Frontotemporal lobar degeneration
The clinical diagnosis of Case 1 was SD, which is characterized by fluent speech output and loss of conceptual knowledge, resulting in loss of understanding of nominal terms, impaired recognition of faces and common objects, and impaired comprehension. This clinical phenotype can develop when the temporal poles are severely involved but other regions are relatively spared.
In a classification of FTD by the Lund and Manchester groups,19 a prototype of the consensus criteria of FTLD,14 three pathological bases of FTLD were divided into the frontal lobe degeneration type, Pick type, and motor neuron disease type. However, this pathological classification is not used now in neuropathological research because many novel disease entities defined by accumulated disease-specific proteins have been proposed. Consequently, the most recent pathological classification proposed in 200715 includes Pick's disease (defined by tau-positive Pick bodies), FTLD-U (ubiquitin-positive tau-negative inclusions, most of which are TDP-43 positive),20 neuronal intermediate filament inclusion disease (neurofilament-positive, α-internexin-positive, and tau-negative inclusions),21–23 and basophilic inclusion body disease (p62-positive, tau-negative, and TDP-43-negative spherical basophilic inclusions).23,24 Severe, circumscribed frontotemporal atrophy, which was regarded as a hallmark of the ‘Pick type’ in the Lund–Manchester criteria, usually develops in all these diseases. Of FTLD-U cases, 5–10% have mutations in the progranulin (PGRN) gene. In addition, several tauopathies in addition to Pick's disease, including corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), argyrophilic grain disease,25 and FTLD with microtubule-associated protein tau gene mutation (FTLD with MAPT mutation), have been included in this classification. Although argyrophilic grain disease usually causes only mild temporal atrophy, some cases exhibit severe atrophy at the site.26–28 The category of dementia lacking distinctive histologic features (DLDH)29 has remained in this classification; however, because a large proportion of DLDH (approximately 90%) is actually FTLD-U,30 it is considered that the frequency DLDH is far lower than believed previously. In fact, Munoz et al.31 reported that the frequency of DLDH was only 6% of clinical FTLD. No Japanese case of FTLD-U with mild cortical atrophy has been reported to date.
Several epidemiological studies have demonstrated that FTLD-U is the most common pathology among FTLD cases, and the frequency of FTLD-U ranges from 30% to 40%.31,32 The second most common pathology may be Pick's disease or CBD, although the results are inconsistent among the series examined.32,33 The clinical characteristics of FTLD-U have been examined mainly in familial cases with PGRN mutations. The most common clinical presentation in FTLD-U with PGRN mutations is FTD.34–36 In addition, several features that are thought to be uncommon in FTLD were noted in FTLD with PGRN mutations, such as forgetfulness or memory loss,36,37 visuospatial dysfunction,37–39 asymmetric paraparesis,37 apraxia,36,38 and visual hallucination,36 which are more suggestive of underlying AD, CBD, or DLB. The CBD-like symptoms (e.g. asymmetric parkinsonism, pyramidal signs, and/or apraxia)40 and PSP-like symptoms41 have also been observed in sporadic FTLD-U. Severe amnesia has also been noted in sporadic FTLD-U.42 Conversely, whether the clinical features of sporadic FTLD-U are similar to those of familial FTLD-U remains unclear. The CBD-like symptoms, including alien-hand sign and early memory impairment, are also encountered in other rare pathological substrates of FTLD, such as basophilic inclusion body disease and neuronal intermediate filament inclusion disease.23
It is of note that although some FTLD-U cases present clinically with SD,11,43 the most common clinical phenotype in FTLD-U with PGRN mutations was reported to be FTD.35 Beck et al.44 also noted that language output impairment, but not impaired semantic memory or impaired comprehension, was common in FTLD-U with PGRN mutations. Like FTLD-U with PGRN mutations, it was reported that Pick's disease patients frequently showed speech output impairment.45 In contrast, to our knowledge there is no previous case of CBD that exhibited SD. Because the cerebral atrophy is usually more pronounced in the convexity of the frontoparietal region in CBD, the low prevalence of SD seems to be reasonable. Considering the possibility that therapies targeting specific histopathologies will be developed in the future, it may be increasingly important to understand the clinical and histopathological characteristics and their relationship in each pathological disease entity of FTLD.
Dementia with Lewy bodies
Approximately 50 years after the first description of Lewy bodies in the nucleus basalis of Meynert and dorsal vagal nucleus by Lewy,46 in 1961 Okazaki et al.47 described two atypical demented cases. As noted in the title ‘Diffuse intracytoplasmic ganglionic inclusions (Lewy type) associated with progressive dementia’, the outstanding pathological feature in these cases was the occurrence of numerous Lewy bodies in the cerebral cortex in addition to the brain stem nuclei. To our knowledge, this was the first report of DLB characterized by many Lewy bodies in the cerebral cortex. Fifteen years later, in 1976, Kosaka et al.48,49 again noticed the association between cortical Lewy bodies and the development of dementia. However, although over 40 years have passed since the first cases were reported, the clinical and pathological features in DLB have not been fully clarified.
The most important issue associated with the accuracy of the clinical diagnosis of DLB may be the fact that, as observed in Case 2 in this paper, Lewy pathology frequently overlaps Alzheimer pathology in the same patient. For example, Uchikado et al.50 demonstrated that, in a large series of pathologically confirmed AD cases (n = 347), only approximately 40% had pure AD, whereas 15% had AD with Lewy pathology consistent with diffuse neocortical-type DLB, 9% had AD with transitional-type DLB, and 0.9% had AD with brain stem-type DLB (i.e. PD). Further, the proportion of AD patients having Lewy bodies in the amygdala was 18%, whereas that of AD with Lewy pathology in the brain stem and/or limbic system but not in the amygdala was 18%. Now, when a case with extensive Alzheimer pathology (i.e. NFT Braak Stage V or VI and probable or definite AD according to the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) criteria) fits the pathological criteria of DLB, the case is usually called ‘AD plus DLB’ or ‘Lewy body variant AD (LBV/AD)’.51,52 Marui et al.53,54 and Iseki55 have proposed an original system for staging Lewy pathology and the classification of LBD. According to their classification system, our Case 2 can be classified as ‘AD form of DLB’.
In clinical practice, it is a critical issue that the clinical presentation of DLB is affected by concomitant Alzheimer pathology and that the clinical presentation of DLB may not be as uniform as believed previously.56 For example, concurrent Alzheimer pathology in DLB cases correlates with less frequent parkinsonism,57,58 less frequent visual hallucinations,59–61 less frequent delusions,59 and less frequent cognitive fluctuation.59 The sensitivity of the diagnostic accuracy of DLB with severe Alzheimer pathology is lower than that of DLB with mild Alzheimer pathology (22% vs 70%).62 Indeed, our Case 2, which had severe Alzheimer pathology, did not show cognitive fluctuation, visual hallucinations, or parkinsonism.
Why the clinical presentation of DLB cases with and without severe Alzheimer pathology is different remains unclear. However, it is considered that the progression pattern of Lewy pathology as well as neuronal loss in at least some DLB cases may be different from that in PD cases, and the pattern may be influenced by Alzheimer pathology. For example, according to the staging system for Lewy pathology by Braak et al.,63–66 Lewy pathology progresses from the medulla oblongata to the cerebral cortex (a bottom-up or caudorostral progression pattern) and the stages are divided into: (i) preclinical (Stages 1–2); (ii) early (Stages 3–4; 35% with clinical PD); and (iii) late (Stages 5–6; 86% with clinical PD).67 However, Gomez-Tortosa et al.68 noticed that DLB does not occur as a severe or long-lasting PD because paralimbic Lewy pathology was significantly correlated with that in the neocortex, but neither was correlated with Lewy pathology in the substantia nigra. Also in a series of LBD from a brain bank in the UK, only approximately 53% of 71 cases fit the caudorostral progression pattern.69 Jellinger57 noticed that among AD cases having Lewy pathology, approximately 70% did not show lesions in the medulla oblongata. Saito et al.70 also noticed the possibility that α-synuclein pathology begins in the amygdala if associated with Alzheimer pathology. Likewise, Yamamoto et al.71 noted that Lewy pathology was distributed predominantly in the cerebrum rather than in the brain stem in DLB with AD. Because α-synuclein pathology also frequently develops in the amygdala in several tauopathies, it is considered that the accumulation of α-synuclein at this site is associated with abnormal tau accumulation.72,73 Conversely, Tsuboi and Dickson74 reported frequent involvement of the amygdala by Lewy pathology and a relatively spared neuronal population in the substantia nigra in DLB cases with mild Alzheimer pathology (mean Braak stage 2.8 ± 0.6) compared with PD cases. These findings suggest that ‘the top-down progression pattern’ of degeneration (i.e. from the cerebrum to the brain stem) is not always associated with severe Alzheimer pathology. Zaccai et al.75 also noted that the progression patterns of Lewy pathology were not associated with the severity of Alzheimer pathology. Interestingly, the first two cases of DLB reported by Okazaki et al.47 clinically exhibited progressive dementia but lacked any parkinsonism stigmata. Further, these cases had numerous Lewy bodies in the cerebral cortex and brain stem nuclei but lacked depigmentation in the substantia nigra. That is, the clinical and pathological features in these cases may be consistent with those in the ‘cerebral-type DLB’ proposed by Kosaka.76 Unfortunately, the presence or absence of neurofibrillary changes in these cases was not described. Although cerebral-type DLB was regarded as very rare, unexpectedly, Zaccai et al.75 recently reported that six of 76 LBD cases (7.9%) showed neocortex-predominant Lewy pathology with very limited involvement of the amygdala and substantia nigra (isolated Lewy bodies or a few Lewy neurites). They called this pathology the ‘cortical form of LBD’.
Somewhat surprisingly, although several studies have demonstrated a correlation between the stage of Lewy pathology and the development of dementia and parkinsonism,77,78 the impact of Lewy pathology on the development of clinical symptoms remains to be elucidated. For example, parkinsonism is correlated with neuronal loss in the substantia nigra, but not with Lewy pathology at this site.79 The fact that some of the cognitively spared individuals have many cortical Lewy bodies has also been noticed repeatedly.64,80,81 Recently, Parkkinen et al.82 reported that 56% of cases in a Finnish autopsy series having widespread cortical Lewy bodies in the limbic system or neocortex did not exhibit either cognitive impairment or parkinsonism. Furthermore, in that series, only 48% of cases of diffuse neocortical type DLB with only mild Alzheimer pathology had dementia and only 54% displayed parkinsonism. Thus, the authors raised the question of whether assessment of Lewy pathology is an assessment of the actual disease process.82
The development of Lewy pathology in the autonomic nervous system was first described in 1961.83 In 1989, Wakabayashi84 first described Lewy pathology in the cardiac sympathetic nerve. Recently, Orimo et al.85–87 reported that all cases of DLB, LBV/AD, and PD showed almost complete loss of nerve fibers in the cardiac sympathetic nerve. In addition, Fujishiro et al.88 disclosed that in PD cases, the cardiac sympathetic nerve denervation correlated with the Braak PD stage as well as with the Hoehn and Yahr clinical stage.89 It is considered that the reduction in the number of these fibers can be evaluated by the decreased cardiac uptake on [123I]-metaiodobenzylguanidine (MIBG) myocardial scintigraphy in the early stage of DLB and PD.90,91 However, as demonstrated in the present paper, whether the cardiac sympathetic nerve in LBV/AD always shows severe degeneration in the early stage remains unclear.12
At present, whether the progression pattern of Lewy pathology is identical among DLB, LBV/AD, and PD remains unclear and the clinical presentation of DLB may be different from that in LBV/AD. Further, it is plausible that the clinical difference between DLB and LBV/AD results in differences in their reported frequencies between neurological departments and psychiatric departments. Thus, I believe that clinicopathological examinations in case series in various clinical settings, including psychiatric hospitals, are necessary for a better understanding of the clinical features in LBD.