Although it has long been recognized that a significant proportion of PD patients develop dementia (12), the pathological substrate for this cognitive dysfunction remained uncertain. In 1961, Okazaki reported finding LBs in the cerebral cortex of two patients with PD and atypical dementia (27).
Although subsequent cases of diffuse Lewy body disease (DLBD) were published, the condition was initially considered rare. In the late 1980s, with greater awareness of cortical LBs and the development of more sensitive staining methods, several groups reported finding cortical LBs in 15-25% of elderly demented patients, both with and without parkinsonism (28,29). It has recently been proposed that dementia associated with Lewy bodies (DLB) represents a recognizable clinicopathological syndrome that may be distinguishable during life from other causes of dementia (30). The proposed diagnostic criteria are purely clinical however, and recommendations as to how to quantitate LBs are only designed to assess the hypothesis that dementia is more likely to occur when LBs are numerous and widespread (i.e., DLB = DLBD) (30). Although numerous cortical LBs are most characteristic of DLB, smaller numbers are found in most (if not all) patients with idiopathic PD, even in the absence of dementia (31). As a result, the clinical and pathological relationship between PD and DLB and the appropriate terminology remains an ongoing source of controversy.
Some cases of DLB show microvacuolation of the superficial neocortex, particularly in the temporal lobe. Cortical LBs occur primarily in small and medium-size pyramidal neurons of the deeper cortical layers and are most abundant in the transentorhinal and cingulate cortex, less numerous in neocortex, and generally spare the hippocampus. They tend to be less well defined and are more difficult to recognize than classical brainstem LBs, using conventional staining methods (Fig. 2A). It is largely the advent of more sensitive immunohistochemical methods of detection (especially for ubiquitin and a-synuclein) that has allowed the extent of cortical LB pathology to be fully appreciated (Fig. 2B).
A distinctive neuritic degeneration was first reported in cases of DLB (32) but has subsequently been found in many cases of PD, as well (33). These abnormally swollen neuronal processes are not seen using hematoxylin and eosin (H&E) or conventional silver stains but are well demonstrated using ubiquitin and a-synuclein immunohistochemistry (Fig. 2C) (19). Often referred to as Lewy neurites, they are most concentrated in the CA2/3 region of the hippocampus but are also found in the amygdala, nucleus basalis, and various brainstem nuclei. In addition to accumulating in neuronal cell bodies and processes, a-synuclein-positive glial inclusions have also been reported in DLB (25,34).
Most, but not all, cases of DLB have some degree of Alzheimer's disease (AD)-like pathology (28,35). Senile plaques (SPs) are the most common finding with the majority being of the "diffuse" type. When neuritic plaques are present, most contain only tau-negative, ubiquitin-positive neurites. Neurofibrillary tangles (NFTs) and neuropil threads, containing paired helical filaments, may be found in the limbic structures and mesial temporal lobe but are uncommon in the neocortex. This pattern of pathology may be sufficient to fulfil pathological criteria for AD that are based on SP numbers (such as CERAD) (36) but not those that stress the importance of NFTs (such as Braak staging) (37). This overlap between DLB and AD pathology, combined with the lack of universally accepted pathological diagnostic criteria for either disorder, has resulted in confusion over the relationship between the conditions and the appropriate terminology. It also raises questions as to the pathological substrate for dementia in DLB patients. Although some studies have shown a correlation between the numbers of cortical LBs and cognitive dysfunction (38-41), others have not (29). This suggests that coexisting AD pathology, Lewy neurites, and/or degeneration of specific neuronal populations could all contribute to dementia, possibly in an additive fashion (42,43).
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