the total number of cortical LB to be the statistically significant predictor of cognitive impairment. This study revealed that LB densities in the cortex, especially in the temporal neocortex, correlated significantly with the cognitive impairment in PD independent of or in addition to Alzheimer-type pathology. Received: 18 August 1997 / Revised, accepted: 2 December 1997     

Lewy body variant of Alzheimer’s disease or cerebral type Lewy body disease? Two autopsy cases of presenile onset with minimal involvement of the brainstem

Lewy bodies (LB) usually extend from the brainstem to the cerebrum in patients with Parkinson’s disease. However, whether the patterns of progression of LB and neuronal loss in Parkinson’s disease are identical to those in other Lewy body diseases (LBD) remains unclear. In addition, pathological data on the autonomic nervous system involvement in LBD are limited. We present here the clinicopathological characteristics of two autopsy cases with both Alzheimer’s disease and dementia with Lewy bodies (DLB), possibly diagnosed as having Lewy body variant of Alzheimer’s disease (LBV/AD). Our patients presented clinically with dementia without parkinsonism. Histopathologically, phosphorylated α‐synuclein‐positive LB and Lewy neurites were abundant in the limbic system, especially in the amygdala, and to a lesser degree, in the neocortex, including the primary motor cortex. The amygdala was also most severely affected by neuronal loss, and the other limbic areas and neocortex were affected to a lesser degree. Despite the existence of a small number of LB and many Lewy neurites, neurons in the brainstem nuclei were relatively well preserved. The Braak stages of concurrent neurofibrillary changes and senile plaques were stage V and C, respectively, in both cases. Tyrosine hydroxylase‐positive nerve fibers were relatively well spared in one case examined compared with Parkinson’s disease cases. Furthermore, many Lewy neurites immunopositive for phosphorylated α‐synuclein were found in the nerve fascicles of the epicardium in one case examined and in Parkinson’s disease cases to a lesser degree. These findings suggest that: (i) in at least some LBV/AD cases, the amygdala develops neuronal loss and Lewy‐related pathology prior to the brainstem nuclei; and (ii) the depletion of nerves in the heart tissue of LBV/AD is not necessarily complete despite the development of Lewy‐related pathology.     

Dementia with Lewy bodies: Reclassification of pathological subtypes and boundary with Parkinson's disease or Alzheimer's disease

The present study is an attempt to reclassify the pathological subtypes of DLB based on both Lewy pathology and Alzheimer pathology, and to clarify the pathological boundary between DLB and Parkinson's disease (PD) or Alzheimer's disease (AD) in autopsied cases, using pathological and immunohistochemical methods. Dementia with Lewy bodies was classified into the limbic type and neocortical type according to the degree of Lewy pathology, including Lewy bodies (LB) and LB‐related neurites, by our staging and was classified into the pure form, common form and AD form according to the degree of Alzheimer pathology including NFT and amyloid deposits by Braak staging. These combined subtypes were lined up on a spectrum not only with Lewy pathology but also with other DLB‐related pathologies including Alzheimer pathology, neuronal loss in the substantia nigra, spongiform change in the transentorhinal cortex and LB‐related neurites in the CA2‐3 region. There were some similarities in both Lewy pathology and other DLB‐related pathologies between PD and DLB, although Lewy pathology of PD was below the lowest stage of Lewy pathology. In contrast, AD did not meet the stages of Lewy pathology, and there were also no similarities in other DLB‐related pathologies between AD and DLB. In addition, LB of AD showed the characteristics different from those of DLB on the coexistence of LB with NFT. These present findings suggest that DLB has pathological continuity with PD, but can be pathologically differentiated from AD. The present study clarified the pathological entity of DLB, compared with PD and AD.     

Cerebral type of Lewy body disease

A cerebral type of Lewy body disease (LBD) is proposed. Lewy body disease was split formerly into three types: brainstem type, transitional type and diffuse type. The diffuse type is now called diffuse Lewy body disease (DLBD). These three types are characterized pathologically by the presence of a large number of Lewy bodies in the CNS. In the brainstem type, Lewy bodies are numerous in the brainstem and diencephalon nuclei, and in DLBD, a vast number are present not only in these nuclei but also in the cerebral cortex and amygdala. In the cerebral type of LBD, as many Lewy bodies are found in the cerebral cortex and in the amygdala as there are in DLBD, but only rarely are they present in the brainstem and diencephalon nuclei. Thus, this type of LBD is different from other types in that it has no parkinson pathology. Therefore, parkinsonism fails to occur throughout the whole clinical course of this disease. The existence of a cerebral type of LBD suggests that Lewy bodies occur in the cerebral cortex earlier than in the brainstem nuclei and that cortical Lewy bodies appear even when the mesocortical dopaminergic system is intact. In addition, this might explain why dementia frequently precedes parkinsonism in DLBD.     

α-Synuclein pathology in the neostriatum in Parkinson’s disease

We immunohistochemically examined the neostriatum from 25 patients with symptomatic and presymptomatic Parkinson’s disease (PD) with various degrees of Lewy body pathology, using anti-phosphorylated α-synuclein (αS) antibody. These patients were classified according to the PD staging proposed by Braak et al. (Neurobiol Aging 24:197–211, 2003): stage II (αS pathology confined to the medulla oblongata and pontine tegmentum), stage III (αS pathology confined to the brainstem), stage IV (limbic stage), and stages V and VI (neocortical stage). αS immunohistochemistry revealed neuronal and glial cytoplasmic inclusions and neuritic changes in the neostriatum. αS inclusions were found in the medium-sized neurons (GABAergic neurons that project to the globus pallidus) and large neurons (cholinergic interneurons); the former began to appear at stage III and the latter was noted at stages V and VI. Neuritic changes and glial inclusions also began to appear at stage III. The numbers of neuronal and glial inclusions, and the extent of neuritic changes, correlated with the PD stage (P < 0.001). These findings suggest that intrinsic neostriatal neurons degenerate through αS aggregation during PD progression.     

The distribution pattern of pathology and cholinergic deficits in amygdaloid complex in Alzheimer's disease and dementia with Lewy bodies

We studied the distribution pattern of pathology and cholinergic deficits in the subnuclei of the amygdaloid complex (AC) in five patients with Alzheimer's disease (AD), eight with dementia with Lewy bodies (DLB) and five normal controls. In controls, the basal nucleus contained the highest choline acetyltransferase activity; the activity in the lateral and central nuclei and those in the cortical, medial and accessory basal nuclei were comparable. In AD, there was a significant decrease in choline acetyltransferase activity in the accessory basal and lateral nuclei, in DLB a significant decrease was observed in the accessory basal, lateral and cortical nuclei. Compared to controls the hyperphosphorylated tau-pathology burden was significantly higher in the basal, central and medial nuclei in AD and in the central, cortical, lateral and medial nuclei in DLB. The amyloid plaque burden was significantly higher in the accessory basal, basal, lateral and cortical nuclei in AD and in all nuclei in DLB. The α-synuclein burden was significantly higher in all nuclei in both AD and DLB. Compared to AD α-synuclein burden was higher in all nuclei in DLB. There were no correlations between the distribution pattern of hyperphosphorylated tau-pathology, amyloid plaques and α-synuclein-positive structures, and choline acetyltransferase activity, except the lateral nucleus in DLB. In conclusion we found no relationship between the pattern of cholinergic deficits and the distribution pattern of lesions in the AC of patients with AD or DLB. Cholinergic deficits were more prominent in the nuclei of basolateral (BL) group in AD, whereas the nuclei of both BL and corticomedial groups were involved in DLB, which may be due to the involvement of both basal forebrain and brainstem cholinergic nuclei in the latter.     

Pathological entity of dementia with Lewy bodies and its differentiation from Alzheimer’s disease

We reclassified the pathological subtypes of dementia with Lewy bodies (DLB), based on both Lewy pathology and Alzheimer pathology, to clarify the pathological entity of DLB and the boundary between DLB and Alzheimers disease (AD) in autopsied cases, using both pathological and immunohistochemical methods. DLB was classified as either limbic type or neocortical type according to the degree of Lewy pathology including Lewy bodies (LB) and LB-related neurites by our staging, and was classified as pure form, common form or AD form according to the degree of Alzheimer pathology including neurofibrillary tangles (NFT) and amyloid deposits by Braak staging. These combined subtypes were lined up on a spectrum, not only with Lewy pathology but also with other DLB-related pathologies including Alzheimer pathology, neuronal loss in the substantia nigra, spongiform change in the transentorhinal cortex and LB-related neurites in the CA2–3 region. In contrast, the Lewy pathology of AD did not meet the stages of Lewy pathology in DLB, and there were scarcely any similarities in other DLB-related pathologies between AD and DLB. In addition, the Lewy pathology of AD had characteristics different from that of DLB, including the coexistence rate of LB with NFT, and the immunohistochemical and immunoelectron microscopic findings of LB and LB-related neurites. These findings suggest that DLB is a distinctive pathological entity that can be differentiated from AD, although it shows some pathological subtypes.     

Lewy body pathology in Alzheimer’s disease

Lewy bodies, the characteristic pathological lesion of substantia nigra neurons in Parkinson's disease (PD), are frequently observed to accompany the amyloid plaque and neurofibrillary tangle pathology of Alzheimer's disease (AD). However the typical anatomic distribution of Lewy bodies in AD is distinct from PD. The most common site of occurrence is the amygdala, where Lewy bodies are observed in approximately 60% of both sporadic and familial AD. Other common sites of occurrence include the periamygdaloid and entorhinal cortex, while neocortical and brainstem areas develop Lewy bodies in a lower percentage of cases. In contrast, dementia with Lewy bodies (DLB), defined by widespread neocortical and brainstem Lewy bodies but frequently accompanied by variable levels of AD-type pathology, represents the other end of a spectrum of pathology associated with dementia. The observation of Lewy bodies in familial AD cases suggests that like neurofibrillary tangles, the formation of Lewy bodies can be induced by the pathological state caused by Abeta-amyloid overproduction. The role of Lewy body formation in the dysfunction and degeneration of neurons remains unclear. The protein alpha-synuclein appears to be an important structural component of Lewy bodies, an observation spurred by the discovery of point mutations in the alpha-synuclein gene linked to rare cases of autosomal dominant PD. Further investigation of alpha-synuclein and its relationship to pathological conditions promoting Lewy body formation in AD, PD, and DLB may yield further insight into pathogenesis of these diseases.     

Alpha-synuclein-positive structures in association with diffuse neurofibrillary tangles with calcification

alpha-Synuclein is known to be a major constituent of the Lewy bodies (LBs) in Parkinson's disease (PD) and the neuronal and glial cytoplasmic inclusions (NCIs, GCIs) in multiple system atrophy. alpha-Synuclein-positive inclusions such as LBs, NCIs and GCIs sometimes show colocalization with tau-positive neurofilaments. Studies using alpha-synuclein immunohistochemistry have often found LBs in the amygdala of patients with familial or sporadic Alzheimer's disease (AD), as well as in patients with Down's syndrome and AD. However, no studies have reported alpha-synuclein-positive structures in cases of diffuse neurofibrillary tangles with calcification (DNTC), which is characterized by numerous neurofibrillary tangles (NFTs) throughout the cerebral cortex but few, if any, senile plaques. We investigated the distribution of alpha-synuclein-positive structures in two cases of DNTC: a 65-year-old woman (brain weight, 850 g) and a 75-year-old woman (brain weight, 800 g). In both cases, severe cerebral atrophy predominant in the temporal lobe was noted. Microscopically, alpha-synuclein-positive intracytoplasmic inclusions and neurites were found in the superior temporal lobe (within the temporal pole), amygdala, parahippocampus, entorhinal cortex and insula, the regions most affected by the NFTs. alpha-Synuclein-positive intracytoplasmic inclusions were rare or absent in other regions of the cerebral cortex and brainstem. This distribution pattern differs from that of PD or dementia with LBs. Our findings suggest that the accumulation pattern of alpha-synuclein is a pathological feature of DNTC, and that DNTC is associated with accumulation of both tau and alpha-synuclein.     

Temporal lobar predominance of TDP-43 neuronal cytoplasmic inclusions in Alzheimer disease

TAR DNA binding protein-43 (TDP-43) immunoreactive neuronal inclusions are detected in 20-30% of Alzheimer disease (AD) brains, but the distribution of this pathology has not been rigorously studied. In this report, we describe region-specific distribution and density of TDP-43 positive neuronal cytoplasmic inclusions (NCIs) in clinically demented individuals with high probability AD pathology, all with Braak neurofibrillary tangle stages of V or VI. Sections of hippocampus, amygdala, as well as temporal, frontal, and parietal neocortex, were analyzed with TDP-43 immunohistochemistry, and the density of NCIs was assessed using a semiquantitative scoring method. Of the 29 cases, six had TDP-43 positive NCIs in the amygdala only and seven had TDP-43 inclusions restricted to amygdala and hippocampus. In 16 cases, TDP-43 immunoreactivity was more widespread, affecting temporal, frontal or parietal neocortex. These findings indicate that medial temporal lobe limbic structures are vulnerable to TDP-43 pathology in advanced AD, and that the amygdala appears to be the most susceptible region. The distribution of the lesions in this cross-sectional analysis may suggest a progression of TDP-43 pathology in AD, with limbic structures in the medial temporal lobe affected first, followed by higher order association cortices.     

Coexistence of Creutzfeldt‐Jakob disease,Lewy body disease,and Alzheimer's disease pathology: An autopsy case showing typical clinical features of Creutzfeldt‐Jakob disease

We report here an autopsy case of sporadic Creutzfeldt‐Jakob disease (CJD) without hereditary burden and with a clinical course typical of sporadic CJD. A 77‐year old man developed memory disturbance, followed by gait disturbance and myoclonus. He died of bronchopneumonia 5 months after the disease onset. Post‐mortem examination revealed neuronal loss, astrocytosis, and patchy spongiosis in the cerebral cortex and lenticular nuclei. Synaptic‐type deposits of prion protein were present in the cerebral cortex. Additionally, Lewy bodies were observed in the cerebral cortex and substantia nigra. Furthermore, senile plaques compatible with definite Alzheimer's disease according to Consortium to Establish a Registry for Alzheimer's disease criteria and neurofibrillary changes of the limbic system consistent with Braak stage IV were found. Based on a review of the published literature, this autopsy case is very rare, and we suppose that the incidence of CJD accompanied by Lewy body disease and Alzheimer's disease is very low.