Original Research Article Dement Geriatr Cogn Disord 2002;13:130–148 Received: February 23, 2001 Revised and accepted: August 27, 2001 Contributions of Other Brain Pathologies in Dementia with Lewy Bodies E. Londos U. Passant J. Risberg L. Gustafson A. Brun Department of Psychogeriatrics and Pathology, University Hospital, Lund, Sweden Key Words Dementia with Lewy bodies W Alzheimer’s disease W Neuropathology W Clinico-pathological correlations W Cerebral blood flow W Blood pressure constellation as in DLB. The case study approach reveals the complexity of the clinico-pathological relationships in dementia that might otherwise be lost in the analysis of larger group data. Copyright © 2002 S. Karger AG, Basel ABC © 2002 S. Karger AG, Basel 1420–8008/02/0133–0130$18.50/0 Fax + 41 61 306 12 34 E-Mail karger@karger.ch www.karger.com Accessible online at: www.karger.com/journals/dem Introduction Dementia syndromes may be classified on the basis of the major type but above all on the basis of the distribution of pathology in the brain. Some disorders mainly affect cortical structures and regions while others have a more subcortical predominance or affect both structural levels. Alzheimer’s disease (AD) and the dominating forms of frontotemporal dementia (FTD) are the major types of predominantly cortical degenerative dementias, while progressive supra-nuclear palsy, Huntington’s disease, Parkinson’s disease (PaD) and Binswanger’s disease show predominant subcortical involvement [1]. Dementia with Lewy bodies (DLB) belongs to the mixed corticalsubcortical category [2]. The characteristic pathological structure, the Lewy body (LB), is localized in both the brain stem, hypothalamus and cortex, in which region Alzheimer-type degeneration is also present in the majority of cases. It has been claimed that DLB causes 10–20% of all organic dementias in the elderly [3–6]. The clinical picture of DLB has been described in consensus docu- Elisabet Londos, MD Department of Psychogeriatrics Lund University Hospital SE–221 85 Lund (Sweden) Tel. +46 46 17 74 63, Fax +46 46 17 74 57, E-Mail elisabet.londos@psykiatr.lu.se Downloaded by: UCL 144.82.238.225 - 5/7/2018 5:29:18 PM Abstract The clinical picture with its pathological correlate was analysed in 16 patients fulfilling consensus criteria for dementia with Lewy bodies (DLB). The cases were part of a larger cohort (n = 200) of patients within a prospective longitudinal study of dementing disorders. Six cases exhibited not only Lewy bodies (LBs) but also other brain pathologies such as Alzheimer changes, multiple infarcts or complete and incomplete white matter infarcts. Degeneration of the nucleus basalis of Meynert and substantia nigra was also seen. The 10 cases without LBs all had Alzheimer changes. In 7 cases, these changes were combined with mainly incomplete frontal white matter infarcts. However, the degeneration of brain stem nuclei was less pronounced in these cases. Symptoms such as fluctuations in cognition, falls and episodic confusion appeared in association with arterial hypotension, which developed during the course of dementia in almost all the 16 cases. The majority of the cases were treated with neuroleptics and other potentially hypotensive medication. This study shows that multiple and different pathological features may contribute to a clinical symptom FTD were applied to their entire medical records. As reported in previous publications, 48 cases fulfilled the clinical criteria for DLB alone or combined with AD (and 45 fulfilled clinical criteria for AD only) [20]. Detailed extensive neuropathological reports with staining methods, including hematoxylin and eosin and ubiquitin for recognition of LBs, were available in all cases. To improve detection of LBs, ·-synuclein staining was also used. However, for technical and economical reasons, not all cases could be restained. Therefore, 16 clinical DLB and 10 clinical AD cases were randomly chosen for neuropathological complementary staining. The selected cases did not differ from the larger clinical DLB group with regard to gender, age at onset of dementia, dementia duration or other clinical aspects. Six clinical DLB and 4 clinical AD cases exhibited LBs neuropathologically. The 6 cases with clinical DLB and LBs verified neuropathologically were further analysed in the present study and compared to the 10 clinical DLB cases without LBs. Neuropathology findings were correlated with clinical ratings, rCBF and DLB symptoms and interpreted individually and according to groups. Neuropathological Methods The neuropathological procedures included whole brain semiserial sectioning with subsequent extensive microscopical analysis, which is a prerequisite for safe neuropathological mapping of the type, severity and distribution of changes and also for the exclusion or verification of other types of brain pathology. Stainings used were hematoxylin and eosin, Luxol fast blue with cresyl violet counterstaining, Congo red, van Gieson-elastica, Campbell and Gallyas Table 1. Basic characteristics of 16 cases with clinically diagnosed DLB Age at onset years Age at death Dementia years duration, years LB-positive cases 1 M 2 F 3 F 4 F 5 M 6 M Mean 71 71 80 65 81 76 74B6.1 76 82 88 73 88 79 81B6.2 5 11 8 8 7 3 7B2.7 Patient Characteristics In the present study, we retrospectively applied the clinical criteria of DLB [7] to a cohort of 200 consecutive neuropathologically investigated dementia cases who were all part of a prospective longitudinal dementia study [19]. All the patients in that study were evaluated and followed clinically. The investigations included neuropsychiatric and neurologic evaluations, neuropsychological assessments and routine laboratory testing combined with different forms of brain imaging such as regional cerebral blood flow (rCBF) measurement, computerized tomography and electroencephalography. The patients had died between 1985 and 1994, which means that the clinical DLB criteria were not yet available when they were diagnosed in vivo. Diagnostic criteria for DLB, AD, vascular dementia (VaD) and LB-negative cases 7 F 8 M 9 M 10 M 11 F 12 F 13 F 14 M 15 M 16 F Mean 76 56 75 74 66 55 54 80 82 74 69B10.7 86 64 81 86 78 63 60 94 83 82 78B11.4 10 8 6 12 12 8 6 14 1 8 8B3.7 Clinical Pathological Correlation in DLB Dement Geriatr Cogn Disord 2002;13:130–148 Patients and Methods Case No. Gender 131 Downloaded by: UCL 144.82.238.225 - 5/7/2018 5:29:18 PM ments [7] as a progressive dementia syndrome with extrapyramidal signs (EPS), fluctuations in cognition, visual hallucinations, neuroleptic sensitivity, multiple falls, auditory hallucinations, delusions, syncope and transient loss of consciousness. A diagnosis of DLB is less likely in the presence of neuroimaging or clinical neurological signs of stroke. The clinical impact of LBs per se is, however, only partially known. The LB, when localized in the brain stem, is a neuropathological hallmark of PaD [8, 9]. It is possible to explain EPS, dysphagia and autonomic failure on the basis of the specific locations of LBs in the substantia nigra (SN), dorsal vagal nucleus and sympathetic ganglia [10–12]. The clinical description of ‘DLB’, however, includes a spectrum of neuropathological pictures, from cases with large amounts of diffusely spread LBs without other pathology, i.e. ‘pure LB’ (also known as ‘diffuse LB disease’ or ‘DLBD pure type’ [13]), to cases with AD and a few nigral LBs (also called ‘the LB variant of AD’ [4, 14], ‘senile dementia of LB type’ [15] or ‘DLBD common type’ [13]). Dementia severity in DLB has been related to the density of LBs in the cortex [3, 16, 17], although in a recent prospective study, no such correlation was found between LBs and clinical features [18]. It seems logical that high-density, massively spread cortical LBs might cause a dementia syndrome. It is, however, more difficult to predict the clinical role of LBs located in the brain stem or the sparse cortical LBs in many cases. It is also difficult to predict the effects of interaction between LBs and other brain pathologies. The aims of the present investigation were to describe and critically compare the clinical and neuropathological data in clinically diagnosed DLB cases with (n = 6) and without (n = 10) LBs and to evaluate the clinical expression of the different brain pathologies in these cases. methods and immunostainings with glial fibrillary acid protein (GFAP), ß-amyloid and ubiquitin. LBs were defined as rounded, non-fibrillary, ubiquitin-immunoreactive inclusions. The regional distribution and severity of the grey matter Alzheimer pathology were mapped semi-quantitatively, combining a number of histological variables such as neuronal loss, gliosis, microvacuolization, neurofibrillary tangles, senile plaques and dystrophic neurites [21]. The vascular pathology was mapped with regard to the regional distribution and severity of complete infarcts and selective incomplete white matter infarcts (SIWI). SIWI is characterized by a reduction of both myelin and oligodendroglial cells with mild astrocytic reaction [22]. In the randomly selected cases, the whole brain semi-serial sectioning investigation was supplemented by the examination of tissue sections from the mesencephalon, cingulate gyrus, hypothalamus, parietal cortex, frontal pole cortex and the basal temporal cortex, which includes the hippocampus, stained with antibodies against ·synuclein, tau, ubiquitin and GFAP. Regional Cerebral Blood Flow The rCBF was assessed by the xenon-133 inhalation method using the Initial Slope Index (ISI) as an indicator of cortical (mainly grey matter) blood flow [23–25]. The inert Á-radiating tracer xenon133 (90 MBq/l) was inhaled for 1 min through a face mask, followed by 10 min breathing ordinary air. Until 1986, rCBF was assessed with a 32-detector device. This was then replaced by a high-resolution recording system with 254 scintillation detectors (Cortexplorer 256 HR, Ceretronix Inc., Randers, Denmark), which gives a spatial resolution of about 1 cm for the superficial cortex. rCBF measurements were available in 15 cases. Five of the present cases had 32detector recordings and the remaining 10 had 254-detector recordings. The individual rCBF results are displayed as interpolated flow maps with colour coding of the regional values as a percentage of the individual mean flow [26]. Rating Scales Clinical rating scales for the recognition of AD, VaD and FTD were applied to the medical records. The clinical usefulness of the scoring profile of these diagnostic rating scales has been validated against neuropathology and brain imaging [19, 27, 28]. The AD score was based on 12 items, with a maximum score of 17; a score of 5 or above indicated AD [19, 29]. The ischemic score was based on 13 items, with a maximum score of 18; a score of 8 or above indicated Table 2. Neuropathological findings in 16 cases with clinically diagnosed DLB Case No. Cortical infarct(s) White matter infarcts SN LC LBs degeneration degeneration frontal 2 3 2 0 0 2 1 3 5 0 0 6 2 2 LB-positive cases 1 parietal central 2 3 4 parietal occipital central frontal small cortical LB-negative cases 7 15 16 occipital subcortical ++ (+) + frontal SN NbM, CG SN temporal SN, NbM, frontal CG, temporal, parietal + ++ + ++ + ++ + occipital 1 1 no occipital 1 1 no small cortical border zone small cortical frontal parietal frontal parietal frontal frontal frontal parietal occipital temporal pons frontal parietal frontal occipital subcortical 0 0 0 0 1 0 0 0 0 0 0 0 no no no no no no 0 0 0 3 no no 8 9 10 11 12 13 14 frontal parietal NbM, SN cortex NbM Degeneration: 1 = mild; 2 = moderate; 3 = severe; 1–5 LBs = +, 6–10 LBs = ++ per small section (cm2). CG = Cingulate gyrus. Dement Geriatr Cogn Disord 2002;13:130–148 Londos/Passant/Risberg/Gustafson/Brun Downloaded by: UCL 144.82.238.225 - 5/7/2018 5:29:18 PM 132 vascular aetiology [30]. The FTD score was based on 9 items, with a maximum score of 13; a score of 5 or above indicated frontal lobe dysfunction [19, 29]. Statistical Methods Student’s t test was used to compare the means of basic characteristics in table 1 and the means of differential diagnostic scoring in table 2. Results The basic characteristics of the 6 LB-positive and 10 LB-negative clinical DLB cases are presented in table 1. These data do not differ significantly from each other or from those of the total group (n = 200) originally investigated. The age at onset of dementia in this group was 70 B 10.3 years, age at death was 77 B 10.1 years and dementia duration was 7 B 3.8 years. The clinical courses of the 6 LB-positive patients are presented in figures 1–6, together with rCBF and neuropathological findings. The patients’ blood pressure is expressed as the mean arterial blood pressure (MABP), which was calculated in the following way: MABP = diastolic + systolic – diastolic 3 Blood pressure recordings from the last month of life were not included. Neuropathology The neuropathological data are presented in tables 2 and 3a, b. Of the LB-positive cases, 4 (No. 1, 2, 4 and 6) had moderate degeneration of the SN, with LBs in 2 cases. One additional case (No. 5) exhibited LBs in the SN without other degenerative changes. LBs were present in the nucleus basalis of Meynert (NbM) or hypothalamus in 4 cases. Four cases had cortical LBs although only a small number was evident in 3 cases. Four cases showed degeneration of the locus coeruleus (LC). The cases with the most LBs also had varying degrees of SN and LC degeneration, ranging from moderate to severe. Vascular patholo- Table 3a. Alzheimer pathology in 6 cases with clinically diagnosed DLB (LB positive) Case No. Local severity (Brun and Englund [21]) Total severity (Brun and Englund [21]) Braak staging [32] Likelihood of AD underlying dementia (NIA-Reagan criteria [33]) 1 frontal temporal hippocampal 1 3 0–1 uncus amygdala parietal 3 3 0–1 mild temporal-limbic, mild cortical (I) III–IV intermediate 2 frontotemporal hippocampal 0 3 3 uncus amygdala parietal 3 0 3 severe temporal-limbic, severe cortical (III) V high 3 frontal temporal hippocampal 0 2 2 amygdala parietal 2 2 moderate temporal-limbic, moderate cortical (II) V high 0 0 no 4 5 frontal temporal hippocampal 0 0 1 amygdala uncus parietal 1 1 0 mild temporal-limbic, cortical (0) III–IV intermediate 6 frontal temporal hippocampal 0 1 0 amygdala parietal 1 1 mild temporal-limbic, mild cortical (atypical) (I) V1 high 1 Degeneration: 0 = not exceeding normal for age; 1 = mild; 2 = moderate; 3 = severe. Temporal-limbic = Involvement of hippocampus, amygdala and entorhinal cortex but not supracallosal limbic (cingulate gyrus) or neocortex; NIA = National Institute on Aging. The patient was difficult to classify according to this staging system. + Dement Geriatr Cogn Disord 2002;13:130–148 133 Downloaded by: UCL 144.82.238.225 - 5/7/2018 5:29:18 PM Clinical Pathological Correlation in DLB Table 3b. Alzheimer pathology in 10 cases with clinically diagnosed DLB (LB negative) Case No. Local severity (Brun and Englund [21]) Total severity (Brun and Englund [21]) Braak Likelihood of AD staging [32] underlying dementia (NIA-Reagan criteria [33]) 7 frontal temporal hippocampal 1 2 3 amygdala parietal 2 2 severe temporal-limbic, moderate cortical (II) VI high 8 frontal temporal hippocampal 3 0 1 amygdala parietal occipital 1 3 3 mild temporal-limbic, severe cortical, frontal accent (III) VI high 9 frontal temporal hippocampal 1 3 2 amygdala uncus parietal 0 3 1 severe temporal-limbic, moderate cortical (II) VI high 10 frontal temporal hippocampal 1 3 3 amygdala uncus parietal 2 1 2 severe temporal-limbic, severe cortical (III) VI high 11 frontal temporal hippocampal 2 2 3 amygdala uncus parietal 2 1 2 severe temporal-limbic, moderate cortical (atypical) (II) VI high 12 frontal temporal hippocampal 2 2 2 amygdala parietal 3 3 severe temporal-limbic, severe cortical (III) VI high 13 frontal temporal hippocampal 2 3 3 amygdala parietal 3 3 severe temporal-limbic, severe cortical (III) VI high 14 frontal temporal hippocampal frontal temporal hippocampal 2 3 3 1 1 1 amygdala parietal 3 3 severe temporal-limbic, severe cortical (III) VI high amygdala uncus parietal 1 1 1 mild temporal-limbic, mild cortical (I) VI high frontal temporal hippocampal 1 2 2 amygdala parietal 2 0 moderate temporal-limbic, moderate cortical II) VI1 high 15 16 gy with cortical and subcortical complete and incomplete infarcts was present in 2 cases (No. 1 and 2). The results of the different neuropathological grading systems for the evaluation of the AD pathology, which were applied to the 6 cases, are shown in table 4. The dementia condition in 3 cases was considered to be due to the AD pathology (highly likely), while in 2 cases, the likelihood was intermediate. 134 Dement Geriatr Cogn Disord 2002;13:130–148 All 10 LB-negative cases had Alzheimer changes, which were combined with SIWI in 7 cases. A frontal location was especially evident in 7 cases. Complete infarcts of varying sizes were present in 5 of these 7 cases. The Alzheimer pathology, when graded according to Brun and Englund [21] and Braak and Braak [32], was generally more severe compared to the grading of the LB-positive cases. Londos/Passant/Risberg/Gustafson/Brun Downloaded by: UCL 144.82.238.225 - 5/7/2018 5:29:18 PM 1 Degeneration: 0 = not exceeding normal for age; 1 = mild; 2 = moderate; 3 = severe. Temporal-limbic = Involvement of hippocampus, amygdala and entorhinal cortex but not supracallosal limbic (cingulate gyrus) or neocortex. NIA = National Institute on Aging. The patient was difficult to classify according to this staging system. Fig. 1. Clinical course and rCBF and neuropathological findings in case 1. a This male patient was a retired schoolteacher who developed dementia at the age of 71. Although one uncle suffered from tremor, there was no family history of dementia. He suffered from long-standing arterial hypertension but there was a marked blood pressure decrease from the age of 75. The initial clinical diagnoses were VaD of Binswanger’s type and vitamin B12 deficiency. He died at the age of 76. b rCBF measurement at the age of 76, after 5 years of dementia, showed a marked general blood flow decrease as well as bilateral, focal flow decreases in temporo-parietal areas. c Neuropathology: mild Alzheimer pathology with temporal-limbic predominance. Moderate, mainly central arteriosclerosis with limited incomplete infarcts of Binswanger type. Moderate degeneration of the SN and LC was also present as well as moderate cerebellar atrophy. LBs were present in the NbM and SN. Clinical Pathological Correlation in DLB Dement Geriatr Cogn Disord 2002;13:130–148 Downloaded by: UCL 144.82.238.225 - 5/7/2018 5:29:18 PM 135 136 Dement Geriatr Cogn Disord 2002;13:130–148 7 years in psychiatric/institutional care. The initial clinical diagnoses were mixed AD and VaD as well as vitamin B12 deficiency. b rCBF measurement at the age of 79, after 8 years of dementia, showed a marked general blood flow decrease and focal decreases in the temporo-parietal and frontal areas bilaterally. c Neuropathology: Alzheimer pathology of varying degrees, with temporal limbic accent, also severe in the parietal cortex, however with sparse vascular amyloidosis. Multiple large infarcts in both grey and white matter in combination with extensive incomplete white matter infarcts. LBs were present in the NbM. Brain weight was 1,000 g. Londos/Passant/Risberg/Gustafson/Brun Downloaded by: UCL 144.82.238.225 - 5/7/2018 5:29:18 PM Fig. 2. Clinical course and rCBF and neuropathological findings in case 2. a This female patient had been working as a hat modiste. She had long-standing arterial hypertension. At the age of 74, she started complaining of diffuse pain and became anxious and restless. She also had visual hallucinations, ‘talked with the furniture’ and was episodically confused. She was referred to the psychogeriatric department at the age of 75. She was described as restless, pacing and constantly calling out ‘help me’. Her blood pressure varied markedly during the course of dementia and seemed to decrease during treatment with neuroleptics. There was a further decrease from the age of 81 after medication was stopped. She died at the age of 82 after Fig. 3. Clinical course and rCBF and neuropathological findings in case 3. a This female patient was a former physiotherapist with a family history of dementia and coronary heart disease. She was an excessive smoker. She complained of diffuse pain and suffered from visual and hearing disabilities, memory disturbances, anxiety and personal neglect. She exhibited recurrent visual and auditory hallucinations and ‘talking to herself’. She showed partial insight and explained that she did this to ‘reduce her loneliness’. She had episodic confusion and fluctuations of consciousness described as ‘attacks of absence, with staring gaze’. Transient ischemic attacks were suspected. She became vocally disruptive, continuously calling out ‘da-da’. Her blood pressure decreased during dementia but seemed to stabilize despite treatment with neuroleptics. At the age of 85, the clinical diagnosis was mixed AD and VaD. She died at the age of 88. b rCBF measurement at the age of 85, after 5 years of dementia, showed a normal general CBF level with a slightly low post-central blood flow level, most marked on the left side, and a slight focal asymmetry in the pre-motor area. c Neuropathology: moderate Alzheimer pathology with a predominantly temporal-limbic location and a very mild amyloid angiopathy. No nigral degeneration and no infarcts. A few LBs were identified frontally. Brain weight was 1,100 g. Clinical Pathological Correlation in DLB Dement Geriatr Cogn Disord 2002;13:130–148 Downloaded by: UCL 144.82.238.225 - 5/7/2018 5:29:18 PM 137 138 Dement Geriatr Cogn Disord 2002;13:130–148 pharmacological treatment she received might have contributed to her hypotension. She died at the age of 73. b rCBF measurement at 67, after 2 years of dementia, showed a slightly decreased general CBF level and focal blood flow decreases frontally on the left side and temporally on the right side. c Neuropathology: predominant frontotemporal encephalopathy of a primary unspecific degenerative type as in fronto-temporal degeneration of non-Alzheimer type. LBs were present in the cingulate gyrus, hypothalamus and SN. Brain weight was 835 g. Londos/Passant/Risberg/Gustafson/Brun Downloaded by: UCL 144.82.238.225 - 5/7/2018 5:29:18 PM Fig. 4. Clinical course and rCBF and neuropathological findings in case 4. a At the age of 70, this previously mentally healthy woman came to the psychiatric clinic. She exhibited emotional indifference, episodic confusion and fluctuations in cognition described as ‘cognitively more clear at certain times during the day’. Her mother had suffered from ‘senile dementia’. The patient was initially diagnosed as having AD, although the psychogeriatric consultant suggested a more frontally located dementia. Her blood pressure decreased markedly and she developed hypotension from the age of 70. The Fig. 5. Clinical course and rCBF and neuropathological findings in case 5. a This previously healthy male patient came from Estonia, where he had worked as a lawyer. At the age of 81, he showed memory disturbances and slight disorientation. He exhibited visual hallucinations in which he ‘picked non-existent things from the walls’. His blood pressure decreased markedly during dementia and the patient became hypotensive. The initial clinical diagnosis was VaD. From the age of 85 until his death at the age of 88, he was cared for at a nursing home and at the psychiatric clinic. b Neuropathology: discrete Alzheimer encephalopathy with temporal-limbic location and unevenly distributed cortical spongiform changes. Mild hydrocephalus. LBs were present in the SN and in the temporal cortex. Brain weight was 1,315 g. The rCBF in this case was performed on the 32-channel device, leading to a technically different illustration, and is therefore not shown. The rCBF findings at 85, 4 years after clinical onset of dementia, were difficult to interpret for technical reasons. It can be tentatively stated that the general CBF level seemed normal but with a marked hemispheric asymmetry and blood flow decreases frontotemporally on the left side and centrally on the right. Clinical Pathological Correlation in DLB Dement Geriatr Cogn Disord 2002;13:130–148 Downloaded by: UCL 144.82.238.225 - 5/7/2018 5:29:18 PM 139 140 Dement Geriatr Cogn Disord 2002;13:130–148 tial diagnoses were PaD with dementia, vitamin B12 deficiency and hypothyreosis. He died at the age of 79. b The rCBF measurement at 76 years, when the patient became demented, showed a slightly decreased general blood flow level and focal decreases in the temporo-parietal, parieto-occipital and frontal areas bilaterally. c Neuropathology: Alzheimer pathology with atypical distribution in the cortex, not accentuated in the amygdala. There was, however, a discrepancy between these changes and spongiosis/gliosis, which was mainly located in frontal areas. There was moderate degeneration of the SN. LBs were present in the mesencephalon, cingulate gyrus and hypothalamus and in the frontal, parietal and temporal cortices. Brain weight was 1,430 g. Londos/Passant/Risberg/Gustafson/Brun Downloaded by: UCL 144.82.238.225 - 5/7/2018 5:29:18 PM Fig. 6. Clinical course and rCBF and neuropathological findings in case 6. a This male patient served in the army and suffered from hearing disability and recurrent headache after an explosion. He had long-standing hypertension that was treated for some years. PaD was diagnosed at the age of 75. He had auditory hallucinations of ‘people singing at night’, vegetative ‘attacks’ of severe stomach pain, excessive sweating and salivation. He also exhibited ‘attacks of absence, loss of muscular tonus and a staring vacant gaze’. He experienced multiple falls. He developed agitation and verbal (threatening) and physical (fighting, kicking and throwing things) aggressiveness. His blood pressure decreased markedly during dementia. He was treated with drugs that could have contributed to the hypotension. The ini- Case No. AD score FTD score Ischemic score Neuropathological diagnosis LB-positive cases 1 7 2 8 3 13 4 8 5 6 6 6 Mean 8.0B2.6 2 2 10 6 6 0 4.3B3.7 9 4 3 2 5 7 5.0B2.6 VaD1 + AD VaD + AD AD FTD AD PaD + AD LB-negative cases 7 11 8 6 9 11 10 7 11 8 12 6 13 11 14 13 15 2 16 8 Mean 8.3B3.3 8 4 5 2 6 4 8 4 0 6 4.7B2.5 3 1 5 7 5 3 4 1 9 5 4.3B2.5 AD + SIWI AD + SIWI AD + SIWI AD + SIWI AD + SIWI AD AD AD + VaD VaD1 + AD AD The predominant neuropathological diagnosis is presented first. AD and FTD scores are based on Moroney et al. [28] and Gustafson and Nilsson [29]. The ischemic score is based on Gustafson and Nilsson [29]. 1 Binswanger type. Diagnostic Rating Scales and Neuropathology The results of the differential diagnostic ratings are presented in table 4 and related to the neuropathological findings in tables 2 and 3a, b. All 6 LB-positive cases had an AD score 66, indicating Alzheimer type of dementia, and showed a significant Alzheimer pathology at the neuropathological examination. Only case 4 exhibited degeneration of a non-Alzheimer type, where involvement of temporo-parietal areas probably contributed to the high AD score. The high ischemic score in case 1 correctly indicated vascular pathology. Case 2, with an AD score of 8 and an ischemic score of 4, had mixed Alzheimer and vascular pathology. The high AD score was probably due to the temporo-parietal co-location of Alzheimer changes and infarcts. The high FTD scores in cases 3, 4 and 5 indicated frontal lobe dysfunction. Case 4 had advanced frontal lobe degenera- Clinical Pathological Correlation in DLB tion (FLD). Cases 3 and 5 showed late onset of dementia as well as the highest age at death. This is commonly associated with a more general distribution of pathology, implying more frontal changes [30, 31]. All patients, except case 3, had neuronal loss and/or LBs in subcortical structures such as the SN. Nine out of the 10 LB-negative cases had an AD score of 6 or more, correctly indicating Alzheimer neuropathological changes. Five cases had an FTD score of 5 or above, indicating frontal lobe dysfunction. Two cases had a comparably high ischemic score (No. 10 and 15), and both of these cases had significant vascular brain pathology. On the other hand, the ischemic score did not indicate vascular pathology in 5 cases who had confirmed neuropathological white matter incomplete infarcts. Three out of 6 cases with frontal SIWI had signs of frontal dysfunction according to the FTD score. rCBF and Neuropathology Patterns The rCBF findings of the 6 LB-positive cases are presented in figures 1–6, while those of the LB-negative cases are illustrated in figure 7. In cases 1, 2, 4 and 5 of the LB-positive cases, the rCBF pathology and neuropathological changes (AD, infarcts, white matter pathology and degeneration of non-Alzheimer type) matched to a major extent (fig. 1–6). The rCBF in case 5 was measured with the 32-detector device, and for technical reasons, the recording was difficult to interpret. In case 3, the rCBF and neuropathological patterns were similar, although the rCBF severity was less marked than that of the neuropathology. In case 6, the frontotemporal areas were relatively spared with regard to rCBF, although the neuropathological study showed diffuse frontal microvacuolization. In all 9 available rCBF recordings for the LB-negative cases, there was a temporo-parietal, sometimes combined with a frontal, blood flow decrease. Six of these had 254detector recordings and are shown in figure 7. Blood Pressure, Pharmacological Treatment and Cardiac Disease As shown in figures 1–6, the MABP decreased in all 6 LB-positive cases during the progression of dementia. The decrease, expressed as a percentage of the last ‘predementia’ MABP value, averaged 28% and ranged from 17 to 37%. Three cases (No. 1, 2 and 6) had a history of hypertension and at least 2 of them had received long-standing antihypertensive treatment. Two cases (No. 1 and 6) were also highly orthostatic, with blood pressure falls from 150/ 105 (lying) to 115/85 (immediately standing) and from Dement Geriatr Cogn Disord 2002;13:130–148 141 Downloaded by: UCL 144.82.238.225 - 5/7/2018 5:29:18 PM Table 4. Differential diagnostic scoring and initial neuropathological diagnosis in 16 cases with clinically diagnosed cases with DLB Fig. 7. rCBF and age at recording in LB-negative cases with clinically diagnosed DLB. rCBF patterns during rest show the vertex view of the cerebral cortex, with the frontal pole at the top and the left hemisphere to the left. The colours represent normalized flow distribution (ISI, regional values as a percentage of the hemisphere mean), as defined by the colour key to the right. Red denotes significant flow increases while green indicates significant flow decreases. 142 Dement Geriatr Cogn Disord 2002;13:130–148 bined with atrial fibrillation in 1 case. Six of the 7 cases who showed an MABP decrease during dementia had been treated with neuroleptics and 2 had also received diuretics. Core Symptoms, Neuroleptic Sensitivity and Neuropathology The core symptoms of the clinical diagnosis of DLB in the 16 cases are presented in table 5 and the neuropathological results in table 2 and 3a, b. There were no major differences in core symptoms between LB-positive and LB-negative cases. Londos/Passant/Risberg/Gustafson/Brun Downloaded by: UCL 144.82.238.225 - 5/7/2018 5:29:18 PM 150/80 to 120/80. Five cases had received neuroleptics. One case (No. 1) had atrial fibrillation. The MABP decreased in 7 of the 10 LB-negative cases during dementia. The corresponding average MABP decrease compared to predementia values was 18%, ranging from a 3% increase to a 36% decrease. One patient (No. 14) had a history of previous hypertension and became hypotensive and orthostatic. Three additional cases (No. 8, 9 and 16) also showed orthostatic blood pressure reactions. Of the 5 cases with cardiac disease, 2 had angina pectoris and 3 had cardiac incompensation, which was com- Table 5. Core criteria and neuroleptic sensitivity in 16 cases with clinically diagnosed DLB Case No. Fluctuations LB-positive cases 1 yes 2 yes 3 yes 4 5 yes yes 6 yes LB-negative cases 7 yes 8 no Hallucinations EPS Neuroleptic sensitivity no visual visual auditory no visual auditory auditory a,b,c,d,e a,b,d,f a,b deterioration rigidity no a,b,c,d a,b,f no neuroleptic treatment rigidity a,b,c,d,e hypersalivation oversedation a,b a,b,d,e,f no severe EPS 9 10 yes yes no visual auditory no no 11 yes hallucinations a,b,c,e,f 12 no a,b,c,d,f 13 yes a,b,c,f oversedation 14 15 16 yes yes yes visual hallucinations visual hallucinations no hallucinations visual hallucinations hypomania hypersalivation oversedation rigidity hypersalivation leaning rigidity a,b,c,d,f no no salivation b,f a,e a = Small-stepped gait; b = (cogwheel) rigidity; c = tremor; d = bradykinesia; e = masked face; f = postural change. Hallucinations Three LB-positive cases had visual hallucinations. All three showed hippocampal and temporal AD; 1 had visual impairment and the other 2 had some kind of occipital pathology (infarct or microvacuolization). All 3 cases with auditory hallucinations (No. 3, 5 and 6) had impaired hearing. Case 6 was the only one who developed delusions and who later received antiparkinson medication. Four LB-negative cases had visual hallucinations. Three had moderate to severe temporal AD and the fourth had occipital pathology. The only LB-negative case with visual impairment also had visual hallucinations. In 1 case, the visual hallucinations were combined with auditory hallucinations. In 2 cases, the type of hallucina- tions was not specified. Both these cases had temporal and hippocampal Alzheimer pathology. Clinical Pathological Correlation in DLB Dement Geriatr Cogn Disord 2002;13:130–148 Extrapyramidal Symptoms All 6 LB-positive cases suffered from some kind of muscular rigidity, while all 4 cases (No. 1, 2, 4 and 6) with SN degeneration had bradykinesia. Three of the 4 cases with SN degeneration exhibited tremor, as opposed to none among the cases without SN degeneration. The cases with SN degeneration had 3 or more EPS. The 2 cases without SN degeneration showed 2 EPS each. Six of the 10 LB-negative cases suffered from muscular rigidity. Five cases had bradykinesia. Three cases displayed mild SN degeneration. There was no specific pattern of EPS in these 3 cases. Six of 7 cases with frontal Downloaded by: UCL 144.82.238.225 - 5/7/2018 5:29:18 PM 143 Neuroleptic Sensitivity Neuroleptic sensitivity was seen in cases 1, 2, 5 and 6 of the LB-positive cases, and the type described is shown in table 5. Moderate SN degeneration was found in 4 cases (No. 1, 2, 4 and 6), of which 3 exhibited LBs. One additional case without SN degeneration also had nigral LBs. Case 4, with SN degeneration and nigral LBs, had not received neuroleptics, and neuroleptic sensitivity was therefore not possible to establish. Two cases had shown EPS before they received neuroleptics. Neuroleptic sensitivity was reported in 6 of the 10 LBnegative cases. None of these had SN degeneration but 4 had frontal white matter pathology. In 7 of 8 cases, EPS were not seen before neuroleptic treatment. Discussion The initial description of DLB [5, 17] was based on neuropathologically studied cases and a specific symptom constellation was defined based on the retrospective analyses of these cases. Our intention was to study the neuropathological picture of cases with clinical DLB by a reverse analytic approach. The expectation was that these cases would present important pathological similarities, even if clinical features do not always indicate identical neuropathology. This study was based on neuropathologically investigated dementia cases (n = 200) within the frame of a longitudinal study [19]. The cases were selected consecutively according to the date of death. Clinical and neuropathological data from these cases have been reported previously [20]. Among 48 cases with a clinical DLB diagnosis, 16 randomly selected cases were investigated with ·-synuclein for sensitive detection of LB pathology (this staining was not available at the initial neuropathological examination). These 16 cases formed the target group for this study. It is important to note that the term ‘diagnosis’ is used here with three different meanings: firstly, the initial clinical diagnosis, which was made when the patients were still alive and when consensus DLB criteria were not yet developed; secondly, the clinical diagnosis, based on retrospective analysis of the total course of illness using established clinical criteria, and thirdly, the neuropathological diagnosis, based on the semi-serial whole brain sectioning technique with possibilities for a topographic 144 Dement Geriatr Cogn Disord 2002;13:130–148 overview and a histopathological description of the brain pathology. Acknowledging that ‘subjective judgements are almost unavoidable in assessing the cause of organic dementia’ [34], both clinically and neuropathologically, we interpreted the cases in accordance with our tradition of clinical investigation in an attempt to evaluate the impact of the various pathological findings on the symptomatology. The cases with LBs are presented individually. In case 1, the symptoms and the differential diagnostic ratings gave rise to a suspicion of probable AD and a clear subcortical, vascular engagement with an insufficient blood pressure reaction. Earlier hypertension and later hypotension in combination with orthostatic blood pressure regulation could have given rise to hypoperfusive episodes with subsequent white matter damage [22]. The rCBF 5 years after onset of the disease and 1 year prior to death showed the classic AD pattern with temporo-parietal blood flow decrease. The EPS could be explained by the nigral degeneration, while the likelihood of Alzheimer pathology underlying the dementia was intermediate according to the National Institute on Aging-Reagan criteria [33]. The contribution of the pronounced vascular white matter damage must, however, be anticipated. The fluctuations could be related to the combination of autonomic instability and vessel pathology [35]. The presence of LBs in autonomic ganglia [36] is another possible explanation, although this structure was not investigated in the present cases. LBs in the NbM could be an indication of a degeneration of this cholinergic source and thereby a further potentiation of the AD component. In case 2, the clinical diagnostic rating indicated a probable AD component, although vascular risk factors such as hypertension and decreasing blood pressure over time were present. The rCBF pattern was in accordance with the classic temporo-parietal AD pattern in combination with bilateral frontal flow decreases, a common pattern in older individuals with more advanced AD [30, 37, 38]. The bilateral, partially temporo-parietal location of the infarcts could have further contributed to the AD symptomatology. The EPS were thought to be the result of the SN degeneration and the frontal subcortical pathology [39]. The strategic location of LBs in the NbM could also have contributed to the dementia, but it is not likely that the LBs were solely responsible. Case 3 exhibited a clinical picture in which diagnostic ratings suggested AD and frontal lobe dysfunction. The mixed AD/VaD diagnosis in vivo was probably influenced by the patient’s vascular risk factors (hypertension, atherosclerotic heart disease, smoking) and some Londos/Passant/Risberg/Gustafson/Brun Downloaded by: UCL 144.82.238.225 - 5/7/2018 5:29:18 PM white matter pathology exhibited EPS; 5 of these had muscular rigidity and 5 had gait disturbance. focal asymmetry in the rCBF pattern. The SN was not degenerated, although the neuroleptic treatment might have contributed to the EPS, indicating a dopaminergic deficiency [40]. The relatively pure Alzheimer pathology possibly forms the basis of the dementia, a fact which was ‘highly’ likely according to the Reagan criteria [33]. The pronounced frontal symptomatology had, however, no clear-cut pathological correlate. The clinical impact of the few LBs in the frontal cortex is uncertain, although the mere presence of LBs may indicate underlying synuclein pathology. Case 4 had a differential diagnostic rating of probable AD but also a marked frontal clinic. Following the rCBF investigation with regional decreases in frontotemporal areas, the diagnosis of FTD was considered. The dementia syndrome could be correlated to the frontotemporal non-Alzheimer degenerative changes. The EPS (also a part of FTD symptomatology) could be explained by the nigral degeneration. The LB pathology might have added to the symptomatology with its strategic location in the NbM and the cingulate gyrus, thus amplifying the clinical AD appearance. LBs in the SN indicate a disruption of dopaminergic subcortico-frontal projections and this possibly adds to the signs of frontal dysfunction in the rCBF measurement. Case 5 had a mixed dementia with an unspecific clinical diagnostic scoring. The brain imaging findings of an asymmetric CBF pattern indicated a vascular genesis. The neuropathological findings of Alzheimer pathology and cortical microvacuolization were diverse and discrete and could additively form the basis of the dementia, a neuropathological situation not uncommon in the age group 1 80 years [41]. However, according to the Reagan criteria [33], the probability of an Alzheimer pathology underlying the dementia was rated as intermediate. LBs were seen in the SN, as possible markers of local damage and as an explanation of the EPS. The LBs in the temporal cortex, if indicative of dysfunction [42], may have added to the temporal lobe symptoms. Case 6 showed the characteristics of PaD, although with cognitive disturbances subsequent to onset. The blood pressure regulation was unstable, with decreasing blood pressure over time. The diagnostic ratings suggested a mixed dementia, i.e. AD and VaD. The rCBF pattern was in accordance with diagnoses for both AD and PaD. The pathology showed a classical PaD picture with subcortical and cortical LBs in combination with Alzheimer pathology forming the basis of the dementia. The Alzheimer pathology contributed ‘highly’ to the dementia, according to the National Institute on Aging-Reagan crite- ria [33], and received a comparatively high Braak staging [32] because of widespread cortical Alzheimer changes, although these changes were generally mild. In contrast, the Brun and Englund [21] grading was ‘mild AD’. In this case, the widespread LBs along dopaminergic subcorticocortical projections may be interpreted as a sign of the severity of the degeneration. A more cautious evaluation of the importance for the dementia state is called for, since cortical LBs in PaD are also seen in non-demented cases [43]. Thus, with the exception of case 5, who had subliminal pathologies and only few LBs, 4 of the cases had additional pathological findings to LBs with a probable impact on the dementia symptomatology. Case 6 was considered to be our most typical DLB case, both clinically and neuropathologically. Visual hallucinations were, however, absent in case 6. Case 4 was the least likely DLB case, since no LBs were found in the brain stem. Neurological signs are often associated with focal brain pathology while neuropsychiatric symptoms such as deceptions, delusions and depression show a less strict coupling to specific brain areas. The findings in our sample indicate a complex background for deceptions and delusions in brain disease. Several cases showed pathology in the hippocampus and the temporal and occipital cortices combined with sensory deficits, a well-known contributory factor to these symptoms [44]. In studies of psychoses and their links to cerebral lesions, cortical as well as subcortical brain abnormalities have been reported [45, 46]. Productive symptoms such as hallucinations and delusions have also been connected to the function of betterpreserved cortical areas [47–49]. There was no obvious association between psychotic symptoms and brain pathology in our patient sample, although cases 1, 5 and 6, who exhibited hallucinations, showed a comparatively low-grade Alzheimer pathology according to the Brun and Englund [21] grading, combined with relatively sparse additional cortical pathology. On the other hand, this occurred in only 2 of 6 hallucinating LB-negative cases. Cognitive fluctuations, confusional episodes, falls and also irritability and aggressiveness seemed to appear during a period of progressive decrease of the arterial blood pressure, regardless of the presence of LBs. Low blood pressure and orthostatic hypotension are common in degenerative dementia as well as VaD [50] and are probably highly hazardous in patients with previous hypertension. This was the case in 3 of our LB-positive and 1 of our LB-negative patients. Previous hypertension combined with antihypertensive medication was associated with a Clinical Pathological Correlation in DLB Dement Geriatr Cogn Disord 2002;13:130–148 Downloaded by: UCL 144.82.238.225 - 5/7/2018 5:29:18 PM 145 146 Dement Geriatr Cogn Disord 2002;13:130–148 Nigral pathology with subsequent dopaminergic deficiency, as well as other subcortical lesions, were prevalent in our cases and probably associated with the DLB symptoms. In conclusion, our pathological data, using the whole brain semi-serial sectioning technique, show that the neuropathological picture of DLB is complex and varies between individual cases. It is generally difficult to evaluate the importance of the LB pathology per se compared to other coexisting pathological changes. The single case analysis points to important clinico-pathological relations, which might be lost when analysing data from larger groups. Since AD and vascular diseases require specific clinical considerations and treatment, it is of great importance to acknowledge and diagnose these, even if an LB pathology is suspected. It is, however, of clinical importance to recognize patients with a symptom constellation caused by deficiencies in the acetylcholine, the dopamine, the noradrenergic and possibly also the serotoninergic system. This may allow a delicate, balanced treatment, which would not only alleviate disabling symptoms but would also avoid symptoms associated with and aggravated by deficient control of blood pressure. In addition, negative effects of treatment can be avoided or minimized in this patient group. Acknowledgements This study was supported by the Alzheimer foundation, Sjöbring foundation and the Swedish Medical Research Council, projects No. 3950 and 4969. We would like to thank Siv Börjesson and Helena Andersson, Department of Psychogeriatrics and Department of Clinical Neuroscience, Lund University, for their skilful help with the figures. We also gratefully acknowledge Kerstin Sturesson, Annette Persson-Prahl and Christina Andersson, Institute of Pathology, and Jessica Nilsson, Biomedical Center, Lund University, who provided valuable histotechnical assistance. Londos/Passant/Risberg/Gustafson/Brun Downloaded by: UCL 144.82.238.225 - 5/7/2018 5:29:18 PM higher risk of dementia in a recent population-based study [51]. Decreasing blood pressure during dementia in clinical DLB was found in our total sample [52]. Unstable blood pressure regulation, arterial hypotension or ischemia are often related to syncope, transient impaired consciousness, unsteady gait, falls and fractures, which constitute supportive criteria in the DLB consensus documents [53–55]. It is suggested that the development of SIWI results from regionally reduced cerebral perfusion due to small vessel disease combined with systemic hypotension and is also coupled to ischemic heart disease [22]. These clinico-pathological findings were more abundant in our LB-negative cases than in the LB-positive cases. Cases with combined Alzheimer and SIWI pathology (most commonly frontally located) share several symptoms with DLB, i.e. fluctuations, confusion, syncope, hallucinations and tonus increase [56], a fact which implies differential diagnostic difficulties. Fluctuations in cognition are conventionally considered a vascular symptom [35], but are also part of the clinical picture in PaD. The vast majority of our 16 cases had a clear decrease in blood pressure associated with the appearance of fluctuations in cognition. Interestingly, 3 LB-positive cases and 1 LBnegative case with moderate to severe degeneration of the LC and subsequently a possible involvement of noradrenergic pathways had ‘fluctuations in cognition and variations of attention and alertness’. Noradrenergic dysfunction has been related to disrupted activity of the attention mechanisms of frontal areas [57]. Three of the LB-positive and 2 of the LB-negative cases had coexistent SN degeneration, which may produce specific attentional deficits in PaD [58]. Another symptom not discussed in the consensus document but reported in 3 of our 6 LB-positive cases (and in 2 LB-negative cases) was diffuse somatic pain, without known aetiology. However, pain is also a common sensory manifestation of PaD [59]. The importance of recognition of the clinical core symptoms of DLB early in the course of dementia has been stressed [60], as this would facilitate the discovery of cases with LBs with less interference from other agedependent brain pathologies and would enable early treatment. Recent publications have reported positive responses to treatment with acetylcholinesterase inhibitors in DLB [61, 62]. A clear cholinergic dysfunction has also been shown in DLB [63]. There was, however, no consistent pattern or any difference between the cases with and without LBs, with respect to the early appearance of the core symptoms. References Clinical Pathological Correlation in DLB 16 Samuel W, Galasko D, Masliah E, Hansen LA: Neocortical Lewy body counts correlate with dementia in the Lewy body variant of Alzheimer’s disease. J Neuropathol Exp Neurol 1996; 55:44–52. 17 Haroutunian V, Serby M, Purohit DP, Perl DP, Marin D, Lantz M, Mohs RC, Davis KL: Contribution of Lewy body inclusions to dementia in patients with and without Alzheimer’s disease neuropathological condition. Arch Neurol 2000;57:1145–1150. 18 McKeith IG, Ballard CG, Perry RH, Ince PG, O’Brien JT, Neill D, Lowery K, Jaros E, Barber R, Thompson P, Swann A, Fairbairn A, Perry EK: Prospective validation of consensus criteria for the diagnosis of dementia with Lewy bodies. Neurology 2000;54:1050–1058. 19 Brun A, Gustafson L: The Lund Longitudinal Dementia Study: A 25-year perspective on neuropathology, differential diagnoses and treatment; in Corain B, Nicolini M, Winblad B, Wisniewski H, Zatta P (eds): Alzheimer’s Disease: Advances in Clinical and Basic Research. New York,Wiley, 1993, pp 4–18. 20 Londos E, Passant U, Brun A, Gustafson L: Clinical Lewy body dementia and the impact of vascular components. Int J Geriatr Psychiatry 2000;15:40–49. 21 Brun A, Englund E: The pattern of degeneration in Alzheimer’s disease. Neuronal loss and histopathological grading. Histopathology 1981;5:549–564. 22 Brun A, Englund E: A white matter disorder in dementia of the Alzheimer type. A pathoanatomical study. Ann Neurol 1986;19:253–262. 23 Obrist WD, Thompson HK, Wang HS, Wilkinson WE: Regional cerebral blood flow by 133xenon inhalation. Stroke 1975;6:245–256. 24 Risberg J, Ali Z, Wilson EM, Wills EL, Halsey JH: Regional cerebral blood flow by 133-xenon inhalation. Stroke 1975;6:142–148. 25 Risberg J: Regional cerebral blood flow measurements by 133Xe-inhalation: Methodology and applications in neuropsychology and psychiatry. Brain Lang 1980;9:9–34. 26 Risberg J: Regional cerebral blood flow; in Hannay JH (ed): Experimental Techniques in Human Neuropsychology. New York, Oxford University Press, 1986, pp 514–543. 27 Risberg J, Gustafson L: 133Xe cerebral blood flow in dementia and in neuropsychiatry research; in Maglistretti PL (ed): Functional Radionuclide Imaging of the Brain. New York, Raven, 1983, pp 151–159. 28 Moroney JT, Bagiella E, Desmond DW, Hachinski VC, Mölsä PK, Gustafson L, Brun A, Fischer P, Erkinjuntti T, Rosen W, Paik MC, Tatemichi TK: Meta-analysis of the Hachinski ischemic score in pathologically verified dementias. Neurology 1997;49:1096–1105. 29 Gustafson L, Nilsson L: Differential diagnosis of presenile dementia on clinical grounds. Acta Psychiatr Scand 1982;65:194–209. 30 Hachinski VC, Iliff LD, Zilkha E, Du Boulay GH, McAllister VL, Marshall J, Russell RW, Symon L: Cerebral blood flow in dementia. Arch Neurol 1975;32:632–637. 31 Brun A: The structural development of Alzheimer’s disease. Dan Med Bull 1985;32(suppl 1):25–27. 32 Braak H, Braak E: Neuropathological staging of Alzheimer-related changes. Acta Neuropathol (Berl) 1991;82:239–259. 33 Consensus recommendations for the postmortem diagnosis of Alzheimer’s disease. The National Institute on Aging, and Reagan Institute Working Group on Diagnostic Criteria for the Neuropathological Assessment of Alzheimer’s Disease. Neurobiol Aging 1997;18(4 suppl):S1–S2. 34 Ulrich J, Probst A, Wuest M: The brain diseases causing senile dementia. A morphological study on 54 consecutive autopsy cases. J Neurol 1986;233:118–122. 35 Mayer-Gross W, Slater E, Roth M: Ageing and the mental diseases of the aged; in Slater E, Roth M (eds): Clinical Psychiatry, ed 3. London, Bailliere, Tindall & Carssell, 1969, pp 533–629. 36 Wakabayashi K, Takahashi H: Neuropathology of autonomic nervous system in Parkinson’s disease. Eur Neurol 1997;38(suppl 2):2–7. 37 Lauter H: Über Spätformen der Alzheimerschen Krankheit und ihre Beziehung zur senilen Demenz. Psychiatr Clin (Basel) 1970;3:169– 189. 38 Risberg J: Cerebral blood flow in dementias. Dan Med Bull 1985;32:48–51. 39 Wallin A, Blennow K: Heterogeneity of vascular dementia: Mechanisms and subgroups. J Geriatr Psychiatry Neurol 1993;6:177–188. 40 McKeith IG, Fairbairn A, Perry R, Thompson P, Perry E: Neuroleptic sensitivity in patients with dementia of Lewy body type. BMJ 1992; 305:673–678. 41 Brun A, Gustafson L, Samuelson S-M, Ericsson C: Neuropathology of late life. Dementia 1992; 3:125–130. 42 Perry R, McKeith I, Perry E: Lewy body dementia – clinical, pathological and neurochemical interconnections. J Neural Transm Suppl 1997;51:95–109. 43 Hughes AJ, Daniel SE, Blankson S, Lees AJ: A clinicopathological study of 100 cases of Parkinson’s disease. Arch Neurol 1993;50:140– 148. 44 Cooper AF, Porter R: Visual acuity and ocular pathology in the paranoid and affective psychoses of later life. J Psychosom Res 1976;20: 107–114. 45 Wertheimer J: Some hypotheses about the genesis of visual hallucinations in dementias; in Katona C, Levy R (eds): Delusions and Hallucinations in Old Age. Glasgow, Gaskell, Bell and Bain, 1992, pp 201–208. 46 Miller BL, Lesser IM, Boone KB, Hill E, Mehringer CM, Wong K: Brain lesions and cognitive function in late-life psychosis. Br J Psychiatry 1991;158:76–82. 47 Gustafson L, Risberg J: Regional cerebral blood flow related to psychiatric symptoms in dementia with onset in the presenile period. Acta Psychiatr Scand 1974;50:516–538. Dement Geriatr Cogn Disord 2002;13:130–148 147 Downloaded by: UCL 144.82.238.225 - 5/7/2018 5:29:18 PM 1 Gustafson L: Clinical classification of dementia conditions. Acta Neurol Scand Suppl 1992; 139:16–20. 2 Neary D: Classification of dementias. Rev Clin Gerontol 1999;9:55–64. 3 Lennox G, Lowe J, Landon M, Byrne EJ, Mayer RJ, Godwin-Austen R: Diffuse Lewy body disease: Correlative neuropathology using anti-ubiquitin immunocytochemistry. J Neurol Neurosurg Psychiatry 1989;52:1236–1247. 4 Hansen LA, Salmon D, Galasko D, Masliah E, Katzman R, DeTeresa R, Thal L, Pay MM, Hofstetter R, Klauber M, Rice M, Butters N, Alford M: The Lewy body variant of Alzheimer’s disease: A clinical and pathological entity. Neurology 1990;40:1–8. 5 Perry RH, Irving D, Blessed G, Fairbairn A, Perry EK: Senile dementia of the Lewy body type. A clinical and neuropathologically distinct form of Lewy body dementia in the elderly. J Neurol Sci 1990;95:119–139. 6 Shergill S, Mullan E, D’Ath P, Katona C: What is the clinical prevalence of Lewy body dementia? Int J Geriatr Psychiatry 1994;9:907–912. 7 McKeith IG, Galasko D, Kosaka K, Perry EK, Dickson DW, Hansen LA, Salmon DP, Lowe J, Mirra SS, Byrne EJ, Lennox G, Quinn NP, Edwardson JA, Ince PG, Bergeron C, Burns A, Miller BL, Lovestone S, Collerton D, Jansen ENH, Ballard C, de Vos RAI, Wilcock GK, Jellinger KA, Perry RH: Consensus guidelines for the clinical and pathological diagnosis of dementia with Lewy bodies (DLB): Report of the consortium on DLB international workshop. Neurology 1996;47:113–124. 8 Greenfield JG, Bosanquet FD: The brainstem lesions in parkinsonism. J Neurol Neurosurg Psychiatry 1953;16:213–226. 9 Bethlem J, DenHartog Jager WA: The incidence and characteristics of Lewy bodies in idiopathic paralysis agitans (Parkinson’s disease). J Neurol Neurosurg Psychiatry 1960;23: 74–80. 10 Trétiakoff C: Contribution à l’étude de l’anatomie pathologique du locus niger de Soemmering; thèse, Paris, 1919. 11 Jackson M, Lennox G, Balsitis M, Lowe J: Lewy body dysphagia. J Neurol Neurosurg Psychiatry 1995;58:756–757. 12 Oppenheimer D: Neuropathology of autonomic failure; in Bannister R (ed): Autonomic Failure. A Textbook of Clinical Disorders of the Autonomic Nervous System, ed 2. Oxford, Oxford University Press, 1988, pp 451–463. 13 Kosaka K: Diffuse Lewy body disease in Japan. J Neurol 1990;237:197–204. 14 Förstl H, Burns A, Luthert P, Cairns N, Levy R: The Lewy body variant of Alzheimer’s disease. Clinical and pathological findings. Br J Psychiatry 1993;162:385–392. 15 Perry RH, Irving D, Blessed G, Perry EK, Fairbairn AF: Clinically and pathologically distinct form of dementia in the elderly. Lancet 1989; i:166. 148 53 Rubenstein LZ, Robbins AS: Falls in the elderly. A clinical perspective. Geriatrics 1984;39: 67–78. 54 Tinetti ME, Williams TF, Mayewski R: Fall risk index for elderly patients based on the number of chronic disabilities. Am J Med 1986;80:429–434. 55 Bradshaw MJ, Edwards RTM: Postural hypotension – pathophysiology and management. Q J Med 1986;231:643–657. 56 Englund E, Brun A, Gustafson L: A white-matter disease in dementia of Alzheimer’s type – clinical and neuropathological correlates. Int J Geriatr Psychiatry 1989;4:87–102. 57 Reikkinen M, Laakso MP, Jäkälä P, Reikkinien P Jr: Clonidin impairs sustained attention in Alzheimer’s disease; in Iqbal K, Swaab B, Wisniewski HM (eds): Alzheimer’s Disease and Related Disorders. New York, Wiley, 1999, pp 641–647. 58 Downes JJ, Roberts AC, Sahakian BJ, Evenden JL, Morris RG, Robbins TW: Impaired extradimensional shift performance in medicated and unmedicated Parkinson’s disease: Evidence for a specific attentional dysfunction. Neuropsychologia 1989;27:1329–1343. Dement Geriatr Cogn Disord 2002;13:130–148 59 Goetz CG, Tanner CM, Levy M, Wilson RS, Garron DC: Pain in Parkinson’s disease. Mov Disord 1986;1:44–49. 60 Lennox GG, Lowe JS: The clinical diagnosis and misdiagnosis of Lewy body dementia; in Perry R, McKeith I, Perry E (eds): Dementia with Lewy Bodies – Clinical, Pathological, and Treatment Issues. New York, Cambridge University Press, 1996, pp 9–20. 61 Shea C, MacKnight C, Rockwood K: Donezepil for treatment of dementia with Lewy bodies: A case series of nine patients. Int Psychogeriatr 1998;10:229–238. 62 McKeith IG, Grace JB, Walker Z, Byrne EJ, Wilkinson D, Stevens T, Perry EK: Rivastigmine in the treatment of dementia with Lewy bodies: Preliminary findings from an open trial. Int J Geriatr Psychiatry 2000;15:387– 392. 63 Perry EK, Haroutunian V, Davis DL, Levy R, Lantos P, Eagger S, Honavar M, Dean A, Griffith M, McKeith IG, Perry R: Neocortical cholinergic activities differentiate Lewy body dementia from classical Alzheimer’s disease. Neuroreport 1994;5:747–749. Londos/Passant/Risberg/Gustafson/Brun Downloaded by: UCL 144.82.238.225 - 5/7/2018 5:29:18 PM 48 Jacoby R, Levy R: Computed tomography in the elderly. II. Senile dementia: Diagnosis and functional impairment. Br J Psychiatry 1980; 136:256–269. 49 Förstl H, Howard R, Almeida OP, Stadtmuller G: Psychotic symptoms and the paraphrenic brain; in Katona C, Levy R (eds): Delusions and Hallucinations in Old Age. Glasgow, Gaskell, Bell and Bain, 1992, pp 153–170. 50 Passant U, Warkentin S, Karlsson S, Nillson K, Edvinsson L, Gustafson L: Orthostatic hypotension in organic dementia: Relationship, cortical blood flow and symptoms. Clin Auton Res 1996;6:29–36. 51 Ruitenberg A, Skoog I, Ott A, Aevarsson O, Witteman JCM, Lernfelt B, van Harskamp F, Hofman A, Breteler MMB: Blood pressure and risk of dementia: Results from the Rotterdam study and Gothenburg H-70 study. Dement Geriatr Cogn Disord 2001;12:33–39. 52 Londos E, Passant U, Gustafson L: Blood pressure and drug treatment in clinically diagnosed Lewy body dementia and Alzheimer’s disease. Arch Gerontol Geriatr 2000;30:35–46.